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Phase 1b/2 Study of Carfilzomib in Relapsed Solid Tumors, Multiple Myeloma, or Lymphoma

Sponsor
Amgen (Industry)
Overall Status
Completed
CT.gov ID
NCT00531284
Collaborator
(none)
184
Enrollment
7
Locations
17
Arms
116.7
Duration (Months)
26.3
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objectives of this Phase 1b/2 study were as follows:

  • Phase 1b (Bolus and Infusion): To evaluate the safety and tolerability of carfilzomib in patients with relapsed solid tumors and in patients with relapsed and/or refractory multiple myeloma and in patients with refractory lymphoma.

  • Phase 2 (Bolus): To evaluate the overall response rate (ORR) after 4 cycles of carfilzomib in patients with relapsed solid tumors.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
184 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase 1b/2, Multicenter Open-label Study of the Safety and Activity of Carfilzomib in Subjects With Relapsed Solid Tumors, Multiple Myeloma or Lymphoma
Study Start Date :
Sep 1, 2007
Actual Primary Completion Date :
Oct 1, 2014
Actual Study Completion Date :
May 22, 2017

Arms and Interventions

Arm Intervention/Treatment
Experimental: Phase 1B Solid Tumors: Carfilzomib 20 mg/m² Bolus

Participants received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

Drug: Carfilzomib
Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion
Other Names:
  • Kyprolis

    		•
    Experimental: Phase 1B Solid Tumors: Carfilzomib 20/27 mg/m² Bolus

    Participants received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 27 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

    Drug: Carfilzomib
    Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion
    Other Names:
  • Kyprolis

    		•
    Experimental: Phase 1B Solid Tumors: Carfilzomib 20/36 mg/m² Bolus

    Participants received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

    Drug: Carfilzomib
    Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion
    Other Names:
  • Kyprolis

    		•
    Experimental: Phase 2 Solid Tumors: Carfilzomib 20/36 mg/m² Bolus

    Participants received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

    Drug: Carfilzomib
    Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion
    Other Names:
  • Kyprolis

    		•
    Experimental: Phase 1B Solid Tumors: Carfilzomib 36 mg/m²

    Participants received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

    Drug: Carfilzomib
    Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion
    Other Names:
  • Kyprolis

    		•
    Experimental: Phase 1B Solid Tumors: Carfilzomib 45 mg/m²

    Participants received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

    Drug: Carfilzomib
    Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion
    Other Names:
  • Kyprolis

    		•
    Experimental: Phase 1B Solid Tumors: Carfilzomib 20/45 mg/m²

    Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

    Drug: Carfilzomib
    Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion
    Other Names:
  • Kyprolis

    		•
    Experimental: Phase 1B Solid Tumors: Carfilzomib 20/56 mg/m²

    Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

    Drug: Carfilzomib
    Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion
    Other Names:
  • Kyprolis

    		•
    Experimental: Phase 1B Solid Tumors: Carfilzomib 20/70 mg/m²

    Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

    Drug: Carfilzomib
    Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion
    Other Names:
  • Kyprolis

    		•
    Experimental: Phase 1b Multiple Myeloma: Carfilzomib 20/36 mg/m²

    Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

    Drug: Carfilzomib
    Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion
    Other Names:
  • Kyprolis

    		•
    Experimental: Phase 1b Multiple Myeloma: Carfilzomib 20/45 mg/m²

    Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

    Drug: Carfilzomib
    Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion
    Other Names:
  • Kyprolis

    		•
    Experimental: Phase 1b Multiple Myeloma: Carfilzomib 20/56 mg/m²

    Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

    Drug: Carfilzomib
    Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion
    Other Names:
  • Kyprolis

    		•
    Experimental: Phase 1b Multiple Myeloma: Carfilzomib 20/70 mg/m²

    Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

    Drug: Carfilzomib
    Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion
    Other Names:
  • Kyprolis

    		•
    Experimental: Phase 1b Lymphoma: Carfilzomib 20/56 mg/m²

    Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

    Drug: Carfilzomib
    Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion
    Other Names:
  • Kyprolis

    		•
    Experimental: Phase 1b Lymphoma: Carfilzomib 20/70 mg/m²

    Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

    Drug: Carfilzomib
    Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion
    Other Names:
  • Kyprolis

    		•
    Experimental: Phase 1b MM: Carfilzomib 20/45 mg/m² + Dexamethasone

    Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

    Drug: Carfilzomib
    Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion
    Other Names:
  • Kyprolis

    • Drug: Dexamethasone
    Administered orally or by IV infusion prior to carfilzomib
    Experimental: Phase 1b MM: Carfilzomib 20/56 mg/m² + Dexamethasone

    Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

    Drug: Carfilzomib
    Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion
    Other Names:
  • Kyprolis

    • Drug: Dexamethasone
    Administered orally or by IV infusion prior to carfilzomib

    Outcome Measures

    Primary Outcome Measures

    1. Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT) [28 days]

      Participants were evaluated for dose-limiting toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (NCI) version 3.0. A DLT was defined as treatment-related ≥ Grade 2 neuropathy with pain, ≥ Grade 3 non-hematologic toxicity, Grade 4 neutropenia or thrombocytopenia lasting 7 or more days, or thrombocytopenia with bleeding. The maximum tolerated dose (MTD) for each of the 3 populations (solid tumor, multiple myeloma, and lymphoma) was defined as the dose level at which < 33% of participants experienced a dose-limiting toxicity during the first 28-day cycle.

    2. Phase 2: Percentage of Participants With an Overall Response After 4 Treatment Cycles [4 months]

      Overall response is defined as participants with a best overall response of complete response (CR), partial response (PR) or stable disease (SD) after 4 cycles, assessed by the Investigator using tumor measurement and according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target and non-target lesions and no new lesions; PR: Disappearance of all target lesions, persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits and no lesions, or, at least a 30% decrease in the size of target lesions and no progression of existing non-target lesions or any new lesions. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest size since the treatment started, and no progression of existing non-target lesions or any new lesions.

    Secondary Outcome Measures

    1. Percentage of Participants With an Overall Response Throughout the Study [Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months.]

      Solid tumor participants were evaluated for disease response according to RECIST, Version 1.1. Multiple myeloma participants were evaluated using the International Myeloma Working Group (IMWG) Uniform Response Criteria with the addition of minimal response (MR) based on the European Group for Blood and Marrow Transplant Group (EBMT). Non-Hodgkin lymphoma (NHL) participants were evaluated using the International Workshop NHL criteria. Waldenström macroglobulinemia (WM) participants were evaluated using Criteria from the Sixth International Workshop for WM. Overall response is defined in Outcome Measure 2 for participants with solid tumors. For NHL, overall response is defined as a best overall response of CR or PR. For multiple myeloma and WM, overall response is defined as participants with a best overall response of stringent complete response (sCR), CR, very good partial response (VGPR) or PR.

    2. Duration of Response [Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months.]

      Duration of response is defined as the time from first evidence of a partial response or better (the first observation of PR before confirmation) to disease progression, with deaths owing to causes other than progression censored.

    3. Progression-Free Survival [Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months.]

      Progression-free survival (PFS) is the time from start of treatment to disease progression or death (due to any cause), whichever occurred first.

    4. Time to Progression [Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months.]

      Time to Progression (TTP) is defined as number of months between start of treatment and first evidence/documentation of disease progression.

    5. Maximum Observed Plasma Concentration of Carfilzomib [Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.]

      Plasma concentrations of carfilzomib were determined by a validated liquid chromatography tandem mass spectrometry method. Concentration values that were below the lower limit of quantification of 0.1 ng/mL were set to zero. Treatment groups receiving the same dose (e.g. 20 mg/m²) were combined for Day 1 analyses.

    6. Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib [Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.]

    7. Area Under the Plasma Concentration-time Curve From Time Zero to the Last Concentration Measured (AUC0-last) for Carfilzomib [Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.]

    8. Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) for Carfilzomib [Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.]

    9. Elimination Half-life (t½) of Carfilzomib [Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.]

    10. Clearance (CL) of Carfilzomib [Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.]

    11. Volume of Distribution at Steady State (Vss) of Carfilzomib [Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.]

    12. Mean Residence Time (MRT) Extrapolated to Infinity for Carfilzomib [Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    Disease related

    Phase 1 Subjects (Bolus and Infusion):
    Solid Tumor:

    • Histologically confirmed advanced solid tumor

    • 1 to 3 prior treatment regimens

    • At least one site of radiographically measurable disease of ≥ 2 cm in the largest dimension by traditional computed tomography (CT) scanning technique or ≥ 1 cm in the largest dimension by spiral CT scanning (per Response Evaluation Criteria in Solid Tumors [RECIST] criteria); or if, in the Principal Investigator's opinion, evaluable disease can be reliably and consistently followed, the subject may be eligible upon approval by the Medical Monitor

    Multiple Myeloma (MM):

    • Relapsed and/or refractory multiple myeloma following 2 or more prior treatment regimens.

    • Measurable disease as indicated by one or more of the following:

    • Serum M-protein ≥ 1 g/dL

    • Urine M-protein ≥ 200 mg/24 hr

    • Serum Free Light Chain: Involved free light chain (FLC) level ≥ 10 mg/dL provided serum FLC ratio is abnormal

    Lymphoma:

    • Histologically or cytologically confirmed lymphoma.

    • Patients must have had an initial diagnosis of indolent non-Hodgkin lymphoma (NHL) (including follicular, small lymphocytic, lymphoplasmacytoid, and marginal zone lymphoma), indolent disease that transformed to a more aggressive subtype, as previously described or patients may have mantle cell lymphoma.

    • Patients are required to have received prior rituximab (alone or combined with other treatment) and are considered refractory to (defined as no response, or progression within 6 months of completing therapy) or intolerant of continued rituximab.

    • Patients may have received up to a maximum of four prior unique chemotherapy regimens, including if not contra-indicated autologous stem-cell transplantation (ASCT).

    • For patients to enroll in the expanded dose group for lymphoma, patients must have measurable disease

    Phase 2 Bolus Subjects:

    -Histologically confirmed advanced solid tumor diagnosis and:

    • Non-small cell lung cancer (NSCLC): Failed at least 1 prior platinum-based chemotherapy regimen but not more than 3 prior therapies for metastatic disease

    • Small cell lung cancer (SCLC): Failed 1 to 3 prior chemotherapy regimens

    • Ovarian: Failed at least 1 prior platinum-based chemotherapy regimen but not more than 4 therapies for metastatic disease

    • Renal: Failed at least 2 prior chemotherapy regimens for metastatic disease

    • Other solid tumor types: Failed at least 1 prior chemotherapy regimen for metastatic or relapsed disease and for which standard of care therapy is no longer effective or does not exist

    • At least one site of radiographically measurable disease of ≥ 2 cm in the largest dimension by traditional CT scanning technique or ≥ 1 cm in the largest dimension by spiral CT scanning (per RECIST criteria); or if, in the Principal Investigator's opinion, evaluable disease can be reliably and consistently followed, the subject may be eligible upon approval by the Medical Monitor

    Demographic

    • Males and females ≥ 18 years of age

    • Life expectancy of more than 3 months

    • Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

    Laboratory

    • Adequate hepatic function, with bilirubin 1.5 times the upper limit of normal (ULN), and alanine aminotransferase (ALT) 3 times ULN

    • Absolute neutrophil count (ANC) > 1000/mm³, hemoglobin ≥ 8 gm/dL for solid tumors or 7.0 gm/dL for MM, and platelet count ≥ 100,000/mm³ for solid tumors or ≥ 30,000/mm³ for MM.

    • Subjects should not have received platelet transfusions for at least 1 week prior to screening

    • Screening ANC should be independent of granulocyte- and granulocyte/macrophage colony stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of pegylated G-CSF for ≥ 2 weeks

    • Subjects may receive red blood cell (RBC) transfusions or receive supportive care with erythropoietin or darbepoetin in accordance with institutional guidelines

    • Calculated or measured creatinine clearance (CrCl) of ≥ 20 mL/minute calculated using the formula of Cockcroft and Gault. Subjects with calculated CrCl < 20 mL/min may be allowed, only with prior approval by the Medical Monitor.

    Ethical/Other

    • Written informed consent in accordance with federal, local, and institutional guidelines

    • Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 3 days of the first dose and agree to use dual methods of contraception during the study and for 3 months following the last dose of study drug. Post-menopausal females (> 45 years old and without menses for > 1 year) and surgically sterilized females are exempt from these requirements. Male subjects must use an effective barrier method of contraception during the study and for 3 months following the last dose if sexually active with a female of childbearing potential.

    Exclusion Criteria:

    Disease Related

    • Chemotherapy with approved or investigational anticancer therapeutics, including steroid therapy, within 3 weeks prior to first dose or 6 weeks for antibody therapy

    • Radiation therapy or immunotherapy within 3 weeks prior to first dose (except for antibody therapy, where 6 weeks is required); localized radiation therapy within 1 week prior to first dose

    • Subjects with prior brain metastases are permitted, but must have completed treatment and have no evidence of active central nervous system (CNS) disease for at least 4 weeks prior to first dose

    • For lymphoma patients; patients with prior stem cell transplant therapy (autologous SCT within the prior 8 weeks; allogeneic SCT within the prior 16 weeks). Patients with prior allogeneic SCT should not have evidence of moderate-to-severe graft-versus-host disease (GVHD)

    • Evidence of CNS lymphoma

    • Participation in an investigational therapeutic study within 3 weeks prior to first dose

    • Prior treatment with carfilzomib

    Concurrent Conditions

    • Major surgery within 3 weeks prior to first dose

    • Congestive heart failure (New York Heart Association class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 3 months prior to first dose

    • Acute active infection requiring systemic antibiotics, antivirals, or antifungals within 2 weeks prior to first dose

    • Known or suspected human immunodeficiency virus (HIV) infection or subjects who are HIV seropositive

    • Active hepatitis A, B, or C infection

    • Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the first dose

    • Subjects with pleural effusions requiring routine thoracentesis or ascites requiring routine paracentesis

    • Subjects at risk* in whom the required program of oral and intravenous fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, cardiac, or renal impairment

    • High risk for Tumor Lysis Syndrome.

    Ethical / Other

    • Female subjects who are pregnant or lactating

    • Any clinically significant psychiatric or medical condition that in the opinion of the Investigator could interfere with protocol adherence or a subject's ability to give informed consent

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Pinnacle Oncology Scottsdale Arizona United States 85258
    2 Tower Cancer Research Foundation Beverly Hills California United States 90210
    3 Northwestern University Chicago Illinois United States 60611
    4 University of Maryland Greenebaum Cancer Center Baltimore Maryland United States 21201
    5 Hackensack University Medical Center Hackensack New Jersey United States 07601
    6 The Sarah Cannon Research Institute Nashville Tennessee United States 37203-1632
    7 South Texas Accelerated Research Therapeutics (START) San Antonio Texas United States 78229

    Sponsors and Collaborators

    • Amgen

    Investigators

    • Study Director: MD, Amgen

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT00531284
    Other Study ID Numbers:
    • PX-171-007
    First Posted:
    Sep 18, 2007
    Last Update Posted:
    Aug 15, 2017
    Last Verified:
    Jul 1, 2017
    Keywords provided by Amgen
    Non-small cell lung carcinoma
    Small-cell lung carcinoma
    Ovarian Cancer
    Renal Cancer
    Other solid tumors
    multiple myeloma
    lymphoma
    Additional relevant MeSH terms:
    Lymphoma
    Lung Neoplasms
    Multiple Myeloma
    Neoplasms, Plasma Cell
    Ovarian Neoplasms
    Small Cell Lung Carcinoma
    Kidney Neoplasms
    Carcinoma, Renal Cell
    Dexamethasone

    Study Results

    Participant Flow

    Recruitment Details Patients with relapsed solid tumors (non-small and small cell lung, ovarian, renal, any other solid tumor type), multiple myeloma or lymphoma were enrolled at 7 sites in the US. Under the original protocol patients received a bolus intravenous (IV) infusion of carfilzomib; patients enrolled under Amendments 2 to 4 received a 30-minute IV infusion.
    Pre-assignment Detail Phase 1b followed a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD). For Phase 2 (bolus), a Simon 2-stage design was planned using the MTD from phase 1b. The first stage of the Simon's 2-stage design was carried out; however, the study did not progress to the second stage.
    Arm/Group Title P1B ST: CFZ 20 mg/m² Bolus P1B ST: CFZ 20/27 mg/m² Bolus P1B ST: CFZ 20/36 mg/m² Bolus P2 ST: CFZ 20/36 mg/m² Bolus P1B ST: CFZ 36 mg/m² P1B ST: CFZ 45 mg/m² P1B ST: CFZ 20/45 mg/m² P1B ST: CFZ 20/56 mg/m² P1B ST: CFZ 20/70 mg/m² P1B MM: CFZ 20/36 mg/m² P1B MM: CFZ 20/45 mg/m² P1b MM: CFZ 20/56 mg/m² P1B MM: CFZ 20/70 mg/m² P1B LYM: CFZ 20/56 mg/m² P1B LYM: CFZ 20/70 mg/m² P1B MM: CFZ 20/45 mg/m² + Dex P1B MM: CFZ 20/56 mg/m² + Dex
    Arm/Group Description Participants with solid tumors (ST) received carfilzomib (CFZ) 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 27 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma (MM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with lymphoma (LYM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with lymphoma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.
    Period Title: Overall Study
    STARTED 3 4 7 65 6 7 6 10 11 4 3 24 2 3 7 14 8
    COMPLETED 0 0 1 2 0 0 0 0 0 0 0 0 0 0 3 2 0
    NOT COMPLETED 3 4 6 63 6 7 6 10 11 4 3 24 2 3 4 12 8

    Baseline Characteristics

    Arm/Group Title P1B ST: CFZ 20 mg/m² Bolus P1B ST: CFZ 20/27 mg/m² Bolus P1B ST: CFZ 20/36 mg/m² Bolus P2 ST: CFZ 20/36 mg/m² Bolus P1B ST: CFZ 36 mg/m² P1B ST: CFZ 45 mg/m² P1B ST: CFZ 20/45 mg/m² P1B ST: CFZ 20/56 mg/m² P1B ST: CFZ 20/70 mg/m² P1B MM: CFZ 20/36 mg/m² P1B MM: CFZ 20/45 mg/m² P1b MM: CFZ 20/56 mg/m² P1B MM: CFZ 20/70 mg/m² P1B LYM: CFZ 20/56 mg/m² P1B LYM: CFZ 20/70 mg/m² P1B MM: CFZ 20/45 mg/m² + Dex P1B MM: CFZ 20/56 mg/m² + Dex Total
    Arm/Group Description Participants with solid tumors (ST) received carfilzomib (CFZ) 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 27 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma (MM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with lymphoma (LYM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with lymphoma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Total of all reporting groups
    Overall Participants 3 4 7 65 6 7 6 10 11 4 3 24 2 3 7 14 8 184
    Age (years) [Mean (Standard Deviation) ]
    Bolus Groups
    47.3
    (14.74)
    60.8
    (8.81)
    60.0
    (11.72)
    62.0
    (9.97)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    62.20
    (10.43)
    30-minute Infusion Groups
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    60.0
    (5.18)
    69.9
    (11.10)
    61.2
    (10.38)
    61.4
    (7.40)
    61.6
    (11.58)
    63.3
    (3.77)
    72.0
    (5.57)
    62.7
    (9.88)
    69.5
    (12.02)
    58.7
    (10.69)
    65.4
    (10.31)
    58.6
    (9.54)
    58.3
    (6.14)
    62.3
    (9.47)
    Sex: Female, Male (Count of Participants)
    Female
    1
    33.3%
    1
    25%
    4
    57.1%
    38
    58.5%
    0
    0%
    4
    57.1%
    3
    50%
    5
    50%
    4
    36.4%
    2
    50%
    1
    33.3%
    7
    29.2%
    1
    50%
    1
    33.3%
    3
    42.9%
    4
    28.6%
    1
    12.5%
    80
    43.5%
    Male
    2
    66.7%
    3
    75%
    3
    42.9%
    27
    41.5%
    6
    100%
    3
    42.9%
    3
    50%
    5
    50%
    7
    63.6%
    2
    50%
    2
    66.7%
    17
    70.8%
    1
    50%
    2
    66.7%
    4
    57.1%
    10
    71.4%
    7
    87.5%
    104
    56.5%
    Eastern Cooperative Oncology Group (ECOG) Performance Status (participants) [Number]
    0
    1
    33.3%
    3
    75%
    4
    57.1%
    27
    41.5%
    2
    33.3%
    1
    14.3%
    0
    0%
    2
    20%
    4
    36.4%
    4
    100%
    0
    0%
    8
    33.3%
    0
    0%
    2
    66.7%
    3
    42.9%
    7
    50%
    5
    62.5%
    73
    39.7%
    1
    2
    66.7%
    1
    25%
    3
    42.9%
    35
    53.8%
    4
    66.7%
    4
    57.1%
    6
    100%
    7
    70%
    7
    63.6%
    0
    0%
    2
    66.7%
    15
    62.5%
    1
    50%
    0
    0%
    3
    42.9%
    6
    42.9%
    3
    37.5%
    99
    53.8%
    2
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    28.6%
    0
    0%
    1
    10%
    0
    0%
    0
    0%
    1
    33.3%
    1
    4.2%
    1
    50%
    1
    33.3%
    1
    14.3%
    1
    7.1%
    0
    0%
    9
    4.9%
    Missing
    0
    0%
    0
    0%
    0
    0%
    3
    4.6%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    3
    1.6%

    Outcome Measures

    1. Primary Outcome
    Title Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT)
    Description Participants were evaluated for dose-limiting toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (NCI) version 3.0. A DLT was defined as treatment-related ≥ Grade 2 neuropathy with pain, ≥ Grade 3 non-hematologic toxicity, Grade 4 neutropenia or thrombocytopenia lasting 7 or more days, or thrombocytopenia with bleeding. The maximum tolerated dose (MTD) for each of the 3 populations (solid tumor, multiple myeloma, and lymphoma) was defined as the dose level at which < 33% of participants experienced a dose-limiting toxicity during the first 28-day cycle.
    Time Frame 28 days

    Outcome Measure Data

    Analysis Population Description
    Dose-limiting toxicity analysis was based on subsets of the safety population including participants exposed to carfilzomib in Cycle 1 who experienced a DLT or completed 28 days of evaluation after the first dose of carfilzomib. Participants enrolled into the expansion cohorts (MTD dose expansion, carfilzomib + DEX) were not evaluated for DLT.
    Arm/Group Title P1B ST: CFZ 20 mg/m² Bolus P1B ST: CFZ 20/27 mg/m² Bolus P1B ST: CFZ 20/36 mg/m² Bolus P1B ST: CFZ 36 mg/m² P1B ST: CFZ 45 mg/m² P1B ST: CFZ 20/45 mg/m² P1B ST: CFZ 20/56 mg/m² P1B ST: CFZ 20/70 mg/m² P1B MM: CFZ 20/36 mg/m² P1B MM: CFZ 20/45 mg/m² P1b MM: CFZ 20/56 mg/m² P1B MM: CFZ 20/70 mg/m² P1B LYM: CFZ 20/56 mg/m² P1B LYM: CFZ 20/70 mg/m²
    Arm/Group Description Participants with solid tumors (ST) received carfilzomib (CFZ) 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 27 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma (MM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with lymphoma (LYM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with lymphoma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.
    Measure Participants 3 3 6 6 6 6 3 6 4 3 6 2 3 7
    Number [participants]
    0
    0%
    0
    0%
    1
    14.3%
    0
    0%
    2
    33.3%
    0
    0%
    0
    0%
    1
    10%
    0
    0%
    0
    0%
    1
    33.3%
    2
    8.3%
    0
    0%
    1
    33.3%
    2. Primary Outcome
    Title Phase 2: Percentage of Participants With an Overall Response After 4 Treatment Cycles
    Description Overall response is defined as participants with a best overall response of complete response (CR), partial response (PR) or stable disease (SD) after 4 cycles, assessed by the Investigator using tumor measurement and according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target and non-target lesions and no new lesions; PR: Disappearance of all target lesions, persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits and no lesions, or, at least a 30% decrease in the size of target lesions and no progression of existing non-target lesions or any new lesions. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest size since the treatment started, and no progression of existing non-target lesions or any new lesions.
    Time Frame 4 months

    Outcome Measure Data

    Analysis Population Description
    Phase 2 Safety population
    Arm/Group Title P2 ST: CFZ 20/36 mg/m² Bolus
    Arm/Group Description Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment.
    Measure Participants 65
    Number (95% Confidence Interval) [percentage of participants]
    15.4
    513.3%
    3. Secondary Outcome
    Title Percentage of Participants With an Overall Response Throughout the Study
    Description Solid tumor participants were evaluated for disease response according to RECIST, Version 1.1. Multiple myeloma participants were evaluated using the International Myeloma Working Group (IMWG) Uniform Response Criteria with the addition of minimal response (MR) based on the European Group for Blood and Marrow Transplant Group (EBMT). Non-Hodgkin lymphoma (NHL) participants were evaluated using the International Workshop NHL criteria. Waldenström macroglobulinemia (WM) participants were evaluated using Criteria from the Sixth International Workshop for WM. Overall response is defined in Outcome Measure 2 for participants with solid tumors. For NHL, overall response is defined as a best overall response of CR or PR. For multiple myeloma and WM, overall response is defined as participants with a best overall response of stringent complete response (sCR), CR, very good partial response (VGPR) or PR.
    Time Frame Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months.

    Outcome Measure Data

    Analysis Population Description
    Safety Population
    Arm/Group Title P1B ST: CFZ 20 mg/m² Bolus P1B ST: CFZ 20/27 mg/m² Bolus P1B ST: CFZ 20/36 mg/m² Bolus P2 ST: CFZ 20/36 mg/m² Bolus P1B ST: CFZ 36 mg/m² P1B ST: CFZ 45 mg/m² P1B ST: CFZ 20/45 mg/m² P1B ST: CFZ 20/56 mg/m² P1B ST: CFZ 20/70 mg/m² P1B MM: CFZ 20/36 mg/m² P1B MM: CFZ 20/45 mg/m² P1b MM: CFZ 20/56 mg/m² P1B MM: CFZ 20/70 mg/m² P1B NHL: CFZ 20/56 mg/m² P1B NHL: CFZ 20/70 mg/m² P1B WM: CFZ 20/56 mg/m² P1B WM: CFZ 20/70 mg/m² P1B MM: CFZ 20/45 mg/m² + Dex P1B MM: CFZ 20/56 mg/m² + Dex
    Arm/Group Description Participants with solid tumors (ST) received carfilzomib (CFZ) 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 27 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma (MM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with non-Hodgkin's lymphoma (NHL) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with non-Hodgkin's lymphoma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with Waldenstrom macroglobulinemia (WM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with Waldenstrom macroglobulinemia (WM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.
    Measure Participants 3 4 7 65 6 7 6 10 11 4 3 24 2 2 3 1 4 14 8
    Number (95% Confidence Interval) [percentage of participants]
    100.0
    3333.3%
    0.0
    0%
    42.9
    612.9%
    38.5
    59.2%
    33.3
    555%
    28.6
    408.6%
    50.0
    833.3%
    10.0
    100%
    36.4
    330.9%
    50.0
    1250%
    33.3
    1110%
    50.0
    208.3%
    50.0
    2500%
    0.0
    0%
    0.0
    0%
    100.0
    714.3%
    100.0
    1250%
    64.3
    34.9%
    37.5
    NaN
    4. Secondary Outcome
    Title Duration of Response
    Description Duration of response is defined as the time from first evidence of a partial response or better (the first observation of PR before confirmation) to disease progression, with deaths owing to causes other than progression censored.
    Time Frame Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months.

    Outcome Measure Data

    Analysis Population Description
    Safety Population with a partial response or better
    Arm/Group Title P1B ST: CFZ 20 mg/m² Bolus P1B ST: CFZ 20/27 mg/m² Bolus P1B ST: CFZ 20/36 mg/m² Bolus P2 ST: CFZ 20/36 mg/m² Bolus P1B ST: CFZ 36 mg/m² P1B ST: CFZ 45 mg/m² P1B ST: CFZ 20/45 mg/m² P1B ST: CFZ 20/56 mg/m² P1B ST: CFZ 20/70 mg/m² P1B MM: CFZ 20/36 mg/m² P1B MM: CFZ 20/45 mg/m² P1b MM: CFZ 20/56 mg/m² P1B MM: CFZ 20/70 mg/m² P1B NHL: CFZ 20/56 mg/m² P1B NHL: CFZ 20/70 mg/m² P1B WM: CFZ 20/56 mg/m² P1B WM: CFZ 20/70 mg/m² P1B MM: CFZ 20/45 mg/m² + Dex P1B MM: CFZ 20/56 mg/m² + Dex
    Arm/Group Description Participants with solid tumors (ST) received carfilzomib (CFZ) 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 27 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma (MM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with non-Hodgkin's lymphoma (NHL) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with non-Hodgkin's lymphoma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with Waldenstrom macroglobulinemia (WM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with Waldenstrom macroglobulinemia (WM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.
    Measure Participants 0 0 2 0 0 0 0 0 0 2 1 12 1 0 0 1 4 9 3
    Median (95% Confidence Interval) [months]
    6.2
    9.3
    5.5
    8.0
    14.8
    NA
    NA
    9.0
    22.6
    5. Secondary Outcome
    Title Progression-Free Survival
    Description Progression-free survival (PFS) is the time from start of treatment to disease progression or death (due to any cause), whichever occurred first.
    Time Frame Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months.

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title P1B ST: CFZ 20 mg/m² Bolus P1B ST: CFZ 20/27 mg/m² Bolus P1B ST: CFZ 20/36 mg/m² Bolus P2 ST: CFZ 20/36 mg/m² Bolus P1B ST: CFZ 36 mg/m² P1B ST: CFZ 45 mg/m² P1B ST: CFZ 20/45 mg/m² P1B ST: CFZ 20/56 mg/m² P1B ST: CFZ 20/70 mg/m² P1B MM: CFZ 20/36 mg/m² P1B MM: CFZ 20/45 mg/m² P1b MM: CFZ 20/56 mg/m² P1B MM: CFZ 20/70 mg/m² P1B NHL: CFZ 20/56 mg/m² P1B NHL: CFZ 20/70 mg/m² P1B WM: CFZ 20/56 mg/m² P1B WM: CFZ 20/70 mg/m² P1B MM: CFZ 20/45 mg/m² + Dex P1B MM: CFZ 20/56 mg/m² + Dex
    Arm/Group Description Participants with solid tumors (ST) received carfilzomib (CFZ) 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 27 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma (MM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with non-Hodgkin's lymphoma (NHL) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with non-Hodgkin's lymphoma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with Waldenstrom macroglobulinemia (WM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with Waldenstrom macroglobulinemia (WM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.
    Measure Participants 3 4 7 65 6 7 6 10 11 4 3 24 2 2 3 1 4 14 8
    Median (95% Confidence Interval) [months]
    5.1
    1.8
    1.8
    1.8
    1.7
    2.9
    1.4
    1.5
    1.6
    5.2
    4.6
    6.9
    9.4
    NA
    1.0
    NA
    NA
    4.6
    11.5
    6. Secondary Outcome
    Title Time to Progression
    Description Time to Progression (TTP) is defined as number of months between start of treatment and first evidence/documentation of disease progression.
    Time Frame Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months.

    Outcome Measure Data

    Analysis Population Description
    Safety population.
    Arm/Group Title P1B ST: CFZ 20 mg/m² Bolus P1B ST: CFZ 20/27 mg/m² Bolus P1B ST: CFZ 20/36 mg/m² Bolus P2 ST: CFZ 20/36 mg/m² Bolus P1B ST: CFZ 36 mg/m² P1B ST: CFZ 45 mg/m² P1B ST: CFZ 20/45 mg/m² P1B ST: CFZ 20/56 mg/m² P1B ST: CFZ 20/70 mg/m² P1B MM: CFZ 20/36 mg/m² P1B MM: CFZ 20/45 mg/m² P1b MM: CFZ 20/56 mg/m² P1B MM: CFZ 20/70 mg/m² P1B NHL: CFZ 20/56 mg/m² P1B NHL: CFZ 20/70 mg/m² P1B WM: CFZ 20/56 mg/m² P1B WM: CFZ 20/70 mg/m² P1B MM: CFZ 20/45 mg/m² + Dex P1B MM: CFZ 20/56 mg/m² + Dex
    Arm/Group Description Participants with solid tumors (ST) received carfilzomib (CFZ) 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 27 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma (MM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with non-Hodgkin's lymphoma (NHL) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with non-Hodgkin's lymphoma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with Waldenstrom macroglobulinemia (WM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with Waldenstrom macroglobulinemia (WM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.
    Measure Participants 3 4 7 65 6 7 6 10 11 4 3 24 2 2 3 1 4 14 8
    Median (95% Confidence Interval) [months]
    5.1
    1.8
    1.8
    1.8
    1.7
    1.6
    1.6
    1.6
    1.6
    5.2
    4.6
    6.9
    9.4
    NA
    1.0
    NA
    NA
    4.6
    11.5
    7. Secondary Outcome
    Title Maximum Observed Plasma Concentration of Carfilzomib
    Description Plasma concentrations of carfilzomib were determined by a validated liquid chromatography tandem mass spectrometry method. Concentration values that were below the lower limit of quantification of 0.1 ng/mL were set to zero. Treatment groups receiving the same dose (e.g. 20 mg/m²) were combined for Day 1 analyses.
    Time Frame Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.

    Outcome Measure Data

    Analysis Population Description
    Safety population with available pharmacokinetic (PK) data. PK analyses were conducted in solid tumor and multiple myeloma groups only and were not conducted for lymphoma or participants enrolled under Amendment 4 (CFX + dexamethasone).
    Arm/Group Title ST: CFZ 20 mg/m² Bolus ST: CFZ 20 mg/m² ST: CFZ 36 mg/m² ST: CFZ 45 mg/m² MM: CFZ 20 mg/m²
    Arm/Group Description Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Day 1. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Day 1. Participants with solid tumors received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Day 1. Participants with solid tumors received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Day 1. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Day 1.
    Measure Participants 30 21 6 6 30
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    2390
    (104)
    914
    (58.2)
    1061
    (50.7)
    1193
    (197.3)
    722
    (62.1)
    8. Secondary Outcome
    Title Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib
    Description
    Time Frame Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.

    Outcome Measure Data

    Analysis Population Description
    Safety population with available pharmacokinetic (PK) data. PK analyses were conducted in solid tumor and multiple myeloma groups only and were not conducted for lymphoma or participants enrolled under Amendment 4 (CFX + dexamethasone).
    Arm/Group Title ST: CFZ 20 mg/m² Bolus ST: CFZ 20 mg/m² ST: CFZ 36 mg/m² ST: CFZ 45 mg/m² MM: CFZ 20 mg/m²
    Arm/Group Description Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Day 1. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Day 1. Participants with solid tumors received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Day 1. Participants with solid tumors received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Day 1. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Day 1.
    Measure Participants 30 21 6 6 30
    Median (Full Range) [hours]
    0.0500
    0.500
    0.258
    0.275
    0.250
    9. Secondary Outcome
    Title Area Under the Plasma Concentration-time Curve From Time Zero to the Last Concentration Measured (AUC0-last) for Carfilzomib
    Description
    Time Frame Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.

    Outcome Measure Data

    Analysis Population Description
    Safety population with available pharmacokinetic (PK) data. PK analyses were conducted in solid tumor and multiple myeloma groups only and were not conducted for lymphoma or participants enrolled under Amendment 4 (CFX + dexamethasone).
    Arm/Group Title ST: CFZ 20 mg/m² Bolus ST: CFZ 20 mg/m² ST: CFZ 36 mg/m² ST: CFZ 45 mg/m² MM: CFZ 20 mg/m²
    Arm/Group Description Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Day 1. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Day 1. Participants with solid tumors received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Day 1. Participants with solid tumors received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Day 1. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Day 1.
    Measure Participants 30 21 6 6 30
    Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]
    251
    (92.0)
    346
    (57.4)
    426
    (70.1)
    536
    (150.4)
    269
    (54.3)
    10. Secondary Outcome
    Title Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) for Carfilzomib
    Description
    Time Frame Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.

    Outcome Measure Data

    Analysis Population Description
    Safety population with available pharmacokinetic (PK) data. PK analyses were conducted in solid tumor and multiple myeloma groups only and were not conducted for lymphoma or participants enrolled under Amendment 4 (CFX + dexamethasone).
    Arm/Group Title ST: CFZ 20 mg/m² Bolus ST: CFZ 20 mg/m² ST: CFZ 36 mg/m² ST: CFZ 45 mg/m² MM: CFZ 20 mg/m²
    Arm/Group Description Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Day 1. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Day 1. Participants with solid tumors received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Day 1. Participants with solid tumors received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Day 1. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Day 1.
    Measure Participants 23 18 6 6 28
    Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]
    223
    (104)
    324
    (52.8)
    426
    (70.1)
    538
    (150.1)
    273
    (55.3)
    11. Secondary Outcome
    Title Elimination Half-life (t½) of Carfilzomib
    Description
    Time Frame Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.

    Outcome Measure Data

    Analysis Population Description
    Safety population with available pharmacokinetic (PK) data. PK analyses were conducted in solid tumor and multiple myeloma groups only and were not conducted for lymphoma or participants enrolled under Amendment 4 (CFX + dexamethasone).
    Arm/Group Title ST: CFZ 20 mg/m² Bolus ST: CFZ 20 mg/m² ST: CFZ 36 mg/m² ST: CFZ 45 mg/m² MM: CFZ 20 mg/m²
    Arm/Group Description Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Day 1. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Day 1. Participants with solid tumors received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Day 1. Participants with solid tumors received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Day 1. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Day 1.
    Measure Participants 23 18 6 6 28
    Median (Full Range) [hours]
    0.444
    0.888
    0.917
    0.952
    0.888
    12. Secondary Outcome
    Title Clearance (CL) of Carfilzomib
    Description
    Time Frame Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.

    Outcome Measure Data

    Analysis Population Description
    Safety population with available pharmacokinetic (PK) data. PK analyses were conducted in solid tumor and multiple myeloma groups only and were not conducted for lymphoma or participants enrolled under Amendment 4 (CFX + dexamethasone).
    Arm/Group Title ST: CFZ 20 mg/m² Bolus ST: CFZ 20 mg/m² ST: CFZ 36 mg/m² ST: CFZ 45 mg/m² MM: CFZ 20 mg/m²
    Arm/Group Description Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Day 1. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Day 1. Participants with solid tumors received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Day 1. Participants with solid tumors received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Day 1. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Day 1.
    Measure Participants 23 18 6 6 28
    Mean (Standard Deviation) [liters/hour]
    263
    (398)
    139
    (70.1)
    182
    (88.8)
    302
    (438)
    164
    (89.6)
    13. Secondary Outcome
    Title Volume of Distribution at Steady State (Vss) of Carfilzomib
    Description
    Time Frame Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.

    Outcome Measure Data

    Analysis Population Description
    Safety population with available pharmacokinetic (PK) data. PK analyses were conducted in solid tumor and multiple myeloma groups only and were not conducted for lymphoma or participants enrolled under Amendment 4 (CFX + dexamethasone).
    Arm/Group Title ST: CFZ 20 mg/m² Bolus ST: CFZ 20 mg/m² ST: CFZ 36 mg/m² ST: CFZ 45 mg/m² MM: CFZ 20 mg/m²
    Arm/Group Description Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Day 1. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Day 1. Participants with solid tumors received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Day 1. Participants with solid tumors received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Day 1. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Day 1.
    Measure Participants 23 18 6 6 27
    Mean (Standard Deviation) [liters]
    27.7
    (48.6)
    31.0
    (21.9)
    22.7
    (24.2)
    113
    (230)
    21.8
    (24.6)
    14. Secondary Outcome
    Title Mean Residence Time (MRT) Extrapolated to Infinity for Carfilzomib
    Description
    Time Frame Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.

    Outcome Measure Data

    Analysis Population Description
    Safety population with available pharmacokinetic (PK) data. PK analyses were conducted in solid tumor and multiple myeloma groups only and were not conducted for lymphoma or participants enrolled under Amendment 4 (CFX + dexamethasone).
    Arm/Group Title ST: CFZ 20 mg/m² Bolus ST: CFZ 20 mg/m² ST: CFZ 36 mg/m² ST: CFZ 45 mg/m² MM: CFZ 20 mg/m²
    Arm/Group Description Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Day 1. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Day 1. Participants with solid tumors received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Day 1. Participants with solid tumors received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Day 1. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Day 1.
    Measure Participants 23 18 6 6 27
    Mean (Standard Deviation) [hours]
    0.0902
    (0.0319)
    0.227
    (0.150)
    0.116
    (0.0828)
    0.205
    (0.156)
    0.117
    (0.0799)

    Adverse Events

    Time Frame From the first administration of carfilzomib and within 30 days after the last dose of study treatment; maximum duration of treatment was 366 days for bolus administration and 1073 days for infusion
    Adverse Event Reporting Description Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold. Summary of Adverse Events includes only those subjects who received at least one dose of investigational product.
    Arm/Group Title P1B ST: CFZ 20 mg/m² Bolus P1B ST: CFZ 20/27 mg/m² Bolus P1B ST: CFZ 20/36 mg/m² Bolus P2 ST: CFZ 20/36 mg/m² Bolus P1B ST: CFZ 36 mg/m² P1B ST: CFZ 45 mg/m² P1B ST: CFZ 20/45 mg/m² P1B ST: CFZ 20/56 mg/m² P1B ST: CFZ 20/70 mg/m² P1B MM: CFZ 20/36 mg/m² P1B MM: CFZ 20/45 mg/m² P1B MM: CFZ 20/56 mg/m² P1B MM: CFZ 20/70 mg/m² P1B LYM: CFZ 20/56 mg/m² P1B LYM: CFZ 20/70 mg/m² P1B MM: CFZ 20/45 mg/m² + Dex P1B MM: CFZ 20/56 mg/m² + Dex
    Arm/Group Description Participants with solid tumors (ST) received carfilzomib (CFZ) 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 27 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma (MM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with lymphoma (LYM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with lymphoma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.
    All Cause Mortality
    P1B ST: CFZ 20 mg/m² Bolus P1B ST: CFZ 20/27 mg/m² Bolus P1B ST: CFZ 20/36 mg/m² Bolus P2 ST: CFZ 20/36 mg/m² Bolus P1B ST: CFZ 36 mg/m² P1B ST: CFZ 45 mg/m² P1B ST: CFZ 20/45 mg/m² P1B ST: CFZ 20/56 mg/m² P1B ST: CFZ 20/70 mg/m² P1B MM: CFZ 20/36 mg/m² P1B MM: CFZ 20/45 mg/m² P1B MM: CFZ 20/56 mg/m² P1B MM: CFZ 20/70 mg/m² P1B LYM: CFZ 20/56 mg/m² P1B LYM: CFZ 20/70 mg/m² P1B MM: CFZ 20/45 mg/m² + Dex P1B MM: CFZ 20/56 mg/m² + Dex
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    P1B ST: CFZ 20 mg/m² Bolus P1B ST: CFZ 20/27 mg/m² Bolus P1B ST: CFZ 20/36 mg/m² Bolus P2 ST: CFZ 20/36 mg/m² Bolus P1B ST: CFZ 36 mg/m² P1B ST: CFZ 45 mg/m² P1B ST: CFZ 20/45 mg/m² P1B ST: CFZ 20/56 mg/m² P1B ST: CFZ 20/70 mg/m² P1B MM: CFZ 20/36 mg/m² P1B MM: CFZ 20/45 mg/m² P1B MM: CFZ 20/56 mg/m² P1B MM: CFZ 20/70 mg/m² P1B LYM: CFZ 20/56 mg/m² P1B LYM: CFZ 20/70 mg/m² P1B MM: CFZ 20/45 mg/m² + Dex P1B MM: CFZ 20/56 mg/m² + Dex
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/3 (33.3%) 1/4 (25%) 4/7 (57.1%) 27/65 (41.5%) 2/6 (33.3%) 4/7 (57.1%) 5/6 (83.3%) 5/10 (50%) 6/11 (54.5%) 2/4 (50%) 0/3 (0%) 11/24 (45.8%) 2/2 (100%) 1/3 (33.3%) 5/7 (71.4%) 5/14 (35.7%) 3/8 (37.5%)
    Blood and lymphatic system disorders
    Anaemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Thrombotic thrombocytopenic purpura 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Cardiac disorders
    Cardiac failure 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Cardiac failure congestive 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 1/7 (14.3%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Coronary artery disease 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Diastolic dysfunction 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Tachycardia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Gastrointestinal disorders
    Abdominal hernia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Abdominal pain 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Ascites 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Constipation 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Diarrhoea 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Gastrointestinal haemorrhage 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Ileus 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Intestinal obstruction 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Large intestinal obstruction 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Vomiting 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    General disorders
    Chest pain 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Chills 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Disease progression 0/3 (0%) 0/4 (0%) 0/7 (0%) 5/65 (7.7%) 0/6 (0%) 0/7 (0%) 2/6 (33.3%) 1/10 (10%) 4/11 (36.4%) 0/4 (0%) 0/3 (0%) 2/24 (8.3%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Infusion related reaction 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Pain 1/3 (33.3%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Pyrexia 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 1/4 (25%) 0/3 (0%) 3/24 (12.5%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Hepatobiliary disorders
    Bile duct obstruction 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Hepatic failure 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 1/7 (14.3%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Hepatorenal failure 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Jaundice cholestatic 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 1/7 (14.3%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Infections and infestations
    Bacteraemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Cellulitis 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Diverticulitis 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Influenza 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Localised infection 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 1/6 (16.7%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Pneumococcal bacteraemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Pneumonia 0/3 (0%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 3/24 (12.5%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 1/8 (12.5%)
    Rhinovirus infection 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Sepsis 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Septic shock 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Staphylococcal bacteraemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Upper respiratory tract infection 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Urinary tract infection 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Injury, poisoning and procedural complications
    Fall 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Investigations
    Troponin I increased 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Metabolism and nutrition disorders
    Dehydration 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Fluid overload 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Hyperglycaemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Hyponatraemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 1/6 (16.7%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Musculoskeletal and connective tissue disorders
    Back pain 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 2/10 (20%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain cancer metastatic 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 1/7 (14.3%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Malignant pleural effusion 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Metastases to meninges 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Metastatic neoplasm 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Tumour lysis syndrome 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Nervous system disorders
    Hemiparesis 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Neuritis 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Spinal cord compression 0/3 (0%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Visual field defect 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Psychiatric disorders
    Mental status changes 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Renal and urinary disorders
    Proteinuria 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 1/2 (50%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Renal failure acute 0/3 (0%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Renal tubular necrosis 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 1/2 (50%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Respiratory, thoracic and mediastinal disorders
    Asthma 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Chronic obstructive pulmonary disease 0/3 (0%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Dyspnoea 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 1/7 (14.3%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 1/3 (33.3%) 2/7 (28.6%) 0/14 (0%) 0/8 (0%)
    Hydropneumothorax 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Hypoxia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 1/6 (16.7%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Laryngeal mass 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Pneumonia aspiration 0/3 (0%) 1/4 (25%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Pneumonitis 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Pulmonary embolism 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Pulmonary hypertension 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Pulmonary oedema 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 1/7 (14.3%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Respiratory distress 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 1/2 (50%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Respiratory failure 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Skin and subcutaneous tissue disorders
    Rash 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Vascular disorders
    Deep vein thrombosis 0/3 (0%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Hypertension 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Other (Not Including Serious) Adverse Events
    P1B ST: CFZ 20 mg/m² Bolus P1B ST: CFZ 20/27 mg/m² Bolus P1B ST: CFZ 20/36 mg/m² Bolus P2 ST: CFZ 20/36 mg/m² Bolus P1B ST: CFZ 36 mg/m² P1B ST: CFZ 45 mg/m² P1B ST: CFZ 20/45 mg/m² P1B ST: CFZ 20/56 mg/m² P1B ST: CFZ 20/70 mg/m² P1B MM: CFZ 20/36 mg/m² P1B MM: CFZ 20/45 mg/m² P1B MM: CFZ 20/56 mg/m² P1B MM: CFZ 20/70 mg/m² P1B LYM: CFZ 20/56 mg/m² P1B LYM: CFZ 20/70 mg/m² P1B MM: CFZ 20/45 mg/m² + Dex P1B MM: CFZ 20/56 mg/m² + Dex
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/3 (100%) 4/4 (100%) 7/7 (100%) 65/65 (100%) 6/6 (100%) 7/7 (100%) 6/6 (100%) 10/10 (100%) 11/11 (100%) 4/4 (100%) 3/3 (100%) 24/24 (100%) 2/2 (100%) 3/3 (100%) 7/7 (100%) 14/14 (100%) 8/8 (100%)
    Blood and lymphatic system disorders
    Anaemia 0/3 (0%) 1/4 (25%) 1/7 (14.3%) 17/65 (26.2%) 1/6 (16.7%) 1/7 (14.3%) 2/6 (33.3%) 4/10 (40%) 3/11 (27.3%) 2/4 (50%) 1/3 (33.3%) 10/24 (41.7%) 1/2 (50%) 1/3 (33.3%) 2/7 (28.6%) 5/14 (35.7%) 3/8 (37.5%)
    Febrile neutropenia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Haemolytic anaemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Iron deficiency anaemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 2/6 (33.3%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Leukocytosis 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Leukopenia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Lymphadenopathy 0/3 (0%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Lymphopenia 0/3 (0%) 1/4 (25%) 3/7 (42.9%) 10/65 (15.4%) 1/6 (16.7%) 2/7 (28.6%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 8/24 (33.3%) 0/2 (0%) 1/3 (33.3%) 1/7 (14.3%) 3/14 (21.4%) 3/8 (37.5%)
    Neutropenia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 4/24 (16.7%) 0/2 (0%) 1/3 (33.3%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Thrombocytopenia 0/3 (0%) 1/4 (25%) 1/7 (14.3%) 1/65 (1.5%) 0/6 (0%) 1/7 (14.3%) 0/6 (0%) 1/10 (10%) 3/11 (27.3%) 1/4 (25%) 1/3 (33.3%) 13/24 (54.2%) 2/2 (100%) 1/3 (33.3%) 3/7 (42.9%) 5/14 (35.7%) 3/8 (37.5%)
    Cardiac disorders
    Angina pectoris 0/3 (0%) 1/4 (25%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Bradycardia 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Diastolic dysfunction 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Intracardiac thrombus 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Palpitations 0/3 (0%) 0/4 (0%) 0/7 (0%) 3/65 (4.6%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Sinus tachycardia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Tachycardia 0/3 (0%) 0/4 (0%) 2/7 (28.6%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 3/24 (12.5%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Ear and labyrinth disorders
    Deafness 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Ear congestion 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Ear discomfort 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Ear pain 0/3 (0%) 1/4 (25%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 2/14 (14.3%) 0/8 (0%)
    Tinnitus 0/3 (0%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Vertigo 0/3 (0%) 1/4 (25%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Eye disorders
    Asthenopia 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Diplopia 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 1/8 (12.5%)
    Dry eye 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Eye irritation 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 1/8 (12.5%)
    Lacrimation increased 0/3 (0%) 0/4 (0%) 0/7 (0%) 4/65 (6.2%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Vision blurred 0/3 (0%) 0/4 (0%) 0/7 (0%) 4/65 (6.2%) 0/6 (0%) 1/7 (14.3%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 2/8 (25%)
    Visual disturbance 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Vitreous floaters 0/3 (0%) 0/4 (0%) 0/7 (0%) 3/65 (4.6%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Gastrointestinal disorders
    Abdominal discomfort 0/3 (0%) 0/4 (0%) 0/7 (0%) 4/65 (6.2%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 2/11 (18.2%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 1/3 (33.3%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Abdominal distension 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 12/65 (18.5%) 1/6 (16.7%) 0/7 (0%) 1/6 (16.7%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 1/14 (7.1%) 0/8 (0%)
    Abdominal pain 0/3 (0%) 0/4 (0%) 0/7 (0%) 14/65 (21.5%) 0/6 (0%) 1/7 (14.3%) 2/6 (33.3%) 0/10 (0%) 2/11 (18.2%) 1/4 (25%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 1/3 (33.3%) 1/7 (14.3%) 0/14 (0%) 2/8 (25%)
    Abdominal pain lower 0/3 (0%) 0/4 (0%) 0/7 (0%) 3/65 (4.6%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Abdominal pain upper 0/3 (0%) 0/4 (0%) 0/7 (0%) 3/65 (4.6%) 0/6 (0%) 1/7 (14.3%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 1/8 (12.5%)
    Ascites 0/3 (0%) 0/4 (0%) 0/7 (0%) 3/65 (4.6%) 0/6 (0%) 1/7 (14.3%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Cheilitis 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 1/3 (33.3%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Constipation 1/3 (33.3%) 1/4 (25%) 1/7 (14.3%) 11/65 (16.9%) 0/6 (0%) 2/7 (28.6%) 2/6 (33.3%) 4/10 (40%) 3/11 (27.3%) 1/4 (25%) 0/3 (0%) 2/24 (8.3%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 2/14 (14.3%) 2/8 (25%)
    Diarrhoea 1/3 (33.3%) 0/4 (0%) 2/7 (28.6%) 18/65 (27.7%) 1/6 (16.7%) 1/7 (14.3%) 2/6 (33.3%) 2/10 (20%) 1/11 (9.1%) 0/4 (0%) 1/3 (33.3%) 6/24 (25%) 1/2 (50%) 1/3 (33.3%) 3/7 (42.9%) 1/14 (7.1%) 3/8 (37.5%)
    Dry mouth 0/3 (0%) 0/4 (0%) 0/7 (0%) 8/65 (12.3%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Dyspepsia 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 3/65 (4.6%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 2/10 (20%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 2/7 (28.6%) 1/14 (7.1%) 2/8 (25%)
    Dysphagia 0/3 (0%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 1/7 (14.3%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Eructation 0/3 (0%) 0/4 (0%) 0/7 (0%) 4/65 (6.2%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Faecal incontinence 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 1/2 (50%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Faeces pale 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Flatulence 0/3 (0%) 0/4 (0%) 0/7 (0%) 6/65 (9.2%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 2/8 (25%)
    Gastric outlet obstruction 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Gastrooesophageal reflux disease 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 1/3 (33.3%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Gingival swelling 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Haemorrhoids 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 1/14 (7.1%) 0/8 (0%)
    Mouth ulceration 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Nausea 0/3 (0%) 0/4 (0%) 4/7 (57.1%) 28/65 (43.1%) 2/6 (33.3%) 4/7 (57.1%) 2/6 (33.3%) 4/10 (40%) 6/11 (54.5%) 3/4 (75%) 2/3 (66.7%) 13/24 (54.2%) 1/2 (50%) 1/3 (33.3%) 1/7 (14.3%) 4/14 (28.6%) 3/8 (37.5%)
    Odynophagia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 1/2 (50%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Oral discomfort 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Oral soft tissue disorder 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Salivary hypersecretion 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Stomach discomfort 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Stomatitis 0/3 (0%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Toothache 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 3/14 (21.4%) 1/8 (12.5%)
    Vomiting 0/3 (0%) 0/4 (0%) 4/7 (57.1%) 18/65 (27.7%) 2/6 (33.3%) 4/7 (57.1%) 2/6 (33.3%) 1/10 (10%) 3/11 (27.3%) 2/4 (50%) 1/3 (33.3%) 8/24 (33.3%) 1/2 (50%) 1/3 (33.3%) 1/7 (14.3%) 4/14 (28.6%) 0/8 (0%)
    General disorders
    Asthenia 0/3 (0%) 0/4 (0%) 4/7 (57.1%) 7/65 (10.8%) 0/6 (0%) 1/7 (14.3%) 2/6 (33.3%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 2/24 (8.3%) 0/2 (0%) 2/3 (66.7%) 1/7 (14.3%) 1/14 (7.1%) 2/8 (25%)
    Axillary pain 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Breakthrough pain 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Catheter related complication 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Catheter site erythema 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 1/3 (33.3%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Chest discomfort 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 3/24 (12.5%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Chest pain 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 5/24 (20.8%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Chills 0/3 (0%) 0/4 (0%) 2/7 (28.6%) 18/65 (27.7%) 1/6 (16.7%) 1/7 (14.3%) 3/6 (50%) 2/10 (20%) 2/11 (18.2%) 1/4 (25%) 2/3 (66.7%) 8/24 (33.3%) 0/2 (0%) 0/3 (0%) 4/7 (57.1%) 0/14 (0%) 1/8 (12.5%)
    Difficulty in walking 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Disease progression 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Fatigue 0/3 (0%) 2/4 (50%) 3/7 (42.9%) 38/65 (58.5%) 0/6 (0%) 4/7 (57.1%) 3/6 (50%) 4/10 (40%) 5/11 (45.5%) 3/4 (75%) 3/3 (100%) 14/24 (58.3%) 2/2 (100%) 2/3 (66.7%) 3/7 (42.9%) 9/14 (64.3%) 5/8 (62.5%)
    Feeling abnormal 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Gait disturbance 0/3 (0%) 0/4 (0%) 0/7 (0%) 3/65 (4.6%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Implant site pain 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Inflammation 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Infusion related reaction 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Infusion site erythema 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 1/6 (16.7%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Infusion site pain 0/3 (0%) 0/4 (0%) 0/7 (0%) 3/65 (4.6%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Infusion site swelling 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Injection site reaction 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 1/7 (14.3%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Irritability 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 2/14 (14.3%) 0/8 (0%)
    Malaise 0/3 (0%) 0/4 (0%) 0/7 (0%) 5/65 (7.7%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Mucosal inflammation 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Non-cardiac chest pain 0/3 (0%) 0/4 (0%) 2/7 (28.6%) 5/65 (7.7%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Oedema 0/3 (0%) 0/4 (0%) 2/7 (28.6%) 2/65 (3.1%) 0/6 (0%) 1/7 (14.3%) 1/6 (16.7%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Oedema peripheral 0/3 (0%) 0/4 (0%) 0/7 (0%) 9/65 (13.8%) 0/6 (0%) 0/7 (0%) 2/6 (33.3%) 3/10 (30%) 1/11 (9.1%) 2/4 (50%) 1/3 (33.3%) 5/24 (20.8%) 0/2 (0%) 1/3 (33.3%) 1/7 (14.3%) 3/14 (21.4%) 1/8 (12.5%)
    Pain 0/3 (0%) 0/4 (0%) 0/7 (0%) 7/65 (10.8%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 1/10 (10%) 1/11 (9.1%) 1/4 (25%) 0/3 (0%) 1/24 (4.2%) 1/2 (50%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Pyrexia 0/3 (0%) 0/4 (0%) 3/7 (42.9%) 17/65 (26.2%) 1/6 (16.7%) 1/7 (14.3%) 2/6 (33.3%) 5/10 (50%) 2/11 (18.2%) 1/4 (25%) 1/3 (33.3%) 13/24 (54.2%) 1/2 (50%) 3/3 (100%) 5/7 (71.4%) 2/14 (14.3%) 4/8 (50%)
    Temperature intolerance 0/3 (0%) 0/4 (0%) 0/7 (0%) 6/65 (9.2%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Thirst 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Hepatobiliary disorders
    Hepatomegaly 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Hyperbilirubinaemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 1/7 (14.3%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Immune system disorders
    Multiple allergies 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Seasonal allergy 0/3 (0%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Infections and infestations
    Bacteraemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Bronchitis 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 2/24 (8.3%) 1/2 (50%) 1/3 (33.3%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Candidiasis 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Cellulitis 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Clostridial infection 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Conjunctivitis infective 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Dental caries 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Diverticulitis 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 1/8 (12.5%)
    Ear infection 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 1/14 (7.1%) 0/8 (0%)
    Enterococcal bacteraemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Escherichia infection 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 1/7 (14.3%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Fungaemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Fungal infection 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Fungal rash 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Gastroenteritis viral 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Gastrointestinal fungal infection 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 1/7 (14.3%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Herpes zoster 0/3 (0%) 0/4 (0%) 0/7 (0%) 3/65 (4.6%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Infection 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Influenza 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Lower respiratory tract infection 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Nasopharyngitis 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 1/3 (33.3%) 4/24 (16.7%) 0/2 (0%) 1/3 (33.3%) 1/7 (14.3%) 0/14 (0%) 2/8 (25%)
    Oral candidiasis 0/3 (0%) 1/4 (25%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Osteomyelitis 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Pneumonia 0/3 (0%) 0/4 (0%) 0/7 (0%) 3/65 (4.6%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 1/3 (33.3%) 3/7 (42.9%) 0/14 (0%) 0/8 (0%)
    Postoperative wound infection 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Rhinitis 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Sinusitis 0/3 (0%) 1/4 (25%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Subcutaneous abscess 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Tooth infection 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Upper respiratory tract infection 0/3 (0%) 0/4 (0%) 0/7 (0%) 4/65 (6.2%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 1/11 (9.1%) 1/4 (25%) 0/3 (0%) 5/24 (20.8%) 1/2 (50%) 0/3 (0%) 3/7 (42.9%) 7/14 (50%) 4/8 (50%)
    Urinary tract infection 0/3 (0%) 0/4 (0%) 2/7 (28.6%) 5/65 (7.7%) 0/6 (0%) 1/7 (14.3%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 1/3 (33.3%) 2/24 (8.3%) 1/2 (50%) 1/3 (33.3%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Viral infection 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Vulvovaginal mycotic infection 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Wound infection 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 1/3 (33.3%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Injury, poisoning and procedural complications
    Back injury 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 1/3 (33.3%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Chest injury 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Compression fracture 0/3 (0%) 1/4 (25%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Contrast media reaction 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Contusion 0/3 (0%) 0/4 (0%) 0/7 (0%) 7/65 (10.8%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Fall 0/3 (0%) 0/4 (0%) 0/7 (0%) 4/65 (6.2%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Feeding tube complication 1/3 (33.3%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Foot fracture 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Incision site complication 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Muscle strain 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Postoperative ileus 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Procedural complication 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Renal injury 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Skin laceration 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 1/6 (16.7%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Tooth fracture 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Wound 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Investigations
    Alanine aminotransferase decreased 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Alanine aminotransferase increased 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 2/14 (14.3%) 1/8 (12.5%)
    Aspartate aminotransferase increased 0/3 (0%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 2/10 (20%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 2/14 (14.3%) 1/8 (12.5%)
    Blood albumin decreased 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Blood alkaline phosphatase increased 0/3 (0%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 1/7 (14.3%) 1/6 (16.7%) 2/10 (20%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Blood bilirubin increased 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Blood creatinine increased 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 11/65 (16.9%) 0/6 (0%) 3/7 (42.9%) 1/6 (16.7%) 3/10 (30%) 2/11 (18.2%) 0/4 (0%) 2/3 (66.7%) 6/24 (25%) 0/2 (0%) 0/3 (0%) 4/7 (57.1%) 1/14 (7.1%) 0/8 (0%)
    Blood lactate dehydrogenase increased 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 3/14 (21.4%) 0/8 (0%)
    Blood magnesium decreased 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Blood phosphorus increased 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Blood potassium decreased 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Blood pressure increased 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 1/14 (7.1%) 0/8 (0%)
    Blood pressure orthostatic decreased 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Blood sodium decreased 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Blood urea increased 0/3 (0%) 0/4 (0%) 0/7 (0%) 3/65 (4.6%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Blood uric acid increased 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 2/6 (33.3%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 3/24 (12.5%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Body temperature increased 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Creatinine renal clearance decreased 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 1/3 (33.3%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Electrocardiogram QT corrected interval prolonged 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Haemoglobin decreased 0/3 (0%) 0/4 (0%) 0/7 (0%) 3/65 (4.6%) 1/6 (16.7%) 1/7 (14.3%) 0/6 (0%) 3/10 (30%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Heart rate increased 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Influenza serology positive 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Lymphocyte count decreased 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 2/10 (20%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 1/3 (33.3%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Methicillin-resistant staphylococcal aureus test positive 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Platelet count decreased 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 1/3 (33.3%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Transaminases increased 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Weight decreased 0/3 (0%) 0/4 (0%) 0/7 (0%) 4/65 (6.2%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Weight increased 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 1/2 (50%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    White blood cell count decreased 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 2/24 (8.3%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Metabolism and nutrition disorders
    Anorexia 0/3 (0%) 0/4 (0%) 2/7 (28.6%) 26/65 (40%) 0/6 (0%) 2/7 (28.6%) 1/6 (16.7%) 0/10 (0%) 2/11 (18.2%) 2/4 (50%) 0/3 (0%) 4/24 (16.7%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 2/8 (25%)
    Decreased appetite 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 2/3 (66.7%) 1/7 (14.3%) 1/14 (7.1%) 0/8 (0%)
    Dehydration 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 9/65 (13.8%) 0/6 (0%) 2/7 (28.6%) 1/6 (16.7%) 0/10 (0%) 3/11 (27.3%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 1/2 (50%) 0/3 (0%) 1/7 (14.3%) 1/14 (7.1%) 0/8 (0%)
    Fluid retention 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 1/14 (7.1%) 0/8 (0%)
    Gout 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Hypercalcaemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 2/24 (8.3%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Hypercholesterolaemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Hyperglycaemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 3/65 (4.6%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 2/10 (20%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 2/24 (8.3%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 3/14 (21.4%) 1/8 (12.5%)
    Hyperkalaemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 4/65 (6.2%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Hyperphosphataemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Hyperuricaemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 3/24 (12.5%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Hypoalbuminaemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Hypocalcaemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 1/6 (16.7%) 0/7 (0%) 1/6 (16.7%) 1/10 (10%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Hypoglycaemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Hypokalaemia 1/3 (33.3%) 1/4 (25%) 3/7 (42.9%) 8/65 (12.3%) 1/6 (16.7%) 1/7 (14.3%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 5/14 (35.7%) 0/8 (0%)
    Hypomagnesaemia 2/3 (66.7%) 0/4 (0%) 0/7 (0%) 4/65 (6.2%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Hyponatraemia 0/3 (0%) 1/4 (25%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 1/7 (14.3%) 0/6 (0%) 4/10 (40%) 1/11 (9.1%) 0/4 (0%) 1/3 (33.3%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 2/14 (14.3%) 0/8 (0%)
    Hypophosphataemia 0/3 (0%) 0/4 (0%) 0/7 (0%) 7/65 (10.8%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 3/14 (21.4%) 0/8 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/3 (0%) 0/4 (0%) 2/7 (28.6%) 10/65 (15.4%) 0/6 (0%) 0/7 (0%) 2/6 (33.3%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 3/24 (12.5%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 5/14 (35.7%) 1/8 (12.5%)
    Back pain 0/3 (0%) 2/4 (50%) 2/7 (28.6%) 15/65 (23.1%) 0/6 (0%) 1/7 (14.3%) 2/6 (33.3%) 3/10 (30%) 1/11 (9.1%) 1/4 (25%) 0/3 (0%) 4/24 (16.7%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 3/14 (21.4%) 2/8 (25%)
    Bone pain 0/3 (0%) 0/4 (0%) 0/7 (0%) 4/65 (6.2%) 0/6 (0%) 1/7 (14.3%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 3/24 (12.5%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Buttock pain 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Chest wall pain 0/3 (0%) 0/4 (0%) 0/7 (0%) 4/65 (6.2%) 2/6 (33.3%) 1/7 (14.3%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 4/14 (28.6%) 1/8 (12.5%)
    Flank pain 0/3 (0%) 0/4 (0%) 0/7 (0%) 4/65 (6.2%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 1/2 (50%) 1/3 (33.3%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Groin pain 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 2/11 (18.2%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Joint range of motion decreased 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Joint swelling 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 5/65 (7.7%) 1/6 (16.7%) 1/7 (14.3%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 1/14 (7.1%) 0/8 (0%)
    Limb discomfort 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 1/2 (50%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Muscle spasms 0/3 (0%) 0/4 (0%) 0/7 (0%) 7/65 (10.8%) 0/6 (0%) 1/7 (14.3%) 1/6 (16.7%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 5/24 (20.8%) 1/2 (50%) 1/3 (33.3%) 2/7 (28.6%) 3/14 (21.4%) 2/8 (25%)
    Muscular weakness 0/3 (0%) 0/4 (0%) 0/7 (0%) 5/65 (7.7%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Musculoskeletal discomfort 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 1/14 (7.1%) 0/8 (0%)
    Musculoskeletal stiffness 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Myalgia 0/3 (0%) 0/4 (0%) 0/7 (0%) 7/65 (10.8%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 3/24 (12.5%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 1/8 (12.5%)
    Myopathy 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Myositis 1/3 (33.3%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Neck pain 0/3 (0%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 1/3 (33.3%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Osteoarthritis 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Pain in extremity 0/3 (0%) 0/4 (0%) 0/7 (0%) 8/65 (12.3%) 0/6 (0%) 2/7 (28.6%) 0/6 (0%) 2/10 (20%) 0/11 (0%) 1/4 (25%) 1/3 (33.3%) 3/24 (12.5%) 0/2 (0%) 1/3 (33.3%) 0/7 (0%) 5/14 (35.7%) 0/8 (0%)
    Pathological fracture 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Shoulder pain 1/3 (33.3%) 1/4 (25%) 0/7 (0%) 6/65 (9.2%) 0/6 (0%) 0/7 (0%) 2/6 (33.3%) 0/10 (0%) 0/11 (0%) 2/4 (50%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 2/14 (14.3%) 0/8 (0%)
    Systemic lupus erythematosus 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain 0/3 (0%) 1/4 (25%) 0/7 (0%) 2/65 (3.1%) 1/6 (16.7%) 1/7 (14.3%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 2/3 (66.7%) 3/24 (12.5%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Colon cancer 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Neoplasm progression 1/3 (33.3%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Nervous system disorders
    Amnesia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 1/6 (16.7%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Areflexia 0/3 (0%) 0/4 (0%) 0/7 (0%) 3/65 (4.6%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Burning sensation 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Cognitive disorder 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 1/3 (33.3%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Coordination abnormal 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Dizziness 0/3 (0%) 1/4 (25%) 1/7 (14.3%) 10/65 (15.4%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 7/24 (29.2%) 0/2 (0%) 2/3 (66.7%) 1/7 (14.3%) 3/14 (21.4%) 1/8 (12.5%)
    Dysaesthesia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Dysgeusia 0/3 (0%) 0/4 (0%) 0/7 (0%) 9/65 (13.8%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Dyskinesia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Dysphasia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Headache 1/3 (33.3%) 1/4 (25%) 4/7 (57.1%) 13/65 (20%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 1/10 (10%) 2/11 (18.2%) 1/4 (25%) 1/3 (33.3%) 8/24 (33.3%) 1/2 (50%) 1/3 (33.3%) 1/7 (14.3%) 5/14 (35.7%) 3/8 (37.5%)
    Hypoaesthesia 0/3 (0%) 0/4 (0%) 0/7 (0%) 11/65 (16.9%) 0/6 (0%) 0/7 (0%) 3/6 (50%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Hyporeflexia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Neuropathic pain 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Neuropathy 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Neuropathy peripheral 1/3 (33.3%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 1/3 (33.3%) 0/7 (0%) 3/14 (21.4%) 0/8 (0%)
    Paraesthesia 0/3 (0%) 0/4 (0%) 0/7 (0%) 6/65 (9.2%) 0/6 (0%) 0/7 (0%) 2/6 (33.3%) 0/10 (0%) 2/11 (18.2%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 3/14 (21.4%) 1/8 (12.5%)
    Peripheral sensory neuropathy 0/3 (0%) 0/4 (0%) 0/7 (0%) 4/65 (6.2%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 1/3 (33.3%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Peroneal nerve palsy 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Psychomotor hyperactivity 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Sinus headache 0/3 (0%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Somnolence 0/3 (0%) 0/4 (0%) 0/7 (0%) 3/65 (4.6%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Speech disorder 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Syncope 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 1/6 (16.7%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Tremor 0/3 (0%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 1/14 (7.1%) 1/8 (12.5%)
    Psychiatric disorders
    Abnormal dreams 0/3 (0%) 1/4 (25%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Agitation 0/3 (0%) 0/4 (0%) 0/7 (0%) 3/65 (4.6%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 1/3 (33.3%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Anxiety 1/3 (33.3%) 0/4 (0%) 0/7 (0%) 9/65 (13.8%) 0/6 (0%) 1/7 (14.3%) 1/6 (16.7%) 1/10 (10%) 1/11 (9.1%) 1/4 (25%) 1/3 (33.3%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Confusional state 0/3 (0%) 1/4 (25%) 1/7 (14.3%) 3/65 (4.6%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 1/2 (50%) 1/3 (33.3%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Depression 0/3 (0%) 0/4 (0%) 0/7 (0%) 4/65 (6.2%) 0/6 (0%) 1/7 (14.3%) 1/6 (16.7%) 0/10 (0%) 1/11 (9.1%) 1/4 (25%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Insomnia 0/3 (0%) 0/4 (0%) 3/7 (42.9%) 9/65 (13.8%) 0/6 (0%) 2/7 (28.6%) 0/6 (0%) 3/10 (30%) 1/11 (9.1%) 0/4 (0%) 1/3 (33.3%) 7/24 (29.2%) 0/2 (0%) 0/3 (0%) 2/7 (28.6%) 5/14 (35.7%) 3/8 (37.5%)
    Mood altered 1/3 (33.3%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Renal and urinary disorders
    Chromaturia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Dysuria 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 1/8 (12.5%)
    Glycosuria 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Haematuria 0/3 (0%) 0/4 (0%) 0/7 (0%) 3/65 (4.6%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 1/2 (50%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Hydronephrosis 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Micturition urgency 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Nephrolithiasis 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Neurogenic bladder 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Nocturia 0/3 (0%) 0/4 (0%) 0/7 (0%) 6/65 (9.2%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Pollakiuria 0/3 (0%) 0/4 (0%) 0/7 (0%) 4/65 (6.2%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 1/3 (33.3%) 2/24 (8.3%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 3/14 (21.4%) 0/8 (0%)
    Proteinuria 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Renal failure 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 1/7 (14.3%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Renal failure acute 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 2/11 (18.2%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Urinary incontinence 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 1/2 (50%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Urinary tract obstruction 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 1/7 (14.3%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Urine flow decreased 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Urine odour abnormal 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Reproductive system and breast disorders
    Erectile dysfunction 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Pelvic pain 1/3 (33.3%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Scrotal oedema 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 1/7 (14.3%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Vaginal haemorrhage 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 1/7 (14.3%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Respiratory, thoracic and mediastinal disorders
    Aspiration 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Atelectasis 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Cough 0/3 (0%) 0/4 (0%) 0/7 (0%) 12/65 (18.5%) 0/6 (0%) 1/7 (14.3%) 2/6 (33.3%) 2/10 (20%) 2/11 (18.2%) 1/4 (25%) 1/3 (33.3%) 7/24 (29.2%) 1/2 (50%) 2/3 (66.7%) 3/7 (42.9%) 8/14 (57.1%) 2/8 (25%)
    Crackles lung 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Dysphonia 0/3 (0%) 0/4 (0%) 0/7 (0%) 4/65 (6.2%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Dyspnoea 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 23/65 (35.4%) 2/6 (33.3%) 2/7 (28.6%) 1/6 (16.7%) 2/10 (20%) 3/11 (27.3%) 1/4 (25%) 0/3 (0%) 12/24 (50%) 0/2 (0%) 2/3 (66.7%) 3/7 (42.9%) 6/14 (42.9%) 2/8 (25%)
    Dyspnoea exacerbated 0/3 (0%) 0/4 (0%) 0/7 (0%) 5/65 (7.7%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Dyspnoea exertional 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/10 (10%) 1/11 (9.1%) 1/4 (25%) 0/3 (0%) 3/24 (12.5%) 1/2 (50%) 0/3 (0%) 1/7 (14.3%) 3/14 (21.4%) 1/8 (12.5%)
    Epistaxis 0/3 (0%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 1/6 (16.7%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 1/3 (33.3%) 2/24 (8.3%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Haemoptysis 0/3 (0%) 0/4 (0%) 0/7 (0%) 5/65 (7.7%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Hiccups 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 1/7 (14.3%) 2/6 (33.3%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Hypoxia 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 2/65 (3.1%) 1/6 (16.7%) 1/7 (14.3%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 3/24 (12.5%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Lung disorder 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Lung infiltration 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 1/3 (33.3%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Nasal congestion 0/3 (0%) 0/4 (0%) 0/7 (0%) 5/65 (7.7%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 1/3 (33.3%) 0/7 (0%) 0/14 (0%) 2/8 (25%)
    Nasal mucosal disorder 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Pharyngolaryngeal pain 0/3 (0%) 0/4 (0%) 0/7 (0%) 3/65 (4.6%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 1/3 (33.3%) 2/24 (8.3%) 1/2 (50%) 0/3 (0%) 0/7 (0%) 2/14 (14.3%) 1/8 (12.5%)
    Pleural effusion 0/3 (0%) 0/4 (0%) 0/7 (0%) 4/65 (6.2%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Pneumonia aspiration 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Postnasal drip 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 2/8 (25%)
    Productive cough 0/3 (0%) 1/4 (25%) 1/7 (14.3%) 4/65 (6.2%) 0/6 (0%) 1/7 (14.3%) 2/6 (33.3%) 1/10 (10%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 2/24 (8.3%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 1/14 (7.1%) 2/8 (25%)
    Pulmonary hypertension 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 2/24 (8.3%) 0/2 (0%) 0/3 (0%) 2/7 (28.6%) 1/14 (7.1%) 2/8 (25%)
    Respiratory failure 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Respiratory tract congestion 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Rhinitis allergic 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 2/24 (8.3%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Rhinorrhoea 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 3/24 (12.5%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 2/8 (25%)
    Rhonchi 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Sinus congestion 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 1/2 (50%) 0/3 (0%) 0/7 (0%) 2/14 (14.3%) 1/8 (12.5%)
    Stridor 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Tachypnoea 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 1/7 (14.3%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Upper respiratory tract congestion 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 1/2 (50%) 1/3 (33.3%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Wheezing 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 2/14 (14.3%) 2/8 (25%)
    Skin and subcutaneous tissue disorders
    Alopecia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 1/8 (12.5%)
    Cold sweat 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 1/14 (7.1%) 0/8 (0%)
    Dry skin 0/3 (0%) 0/4 (0%) 0/7 (0%) 10/65 (15.4%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Erythema 0/3 (0%) 0/4 (0%) 0/7 (0%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Hyperhidrosis 0/3 (0%) 0/4 (0%) 0/7 (0%) 5/65 (7.7%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Leukoplakia 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Night sweats 0/3 (0%) 0/4 (0%) 0/7 (0%) 9/65 (13.8%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 2/24 (8.3%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)
    Palmar erythema 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 1/2 (50%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Pruritus 0/3 (0%) 0/4 (0%) 0/7 (0%) 10/65 (15.4%) 0/6 (0%) 1/7 (14.3%) 2/6 (33.3%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 1/14 (7.1%) 0/8 (0%)
    Rash 0/3 (0%) 1/4 (25%) 1/7 (14.3%) 6/65 (9.2%) 0/6 (0%) 1/7 (14.3%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 2/24 (8.3%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 2/8 (25%)
    Rash erythematous 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Rash maculo-papular 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Skin lesion 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Skin tightness 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Swelling face 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 1/4 (25%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 0/8 (0%)
    Vascular disorders
    Deep vein thrombosis 0/3 (0%) 0/4 (0%) 0/7 (0%) 0/65 (0%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Flushing 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 1/11 (9.1%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 1/8 (12.5%)
    Haematoma 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Hot flush 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 3/65 (4.6%) 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 1/24 (4.2%) 0/2 (0%) 0/3 (0%) 1/7 (14.3%) 1/14 (7.1%) 0/8 (0%)
    Hypertension 0/3 (0%) 0/4 (0%) 1/7 (14.3%) 5/65 (7.7%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 2/11 (18.2%) 2/4 (50%) 1/3 (33.3%) 9/24 (37.5%) 1/2 (50%) 1/3 (33.3%) 1/7 (14.3%) 6/14 (42.9%) 2/8 (25%)
    Hypotension 0/3 (0%) 1/4 (25%) 1/7 (14.3%) 2/65 (3.1%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 2/11 (18.2%) 0/4 (0%) 1/3 (33.3%) 1/24 (4.2%) 1/2 (50%) 0/3 (0%) 0/7 (0%) 1/14 (7.1%) 0/8 (0%)
    Orthostatic hypotension 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 0/2 (0%) 0/3 (0%) 0/7 (0%) 0/14 (0%) 1/8 (12.5%)
    Phlebitis 0/3 (0%) 0/4 (0%) 0/7 (0%) 1/65 (1.5%) 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/10 (0%) 0/11 (0%) 0/4 (0%) 0/3 (0%) 0/24 (0%) 1/2 (50%) 0/3 (0%) 1/7 (14.3%) 0/14 (0%) 0/8 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.

    Results Point of Contact

    Name/Title Study Director
    Organization Amgen, Inc.
    Phone 866-572-6436
    Email
    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT00531284
    Other Study ID Numbers:
    • PX-171-007
    First Posted:
    Sep 18, 2007
    Last Update Posted:
    Aug 15, 2017
    Last Verified:
    Jul 1, 2017