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CHAMPION 1: A Study of Weekly Carfilzomib in Combination With Dexamethasone for Progressive Multiple Myeloma

Sponsor
Amgen (Industry)
Overall Status
Completed
CT.gov ID
NCT01677858
Collaborator
(none)
116
Enrollment
35
Locations
1
Arm
75.9
Duration (Months)
3.3
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The study had the following primary objectives:

  • Phase 1: to determine the maximum tolerated dose (MTD) of once-weekly (QW) carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior therapies

  • Phase 2: to estimate the overall response rate (ORR) for patients with relapsed or refractory multiple myeloma who received 1 to 3 prior therapies treated with carfilzomib and dexamethasone QW at the MTD established in phase 1.

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

Detailed Description

This is a Phase 1/2, multicenter, single-arm, nonrandomized, open-label and dose-escalation study of weekly carfilzomib and dexamethasone for patients with progressive multiple myeloma. The Phase 1 dose escalation portion will enroll patients into sequential dose-escalating cohorts consisting of 3 patients each to establish the maximum tolerated dose (MTD) of carfilzomib administered weekly as a 30 minute intravenous (IV) infusion with dexamethasone. The Phase 2 portion will enroll patients using the MTD established for carfilzomib from the Phase 1 portion of the study. Dexamethasone will be administered IV or orally at the same dose and schedule as used in the Phase 1 portion of the study.

Study Design

Study Type:
Interventional
Actual Enrollment :
116 participants
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1/2 Study of Weekly Carfilzomib in Combination With Dexamethasone for Progressive Multiple Myeloma
Study Start Date :
Jul 4, 2012
Actual Primary Completion Date :
Jul 22, 2016
Actual Study Completion Date :
Oct 31, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Carfilzomib

In phase 1 participants were assigned to one of four sequential dose-escalating cohorts to receive 45, 56, 70 or 88 mg/m² carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. In phase 2 participants received carfilzomib at the maximum tolerated dose (MTD) established in the Phase 1 portion of the study on days 1, 8 and 15 plus 40 mg dexamethasone IV or orally at the same schedule as used in the Phase 1 portion of the study. Participants were treated until confirmed progressive disease, unacceptable toxicity, withdrew consent for further treatment, were lost to follow-up, died, or the sponsor closed the study.

Drug: Carfilzomib
Carfilzomib was administered as a 30-minute IV infusion on days 1, 8, and 15 of each 28-day treatment cycle.
Other Names:
  • Krypolis

    • Drug: Dexamethasone
    Dexamethasone was administered at a dose of 40 mg IV or orally (PO) on days 1, 8, 15, and 22 for the first 8 cycles; starting with cycle 9 dexamethasone was administered on days 1, 8, and 15.

    Outcome Measures

    Primary Outcome Measures

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

      The MTD was defined as the highest carfilzomib dose at which < 33% of participants had a treatment-related DLT during the first 28-day cycle. A DLT was categorized as nonhematologic or hematologic and defined as follows: Nonhematologic: ≥ grade 3 nonhematological toxicity (excluding nausea, vomiting, diarrhea, fatigue lasting < 14 days, increased serum creatinine or electrolyte abnormalities not clinically significant or requiring treatment) ≥ grade 3 acute kidney injury (creatinine > 3 x baseline or > 4.0 mg/dL) lasting > 72 hours ≥ grade 3 nausea, vomiting, or diarrhea uncontrolled by maximal antiemetic/antidiarrheal therapy Hematologic: grade 4 neutropenia (absolute neutrophil count [ANC] < 500/mm³) for > 7 days febrile neutropenia (ANC < 1000/mm³ with a fever ≥ 38.3ºC) of any duration grade 4 thrombocytopenia (< 25 000/mm³) for > 14 days, despite holding treatment grade 3 or 4 thrombocytopenia (< lower limit of normal) associated with > grade 1 bleeding

    2. Overall Response Rate (ORR) [Disease response was assessed once every treatment cycle (28 days) and 30 days after last dose; the median overall treatment duration was 33.6 weeks.]

      Disease response was evaluated by the investigator according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC). ORR was defined as the percentage of participants with a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). sCR: As for CR, normal serum free light chain (SFLC) ratio and no clonal cells in bone marrow (BM). CR: No immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and < 5% plasma cells in BM. VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% reduction in serum M-protein with urine M-protein <100 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline. PR: ≥ 50% reduction of serum M-protein and reduction in urine M-protein by ≥ 90% or to < 200 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline.

    Secondary Outcome Measures

    1. Clinical Benefit Response Rate [Disease response was assessed once every treatment cycle (28 days) and 30 days after last dose; the median overall treatment duration was 33.6 weeks.]

      Clinical benefit rate was defined as the percentage of participants whose best response was sCR, CR, VGPR, PR, or minimal response (MR), where MR is defined by the European Group for Blood and Marrow Transplant (EBMT) criteria as a 25% to 49% reduction in the level of serum M-protein or a 50% to 89% reduction in 24-hour urinary M-protein, which still exceeds 200 mg /24 hour, maintained for a minimum of 8 weeks.

    2. Progression-free Survival [From randomization until the data cut-off date of 22 July 2016; median follow-up time for PFS was 13.8 months]

      Progression-free survival (PFS) was defined as the time from first dose to the earlier of disease progression or death due to any cause. The duration of PFS was calculated using Kaplan-Meier methods; participants with no baseline and/or post-baseline disease assessments, who started a new anticancer therapy before documentation of disease progression or death, died or had disease progression immediately after more than 1 consecutively missed disease assessment visit or who were alive without documentation of disease progression before the data cutoff date were censored. Participants were evaluated for disease response and progression by the investigator according to the IMWG-URC.

    3. Time To Progression [From randomization until the data cut-off date of 22 July 2016; median follow-up time for TTP was 13.4 months]

      Time to progression (TTP) was defined as the time from first dose to disease progression evaluated by the investigator according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC). TTP was calculated using Kaplan-Meier methods; participants with no baseline and/or post-baseline disease assessments, who started a new anticancer therapy before documentation of disease progression or death, died or had disease progression immediately after more than 1 consecutively missed disease assessment visit or who were alive without documentation of disease progression before the data cutoff date were censored.

    4. Duration of Response [From randomization until the data cut-off date of 22 July 2016; median follow-up time for DOR was 14.3 months]

      Duration of response (DOR) was defined as the time from first evidence of PR or better to disease progression or death due to any cause. DOR was calculated using Kaplan-Meier methods; Participants with no baseline disease assessments, starting a new anticancer therapy before documentation of disease progression or death, death or disease progression immediately after more than 1 consecutively missed disease assessment visit, or alive without documentation of disease progression before the data cut-off date were censored.

    5. Number of Participants With Adverse Events [From the first day of study treatment and within 30 days of the last day of study treatment; median duration of treatment was 33.6 weeks.]

      Adverse events were graded using National Cancer Institute-Common Terminology Criteria for Adverse Events (version 4.03).

    6. Time to Maximum Plasma Concentration of Carfilzomib [Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.]

    7. Maximum Plasma Concentration of Carfilzomib [Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.]

    8. Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Carfilzomib [Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.]

    9. Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUCinf) fo Carfilzomib [Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.]

    10. Area Under the Plasma Concentration-time Curve During the Dosing Interval (0-168 Hours) for Carfilzomib [Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.]

    11. Volume of Distribution Observed at Steady State (Vss) for Carfilzomib [Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.]

    12. Terminal Half-life (T1/2,z) for Carfilzomib [Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.]

    13. Clearance of Carfilzomib After IV Infusion [Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.]

    14. Mean Residence Time Observed From Time Zero to Infinity (MRT0-∞) for Carfilzomib [Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 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:

    1. Multiple myeloma with relapsing or progressive disease at study entry

    2. Measurable disease, as defined by 1 or more of the following (assessed within 21 days prior to enrollment):

    3. Serum M-protein ≥ 0.5 g/dL, or

    4. Urine M-protein ≥ 200 mg/24 hours, or

    5. Only in patients who do not meet a or b, then use serum free light chain (SFLC) > 100 mg/L (involved light chain) and an abnormal kappa/lambda ratio

    6. Prior treatment with 1 to 3 prior regimens for multiple myeloma for Phase 1 and Phase 2 (induction therapy followed by stem cell transplant and consolidation/maintenance therapy will be considered as 1 line of therapy

    7. Age ≥ 18 years

    8. Life expectancy ≥ 6 months

    9. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

    10. Adequate hepatic function within 21 days prior to enrollment, with bilirubin < 1.5 × the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 × ULN

    11. Left ventricular ejection fraction (LVEF) ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated acquisition scan (MUGA) is acceptable if ECHO is not available

    12. Absolute neutrophil count (ANC) ≥ 1000/mm³ within 21 days prior to enrollment. Screening ANC is to be independent of growth factor support for ≥ 1 week

    13. Hemoglobin ≥ 8.0 g/dL within 21 days prior to enrollment. Use of erythropoietic stimulating factors and red blood cell (RBC) transfusions per institutional guidelines is allowed; however, most recent RBC transfusion must have been at least 7 days prior to obtaining screening hemoglobin

    14. Platelet count ≥ 50,000/mm³ (≥ 30,000/mm³ if myeloma involvement in the bone marrow is

    50%) within 21 days prior to enrollment. Patients must not have received platelet transfusions for at least 7 days prior to obtaining the screening platelet count

    1. Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/min within 21 days prior to enrollment. Calculation based on standard formula, such as the Cockcroft and Gault: [(140 - Age) x Mass (kg) / (72 x Creatinine mg/dL)]; multiply result by 0.85 if female

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

    3. Female patients of childbearing potential (FCBP) must have a negative serum pregnancy test within 21 days prior to enrollment and agree to use an effective method of contraception during and for 3 months following last dose of drug (more frequent pregnancy tests may be conducted if required per local regulations). Postmenopausal females (> 45 years old and without menses for > 1 year) and surgically sterilized females are exempt from a pregnancy test

    4. Male patients must agree to use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with an FCBP

    Exclusion Criteria:

    1. Multiple myeloma of Immunoglobulin M (IgM) subtype

    2. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)

    3. Plasma cell leukemia (> 2.0 × 10^9/L circulating plasma cells by standard differential)

    4. Waldenström's macroglobulinemia

    5. Amyloidosis

    6. Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 7 days prior to enrollment

    7. Cytotoxic chemotherapy with approved or investigational anticancer therapeutics within 28 days prior to enrollment

    8. Treatment with bortezomib (Velcade®), thalidomide (Thalomid®) or lenalidomide (Revlimid®) within 21 days prior to enrollment

    9. Focal radiation therapy within 7 days prior to enrollment. Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to enrollment (ie, prior radiation must have been to < 30% of the bone marrow)

    10. Immunotherapy within 21 days prior to enrollment

    11. Major surgery within 21 days prior to enrollment

    12. Active congestive heart failure (New York Heart Association [NYHA] Classes III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within 6 months prior to enrollment

    13. Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B virus [HBV]), or antifungal agents within 14 days prior to enrollment

    14. Known human immunodeficiency virus (HIV) seropositivity

    15. Known hepatitis B or C virus infection (except for patients with HBV who are receiving and responding to HBV antiviral therapy: these patients are allowed)

    16. Patients with known cirrhosis

    17. Second malignancy within the past 3 years, except:

    18. Adequately treated basal cell or squamous cell skin cancer

    19. Carcinoma in situ of the cervix

    20. Prostate cancer < Gleason score 6 with stable prostate-specific antigen (PSA) over 12 months

    21. Breast carcinoma in situ with full surgical resection

    22. Treated medullary or papillary thyroid cancer

    23. Patients with myelodysplastic syndrome

    24. Significant neuropathy (Grades 3 to 4) within 14 days prior to enrollment

    25. Female patients who are pregnant or lactating

    26. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)

    27. Prior carfilzomib treatment

    28. Prior participation in any Onyx-sponsored Phase 3 trial

    29. Patients with contraindication to dexamethasone

    30. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment

    31. Ongoing graft-versus-host disease

    32. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to enrollment

    33. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment

    34. Any other clinically significant medical disease or psychiatric condition that, in the Investigator's opinion, may interfere with protocol adherence or a patient's ability to give informed consent

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Arizona Oncology Associates Tucson Arizona United States
    2 Comprehensive Blood and Cancer Center (CCBC) Bakersfield California United States
    3 California Cancer Associates for Research and Excellence Encinitas California United States
    4 Robert A. Moss, M.D., FACP, Inc. Fountain Valley California United States
    5 California Cancer Associates for Research and Excellence Fresno California United States
    6 Cedars-Sinai Medical Center Los Angeles California United States
    7 Monterey Bay Oncology Salinas California United States
    8 Sansum Clinic Santa Barbara California United States
    9 Central Coast Medical Oncology Corporation Santa Maria California United States
    10 James R. Berenson M.D. Inc. West Hollywood California United States
    11 The Oncology Insititute of Hope and Innovation Whittier California United States
    12 Rocky Mountain Cancer Centers Denver Colorado United States
    13 Florida Cancer Specialists - South Fort Myers Florida United States
    14 Florida Cancer Specialists - North Tampa Florida United States
    15 Illinois Cancer Care Galesburg Illinois United States
    16 Illinois Cancer Specialists Hinsdale Illinois United States
    17 Illinois Cancer Specialists Niles Illinois United States
    18 Fort Wayne Oncology & Hematology Fort Wayne Indiana United States
    19 Horizon Oncology Research, Inc. Lafayette Indiana United States
    20 Center for Cancer and Blood Disorders (CCBD) Bethesda Maryland United States
    21 Hematology-Oncology Associates of Northern NJ, PA Morristown New Jersey United States
    22 New Mexico Cancer Care Alliance Albuquerque New Mexico United States
    23 Clinical Research Alliance New York New York United States
    24 Hudson Valley Hematology Oncology Associates Poughkeepsie New York United States
    25 Willamette Valley Cancer Institute and Research Center Eugene Oregon United States
    26 Tennessee Oncology, PLLC Chattanooga Tennessee United States
    27 St. Joseph Regional Cancer Center Bryan Texas United States
    28 Millennium Oncology Houston Texas United States
    29 Waldron Medical Research and Development Center Houston Texas United States
    30 Cancer Care Centers of South Texas San Antonio Texas United States
    31 Center at Cancer Therapy & Research Center at The University of Texas Health Science Center at San Antonio San Antonio Texas United States
    32 Blood and Cancer Center of East Texas Tyler Texas United States
    33 Shenandoah Oncology, PC Winchester Virginia United States
    34 Northwest Cancer Specialists Vancouver Washington United States
    35 Yakima Valley Memorial Hospital/ North Star Lodge Yakima Washington United States

    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:
    NCT01677858
    Other Study ID Numbers:
    • 2012-002
    • 20130403
    First Posted:
    Sep 3, 2012
    Last Update Posted:
    Dec 19, 2018
    Last Verified:
    Apr 1, 2018
    Additional relevant MeSH terms:
    Multiple Myeloma
    Neoplasms, Plasma Cell
    Dexamethasone

    Study Results

    Participant Flow

    Recruitment Details This study was conducted at 32 centers in the United States. Participants were enrolled from September 2012 to September 2014.
    Pre-assignment Detail In phase 1 participants were enrolled into 1 of 4 sequential dose-escalating cohorts to establish the maximum tolerated dose (MTD) of carfilzomib plus dexamethasone. In phase 2 participants were enrolled to evaluate the efficacy and safety of carfilzomib plus dexamethasone at the MTD established in phase 1.
    Arm/Group Title Phase 1: Carfilzomib 45 mg/m² Phase 1: Carfilzomib 56 mg/m² Phase 1: Carfilzomib 70 mg/m² Phase 1: Carfilzomib 88 mg/m² Phase 2: Carfilzomib 70 mg/m²
    Arm/Group Description Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 45 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 56 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 88 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
    Period Title: Overall Study
    STARTED 3 3 15 6 89
    COMPLETED 0 1 1 0 4
    NOT COMPLETED 3 2 14 6 85

    Baseline Characteristics

    Arm/Group Title Phase 1: Carfilzomib 45 mg/m² Phase 1: Carfilzomib 56 mg/m² Phase 1: Carfilzomib 70 mg/m² Phase 1: Carfilzomib 88 mg/m² Phase 2: Carfilzomib 70 mg/m² Total
    Arm/Group Description Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 45 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 56 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 88 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Total of all reporting groups
    Overall Participants 3 3 15 6 89 116
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    69.3
    (15.6)
    73.7
    (2.1)
    62.4
    (10.4)
    58.2
    (8.8)
    68.7
    (9.6)
    67.5
    (10.1)
    Sex: Female, Male (Count of Participants)
    Female
    1
    33.3%
    2
    66.7%
    4
    26.7%
    5
    83.3%
    40
    44.9%
    52
    44.8%
    Male
    2
    66.7%
    1
    33.3%
    11
    73.3%
    1
    16.7%
    49
    55.1%
    64
    55.2%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    10
    11.2%
    11
    9.5%
    Not Hispanic or Latino
    3
    100%
    3
    100%
    15
    100%
    5
    83.3%
    79
    88.8%
    105
    90.5%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race/Ethnicity, Customized (Count of Participants)
    White
    3
    100%
    2
    66.7%
    11
    73.3%
    6
    100%
    79
    88.8%
    101
    87.1%
    Black or African American
    0
    0%
    1
    33.3%
    2
    13.3%
    0
    0%
    6
    6.7%
    9
    7.8%
    Asian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.1%
    1
    0.9%
    American Indian or Alaskan Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.1%
    1
    0.9%
    Other
    0
    0%
    0
    0%
    2
    13.3%
    0
    0%
    1
    1.1%
    3
    2.6%
    Unknown
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.1%
    1
    0.9%
    Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
    0 (Fully active)
    1
    33.3%
    2
    66.7%
    6
    40%
    3
    50%
    39
    43.8%
    51
    44%
    1 (Restrictive but ambulatory)
    2
    66.7%
    1
    33.3%
    9
    60%
    3
    50%
    50
    56.2%
    65
    56%

    Outcome Measures

    1. Primary Outcome
    Title Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs)
    Description The MTD was defined as the highest carfilzomib dose at which < 33% of participants had a treatment-related DLT during the first 28-day cycle. A DLT was categorized as nonhematologic or hematologic and defined as follows: Nonhematologic: ≥ grade 3 nonhematological toxicity (excluding nausea, vomiting, diarrhea, fatigue lasting < 14 days, increased serum creatinine or electrolyte abnormalities not clinically significant or requiring treatment) ≥ grade 3 acute kidney injury (creatinine > 3 x baseline or > 4.0 mg/dL) lasting > 72 hours ≥ grade 3 nausea, vomiting, or diarrhea uncontrolled by maximal antiemetic/antidiarrheal therapy Hematologic: grade 4 neutropenia (absolute neutrophil count [ANC] < 500/mm³) for > 7 days febrile neutropenia (ANC < 1000/mm³ with a fever ≥ 38.3ºC) of any duration grade 4 thrombocytopenia (< 25 000/mm³) for > 14 days, despite holding treatment grade 3 or 4 thrombocytopenia (< lower limit of normal) associated with > grade 1 bleeding
    Time Frame 28 days

    Outcome Measure Data

    Analysis Population Description
    Participants in phase 1 who received at least 1 dose of any investigational product (carfilzomib or dexamethasone).
    Arm/Group Title Phase 1 Carfilzomib 45 mg/m² Phase 1: Carfilzomib 56 mg/m² Phase 1: Carfilzomib 70 mg/m² Phase 1: Carfilzomib 88 mg/m²
    Arm/Group Description Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 45 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 56 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 88 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
    Measure Participants 3 3 15 6
    Number [participants]
    0
    0%
    0
    0%
    1
    6.7%
    2
    33.3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 1 Carfilzomib 45 mg/m², Phase 1: Carfilzomib 56 mg/m², Phase 1: Carfilzomib 70 mg/m², Phase 1: Carfilzomib 88 mg/m²
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Maximum Tolerated Dose (mg/m²)
    Estimated Value 70
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Primary Outcome
    Title Overall Response Rate (ORR)
    Description Disease response was evaluated by the investigator according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC). ORR was defined as the percentage of participants with a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). sCR: As for CR, normal serum free light chain (SFLC) ratio and no clonal cells in bone marrow (BM). CR: No immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and < 5% plasma cells in BM. VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% reduction in serum M-protein with urine M-protein <100 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline. PR: ≥ 50% reduction of serum M-protein and reduction in urine M-protein by ≥ 90% or to < 200 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline.
    Time Frame Disease response was assessed once every treatment cycle (28 days) and 30 days after last dose; the median overall treatment duration was 33.6 weeks.

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of any investigational product (carfilzomib or dexamethasone).
    Arm/Group Title Phase 1: Carfilzomib 45 mg/m² Phase 1: Carfilzomib 56 mg/m² Phase 1: Carfilzomib 70 mg/m² Phase 1: Carfilzomib 88 mg/m² Phase 2: Carfilzomib 70 mg/m² Phase 1+2: Carfilzomib 70 mg/m²
    Arm/Group Description Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 45 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 56 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 88 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
    Measure Participants 3 3 15 6 89 104
    Number (95% Confidence Interval) [percentage of participants]
    33.3
    1110%
    100
    3333.3%
    93.3
    622%
    66.7
    1111.7%
    74.2
    83.4%
    76.9
    66.3%
    3. Secondary Outcome
    Title Clinical Benefit Response Rate
    Description Clinical benefit rate was defined as the percentage of participants whose best response was sCR, CR, VGPR, PR, or minimal response (MR), where MR is defined by the European Group for Blood and Marrow Transplant (EBMT) criteria as a 25% to 49% reduction in the level of serum M-protein or a 50% to 89% reduction in 24-hour urinary M-protein, which still exceeds 200 mg /24 hour, maintained for a minimum of 8 weeks.
    Time Frame Disease response was assessed once every treatment cycle (28 days) and 30 days after last dose; the median overall treatment duration was 33.6 weeks.

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of any investigational product (carfilzomib or dexamethasone).
    Arm/Group Title Phase 1: Carfilzomib 45 mg/m² Phase 1: Carfilzomib 56 mg/m² Phase 1: Carfilzomib 70 mg/m² Phase 1: Carfilzomib 88 mg/m² Phase 2: Carfilzomib 70 mg/m² Phase 1+2: Carfilzomib 70 mg/m²
    Arm/Group Description Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 45 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 56 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 88 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
    Measure Participants 3 3 15 6 89 104
    Number (95% Confidence Interval) [percentage of participants]
    66.7
    2223.3%
    100.0
    3333.3%
    100.0
    666.7%
    83.3
    1388.3%
    80.9
    90.9%
    83.7
    72.2%
    4. Secondary Outcome
    Title Progression-free Survival
    Description Progression-free survival (PFS) was defined as the time from first dose to the earlier of disease progression or death due to any cause. The duration of PFS was calculated using Kaplan-Meier methods; participants with no baseline and/or post-baseline disease assessments, who started a new anticancer therapy before documentation of disease progression or death, died or had disease progression immediately after more than 1 consecutively missed disease assessment visit or who were alive without documentation of disease progression before the data cutoff date were censored. Participants were evaluated for disease response and progression by the investigator according to the IMWG-URC.
    Time Frame From randomization until the data cut-off date of 22 July 2016; median follow-up time for PFS was 13.8 months

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of any investigational product (carfilzomib or dexamethasone).
    Arm/Group Title Phase 1: Carfilzomib 45 mg/m² Phase 1: Carfilzomib 56 mg/m² Phase 1: Carfilzomib 70 mg/m² Phase 1: Carfilzomib 88 mg/m² Phase 2: Carfilzomib 70 mg/m² Phase 1+2: Carfilzomib 70 mg/m²
    Arm/Group Description Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 45 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 56 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 88 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
    Measure Participants 3 3 15 6 89 104
    Median (95% Confidence Interval) [months]
    13.6
    NA
    21.0
    12.9
    15.3
    16.2
    5. Secondary Outcome
    Title Time To Progression
    Description Time to progression (TTP) was defined as the time from first dose to disease progression evaluated by the investigator according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC). TTP was calculated using Kaplan-Meier methods; participants with no baseline and/or post-baseline disease assessments, who started a new anticancer therapy before documentation of disease progression or death, died or had disease progression immediately after more than 1 consecutively missed disease assessment visit or who were alive without documentation of disease progression before the data cutoff date were censored.
    Time Frame From randomization until the data cut-off date of 22 July 2016; median follow-up time for TTP was 13.4 months

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of any investigational product (carfilzomib or dexamethasone).
    Arm/Group Title Phase 1: Carfilzomib 45 mg/m² Phase 1: Carfilzomib 56 mg/m² Phase 1: Carfilzomib 70 mg/m² Phase 1: Carfilzomib 88 mg/m² Phase 2: Carfilzomib 70 mg/m² Phase 1+2: Carfilzomib 70 mg/m²
    Arm/Group Description Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 45 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 56 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 88 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
    Measure Participants 3 3 15 6 89 104
    Median (95% Confidence Interval) [months]
    13.6
    NA
    21.0
    12.9
    16.2
    17.2
    6. Secondary Outcome
    Title Duration of Response
    Description Duration of response (DOR) was defined as the time from first evidence of PR or better to disease progression or death due to any cause. DOR was calculated using Kaplan-Meier methods; Participants with no baseline disease assessments, starting a new anticancer therapy before documentation of disease progression or death, death or disease progression immediately after more than 1 consecutively missed disease assessment visit, or alive without documentation of disease progression before the data cut-off date were censored.
    Time Frame From randomization until the data cut-off date of 22 July 2016; median follow-up time for DOR was 14.3 months

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of any investigational product (carfilzomib or dexamethasone) with a best overall response of sCR, CR, VGPR, or PR.
    Arm/Group Title Phase 1: Carfilzomib 45 mg/m² Phase 1: Carfilzomib 56 mg/m² Phase 1: Carfilzomib 70 mg/m² Phase 1: Carfilzomib 88 mg/m² Phase 2: Carfilzomib 70 mg/m² Phase 1+2: Carfilzomib 70 mg/m²
    Arm/Group Description Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 45 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 56 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 88 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
    Measure Participants 1 3 14 4 66 80
    Median (95% Confidence Interval) [months]
    18.9
    NA
    16.3
    11.9
    18.0
    18.0
    7. Secondary Outcome
    Title Number of Participants With Adverse Events
    Description Adverse events were graded using National Cancer Institute-Common Terminology Criteria for Adverse Events (version 4.03).
    Time Frame From the first day of study treatment and within 30 days of the last day of study treatment; median duration of treatment was 33.6 weeks.

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of any investigational product (carfilzomib or dexamethasone).
    Arm/Group Title Phase 1: Carfilzomib 45 mg/m² Phase 1: Carfilzomib 56 mg/m² Phase 1: Carfilzomib 70 mg/m² Phase 1: Carfilzomib 88 mg/m² Phase 2: Carfilzomib 70 mg/m²
    Arm/Group Description Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 45 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 56 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 88 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
    Measure Participants 3 3 15 6 89
    All adverse events
    3
    100%
    3
    100%
    15
    100%
    6
    100%
    89
    100%
    Adverse events ≥ grade 3
    1
    33.3%
    2
    66.7%
    9
    60%
    5
    83.3%
    60
    67.4%
    Serious adverse events
    1
    33.3%
    0
    0%
    4
    26.7%
    1
    16.7%
    35
    39.3%
    AE leading to discontinuation of carfilzomib & dex
    0
    0%
    0
    0%
    2
    13.3%
    3
    50%
    14
    15.7%
    AE leading to discontinuation of carfilzomib
    0
    0%
    0
    0%
    2
    13.3%
    3
    50%
    14
    15.7%
    Fatal adverse events
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    5
    5.6%
    8. Secondary Outcome
    Title Time to Maximum Plasma Concentration of Carfilzomib
    Description
    Time Frame Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) analyses were conducted for participants assigned to cohorts 3 and 4 in phase 1 (70 and 88 mg/m² carfilzomib) and a subset of participants in phase 2; only participants for whom PK parameters could be calculated were included in the analyses.
    Arm/Group Title Carfilzomib 20 mg/m² Carfilzomib 70 mg/m² Carfilzomib 88 mg/m²
    Arm/Group Description Participants in phase 1 and phase 2 received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on day 1 cycle 1. Participants in phase 1 and phase 2 received carfilzomib 70 mg/m² administered by intravenous (IV) infusion from day 8 cycle 1 onwards. Participants in phase 1 received carfilzomib 88 mg/m² administered by intravenous (IV) infusion from day 8 cycle 1 onwards.
    Measure Participants 26 21 5
    Median (Full Range) [hours]
    0.25
    0.25
    0.25
    9. Secondary Outcome
    Title Maximum Plasma Concentration of Carfilzomib
    Description
    Time Frame Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) analyses were conducted for participants assigned to cohorts 3 and 4 in phase 1 (70 and 88 mg/m² carfilzomib) and a subset of participants in phase 2; only participants for whom PK parameters could be calculated were included in the analyses.
    Arm/Group Title Carfilzomib 20 mg/m² Carfilzomib 70 mg/m² Carfilzomib 88 mg/m²
    Arm/Group Description Participants in phase 1 and phase 2 received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on day 1 cycle 1. Participants in phase 1 and phase 2 received carfilzomib 70 mg/m² administered by intravenous (IV) infusion from day 8 cycle 1 onwards. Participants in phase 1 received carfilzomib 88 mg/m² administered by intravenous (IV) infusion from day 8 cycle 1 onwards.
    Measure Participants 26 21 5
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    789
    (65.5)
    2390
    (30.7)
    3090
    (27.3)
    10. Secondary Outcome
    Title Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Carfilzomib
    Description
    Time Frame Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) analyses were conducted for participants assigned to cohorts 3 and 4 in phase 1 (70 and 88 mg/m² carfilzomib) and a subset of participants in phase 2; only participants for whom PK parameters could be calculated were included in the analyses.
    Arm/Group Title Carfilzomib 20 mg/m² Carfilzomib 70 mg/m² Carfilzomib 88 mg/m²
    Arm/Group Description Participants in phase 1 and phase 2 received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on day 1 cycle 1. Participants in phase 1 and phase 2 received carfilzomib 70 mg/m² administered by intravenous (IV) infusion from day 8 cycle 1 onwards. Participants in phase 1 received carfilzomib 88 mg/m² administered by intravenous (IV) infusion from day 8 cycle 1 onwards.
    Measure Participants 26 21 5
    Geometric Mean (Geometric Coefficient of Variation) [hr*ng/mL]
    281
    (52.7)
    1040
    (21.7)
    1210
    (31.4)
    11. Secondary Outcome
    Title Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUCinf) fo Carfilzomib
    Description
    Time Frame Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) analyses were conducted for participants assigned to cohorts 3 and 4 in phase 1 (70 and 88 mg/m² carfilzomib) and a subset of participants in phase 2; only participants for whom PK parameters could be calculated were included in the analyses.
    Arm/Group Title Carfilzomib 20 mg/m² Carfilzomib 70 mg/m² Carfilzomib 88 mg/m²
    Arm/Group Description Participants in phase 1 and phase 2 received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on day 1 cycle 1. Participants in phase 1 and phase 2 received carfilzomib 70 mg/m² administered by intravenous (IV) infusion from day 8 cycle 1 onwards. Participants in phase 1 received carfilzomib 88 mg/m² administered by intravenous (IV) infusion from day 8 cycle 1 onwards.
    Measure Participants 25 16 4
    Geometric Mean (Geometric Coefficient of Variation) [hr*ng/mL]
    259
    (28.0)
    1040
    (21.6)
    1160
    (34.8)
    12. Secondary Outcome
    Title Area Under the Plasma Concentration-time Curve During the Dosing Interval (0-168 Hours) for Carfilzomib
    Description
    Time Frame Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) analyses were conducted for participants assigned to cohorts 3 and 4 in phase 1 (70 and 88 mg/m² carfilzomib) and a subset of participants in phase 2; only participants for whom PK parameters could be calculated were included in the analyses.
    Arm/Group Title Carfilzomib 20 mg/m² Carfilzomib 70 mg/m² Carfilzomib 88 mg/m²
    Arm/Group Description Participants in phase 1 and phase 2 received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on day 1 cycle 1. Participants in phase 1 and phase 2 received carfilzomib 70 mg/m² administered by intravenous (IV) infusion from day 8 cycle 1 onwards. Participants in phase 1 received carfilzomib 88 mg/m² administered by intravenous (IV) infusion from day 8 cycle 1 onwards.
    Measure Participants 25 16 4
    Geometric Mean (Geometric Coefficient of Variation) [hr*ng/mL]
    259
    (28.0)
    1040
    (21.6)
    1160
    (34.8)
    13. Secondary Outcome
    Title Volume of Distribution Observed at Steady State (Vss) for Carfilzomib
    Description
    Time Frame Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) analyses were conducted for participants assigned to cohorts 3 and 4 in phase 1 (70 and 88 mg/m² carfilzomib) and a subset of participants in phase 2; only participants for whom PK parameters could be calculated were included in the analyses.
    Arm/Group Title Carfilzomib 20 mg/m² Carfilzomib 70 mg/m² Carfilzomib 88 mg/m²
    Arm/Group Description Participants in phase 1 and phase 2 received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on day 1 cycle 1. Participants in phase 1 and phase 2 received carfilzomib 70 mg/m² administered by intravenous (IV) infusion from day 8 cycle 1 onwards. Participants in phase 1 received carfilzomib 88 mg/m² administered by intravenous (IV) infusion from day 8 cycle 1 onwards.
    Measure Participants 24 16 4
    Geometric Mean (Geometric Coefficient of Variation) [liters]
    17.0
    (133.3)
    14.2
    (54.2)
    7.87
    (78.4)
    14. Secondary Outcome
    Title Terminal Half-life (T1/2,z) for Carfilzomib
    Description
    Time Frame Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) analyses were conducted for participants assigned to cohorts 3 and 4 in phase 1 (70 and 88 mg/m² carfilzomib) and a subset of participants in phase 2; only participants for whom PK parameters could be calculated were included in the analyses.
    Arm/Group Title Carfilzomib 20 mg/m² Carfilzomib 70 mg/m² Carfilzomib 88 mg/m²
    Arm/Group Description Participants in phase 1 and phase 2 received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on day 1 cycle 1. Participants in phase 1 and phase 2 received carfilzomib 70 mg/m² administered by intravenous (IV) infusion from day 8 cycle 1 onwards. Participants in phase 1 received carfilzomib 88 mg/m² administered by intravenous (IV) infusion from day 8 cycle 1 onwards.
    Measure Participants 25 15 4
    Geometric Mean (Geometric Coefficient of Variation) [hours]
    0.648
    (49)
    0.883
    (24.6)
    0.816
    (17.1)
    15. Secondary Outcome
    Title Clearance of Carfilzomib After IV Infusion
    Description
    Time Frame Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) analyses were conducted for participants assigned to cohorts 3 and 4 in phase 1 (70 and 88 mg/m² carfilzomib) and a subset of participants in phase 2; only participants for whom PK parameters could be calculated were included in the analyses.
    Arm/Group Title Carfilzomib 20 mg/m² Carfilzomib 70 mg/m² Carfilzomib 88 mg/m²
    Arm/Group Description Participants in phase 1 and phase 2 received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on day 1 cycle 1. Participants in phase 1 and phase 2 received carfilzomib 70 mg/m² administered by intravenous (IV) infusion from day 8 cycle 1 onwards. Participants in phase 1 received carfilzomib 88 mg/m² administered by intravenous (IV) infusion from day 8 cycle 1 onwards.
    Measure Participants 25 16 4
    Geometric Mean (Geometric Coefficient of Variation) [liters/hour]
    147
    (31.0)
    131
    (29.6)
    138
    (35.0)
    16. Secondary Outcome
    Title Mean Residence Time Observed From Time Zero to Infinity (MRT0-∞) for Carfilzomib
    Description
    Time Frame Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) analyses were conducted for participants assigned to cohorts 3 and 4 in phase 1 (70 and 88 mg/m² carfilzomib) and a subset of participants in phase 2; only participants for whom PK parameters could be calculated were included in the analyses.
    Arm/Group Title Carfilzomib 20 mg/m² Carfilzomib 70 mg/m² Carfilzomib 88 mg/m²
    Arm/Group Description Participants in phase 1 and phase 2 received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on day 1 cycle 1. Participants in phase 1 and phase 2 received carfilzomib 70 mg/m² administered by intravenous (IV) infusion from day 8 cycle 1 onwards. Participants in phase 1 received carfilzomib 88 mg/m² administered by intravenous (IV) infusion from day 8 cycle 1 onwards.
    Measure Participants 24 16 4
    Geometric Mean (Geometric Coefficient of Variation) [hours]
    0.118
    (130.5)
    0.108
    (55.4)
    0.0571
    (110.0)

    Adverse Events

    Time Frame From the first day of study treatment and within 30 days of the last day of study treatment; median duration of treatment was 33.6 weeks.
    Adverse Event Reporting Description Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
    Arm/Group Title Phase 1: Carfilzomib 45 mg/m² Phase 1: Carfilzomib 56 mg/m² Phase 1: Carfilzomib 70 mg/m² Phase 1: Carfilzomib 88 mg/m² Phase 2: Carfilzomib 70 mg/m²
    Arm/Group Description Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 45 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 56 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 88 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
    All Cause Mortality
    Phase 1: Carfilzomib 45 mg/m² Phase 1: Carfilzomib 56 mg/m² Phase 1: Carfilzomib 70 mg/m² Phase 1: Carfilzomib 88 mg/m² Phase 2: Carfilzomib 70 mg/m²
    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)
    Serious Adverse Events
    Phase 1: Carfilzomib 45 mg/m² Phase 1: Carfilzomib 56 mg/m² Phase 1: Carfilzomib 70 mg/m² Phase 1: Carfilzomib 88 mg/m² Phase 2: Carfilzomib 70 mg/m²
    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%) 0/3 (0%) 4/15 (26.7%) 1/6 (16.7%) 35/89 (39.3%)
    Blood and lymphatic system disorders
    Anaemia 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Febrile neutropenia 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Thrombocytopenia 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 2/89 (2.2%)
    Cardiac disorders
    Acute myocardial infarction 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Atrial fibrillation 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 2/89 (2.2%)
    Cardiac failure congestive 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 2/89 (2.2%)
    Cardio-respiratory arrest 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Sinus tachycardia 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Gastrointestinal disorders
    Gastrointestinal haemorrhage 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    General disorders
    Asthenia 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 2/89 (2.2%)
    Disease progression 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Pain 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Pyrexia 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Infections and infestations
    Influenza 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 2/89 (2.2%)
    Lung infection 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Pneumocystis jirovecii pneumonia 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Pneumonia 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 4/89 (4.5%)
    Pneumonia influenzal 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Sepsis 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 5/89 (5.6%)
    Septic shock 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Urinary tract infection 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 1/89 (1.1%)
    Injury, poisoning and procedural complications
    Haematuria traumatic 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Hip fracture 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 2/89 (2.2%)
    Lumbar vertebral fracture 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Investigations
    Blood creatinine increased 1/3 (33.3%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 0/89 (0%)
    Metabolism and nutrition disorders
    Hypercalcaemia 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Hyperkalaemia 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Hyponatraemia 1/3 (33.3%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 0/89 (0%)
    Metabolic acidosis 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Back pain 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Musculoskeletal chest pain 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 2/89 (2.2%)
    Pain in extremity 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Prostate cancer 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Nervous system disorders
    Aphasia 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Encephalopathy 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Hypertensive encephalopathy 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Ischaemic stroke 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Spinal cord compression 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 2/89 (2.2%)
    Syncope 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 2/89 (2.2%)
    Psychiatric disorders
    Delirium 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Renal and urinary disorders
    Acute kidney injury 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 6/89 (6.7%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Chronic obstructive pulmonary disease 0/3 (0%) 0/3 (0%) 2/15 (13.3%) 0/6 (0%) 3/89 (3.4%)
    Dyspnoea 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Hypoxia 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Pneumonitis 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Respiratory failure 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Vascular disorders
    Aortic dissection 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Deep vein thrombosis 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Other (Not Including Serious) Adverse Events
    Phase 1: Carfilzomib 45 mg/m² Phase 1: Carfilzomib 56 mg/m² Phase 1: Carfilzomib 70 mg/m² Phase 1: Carfilzomib 88 mg/m² Phase 2: Carfilzomib 70 mg/m²
    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%) 15/15 (100%) 6/6 (100%) 87/89 (97.8%)
    Blood and lymphatic system disorders
    Anaemia 1/3 (33.3%) 2/3 (66.7%) 5/15 (33.3%) 1/6 (16.7%) 25/89 (28.1%)
    Neutropenia 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 1/6 (16.7%) 8/89 (9%)
    Thrombocytopenia 0/3 (0%) 0/3 (0%) 3/15 (20%) 1/6 (16.7%) 22/89 (24.7%)
    Thrombocytosis 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Cardiac disorders
    Arrhythmia 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Palpitations 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 4/89 (4.5%)
    Tachycardia 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 5/89 (5.6%)
    Congenital, familial and genetic disorders
    Porokeratosis 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Eye disorders
    Amblyopia 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Blindness 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Cataract 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 1/6 (16.7%) 2/89 (2.2%)
    Conjunctival haemorrhage 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 1/89 (1.1%)
    Dry eye 0/3 (0%) 1/3 (33.3%) 1/15 (6.7%) 1/6 (16.7%) 1/89 (1.1%)
    Eye discharge 0/3 (0%) 1/3 (33.3%) 1/15 (6.7%) 0/6 (0%) 1/89 (1.1%)
    Eye irritation 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Eye pruritus 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Glaucoma 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Periorbital oedema 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Photophobia 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Vision blurred 0/3 (0%) 2/3 (66.7%) 1/15 (6.7%) 2/6 (33.3%) 5/89 (5.6%)
    Visual acuity reduced 1/3 (33.3%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 0/89 (0%)
    Visual impairment 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 2/89 (2.2%)
    Gastrointestinal disorders
    Abdominal discomfort 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 1/6 (16.7%) 4/89 (4.5%)
    Abdominal distension 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 1/6 (16.7%) 3/89 (3.4%)
    Abdominal pain 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 8/89 (9%)
    Abdominal pain upper 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 1/6 (16.7%) 0/89 (0%)
    Constipation 1/3 (33.3%) 1/3 (33.3%) 6/15 (40%) 1/6 (16.7%) 11/89 (12.4%)
    Diarrhoea 2/3 (66.7%) 0/3 (0%) 9/15 (60%) 2/6 (33.3%) 26/89 (29.2%)
    Dyspepsia 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 5/89 (5.6%)
    Epigastric discomfort 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Flatulence 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 2/89 (2.2%)
    Gastrointestinal tract irritation 1/3 (33.3%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 0/89 (0%)
    Gastrooesophageal reflux disease 1/3 (33.3%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 3/89 (3.4%)
    Gingival pain 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 1/89 (1.1%)
    Hypoaesthesia oral 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Loose tooth 1/3 (33.3%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Nausea 0/3 (0%) 1/3 (33.3%) 7/15 (46.7%) 3/6 (50%) 36/89 (40.4%)
    Rectal haemorrhage 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 2/89 (2.2%)
    Sensitivity of teeth 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 1/89 (1.1%)
    Stomatitis 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 3/89 (3.4%)
    Tooth loss 1/3 (33.3%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Toothache 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Vomiting 0/3 (0%) 0/3 (0%) 4/15 (26.7%) 2/6 (33.3%) 13/89 (14.6%)
    General disorders
    Asthenia 0/3 (0%) 1/3 (33.3%) 4/15 (26.7%) 0/6 (0%) 9/89 (10.1%)
    Chest discomfort 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 3/89 (3.4%)
    Chills 0/3 (0%) 1/3 (33.3%) 4/15 (26.7%) 0/6 (0%) 5/89 (5.6%)
    Cyst 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 0/6 (0%) 0/89 (0%)
    Fatigue 3/3 (100%) 2/3 (66.7%) 9/15 (60%) 3/6 (50%) 47/89 (52.8%)
    Feeling hot 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Influenza like illness 1/3 (33.3%) 0/3 (0%) 2/15 (13.3%) 0/6 (0%) 3/89 (3.4%)
    Infusion site extravasation 0/3 (0%) 0/3 (0%) 3/15 (20%) 0/6 (0%) 3/89 (3.4%)
    Infusion site pain 0/3 (0%) 1/3 (33.3%) 3/15 (20%) 1/6 (16.7%) 7/89 (7.9%)
    Malaise 0/3 (0%) 0/3 (0%) 4/15 (26.7%) 2/6 (33.3%) 5/89 (5.6%)
    Mucosal inflammation 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 1/89 (1.1%)
    Oedema peripheral 0/3 (0%) 1/3 (33.3%) 4/15 (26.7%) 0/6 (0%) 20/89 (22.5%)
    Pain 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 1/6 (16.7%) 7/89 (7.9%)
    Peripheral swelling 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 4/89 (4.5%)
    Pyrexia 0/3 (0%) 0/3 (0%) 7/15 (46.7%) 3/6 (50%) 22/89 (24.7%)
    Sluggishness 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Submandibular mass 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Hepatobiliary disorders
    Cholelithiasis 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Infections and infestations
    Bronchitis 0/3 (0%) 1/3 (33.3%) 1/15 (6.7%) 0/6 (0%) 7/89 (7.9%)
    Cellulitis 0/3 (0%) 0/3 (0%) 3/15 (20%) 0/6 (0%) 3/89 (3.4%)
    Clostridium difficile infection 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Cystitis 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Fungal skin infection 0/3 (0%) 1/3 (33.3%) 1/15 (6.7%) 0/6 (0%) 1/89 (1.1%)
    Herpes zoster 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Influenza 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 1/6 (16.7%) 3/89 (3.4%)
    Joint abscess 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Localised infection 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Lung infection 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Mycobacterium avium complex infection 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Nasopharyngitis 0/3 (0%) 1/3 (33.3%) 1/15 (6.7%) 2/6 (33.3%) 9/89 (10.1%)
    Oral candidiasis 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 2/89 (2.2%)
    Oral herpes 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Paronychia 0/3 (0%) 0/3 (0%) 2/15 (13.3%) 0/6 (0%) 1/89 (1.1%)
    Pneumonia 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 6/89 (6.7%)
    Sinusitis 0/3 (0%) 0/3 (0%) 2/15 (13.3%) 0/6 (0%) 8/89 (9%)
    Tinea pedis 0/3 (0%) 1/3 (33.3%) 3/15 (20%) 0/6 (0%) 0/89 (0%)
    Tinea versicolour 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Tooth abscess 0/3 (0%) 1/3 (33.3%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Tooth infection 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 1/89 (1.1%)
    Upper respiratory tract infection 1/3 (33.3%) 2/3 (66.7%) 12/15 (80%) 2/6 (33.3%) 25/89 (28.1%)
    Urinary tract infection 1/3 (33.3%) 1/3 (33.3%) 2/15 (13.3%) 1/6 (16.7%) 10/89 (11.2%)
    Injury, poisoning and procedural complications
    Contusion 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 0/6 (0%) 8/89 (9%)
    Facial bones fracture 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Fall 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 1/6 (16.7%) 2/89 (2.2%)
    Foot fracture 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 1/89 (1.1%)
    Infusion related reaction 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Laceration 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 2/6 (33.3%) 0/89 (0%)
    Ligament sprain 0/3 (0%) 0/3 (0%) 0/15 (0%) 2/6 (33.3%) 2/89 (2.2%)
    Post procedural complication 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Spinal compression fracture 1/3 (33.3%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 0/89 (0%)
    Investigations
    Alanine aminotransferase increased 0/3 (0%) 1/3 (33.3%) 1/15 (6.7%) 0/6 (0%) 2/89 (2.2%)
    Aspartate aminotransferase increased 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 1/6 (16.7%) 2/89 (2.2%)
    Blood alkaline phosphatase increased 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Blood creatinine increased 1/3 (33.3%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 13/89 (14.6%)
    Blood glucose increased 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 0/6 (0%) 0/89 (0%)
    Blood magnesium decreased 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 0/6 (0%) 0/89 (0%)
    Blood potassium decreased 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Blood pressure increased 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Blood sodium decreased 1/3 (33.3%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 0/89 (0%)
    Blood testosterone decreased 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Blood urea increased 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 1/89 (1.1%)
    Cardiac murmur 0/3 (0%) 2/3 (66.7%) 0/15 (0%) 0/6 (0%) 2/89 (2.2%)
    Haematocrit decreased 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Heart rate increased 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 1/89 (1.1%)
    Neutrophil count increased 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Platelet count decreased 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 7/89 (7.9%)
    Protein total decreased 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 1/89 (1.1%)
    Urine output decreased 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 1/89 (1.1%)
    Weight decreased 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 1/6 (16.7%) 4/89 (4.5%)
    Weight increased 0/3 (0%) 0/3 (0%) 2/15 (13.3%) 1/6 (16.7%) 4/89 (4.5%)
    White blood cell count decreased 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 3/89 (3.4%)
    White blood cell count increased 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 1/6 (16.7%) 0/89 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 0/3 (0%) 1/3 (33.3%) 2/15 (13.3%) 0/6 (0%) 13/89 (14.6%)
    Dehydration 1/3 (33.3%) 0/3 (0%) 2/15 (13.3%) 0/6 (0%) 7/89 (7.9%)
    Fluid retention 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 1/89 (1.1%)
    Hyperglycaemia 0/3 (0%) 0/3 (0%) 2/15 (13.3%) 1/6 (16.7%) 8/89 (9%)
    Hyperkalaemia 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 8/89 (9%)
    Hypokalaemia 1/3 (33.3%) 0/3 (0%) 2/15 (13.3%) 0/6 (0%) 9/89 (10.1%)
    Hypophosphataemia 0/3 (0%) 0/3 (0%) 2/15 (13.3%) 0/6 (0%) 6/89 (6.7%)
    Iron deficiency 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Vitamin D deficiency 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/3 (0%) 2/3 (66.7%) 5/15 (33.3%) 0/6 (0%) 15/89 (16.9%)
    Arthritis 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Back pain 2/3 (66.7%) 0/3 (0%) 5/15 (33.3%) 1/6 (16.7%) 18/89 (20.2%)
    Bone pain 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 0/6 (0%) 3/89 (3.4%)
    Flank pain 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 4/89 (4.5%)
    Groin pain 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 0/6 (0%) 2/89 (2.2%)
    Muscle spasms 0/3 (0%) 0/3 (0%) 6/15 (40%) 1/6 (16.7%) 10/89 (11.2%)
    Muscular weakness 0/3 (0%) 0/3 (0%) 5/15 (33.3%) 0/6 (0%) 12/89 (13.5%)
    Musculoskeletal chest pain 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 1/6 (16.7%) 9/89 (10.1%)
    Musculoskeletal discomfort 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 0/6 (0%) 0/89 (0%)
    Musculoskeletal pain 0/3 (0%) 0/3 (0%) 2/15 (13.3%) 0/6 (0%) 6/89 (6.7%)
    Musculoskeletal stiffness 1/3 (33.3%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Myalgia 0/3 (0%) 1/3 (33.3%) 1/15 (6.7%) 0/6 (0%) 5/89 (5.6%)
    Myopathy 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 2/89 (2.2%)
    Neck pain 0/3 (0%) 0/3 (0%) 2/15 (13.3%) 0/6 (0%) 3/89 (3.4%)
    Osteoarthritis 0/3 (0%) 2/3 (66.7%) 0/15 (0%) 0/6 (0%) 0/89 (0%)
    Osteonecrosis of jaw 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 1/6 (16.7%) 1/89 (1.1%)
    Pain in extremity 0/3 (0%) 1/3 (33.3%) 4/15 (26.7%) 3/6 (50%) 14/89 (15.7%)
    Pain in jaw 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 1/6 (16.7%) 0/89 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma 1/3 (33.3%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 1/89 (1.1%)
    Benign neoplasm of skin 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Melanocytic naevus 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Squamous cell carcinoma 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 1/89 (1.1%)
    Nervous system disorders
    Burning sensation 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Dizziness 1/3 (33.3%) 0/3 (0%) 5/15 (33.3%) 0/6 (0%) 14/89 (15.7%)
    Dizziness postural 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Dysgeusia 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 0/6 (0%) 4/89 (4.5%)
    Facial paralysis 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Headache 0/3 (0%) 2/3 (66.7%) 6/15 (40%) 4/6 (66.7%) 26/89 (29.2%)
    Hypoaesthesia 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 2/89 (2.2%)
    Memory impairment 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 1/89 (1.1%)
    Migraine 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Neuropathy peripheral 0/3 (0%) 1/3 (33.3%) 4/15 (26.7%) 0/6 (0%) 6/89 (6.7%)
    Paraesthesia 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 2/89 (2.2%)
    Peripheral sensory neuropathy 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 3/89 (3.4%)
    Psychomotor hyperactivity 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Spinal cord compression 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Visual field defect 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Psychiatric disorders
    Affective disorder 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Agitation 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 1/6 (16.7%) 1/89 (1.1%)
    Anger 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 0/6 (0%) 0/89 (0%)
    Anxiety 0/3 (0%) 1/3 (33.3%) 1/15 (6.7%) 1/6 (16.7%) 11/89 (12.4%)
    Depression 0/3 (0%) 1/3 (33.3%) 1/15 (6.7%) 1/6 (16.7%) 5/89 (5.6%)
    Insomnia 2/3 (66.7%) 2/3 (66.7%) 5/15 (33.3%) 3/6 (50%) 29/89 (32.6%)
    Irritability 1/3 (33.3%) 0/3 (0%) 2/15 (13.3%) 0/6 (0%) 1/89 (1.1%)
    Mood altered 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 1/89 (1.1%)
    Reproductive system and breast disorders
    Testicular pain 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Respiratory, thoracic and mediastinal disorders
    Bradypnoea 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Cough 0/3 (0%) 0/3 (0%) 5/15 (33.3%) 2/6 (33.3%) 25/89 (28.1%)
    Dry throat 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Dysphonia 0/3 (0%) 1/3 (33.3%) 1/15 (6.7%) 1/6 (16.7%) 1/89 (1.1%)
    Dyspnoea 1/3 (33.3%) 1/3 (33.3%) 5/15 (33.3%) 2/6 (33.3%) 25/89 (28.1%)
    Dyspnoea exertional 0/3 (0%) 0/3 (0%) 2/15 (13.3%) 1/6 (16.7%) 3/89 (3.4%)
    Epistaxis 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 5/89 (5.6%)
    Haemoptysis 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Hiccups 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 2/89 (2.2%)
    Hypoxia 0/3 (0%) 0/3 (0%) 0/15 (0%) 0/6 (0%) 5/89 (5.6%)
    Nasal congestion 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 2/6 (33.3%) 2/89 (2.2%)
    Oropharyngeal pain 0/3 (0%) 0/3 (0%) 3/15 (20%) 2/6 (33.3%) 5/89 (5.6%)
    Pleural effusion 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 2/89 (2.2%)
    Productive cough 0/3 (0%) 1/3 (33.3%) 1/15 (6.7%) 2/6 (33.3%) 7/89 (7.9%)
    Pulmonary congestion 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Rhinorrhoea 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 2/89 (2.2%)
    Rhonchi 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 1/89 (1.1%)
    Sinus congestion 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 6/89 (6.7%)
    Sputum discoloured 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 1/6 (16.7%) 0/89 (0%)
    Throat irritation 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 0/89 (0%)
    Upper-airway cough syndrome 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 1/6 (16.7%) 2/89 (2.2%)
    Wheezing 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 3/89 (3.4%)
    Skin and subcutaneous tissue disorders
    Actinic keratosis 1/3 (33.3%) 0/3 (0%) 1/15 (6.7%) 1/6 (16.7%) 3/89 (3.4%)
    Dermatitis 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 1/89 (1.1%)
    Dry skin 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 3/89 (3.4%)
    Ecchymosis 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 2/89 (2.2%)
    Erythema 0/3 (0%) 1/3 (33.3%) 0/15 (0%) 0/6 (0%) 1/89 (1.1%)
    Hyperhidrosis 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 1/6 (16.7%) 3/89 (3.4%)
    Hyperkeratosis 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 1/89 (1.1%)
    Night sweats 0/3 (0%) 0/3 (0%) 2/15 (13.3%) 0/6 (0%) 2/89 (2.2%)
    Pruritus 0/3 (0%) 0/3 (0%) 2/15 (13.3%) 0/6 (0%) 7/89 (7.9%)
    Pruritus generalised 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 1/89 (1.1%)
    Rash 0/3 (0%) 1/3 (33.3%) 3/15 (20%) 1/6 (16.7%) 13/89 (14.6%)
    Rash maculo-papular 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 4/89 (4.5%)
    Rash pruritic 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 3/89 (3.4%)
    Skin lesion 1/3 (33.3%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 2/89 (2.2%)
    Swelling face 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 1/89 (1.1%)
    Urticaria 0/3 (0%) 0/3 (0%) 0/15 (0%) 1/6 (16.7%) 2/89 (2.2%)
    Vascular disorders
    Hypertension 1/3 (33.3%) 0/3 (0%) 2/15 (13.3%) 2/6 (33.3%) 16/89 (18%)
    Hypotension 0/3 (0%) 0/3 (0%) 2/15 (13.3%) 0/6 (0%) 3/89 (3.4%)
    Phlebitis 0/3 (0%) 0/3 (0%) 1/15 (6.7%) 0/6 (0%) 1/89 (1.1%)

    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:
    NCT01677858
    Other Study ID Numbers:
    • 2012-002
    • 20130403
    First Posted:
    Sep 3, 2012
    Last Update Posted:
    Dec 19, 2018
    Last Verified:
    Apr 1, 2018