Clinical trial NCT01677858: A Study of Weekly Carfilzomib in Combination With Dexamethasone for Progressive Multiple Myeloma
Official title: A Phase 1/2 Study of Weekly Carfilzomib in Combination With Dexamethasone for Progressive Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2012-09-03
Enrollment: 116
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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 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

Primary outcomes:
measure: Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs)
timeFrame: 28 days
measure: Overall Response Rate (ORR)
timeFrame: 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.
Secondary outcomes:
measure: Clinical Benefit Response Rate
timeFrame: 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.
measure: Progression-free Survival
timeFrame: From randomization until the data cut-off date of 22 July 2016; median follow-up time for PFS was 13.8 months
measure: Time To Progression
timeFrame: From randomization until the data cut-off date of 22 July 2016; median follow-up time for TTP was 13.4 months
measure: Duration of Response
timeFrame: From randomization until the data cut-off date of 22 July 2016; median follow-up time for DOR was 14.3 months
measure: Number of Participants With Adverse Events
timeFrame: 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.
measure: Time to Maximum Plasma Concentration of Carfilzomib
timeFrame: 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.
measure: Maximum Plasma Concentration of Carfilzomib
timeFrame: 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.
measure: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Carfilzomib
timeFrame: 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.
measure: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUCinf) fo Carfilzomib
timeFrame: 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.
measure: Area Under the Plasma Concentration-time Curve During the Dosing Interval (0-168 Hours) for Carfilzomib
timeFrame: 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.
measure: Volume of Distribution Observed at Steady State (Vss) for Carfilzomib
timeFrame: 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.
measure: Terminal Half-life (T1/2,z) for Carfilzomib
timeFrame: 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.
measure: Clearance of Carfilzomib After IV Infusion
timeFrame: 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.
measure: Mean Residence Time Observed From Time Zero to Infinity (MRT0-∞) for Carfilzomib
timeFrame: 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.
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Arizona Oncology Associates
state: Arizona
city: Bakersfield
country: United States
facility: Comprehensive Blood and Cancer Center (CCBC)
state: California
city: Encinitas
country: United States
facility: California Cancer Associates for Research and Excellence
state: California
city: Fountain Valley
country: United States
facility: Robert A. Moss, M.D., FACP, Inc.
state: California
city: Fresno
country: United States
facility: California Cancer Associates for Research and Excellence
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Salinas
country: United States
facility: Monterey Bay Oncology
state: California
city: Santa Barbara
country: United States
facility: Sansum Clinic
state: California
city: Santa Maria
country: United States
facility: Central Coast Medical Oncology Corporation
state: California
city: West Hollywood
country: United States
facility: James R. Berenson M.D. Inc.
state: California
city: Whittier
country: United States
facility: The Oncology Insititute of Hope and Innovation
state: California
city: Denver
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Fort Myers
country: United States
facility: Florida Cancer Specialists - South
state: Florida
city: Tampa
country: United States
facility: Florida Cancer Specialists - North
state: Florida
city: Galesburg
country: United States
facility: Illinois Cancer Care
state: Illinois
city: Hinsdale
country: United States
facility: Illinois Cancer Specialists
state: Illinois
city: Niles
country: United States
facility: Illinois Cancer Specialists
state: Illinois
city: Fort Wayne
country: United States
facility: Fort Wayne Oncology & Hematology
state: Indiana
city: Lafayette
country: United States
facility: Horizon Oncology Research, Inc.
state: Indiana
city: Bethesda
country: United States
facility: Center for Cancer and Blood Disorders (CCBD)
state: Maryland
city: Morristown
country: United States
facility: Hematology-Oncology Associates of Northern NJ, PA
state: New Jersey
city: Albuquerque
country: United States
facility: New Mexico Cancer Care Alliance
state: New Mexico
city: New York
country: United States
facility: Clinical Research Alliance
state: New York
city: Poughkeepsie
country: United States
facility: Hudson Valley Hematology Oncology Associates
state: New York
city: Eugene
country: United States
facility: Willamette Valley Cancer Institute and Research Center
state: Oregon
city: Chattanooga
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Bryan
country: United States
facility: St. Joseph Regional Cancer Center
state: Texas
city: Houston
country: United States
facility: Millennium Oncology
state: Texas
city: Houston
country: United States
facility: Waldron Medical Research and Development Center
state: Texas
city: San Antonio
country: United States
facility: Cancer Care Centers of South Texas
state: Texas
city: San Antonio
country: United States
facility: Center at Cancer Therapy & Research Center at The University of Texas Health Science Center at San Antonio
state: Texas
city: Tyler
country: United States
facility: Blood and Cancer Center of East Texas
state: Texas
city: Winchester
country: United States
facility: Shenandoah Oncology, PC
state: Virginia
city: Vancouver
country: United States
facility: Northwest Cancer Specialists
state: Washington
city: Yakima
country: United States
facility: Yakima Valley Memorial Hospital/ North Star Lodge
state: Washington
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Moreau P, Stewart KA, Dimopoulos M, Siegel D, Facon T, Berenson J, Raje N, Berdeja JG, Orlowski RZ, Yang H, Ma H, Klippel Z, Zahlten-Kumeli A, Mezzi K, Iskander K, Mateos MV. Once-weekly (70 mg/m2 ) vs twice-weekly (56 mg/m2 ) dosing of carfilzomib in patients with relapsed or refractory multiple myeloma: A post hoc analysis of the ENDEAVOR, A.R.R.O.W., and CHAMPION-1 trials. Cancer Med. 2020 May;9(9):2989-2996. doi: 10.1002/cam4.2945. Epub 2020 Feb 28.
citation: Berenson JR, Cartmell A, Bessudo A, Lyons RM, Harb W, Tzachanis D, Agajanian R, Boccia R, Coleman M, Moss RA, Rifkin RM, Patel P, Dixon S, Ou Y, Anderl J, Aggarwal S, Berdeja JG. CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma. Blood. 2016 Jun 30;127(26):3360-8. doi: 10.1182/blood-2015-11-683854. Epub 2016 May 12.