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

NCT ID: NCT01677858

Last Updated: 2022-09-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 116 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-07-04
• Study Completion Date: 2018-10-31

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.

Conditions

Multiple Myeloma

Study Design

• Allocation Method: NA
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

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

Dexamethasone

Intervention Type: 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.

Interventions

Carfilzomib

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

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Krypolis

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Amgen

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

MD

Role: STUDY_DIRECTOR

Amgen

Locations

Arizona Oncology Associates

Tucson, Arizona, United States

Comprehensive Blood and Cancer Center (CCBC)

Bakersfield, California, United States

California Cancer Associates for Research and Excellence

Encinitas, California, United States

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

Fountain Valley, California, United States

California Cancer Associates for Research and Excellence

Fresno, California, United States

Cedars-Sinai Medical Center

Los Angeles, California, United States

Monterey Bay Oncology

Salinas, California, United States

Sansum Clinic

Santa Barbara, California, United States

Central Coast Medical Oncology Corporation

Santa Maria, California, United States

James R. Berenson M.D. Inc.

West Hollywood, California, United States

The Oncology Insititute of Hope and Innovation

Whittier, California, United States

Rocky Mountain Cancer Centers

Denver, Colorado, United States

Florida Cancer Specialists - South

Fort Myers, Florida, United States

Florida Cancer Specialists - North

Tampa, Florida, United States

Illinois Cancer Care

Galesburg, Illinois, United States

Illinois Cancer Specialists

Hinsdale, Illinois, United States

Illinois Cancer Specialists

Niles, Illinois, United States

Fort Wayne Oncology & Hematology

Fort Wayne, Indiana, United States

Horizon Oncology Research, Inc.

Lafayette, Indiana, United States

Center for Cancer and Blood Disorders (CCBD)

Bethesda, Maryland, United States

Hematology-Oncology Associates of Northern NJ, PA

Morristown, New Jersey, United States

New Mexico Cancer Care Alliance

Albuquerque, New Mexico, United States

Clinical Research Alliance

New York, New York, United States

Hudson Valley Hematology Oncology Associates

Poughkeepsie, New York, United States

Willamette Valley Cancer Institute and Research Center

Eugene, Oregon, United States

Tennessee Oncology, PLLC

Chattanooga, Tennessee, United States

St. Joseph Regional Cancer Center

Bryan, Texas, United States

Millennium Oncology

Houston, Texas, United States

Waldron Medical Research and Development Center

Houston, Texas, United States

Cancer Care Centers of South Texas

San Antonio, Texas, United States

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

San Antonio, Texas, United States

Blood and Cancer Center of East Texas

Tyler, Texas, United States

Shenandoah Oncology, PC

Winchester, Virginia, United States

Northwest Cancer Specialists

Vancouver, Washington, United States

Yakima Valley Memorial Hospital/ North Star Lodge

Yakima, Washington, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 32108443 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27207788 (View on PubMed)

Other Identifiers

20130403

Identifier Type: OTHER

Identifier Source: secondary_id

2012-002

Identifier Type: -

Identifier Source: org_study_id