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

Multiple Myeloma Clinical Trial

— CHAMPION 1  

Official title:

A Phase 1/2 Study of Weekly Carfilzomib in Combination With Dexamethasone for Progressive Multiple Myeloma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01677858
• Other study ID #: 2012-002
• Secondary ID: 20130403
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: July 4, 2012
• Est. completion date: October 31, 2018

Study information

• Verified date: September 2022
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 116
• Est. completion date: October 31, 2018
• Est. primary completion date: July 22, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

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

Locations

Country	Name	City	State
United States	New Mexico Cancer Care Alliance	Albuquerque	New Mexico
United States	Comprehensive Blood and Cancer Center (CCBC)	Bakersfield	California
United States	Center for Cancer and Blood Disorders (CCBD)	Bethesda	Maryland
United States	St. Joseph Regional Cancer Center	Bryan	Texas
United States	Tennessee Oncology, PLLC	Chattanooga	Tennessee
United States	Rocky Mountain Cancer Centers	Denver	Colorado
United States	California Cancer Associates for Research and Excellence	Encinitas	California
United States	Willamette Valley Cancer Institute and Research Center	Eugene	Oregon
United States	Florida Cancer Specialists - South	Fort Myers	Florida
United States	Fort Wayne Oncology & Hematology	Fort Wayne	Indiana
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	Illinois Cancer Care	Galesburg	Illinois
United States	Illinois Cancer Specialists	Hinsdale	Illinois
United States	Millennium Oncology	Houston	Texas
United States	Waldron Medical Research and Development Center	Houston	Texas
United States	Horizon Oncology Research, Inc.	Lafayette	Indiana
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Hematology-Oncology Associates of Northern NJ, PA	Morristown	New Jersey
United States	Clinical Research Alliance	New York	New York
United States	Illinois Cancer Specialists	Niles	Illinois
United States	Hudson Valley Hematology Oncology Associates	Poughkeepsie	New York
United States	Monterey Bay Oncology	Salinas	California
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	Sansum Clinic	Santa Barbara	California
United States	Central Coast Medical Oncology Corporation	Santa Maria	California
United States	Florida Cancer Specialists - North	Tampa	Florida
United States	Arizona Oncology Associates	Tucson	Arizona
United States	Blood and Cancer Center of East Texas	Tyler	Texas
United States	Northwest Cancer Specialists	Vancouver	Washington
United States	James R. Berenson M.D. Inc.	West Hollywood	California
United States	The Oncology Insititute of Hope and Innovation	Whittier	California
United States	Shenandoah Oncology, PC	Winchester	Virginia
United States	Yakima Valley Memorial Hospital/ North Star Lodge	Yakima	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Country where clinical trial is conducted

United States, 

References & Publications (1)

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/m(2) ) vs twice-weekly (56 mg/m(2) ) 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Clinical Benefit Response Rate	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.	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	Progression-free Survival	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.	From randomization until the data cut-off date of 22 July 2016; median follow-up time for PFS was 13.8 months
Secondary	Time To Progression	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.	From randomization until the data cut-off date of 22 July 2016; median follow-up time for TTP was 13.4 months
Secondary	Duration of Response	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.	From randomization until the data cut-off date of 22 July 2016; median follow-up time for DOR was 14.3 months
Secondary	Number of Participants With Adverse Events	Adverse events were graded using National Cancer Institute-Common Terminology Criteria for Adverse Events (version 4.03).	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	Mean Residence Time Observed From Time Zero to Infinity (MRT0-8) 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.