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Safety Study of the Proteasome Inhibitor PR-171 (Carfilzomib for Injection) in Patients With Hematological Malignancies

Sponsor
Amgen (Industry)
Overall Status
Completed
CT.gov ID
NCT00150462
Collaborator
(none)
48
Enrollment
5
Locations
11
Arms
49
Duration (Months)
9.6
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to test the safety and tolerability of carfilzomib at different dose levels on hematological cancers such as multiple myeloma, non-Hodgkin's lymphoma, Hodgkin's disease, or Waldenstrom's macroglobulinemia. Carfilzomib is a proteasome inhibitor, an enzyme responsible for degrading a wide variety of cellular proteins.

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
48 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I Study of the Safety and Pharmacokinetics of Escalating Intravenous Doses of the Proteasome Inhibitor PR-171 in Patients With Hematological Malignancies
Study Start Date :
Sep 1, 2005
Actual Primary Completion Date :
Oct 1, 2009
Actual Study Completion Date :
Oct 1, 2009

Arms and Interventions

Arm Intervention/Treatment
Experimental: CFZ 1.2 mg/m²

Participants received carfilzomib (CFZ) 1.2 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles.

Drug: Carfilzomib
Administered as an IV bolus dose
Other Names:
  • PR-171
  • Kyprolis

    		•
    Experimental: CFZ 2.4 mg/m²

    Participants received carfilzomib 2.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles.

    Drug: Carfilzomib
    Administered as an IV bolus dose
    Other Names:
  • PR-171
  • Kyprolis

    		•
    Experimental: CFZ 4.0 mg/m²

    Participants received carfilzomib 4.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles.

    Drug: Carfilzomib
    Administered as an IV bolus dose
    Other Names:
  • PR-171
  • Kyprolis

    		•
    Experimental: CFZ 6.0 mg/m²

    Participants received carfilzomib 6.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles.

    Drug: Carfilzomib
    Administered as an IV bolus dose
    Other Names:
  • PR-171
  • Kyprolis

    		•
    Experimental: CFZ 8.4 mg/m²

    Participants received carfilzomib 8.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles.

    Drug: Carfilzomib
    Administered as an IV bolus dose
    Other Names:
  • PR-171
  • Kyprolis

    		•
    Experimental: CFZ 11.0 mg/m²

    Participants received carfilzomib 11.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles.

    Drug: Carfilzomib
    Administered as an IV bolus dose
    Other Names:
  • PR-171
  • Kyprolis

    		•
    Experimental: CFZ 15.0 mg/m²

    Participants received carfilzomib 115.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles.

    Drug: Carfilzomib
    Administered as an IV bolus dose
    Other Names:
  • PR-171
  • Kyprolis

    		•
    Experimental: CFZ 20.0 mg/m²

    Participants received carfilzomib 20.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles.

    Drug: Carfilzomib
    Administered as an IV bolus dose
    Other Names:
  • PR-171
  • Kyprolis

    		•
    Experimental: CFZ 27.0 mg/m²

    Participants received carfilzomib 27.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles.

    Drug: Carfilzomib
    Administered as an IV bolus dose
    Other Names:
  • PR-171
  • Kyprolis

    		•
    Experimental: CFZ 20/27 mg/m²

    Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles.

    Drug: Carfilzomib
    Administered as an IV bolus dose
    Other Names:
  • PR-171
  • Kyprolis

    		•
    Experimental: CFZ 20/27 mg/m² + DEX

    Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants also received 20 mg dexamethasone (DEX) administered before each dose of carfilzomib (i.e. 40 mg weekly).

    Drug: Carfilzomib
    Administered as an IV bolus dose
    Other Names:
  • PR-171
  • Kyprolis

    • Drug: Dexamethasone
    Administered orally prior to carfilzomib

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Dose-limiting Toxicities (DLTs) [28 days]

      A DLT was defined as any of the following occurring in the first 28 days of study participation: Nonhematologic: > Grade 2 neuropathy with pain ≥ Grade 3 nonhematologic toxicity (excluding nausea, vomiting, or diarrhea) ≥ Grade 3 nausea, vomiting, or diarrhea uncontrolled by maximal antiemetic/antidiarrheal therapy Hematologic: Grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 10ˆ9/L) lasting ≥ 14 days without hematopoietic growth factor support Febrile neutropenia (ANC < 1.0 × 10ˆ9/L with a fever ≥ 38.3°C) Grade 4 thrombocytopenia (platelets < 25.0 × 10ˆ9/L) or thrombocytopenia associated with bleeding. Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (NCI) version 3.0.

    2. Maximum Observed Plasma Concentration of Carfilzomib (Cmax) [Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose.]

    3. Time to Maximum Observed Plasma Concentration of Carfilzomib (Tmax) [Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose.]

    4. Area Under the Concentration-time Curve to Last Measureable Timepoint (AUClast) for Carfilzomib [Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose.]

    5. Area Under the Concentration-time Curve Extrapolated to Infinity (AUCinf) for Carfilzomib [Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose.]

    Secondary Outcome Measures

    1. Best Clinical Response to Treatment [From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase.]

      Disease response criteria for NHL were according to the International Working Group Criteria for Non-Hodgkin's Lymphoma. Disease response criteria for Multiple Myeloma were according to the European Group for Blood and Marrow Transplantation (EBMT). Disease response criteria for WM were according to the consensus panel recommendations from the Second International Workshop on Waldenström's Macroglobulinemia. The disease response criteria for Hodgkin's Lymphoma are defined as follows: Complete response: total resolution of measurable disease parameters. Partial response: a ≥ 50% resolution without the appearance of new disease. Stable disease: between < 50% resolution and ≤ 25% increases in measurable disease parameters without appearance of new disease. Progressive disease: an increase of > 25% in measurable disease parameters. Best clinical response is the best response observed from the start of study treatment until disease progression or death.

    2. Duration of Response [From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase.]

      Duration of objective response is defined as the time from the date of first documented assessment of clinical response (confirmed or unconfirmed complete response, partial response, or minimal response) to the date of documented assessment of progressive disease or death, whichever comes first, plus one day. Participants without tumor progression or death were censored at the date of their last valid clinical response assessment. Median duration of response was calculated using the Kaplan-Meier method.

    3. Time to Progression [From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase.]

      Time to progressive disease is defined as the time from the date of Cycle 1, Day 1 of treatment to the date of documented assessment of progressive disease, plus one day. Participants without tumor progression were censored at the date of their last clinical response assessment. Median time to progression was calculated using the Kaplan-Meier method.

    4. Progression-free Survival [From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase.]

      Progression-free survival is defined as the time from the date of Cycle 1, Day 1 of treatment to the date of documented assessment of progressive disease or death, whichever comes first, plus one day. Participants without tumor progression or death were censored at the date of their last valid clinical response assessment. Median progression-free survival was calculated using the Kaplan-Meier method.

    Eligibility Criteria

    Criteria

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

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

    2. Males and females ≥18 years of age

    3. Histologically confirmed diagnosis of one of the hematologic malignancies below:

    • Multiple myeloma (MM)

    • Non-Hodgkin's lymphoma (NHL)

    • Waldenström's Macroglobulinemia (WM)

    • Hodgkin's disease (HD)

    1. Subjects who are refractory or relapsed following at least two prior therapies

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

    3. Adequate cardiovascular function without symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction in the previous six months

    4. Adequate hepatic function, with bilirubin < 2.0 times the upper limit of normal, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of < 3.0 times the upper limit of normal

    5. Total white blood cell (WBC) count ≥ 2,000/mm³, absolute neutrophil count (ANC) ≥ 1000/mm³, hemoglobin ≥ 8.0 g/dL, and platelet count ≥ 50,000/mm³

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

    • Subjects receiving supportive care including erythropoietin, darbepoetin and/or bisphosphonates can continue to do so, but must be transfusion independent; subjects receiving erythropoietic support must remain on the same dose for the first 28 days of study participation

    1. An estimated creatinine clearance of ≥ 30 mL/min, calculated using the formula of Cockroft and Gault

    2. Serum creatinine ≤ 2.0 mg/dL

    3. Uric acid, if elevated, must be corrected to within laboratory normal range prior to dosing

    4. Female subjects of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test. Male subjects must use an effective barrier method of contraception throughout the study and for three months following the last dose if sexually active with a female of child-bearing potential.

    Exclusion Criteria:

    1. Female subjects who are pregnant or lactating

    2. Subjects who are transfusion dependent

    3. Subjects with NHL or HL who have received steroid therapy in the previous seven days

    4. Subjects with MM or Waldenström's Macroglobulinemia who have received steroid therapy in the previous three weeks, except for MM subjects in the Carfilzomib + DEX Expansion Cohort, where previous treatment with dexamethasone will be allowed. The dose and schedule of administration of dexamethasone will be adjusted to that used in the protocol

    5. Radiation, chemotherapy, or immunotherapy in the previous four weeks, or subjects who, in the judgment of the Investigator, have not recovered from the effects of previous therapy

    6. For the Dose Escalation period, subjects who have received prior radioimmunotherapy with anti-cluster of differentiation (CD)20 monoclonal antibodies such as Bexxar® or Zevalin®; subjects treated with these products will be allowed in the Dose Expansion period

    7. Subjects who have received allogeneic stem cell transplant therapy

    8. Subjects with NHL or HL who have received autologous stem cell transplant therapy and have relapsed within 100 days of therapy

    9. Rituxan therapy within three months before Day 1 unless there is evidence of disease progression

    10. Major surgery within three weeks before Day 1

    11. Congestive heart failure (CHF) (New York Heart Association class III to IV)

    12. Acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose

    13. Subjects who are known or suspected of having human immunodeficiency virus (HIV) infection or who are HIV seropositive

    14. Active hepatitis A, B, or C infection; or positive for Hepatitis C ribonucleic acid (RNA) or hepatitis B antigen

    15. Non-hematologic malignancy within the past three years except a) adequately treated basal cell or squamous cell skin cancer, b) carcinoma in situ of the cervix, or c) prostate cancer with stable prostate specific antigen (PSA) levels for three years

    16. Subjects with treatment-related myelodysplastic disorder

    17. Subjects with known brain metastasis (active central nervous system [CNS] disease only)

    18. Serious psychiatric or medical conditions that could interfere with treatment

    19. Participation in an investigational therapeutic study within one month prior to Day 1

    20. Significant neurotoxicity (Grade 2 or higher with pain) at the time of study initiation

    21. Concurrent therapy with approved or investigative anticancer therapeutics

    22. Subjects with previous hypersensitivity to bortezomib injection

    23. Subjects with contraindications to receiving allopurinol

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

    25. Subjects with known or suspected amyloidosis

    26. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Tower Cancer Research Foundation Beverly Hills California United States 90211-1850
    2 H. Lee Moffitt Cancer Center and Research Institute Tampa Florida United States 33612
    3 Memorial Sloan Kettering Cancer Center New York New York United States 10021
    4 Weil Medical College of Cornell University New York New York United States 10021
    5 Herbert Irving Comprehensive Cancer Center, Columbia University New York New York United States 10032

    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:
    NCT00150462
    Other Study ID Numbers:
    • PX-171-002
    First Posted:
    Sep 8, 2005
    Last Update Posted:
    May 2, 2017
    Last Verified:
    Apr 1, 2017
    Keywords provided by Amgen
    Hematological
    Proteasome
    Myeloma
    Lymphoma
    Additional relevant MeSH terms:
    Multiple Myeloma
    Waldenstrom Macroglobulinemia
    Hematologic Neoplasms
    Hodgkin Disease
    Dexamethasone

    Study Results

    Participant Flow

    Recruitment Details Adults with with multiple myeloma (MM)-both secretory and nonsecretory, non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), or Waldenström's macroglobulinemia (WM) were eligible for enrollment in this study.
    Pre-assignment Detail The study was divided into a sequential Dose Escalation phase (Part 1; Arms 1-9), followed by a Dose Expansion phase (Part 2; Arms 10-11) consisting of a carfilzomib-only cohort and a carfilzomib-plus dexamethasone cohort.
    Arm/Group Title CFZ 1.2 mg/m² CFZ 2.4 mg/m² CFZ 4.0 mg/m² CFZ 6.0 mg/m² CFZ 8.4 mg/m² CFZ 11.0 mg/m² CFZ 15.0 mg/m² CFZ 20.0 mg/m² CFZ 27.0 mg/m² CFZ 20/27 mg/m² CFZ 20/27 mg/m² + DEX
    Arm/Group Description Participants received carfilzomib (CFZ) 1.2 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 2.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 4.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 6.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 8.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 11.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 15.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 27.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants also received 20 mg dexamethasone (DEX) administered before each dose of carfilzomib (i.e. 40 mg weekly).
    Period Title: Overall Study
    STARTED 3 3 4 3 3 4 3 8 6 7 4
    COMPLETED 0 0 0 0 0 0 0 0 0 1 1
    NOT COMPLETED 3 3 4 3 3 4 3 8 6 6 3

    Baseline Characteristics

    Arm/Group Title CFZ 1.2 mg/m² CFZ 2.4 mg/m² CFZ 4.0 mg/m² CFZ 6.0 mg/m² CFZ 8.4 mg/m² CFZ 11.0 mg/m² CFZ 15.0 mg/m² CFZ 20.0 mg/m² CFZ 27.0 mg/m² CFZ 20/27 mg/m² CFZ 20/27 mg/m² + DEX Total
    Arm/Group Description Participants received carfilzomib (CFZ) 1.2 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 2.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 4.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 6.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 8.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 11.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 15.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 27.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants also received 20 mg dexamethasone (DEX) administered before each dose of carfilzomib (i.e. 40 mg weekly). Total of all reporting groups
    Overall Participants 3 3 4 3 3 4 3 8 6 7 4 48
    Age (years) [Mean (Standard Deviation) ]
    Dose Escalation (Part 1)
    62.5
    (17.47)
    69.6
    (4.80)
    55.3
    (21.71)
    51.7
    (6.20)
    61.6
    (9.15)
    61.3
    (3.76)
    50.3
    (12.99)
    60.6
    (11.99)
    67.6
    (9.82)
    NA
    (NA)
    NA
    (NA)
    60.6
    (12.25)
    Dose Expansion (Part 2)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    66.3
    (9.21)
    54.3
    (13.57)
    61.9
    (11.96)
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    2
    66.7%
    3
    75%
    2
    66.7%
    1
    33.3%
    4
    100%
    1
    33.3%
    2
    25%
    2
    33.3%
    2
    28.6%
    3
    75%
    22
    45.8%
    Male
    3
    100%
    1
    33.3%
    1
    25%
    1
    33.3%
    2
    66.7%
    0
    0%
    2
    66.7%
    6
    75%
    4
    66.7%
    5
    71.4%
    1
    25%
    26
    54.2%
    Race/Ethnicity, Customized (participants) [Number]
    African American
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    14.3%
    1
    25%
    3
    6.3%
    Caucasian
    3
    100%
    2
    66.7%
    3
    75%
    3
    100%
    2
    66.7%
    4
    100%
    3
    100%
    7
    87.5%
    6
    100%
    6
    85.7%
    3
    75%
    42
    87.5%
    Hispanic
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    2.1%
    Native American
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    0
    0%
    0
    0%
    2
    4.2%
    Disease Diagnosis (participants) [Number]
    Multiple Myeloma
    0
    0%
    3
    100%
    0
    0%
    2
    66.7%
    1
    33.3%
    2
    50%
    2
    66.7%
    6
    75%
    5
    83.3%
    3
    42.9%
    4
    100%
    28
    58.3%
    Non-Hodgkin's Lymphoma
    3
    100%
    0
    0%
    3
    75%
    1
    33.3%
    2
    66.7%
    2
    50%
    1
    33.3%
    2
    25%
    1
    16.7%
    2
    28.6%
    0
    0%
    17
    35.4%
    Waldenstrom's Macroglobulinemia
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    28.6%
    0
    0%
    2
    4.2%
    Hodgkin's Disease
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    2.1%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Dose-limiting Toxicities (DLTs)
    Description A DLT was defined as any of the following occurring in the first 28 days of study participation: Nonhematologic: > Grade 2 neuropathy with pain ≥ Grade 3 nonhematologic toxicity (excluding nausea, vomiting, or diarrhea) ≥ Grade 3 nausea, vomiting, or diarrhea uncontrolled by maximal antiemetic/antidiarrheal therapy Hematologic: Grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 10ˆ9/L) lasting ≥ 14 days without hematopoietic growth factor support Febrile neutropenia (ANC < 1.0 × 10ˆ9/L with a fever ≥ 38.3°C) Grade 4 thrombocytopenia (platelets < 25.0 × 10ˆ9/L) or thrombocytopenia associated with bleeding. Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (NCI) version 3.0.
    Time Frame 28 days

    Outcome Measure Data

    Analysis Population Description
    Safety-evaluable: All participants who were enrolled and received at least 1 dose of carfilzomib
    Arm/Group Title CFZ 1.2 mg/m² CFZ 2.4 mg/m² CFZ 4.0 mg/m² CFZ 6.0 mg/m² CFZ 8.4 mg/m² CFZ 11.0 mg/m² CFZ 15.0 mg/m² CFZ 20.0 mg/m² CFZ 27.0 mg/m² CFZ 20/27 mg/m² CFZ 20/27 mg/m² + DEX
    Arm/Group Description Participants received carfilzomib (CFZ) 1.2 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 2.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 4.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 6.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 8.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 11.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 15.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 27.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants also received 20 mg dexamethasone (DEX) administered before each dose of carfilzomib (i.e. 40 mg weekly).
    Measure Participants 3 3 4 3 3 4 3 8 6 7 4
    Number [participants]
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    1
    16.7%
    0
    0%
    1
    25%
    2. Primary Outcome
    Title Maximum Observed Plasma Concentration of Carfilzomib (Cmax)
    Description
    Time Frame Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose.

    Outcome Measure Data

    Analysis Population Description
    Participants with available pharmacokinetic (PK) data. Cmax was only determined for cohorts receiving carfilzomib ≥ 11 mg/m². For cohorts with carfilzomib dose at 1.2-8.4 mg/m², carfilzomib was measurable at too few time points to allow a good estimation. Participants in the two Dose Expansion cohorts (20/27 mg/m²) were combined for PK analyses.
    Arm/Group Title CFZ 1.2 mg/m² CFZ 2.4 mg/m² CFZ 4.0 mg/m² CFZ 6.0 mg/m² CFZ 8.4 mg/m² CFZ 11.0 mg/m² CFZ 15.0 mg/m² CFZ 20.0 mg/m² CFZ 27.0 mg/m² CFZ 20/27 mg/m² (±DEX)
    Arm/Group Description Participants received carfilzomib (CFZ) 1.2 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 2.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 4.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 6.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 8.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 11.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 15.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 27.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants in the Dose Expansion phase received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles.
    Measure Participants 0 0 0 0 0 3 3 8 5 8
    Mean (Standard Deviation) [ng/mL]
    505.17
    (485.12)
    142.67
    (97.22)
    527.50
    (405.59)
    406.08
    (517.29)
    390.66
    (492.92)
    3. Secondary Outcome
    Title Best Clinical Response to Treatment
    Description Disease response criteria for NHL were according to the International Working Group Criteria for Non-Hodgkin's Lymphoma. Disease response criteria for Multiple Myeloma were according to the European Group for Blood and Marrow Transplantation (EBMT). Disease response criteria for WM were according to the consensus panel recommendations from the Second International Workshop on Waldenström's Macroglobulinemia. The disease response criteria for Hodgkin's Lymphoma are defined as follows: Complete response: total resolution of measurable disease parameters. Partial response: a ≥ 50% resolution without the appearance of new disease. Stable disease: between < 50% resolution and ≤ 25% increases in measurable disease parameters without appearance of new disease. Progressive disease: an increase of > 25% in measurable disease parameters. Best clinical response is the best response observed from the start of study treatment until disease progression or death.
    Time Frame From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase.

    Outcome Measure Data

    Analysis Population Description
    Biologic response-evaluable: All participants who received at least 1 cycle of carfilzomib and had both baseline and at least 1 post-baseline disease assessment.
    Arm/Group Title CFZ 1.2 mg/m² CFZ 2.4 mg/m² CFZ 4.0 mg/m² CFZ 6.0 mg/m² CFZ 8.4 mg/m² CFZ 11.0 mg/m² CFZ 15.0 mg/m² CFZ 20.0 mg/m² CFZ 27.0 mg/m² CFZ 20/27 mg/m² CFZ 20/27 mg/m² + DEX
    Arm/Group Description Participants received carfilzomib (CFZ) 1.2 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 2.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 4.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 6.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 8.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 11.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 15.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 27.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants also received 20 mg dexamethasone (DEX) administered before each dose of carfilzomib (i.e. 40 mg weekly).
    Measure Participants 1 2 3 2 3 3 2 6 5 6 3
    Complete Response
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Partial Response
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    1
    12.5%
    2
    33.3%
    2
    28.6%
    0
    0%
    Minimal Response
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    1
    25%
    Stable Disease/No Change
    0
    0%
    1
    33.3%
    1
    25%
    2
    66.7%
    1
    33.3%
    1
    25%
    0
    0%
    2
    25%
    1
    16.7%
    2
    28.6%
    0
    0%
    Progressive Disease
    1
    33.3%
    1
    33.3%
    1
    25%
    0
    0%
    2
    66.7%
    2
    50%
    1
    33.3%
    3
    37.5%
    1
    16.7%
    2
    28.6%
    2
    50%
    Unknown
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    4. Secondary Outcome
    Title Duration of Response
    Description Duration of objective response is defined as the time from the date of first documented assessment of clinical response (confirmed or unconfirmed complete response, partial response, or minimal response) to the date of documented assessment of progressive disease or death, whichever comes first, plus one day. Participants without tumor progression or death were censored at the date of their last valid clinical response assessment. Median duration of response was calculated using the Kaplan-Meier method.
    Time Frame From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase.

    Outcome Measure Data

    Analysis Population Description
    Biologic response-evaluable participants with an objective response
    Arm/Group Title CFZ 1.2 mg/m² CFZ 2.4 mg/m² CFZ 4.0 mg/m² CFZ 6.0 mg/m² CFZ 8.4 mg/m² CFZ 11.0 mg/m² CFZ 15.0 mg/m² CFZ 20.0 mg/m² CFZ 27.0 mg/m² CFZ 20/27 mg/m² CFZ 20/27 mg/m² + DEX
    Arm/Group Description Participants received carfilzomib (CFZ) 1.2 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 2.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 4.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 6.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 8.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 11.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 15.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 27.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15, and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15, and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants also received 20 mg dexamethasone (DEX) administered before each dose of carfilzomib (i.e. 40 mg weekly).
    Measure Participants 0 0 0 0 0 0 1 1 3 2 1
    Median (Full Range) [days]
    308.0
    176.0
    225.0
    NA
    NA
    5. Secondary Outcome
    Title Time to Progression
    Description Time to progressive disease is defined as the time from the date of Cycle 1, Day 1 of treatment to the date of documented assessment of progressive disease, plus one day. Participants without tumor progression were censored at the date of their last clinical response assessment. Median time to progression was calculated using the Kaplan-Meier method.
    Time Frame From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase.

    Outcome Measure Data

    Analysis Population Description
    Biologic response-evaluable population
    Arm/Group Title CFZ 1.2 mg/m² CFZ 2.4 mg/m² CFZ 4.0 mg/m² CFZ 6.0 mg/m² CFZ 8.4 mg/m² CFZ 11.0 mg/m² CFZ 15.0 mg/m² CFZ 20.0 mg/m² CFZ 27.0 mg/m² CFZ 20/27 mg/m² CFZ 20/27 mg/m² + DEX
    Arm/Group Description Participants received carfilzomib (CFZ) 1.2 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 2.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 4.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 6.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 8.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 11.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 15.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 27.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants also received 20 mg dexamethasone (DEX) administered before each dose of carfilzomib (i.e. 40 mg weekly).
    Measure Participants 1 2 3 2 3 3 2 6 5 6 3
    Median (Full Range) [days]
    114.0
    232.0
    NA
    NA
    55.0
    48.0
    186.0
    110.5
    225.0
    NA
    49.0
    6. Secondary Outcome
    Title Progression-free Survival
    Description Progression-free survival is defined as the time from the date of Cycle 1, Day 1 of treatment to the date of documented assessment of progressive disease or death, whichever comes first, plus one day. Participants without tumor progression or death were censored at the date of their last valid clinical response assessment. Median progression-free survival was calculated using the Kaplan-Meier method.
    Time Frame From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase.

    Outcome Measure Data

    Analysis Population Description
    Biologic response-evaluable population
    Arm/Group Title CFZ 1.2 mg/m² CFZ 2.4 mg/m² CFZ 4.0 mg/m² CFZ 6.0 mg/m² CFZ 8.4 mg/m² CFZ 11.0 mg/m² CFZ 15.0 mg/m² CFZ 20.0 mg/m² CFZ 27.0 mg/m² CFZ 20/27 mg/m² CFZ 20/27 mg/m² + DEX
    Arm/Group Description Participants received carfilzomib (CFZ) 1.2 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 2.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 4.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 6.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 8.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 11.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 15.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 27.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants also received 20 mg dexamethasone (DEX) administered before each dose of carfilzomib (i.e. 40 mg weekly).
    Measure Participants 1 2 3 2 3 3 2 6 5 6 3
    Median (Full Range) [days]
    114.0
    232.0
    NA
    NA
    55.0
    48.0
    186.0
    110.5
    225.0
    NA
    49.0
    7. Primary Outcome
    Title Time to Maximum Observed Plasma Concentration of Carfilzomib (Tmax)
    Description
    Time Frame Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose.

    Outcome Measure Data

    Analysis Population Description
    Participants with available pharmacokinetic (PK) data. Tmax was only determined for cohorts receiving carfilzomib ≥ 11 mg/m². For cohorts with carfilzomib dose at 1.2-8.4 mg/m², carfilzomib was measurable at too few time points to allow a good estimation. Participants in the two Dose Expansion cohorts (20/27 mg/m²) were combined for PK analyses.
    Arm/Group Title CFZ 1.2 mg/m² CFZ 2.4 mg/m² CFZ 4.0 mg/m² CFZ 6.0 mg/m² CFZ 8.4 mg/m² CFZ 11.0 mg/m² CFZ 15.0 mg/m² CFZ 20.0 mg/m² CFZ 27.0 mg/m² CFZ 20/27 mg/m² (±DEX)
    Arm/Group Description Participants received carfilzomib (CFZ) 1.2 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 2.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 4.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 6.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 8.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 11.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 15.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 27.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants in the Dose Expansion phase received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles.
    Measure Participants 0 0 0 0 0 3 3 8 5 8
    Mean (Standard Deviation) [minutes]
    5
    (0)
    6
    (1)
    7
    (2)
    6
    (2)
    16
    (11)
    8. Primary Outcome
    Title Area Under the Concentration-time Curve to Last Measureable Timepoint (AUClast) for Carfilzomib
    Description
    Time Frame Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose.

    Outcome Measure Data

    Analysis Population Description
    Participants with available pharmacokinetic (PK) data. AUClast was only determined for cohorts receiving carfilzomib ≥ 11 mg/m². For cohorts with carfilzomib dose at 1.2-8.4 mg/m², carfilzomib was measurable at too few time points to allow a good estimation. Participants in the two Dose Expansion cohorts (20/27 mg/m²) were combined for PK analyses.
    Arm/Group Title CFZ 1.2 mg/m² CFZ 2.4 mg/m² CFZ 4.0 mg/m² CFZ 6.0 mg/m² CFZ 8.4 mg/m² CFZ 11.0 mg/m² CFZ 15.0 mg/m² CFZ 20.0 mg/m² CFZ 27.0 mg/m² CFZ 20/27 mg/m² (±DEX)
    Arm/Group Description Participants received carfilzomib (CFZ) 1.2 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 2.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 4.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 6.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 8.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 11.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 15.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 27.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants in the Dose Expansion phase received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles.
    Measure Participants 0 0 0 0 0 3 3 8 5 8
    Mean (Standard Deviation) [ng*minute/mL]
    4049
    (3695)
    1414
    (919)
    4911
    (3495)
    3409
    (3964)
    4970
    (5817)
    9. Primary Outcome
    Title Area Under the Concentration-time Curve Extrapolated to Infinity (AUCinf) for Carfilzomib
    Description
    Time Frame Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose.

    Outcome Measure Data

    Analysis Population Description
    Participants with available pharmacokinetic (PK) data. AUCinf was only determined for cohorts receiving carfilzomib ≥ 11 mg/m². For cohorts with carfilzomib dose at 1.2-8.4 mg/m², carfilzomib was measurable at too few time points to allow a good estimation. Participants in the two Dose Expansion cohorts (20/27 mg/m²) were combined for PK analyses.
    Arm/Group Title CFZ 1.2 mg/m² CFZ 2.4 mg/m² CFZ 4.0 mg/m² CFZ 6.0 mg/m² CFZ 8.4 mg/m² CFZ 11.0 mg/m² CFZ 15.0 mg/m² CFZ 20.0 mg/m² CFZ 27.0 mg/m² CFZ 20/27 mg/m² (±DEX)
    Arm/Group Description Participants received carfilzomib (CFZ) 1.2 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 2.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 4.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 6.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 8.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 11.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 15.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 27.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants in the Dose Expansion phase received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles.
    Measure Participants 0 0 0 0 0 3 3 8 5 8
    Mean (Standard Deviation) [ng*minute/mL]
    4056
    (3698)
    1420
    (922)
    4942
    (3497)
    3417
    (3962)
    4997
    (5812)

    Adverse Events

    Time Frame From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase.
    Adverse Event Reporting Description Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
    Arm/Group Title CFZ 1.2 mg/m² CFZ 2.4 mg/m² CFZ 4.0 mg/m² CFZ 6.0 mg/m² CFZ 8.4 mg/m² CFZ 11.0 mg/m² CFZ 15.0 mg/m² CFZ 20.0 mg/m² CFZ 27.0 mg/m² CFZ 20/27 mg/m² CFZ 20/27 mg/m² + DEX
    Arm/Group Description Participants received carfilzomib (CFZ) 1.2 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 2.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 4.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 6.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 8.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 11.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 15.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 27.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants also received 20 mg dexamethasone (DEX) administered before each dose of carfilzomib (i.e. 40 mg weekly).
    All Cause Mortality
    CFZ 1.2 mg/m² CFZ 2.4 mg/m² CFZ 4.0 mg/m² CFZ 6.0 mg/m² CFZ 8.4 mg/m² CFZ 11.0 mg/m² CFZ 15.0 mg/m² CFZ 20.0 mg/m² CFZ 27.0 mg/m² CFZ 20/27 mg/m² CFZ 20/27 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
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    CFZ 1.2 mg/m² CFZ 2.4 mg/m² CFZ 4.0 mg/m² CFZ 6.0 mg/m² CFZ 8.4 mg/m² CFZ 11.0 mg/m² CFZ 15.0 mg/m² CFZ 20.0 mg/m² CFZ 27.0 mg/m² CFZ 20/27 mg/m² CFZ 20/27 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
    Total 2/3 (66.7%) 1/3 (33.3%) 3/4 (75%) 2/3 (66.7%) 2/3 (66.7%) 2/4 (50%) 1/3 (33.3%) 3/8 (37.5%) 4/6 (66.7%) 3/7 (42.9%) 2/4 (50%)
    Blood and lymphatic system disorders
    Anaemia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Febrile neutropenia 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Hyperviscosity syndrome 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Thrombocytopenia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Gastrointestinal disorders
    Abdominal distension 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Abdominal pain upper 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Pancreatitis 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Upper gastrointestinal haemorrhage 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    General disorders
    Multi-organ failure 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Non-cardiac chest pain 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Pain 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Pyrexia 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Infections and infestations
    Bronchitis 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Pneumonia 1/3 (33.3%) 1/3 (33.3%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Sepsis 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Septic shock 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Sinusitis 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Injury, poisoning and procedural complications
    Rib fracture 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Investigations
    Aspartate aminotransferase increased 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Glomerular filtration rate decreased 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Metabolism and nutrition disorders
    Dehydration 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Hypocalcaemia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Hyponatraemia 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Musculoskeletal and connective tissue disorders
    Pain in extremity 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Pathological fracture 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour associated fever 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Nervous system disorders
    Speech disorder 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Spinal cord compression 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Syncope 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Unresponsive to verbal stimuli 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Psychiatric disorders
    Mental status changes 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Renal and urinary disorders
    Renal failure 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Renal failure acute 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea exacerbated 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Hypoxia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 1/4 (25%)
    Pleural effusion 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 1/4 (25%)
    Vascular disorders
    Hypotension 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 1/4 (25%)
    Other (Not Including Serious) Adverse Events
    CFZ 1.2 mg/m² CFZ 2.4 mg/m² CFZ 4.0 mg/m² CFZ 6.0 mg/m² CFZ 8.4 mg/m² CFZ 11.0 mg/m² CFZ 15.0 mg/m² CFZ 20.0 mg/m² CFZ 27.0 mg/m² CFZ 20/27 mg/m² CFZ 20/27 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
    Total 3/3 (100%) 3/3 (100%) 4/4 (100%) 3/3 (100%) 3/3 (100%) 4/4 (100%) 3/3 (100%) 8/8 (100%) 6/6 (100%) 7/7 (100%) 4/4 (100%)
    Blood and lymphatic system disorders
    Anaemia 1/3 (33.3%) 3/3 (100%) 0/4 (0%) 2/3 (66.7%) 0/3 (0%) 1/4 (25%) 2/3 (66.7%) 4/8 (50%) 4/6 (66.7%) 4/7 (57.1%) 4/4 (100%)
    Febrile neutropenia 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Leukopenia 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 1/4 (25%)
    Lymph node pain 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Lymphopenia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Neutropenia 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 2/8 (25%) 0/6 (0%) 1/7 (14.3%) 2/4 (50%)
    Pancytopenia 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Thrombocytopenia 0/3 (0%) 1/3 (33.3%) 3/4 (75%) 1/3 (33.3%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 3/8 (37.5%) 3/6 (50%) 4/7 (57.1%) 3/4 (75%)
    Cardiac disorders
    Bradycardia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Cardiac flutter 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Cardiomegaly 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Sinus tachycardia 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Tachycardia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 1/7 (14.3%) 1/4 (25%)
    Ear and labyrinth disorders
    Deafness 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Ear pain 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Tinnitus 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Vertigo 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Eye disorders
    Cataract 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Conjunctival hyperaemia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Dry eye 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 1/7 (14.3%) 0/4 (0%)
    Exophthalmos 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Eye pain 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Eyelid irritation 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Eyelid oedema 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Ocular hyperaemia 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Vision blurred 2/3 (66.7%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Gastrointestinal disorders
    Abdominal distension 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Abdominal pain 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 1/8 (12.5%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Abdominal pain upper 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Cheilitis 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Constipation 2/3 (66.7%) 0/3 (0%) 2/4 (50%) 1/3 (33.3%) 2/3 (66.7%) 2/4 (50%) 0/3 (0%) 4/8 (50%) 3/6 (50%) 2/7 (28.6%) 0/4 (0%)
    Diarrhoea 0/3 (0%) 1/3 (33.3%) 2/4 (50%) 2/3 (66.7%) 1/3 (33.3%) 2/4 (50%) 0/3 (0%) 2/8 (25%) 2/6 (33.3%) 3/7 (42.9%) 2/4 (50%)
    Dry mouth 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Dyspepsia 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 2/8 (25%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Dysphagia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Epigastric discomfort 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Faeces discoloured 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Gingival bleeding 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Gingival pain 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Gingivitis 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Glossodynia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Inguinal hernia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Nausea 2/3 (66.7%) 0/3 (0%) 3/4 (75%) 1/3 (33.3%) 2/3 (66.7%) 2/4 (50%) 3/3 (100%) 5/8 (62.5%) 4/6 (66.7%) 3/7 (42.9%) 0/4 (0%)
    Oedema mouth 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Oesophageal pain 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Small intestinal obstruction 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Stomatitis 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 2/6 (33.3%) 0/7 (0%) 0/4 (0%)
    Vomiting 0/3 (0%) 0/3 (0%) 3/4 (75%) 2/3 (66.7%) 1/3 (33.3%) 3/4 (75%) 1/3 (33.3%) 2/8 (25%) 1/6 (16.7%) 1/7 (14.3%) 0/4 (0%)
    General disorders
    Adverse drug reaction 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Asthenia 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Catheter site haematoma 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Catheter site pain 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Chest discomfort 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Chills 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 3/8 (37.5%) 2/6 (33.3%) 2/7 (28.6%) 0/4 (0%)
    Face oedema 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Fatigue 2/3 (66.7%) 0/3 (0%) 3/4 (75%) 1/3 (33.3%) 1/3 (33.3%) 3/4 (75%) 3/3 (100%) 3/8 (37.5%) 3/6 (50%) 4/7 (57.1%) 1/4 (25%)
    Generalised oedema 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Infusion related reaction 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Infusion site erythema 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Infusion site pain 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 1/7 (14.3%) 0/4 (0%)
    Injection site haemorrhage 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Malaise 2/3 (66.7%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Mucosal inflammation 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Non-cardiac chest pain 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 1/4 (25%)
    Oedema 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Oedema peripheral 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/3 (33.3%) 1/3 (33.3%) 0/4 (0%) 1/3 (33.3%) 1/8 (12.5%) 2/6 (33.3%) 3/7 (42.9%) 0/4 (0%)
    Pain 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 1/8 (12.5%) 1/6 (16.7%) 1/7 (14.3%) 0/4 (0%)
    Pitting oedema 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Pyrexia 1/3 (33.3%) 1/3 (33.3%) 3/4 (75%) 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 2/3 (66.7%) 2/8 (25%) 3/6 (50%) 3/7 (42.9%) 0/4 (0%)
    Immune system disorders
    Drug hypersensitivity 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Infections and infestations
    Bronchiolitis 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Bronchitis 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Candidiasis 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Ear infection 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Echinococciasis 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Folliculitis 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Fungal infection 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 1/4 (25%)
    Furuncle 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Herpes simplex 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 2/8 (25%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Herpes zoster 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Infection 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Lung infection 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 1/4 (25%)
    Nasopharyngitis 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Oral candidiasis 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 2/8 (25%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Pneumonia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Pneumonia primary atypical 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Sinusitis 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Staphylococcal infection 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Upper respiratory tract infection 0/3 (0%) 2/3 (66.7%) 1/4 (25%) 1/3 (33.3%) 1/3 (33.3%) 1/4 (25%) 1/3 (33.3%) 1/8 (12.5%) 2/6 (33.3%) 1/7 (14.3%) 1/4 (25%)
    Urinary tract infection 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 2/4 (50%)
    Injury, poisoning and procedural complications
    Contusion 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Fall 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 1/7 (14.3%) 0/4 (0%)
    Investigations
    Alanine aminotransferase increased 1/3 (33.3%) 1/3 (33.3%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 1/4 (25%)
    Aspartate aminotransferase increased 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 1/4 (25%)
    Atrial natriuretic peptide increased 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Blood alkaline phosphatase increased 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 1/4 (25%)
    Blood amylase increased 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Blood bilirubin increased 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Blood creatinine increased 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/3 (33.3%) 1/3 (33.3%) 1/4 (25%) 1/3 (33.3%) 1/8 (12.5%) 3/6 (50%) 2/7 (28.6%) 1/4 (25%)
    Blood lactate dehydrogenase increased 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Blood magnesium decreased 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/3 (33.3%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Blood phosphorus decreased 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Blood phosphorus increased 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Blood potassium decreased 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Blood pressure increased 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Blood sodium decreased 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Blood urea increased 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 1/8 (12.5%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Body temperature increased 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Electrocardiogram QT corrected interval prolonged 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Gamma-glutamyltransferase increased 1/3 (33.3%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Haematocrit decreased 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Haemoglobin decreased 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 1/3 (33.3%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Lipase increased 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Lymphocyte count increased 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Neutrophil count decreased 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Oxygen saturation decreased 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Platelet count decreased 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Red blood cell count decreased 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Transaminases increased 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Troponin I increased 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Urine output decreased 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Weight decreased 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Weight increased 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    White blood cell count decreased 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Metabolism and nutrition disorders
    Anorexia 2/3 (66.7%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 1/3 (33.3%) 3/8 (37.5%) 3/6 (50%) 1/7 (14.3%) 0/4 (0%)
    Decreased appetite 1/3 (33.3%) 0/3 (0%) 1/4 (25%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 1/4 (25%)
    Dehydration 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 1/3 (33.3%) 1/8 (12.5%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Fluid overload 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Fluid retention 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Hypercalcaemia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 2/6 (33.3%) 0/7 (0%) 0/4 (0%)
    Hypercholesterolaemia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Hyperglycaemia 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 2/3 (66.7%) 0/4 (0%) 0/3 (0%) 4/8 (50%) 1/6 (16.7%) 2/7 (28.6%) 0/4 (0%)
    Hyperkalaemia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 2/7 (28.6%) 1/4 (25%)
    Hypermagnesaemia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 2/4 (50%)
    Hypernatraemia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Hyperphosphataemia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Hyperuricaemia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Hypoalbuminaemia 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 2/7 (28.6%) 1/4 (25%)
    Hypocalcaemia 1/3 (33.3%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 1/4 (25%)
    Hypoglycaemia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 1/4 (25%)
    Hypokalaemia 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Hypomagnesaemia 1/3 (33.3%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 1/6 (16.7%) 1/7 (14.3%) 1/4 (25%)
    Hyponatraemia 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 2/7 (28.6%) 0/4 (0%)
    Hypophosphataemia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 1/7 (14.3%) 1/4 (25%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%) 5/6 (83.3%) 0/7 (0%) 1/4 (25%)
    Back pain 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/3 (33.3%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 1/8 (12.5%) 2/6 (33.3%) 0/7 (0%) 0/4 (0%)
    Bone pain 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 1/8 (12.5%) 1/6 (16.7%) 0/7 (0%) 1/4 (25%)
    Chest wall pain 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Flank pain 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Groin pain 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Muscle spasms 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Musculoskeletal discomfort 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Myalgia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Osteolysis 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Pain in extremity 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Pain in jaw 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Shoulder pain 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 1/3 (33.3%) 2/4 (50%) 1/3 (33.3%) 0/8 (0%) 3/6 (50%) 0/7 (0%) 0/4 (0%)
    Tendonitis 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lipoma 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Skin cancer 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Nervous system disorders
    Asterixis 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Dizziness 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Encephalopathy 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Headache 1/3 (33.3%) 0/3 (0%) 2/4 (50%) 1/3 (33.3%) 2/3 (66.7%) 1/4 (25%) 0/3 (0%) 2/8 (25%) 2/6 (33.3%) 1/7 (14.3%) 1/4 (25%)
    Hypoaesthesia 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Lethargy 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Memory impairment 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Neuropathy 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Neuropathy peripheral 0/3 (0%) 0/3 (0%) 2/4 (50%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Paraesthesia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 1/4 (25%)
    Sinus headache 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Somnolence 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Psychiatric disorders
    Anxiety 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 2/8 (25%) 3/6 (50%) 0/7 (0%) 0/4 (0%)
    Confusional state 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Depression 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Insomnia 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 3/6 (50%) 3/7 (42.9%) 1/4 (25%)
    Paranoia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Renal and urinary disorders
    Bladder disorder 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Bladder spasm 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Dysuria 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 3/8 (37.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Renal failure 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Renal failure acute 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Cough 0/3 (0%) 1/3 (33.3%) 2/4 (50%) 1/3 (33.3%) 3/3 (100%) 2/4 (50%) 1/3 (33.3%) 0/8 (0%) 4/6 (66.7%) 3/7 (42.9%) 1/4 (25%)
    Crackles lung 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Dry throat 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Dysphonia 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Dyspnoea 1/3 (33.3%) 1/3 (33.3%) 0/4 (0%) 1/3 (33.3%) 1/3 (33.3%) 0/4 (0%) 2/3 (66.7%) 4/8 (50%) 2/6 (33.3%) 1/7 (14.3%) 1/4 (25%)
    Dyspnoea exertional 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 2/8 (25%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Epistaxis 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 1/4 (25%)
    Hiccups 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Hypoxia 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Nasal congestion 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 1/3 (33.3%) 2/3 (66.7%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Pharyngolaryngeal pain 0/3 (0%) 0/3 (0%) 1/4 (25%) 2/3 (66.7%) 1/3 (33.3%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 1/7 (14.3%) 1/4 (25%)
    Pleural effusion 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Postnasal drip 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Productive cough 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 2/8 (25%) 0/6 (0%) 0/7 (0%) 1/4 (25%)
    Pulmonary congestion 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Pulmonary hypertension 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Pulmonary oedema 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Respiratory tract congestion 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Rhinorrhoea 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Rhonchi 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Sinus congestion 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Upper respiratory tract congestion 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Wheezing 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Skin and subcutaneous tissue disorders
    Alopecia 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/3 (33.3%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 2/6 (33.3%) 0/7 (0%) 0/4 (0%)
    Cold sweat 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Decubitus ulcer 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Dry skin 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Ecchymosis 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Hyperhidrosis 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Hypotrichosis 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Increased tendency to bruise 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 1/7 (14.3%) 0/4 (0%)
    Night sweats 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Pain of skin 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Pruritus 1/3 (33.3%) 0/3 (0%) 2/4 (50%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Rash 1/3 (33.3%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Rash generalised 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Rash pruritic 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%)
    Skin discolouration 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Surgical and medical procedures
    Nasal sinus drainage 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Vascular disorders
    Aneurysm 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Deep vein thrombosis 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Haematoma 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/3 (33.3%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%)
    Hypertension 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/3 (33.3%) 0/3 (0%) 1/4 (25%) 0/3 (0%) 1/8 (12.5%) 3/6 (50%) 0/7 (0%) 0/4 (0%)
    Hypotension 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/3 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%)
    Orthostatic hypotension 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/3 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/4 (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:
    NCT00150462
    Other Study ID Numbers:
    • PX-171-002
    First Posted:
    Sep 8, 2005
    Last Update Posted:
    May 2, 2017
    Last Verified:
    Apr 1, 2017