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

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01677858
First Posted: September 3, 2012
Last Update Posted: September 20, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Amgen
  Purpose

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 Intervention Phase
Multiple Myeloma Drug: Carfilzomib Drug: Dexamethasone Phase 1 Phase 2

Study Type: Interventional
Study Design: 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

Resource links provided by NLM:


Further study details as provided by Amgen:

Primary Outcome Measures:
  • Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) [ Time Frame: 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

  • Overall Response Rate (ORR) [ 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. ]

    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:
  • Clinical Benefit Response Rate [ 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. ]
    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.

  • Progression-free Survival [ Time Frame: 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.


  • Time To Progression [ Time Frame: 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.

  • Duration of Response [ Time Frame: 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.

  • Number of Participants With 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 events were graded using National Cancer Institute-Common Terminology Criteria for Adverse Events (version 4.03).

  • Time to Maximum Plasma Concentration of Carfilzomib [ 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. ]
  • Maximum Plasma Concentration of Carfilzomib [ 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. ]
  • Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Carfilzomib [ 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. ]
  • Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUCinf) fo Carfilzomib [ 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. ]
  • Area Under the Plasma Concentration-time Curve During the Dosing Interval (0-168 Hours) for Carfilzomib [ 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. ]
  • Volume of Distribution Observed at Steady State (Vss) for Carfilzomib [ 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. ]
  • Terminal Half-life (T1/2,z) for Carfilzomib [ 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. ]
  • Clearance of Carfilzomib After IV Infusion [ 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. ]
  • Mean Residence Time Observed From Time Zero to Infinity (MRT0-∞) for Carfilzomib [ 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. ]

Enrollment: 116
Study Start Date: July 4, 2012
Estimated Study Completion Date: December 31, 2017
Primary Completion Date: July 22, 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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.

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.
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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):

    1. Serum M-protein ≥ 0.5 g/dL, or
    2. Urine M-protein ≥ 200 mg/24 hours, or
    3. 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
  3. 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
  4. Age ≥ 18 years
  5. Life expectancy ≥ 6 months
  6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. Written informed consent in accordance with federal, local, and institutional guidelines
  14. 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
  15. 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:

    1. Adequately treated basal cell or squamous cell skin cancer
    2. Carcinoma in situ of the cervix
    3. Prostate cancer < Gleason score 6 with stable prostate-specific antigen (PSA) over 12 months
    4. Breast carcinoma in situ with full surgical resection
    5. Treated medullary or papillary thyroid cancer
  18. Patients with myelodysplastic syndrome
  19. Significant neuropathy (Grades 3 to 4) within 14 days prior to enrollment
  20. Female patients who are pregnant or lactating
  21. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)
  22. Prior carfilzomib treatment
  23. Prior participation in any Onyx-sponsored Phase 3 trial
  24. Patients with contraindication to dexamethasone
  25. 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
  26. Ongoing graft-versus-host disease
  27. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to enrollment
  28. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment
  29. 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
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01677858


  Show 35 Study Locations
Sponsors and Collaborators
Amgen
Investigators
Study Director: MD Amgen
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT01677858     History of Changes
Other Study ID Numbers: 2012-002
20130403 ( Other Identifier: Amgen Inc. )
First Submitted: August 30, 2012
First Posted: September 3, 2012
Results First Submitted: July 11, 2017
Results First Posted: August 9, 2017
Last Update Posted: September 20, 2017
Last Verified: July 2017

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
BB 1101
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors