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

NCT01677858 | Completed Phase 1 Results DMC

• 2 other identifiers: 2012-00220130403
• Study Type: interventional
• Target: 116
• Locations: 1 country
• Sites: 35

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.

Conditions

Multiple Myeloma

Outcome Measures

Primary Outcomes (2)

• Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs)

  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

  28 days

• Overall Response Rate (ORR)

  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.

  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 (14)

• 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.

• 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

• 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

• 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

• 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.

Study Arms (1)

Carfilzomib

EXPERIMENTAL

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; Drug: Dexamethasone

Interventions

Carfilzomib DRUG

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

Also known as: Krypolis

Carfilzomib

Dexamethasone DRUG

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.

Carfilzomib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Multiple myeloma with relapsing or progressive disease at study entry
• Measurable disease, as defined by 1 or more of the following (assessed within 21 days prior to enrollment):
• Serum M-protein ≥ 0.5 g/dL, or
• Urine M-protein ≥ 200 mg/24 hours, or
• 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
• 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
• Age ≥ 18 years
• Life expectancy ≥ 6 months
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• 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
• 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
• 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
• 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
• 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
• 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

You may not qualify if:

• Multiple myeloma of Immunoglobulin M (IgM) subtype
• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
• Plasma cell leukemia (\> 2.0 × 10\^9/L circulating plasma cells by standard differential)
• Waldenström's macroglobulinemia
• Amyloidosis
• Glucocorticoid therapy (prednisone \> 30 mg/day or equivalent) within 7 days prior to enrollment
• Cytotoxic chemotherapy with approved or investigational anticancer therapeutics within 28 days prior to enrollment
• Treatment with bortezomib (Velcade®), thalidomide (Thalomid®) or lenalidomide (Revlimid®) within 21 days prior to enrollment
• 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)
• Immunotherapy within 21 days prior to enrollment
• Major surgery within 21 days prior to enrollment
• 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
• 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
• Known human immunodeficiency virus (HIV) seropositivity
• 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)

Sponsors & Collaborators

• Amgen: lead

Study Sites (35)

Arizona Oncology Associates

Tucson, Arizona, United States

Location

Comprehensive Blood and Cancer Center (CCBC)

Bakersfield, California, United States

Location

California Cancer Associates for Research and Excellence

Encinitas, California, United States

Location

Robert A. Moss, M.D., FACP, Inc.

Fountain Valley, California, United States

Location

California Cancer Associates for Research and Excellence

Fresno, California, United States

Location

Cedars-Sinai Medical Center

Los Angeles, California, United States

Location

Monterey Bay Oncology

Salinas, California, United States

Location

Sansum Clinic

Santa Barbara, California, United States

Location

Central Coast Medical Oncology Corporation

Santa Maria, California, United States

Location

James R. Berenson M.D. Inc.

West Hollywood, California, United States

Location

The Oncology Insititute of Hope and Innovation

Whittier, California, United States

Location

Rocky Mountain Cancer Centers

Denver, Colorado, United States

Location

Florida Cancer Specialists - South

Fort Myers, Florida, United States

Location

Florida Cancer Specialists - North

Tampa, Florida, United States

Location

Illinois Cancer Care

Galesburg, Illinois, United States

Location

Illinois Cancer Specialists

Hinsdale, Illinois, United States

Location

Illinois Cancer Specialists

Niles, Illinois, United States

Location

Fort Wayne Oncology & Hematology

Fort Wayne, Indiana, United States

Location

Horizon Oncology Research, Inc.

Lafayette, Indiana, United States

Location

Center for Cancer and Blood Disorders (CCBD)

Bethesda, Maryland, United States

Location

Hematology-Oncology Associates of Northern NJ, PA

Morristown, New Jersey, United States

Location

New Mexico Cancer Care Alliance

Albuquerque, New Mexico, United States

Location

Clinical Research Alliance

New York, New York, United States

Location

Hudson Valley Hematology Oncology Associates

Poughkeepsie, New York, United States

Location

Willamette Valley Cancer Institute and Research Center

Eugene, Oregon, United States

Location

Tennessee Oncology, PLLC

Chattanooga, Tennessee, United States

Location

St. Joseph Regional Cancer Center

Bryan, Texas, United States

Location

Millennium Oncology

Houston, Texas, United States

Location

Waldron Medical Research and Development Center

Houston, Texas, United States

Location

Cancer Care Centers of South Texas

San Antonio, Texas, United States

Location

Center at Cancer Therapy & Research Center at The University of Texas Health Science Center at San Antonio

San Antonio, Texas, United States

Location

Blood and Cancer Center of East Texas

Tyler, Texas, United States

Location

Shenandoah Oncology, PC

Winchester, Virginia, United States

Location

Northwest Cancer Specialists

Vancouver, Washington, United States

Location

Yakima Valley Memorial Hospital/ North Star Lodge

Yakima, Washington, United States

Location

Related Publications (2)

• 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.

  PMID: 32108443 BACKGROUND

• 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.

  PMID: 27207788 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

carfilzomib; Dexamethasone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Results Point of Contact

• Title: Study Director
• Organization: Amgen Inc.

866-572-6436

Study Officials

• MD

  Amgen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 30, 2012
• First Posted: September 3, 2012
• Study Start: July 4, 2012
• Primary Completion: July 22, 2016
• Study Completion: October 31, 2018
• Last Updated: September 23, 2022
• Results First Posted: August 9, 2017

Record last verified: 2022-09

Locations

US (35)