Phase 1b Study of Weekly Carfilzomib in Combination With Lenalidomide and Dexamethasone in Subjects With Multiple Myeloma

Phase 1b Study of Carfilzomib Administered Once Weekly in Combination With Lenalidomide and Dexamethasone in Subjects With Multiple Myeloma

The purpose of the study is to assess the safety, tolerability and activity of a once-weekly regimen of carfilzomib in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Carfilzomib; Drug: Lenalidomide; Drug: Dexamethasone

• Study Type: Interventional
• Enrollment (Actual): 107
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Bakersfield, California, United States, 93309
      • Research Site
    • Bakersfield, California, United States
      • CBCC Global Research, Inc. at Comprehensive Blood and Cancer Center
    • Burbank, California, United States, 91505
      • Research Site
    • Burbank, California, United States
      • Providence Saint Joseph Medical Center
    • Fountain Valley, California, United States, 92708
      • Research Site
    • Fountain Valley, California, United States
      • Compassionate Care Research Group, Inc.
    • Los Angeles, California, United States, 90017
      • Research Site
    • Los Angeles, California, United States, 90095-1686
      • Research Site
    • Los Angeles, California, United States
      • Los Angeles Hematology / Oncology Medical Group
    • Whittier, California, United States, 90603
      • Research Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Research Site
    • Aurora, Colorado, United States
      • University of Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20057
      • Research Site
    • Washington, District of Columbia, United States
      • Lombardi Cancer Center, Pediatric Hematology Oncology
  • Florida
    • Fort Myers, Florida, United States
      • Florida Cancer Specialists
    • Fort Myers, Florida, United States, 33905
      • Research Site
    • Tampa, Florida, United States, 33612
      • Research Site
    • Tampa, Florida, United States
      • H. Lee Moffitt Cancer Center & Research Institute
    • West Palm Beach, Florida, United States, 33401
      • Research Site
    • West Palm Beach, Florida, United States
      • Florida Cancer Specialists
  • Illinois
    • Chicago, Illinois, United States
      • University of Chicago Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Research Site
    • Boston, Massachusetts, United States
      • Dana Farber Partners Cancer Care
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Research Site
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Research Site
    • Hackensack, New Jersey, United States
      • John Theurer Cancer Center at Hackensack University Medical Center
  • New York
    • New York, New York, United States, 10021
      • Research Site
    • New York, New York, United States, 10065
      • Research Site
    • New York, New York, United States
      • Memorial Sloan Kettering
    • New York, New York, United States
      • Weill Cornell Medical College
    • New York, New York, United States
      • Clinical Research Alliance
    • New York, New York, United States
      • Morton Coleman, MD
    • Stony Brook, New York, United States, 11794
      • Research Site
    • Stony Brook, New York, United States
      • Stony Brook University Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Research Site
    • Durham, North Carolina, United States
      • Durham Veterans Affairs Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Research Site
    • Cincinnati, Ohio, United States
      • Sarah Cannon Research Institute
  • Oregon
    • Bend, Oregon, United States, 97701
      • Research Site
    • Bend, Oregon, United States
      • Bend Memorial Clinic
  • South Carolina
    • Charleston, South Carolina, United States, 29424
      • Research Site
    • Charleston, South Carolina, United States
      • Medical University of South Carolina, Hollings Cancer Center
    • Greenville, South Carolina, United States, 29607
      • Research Site
    • Greenville, South Carolina, United States
      • Greenville Health System
    • Greenville, South Carolina, United States
      • Saint Francis Hospital Cancer Center
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Research Site
    • Sioux Falls, South Dakota, United States
      • Avera Cancer Institute
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Research Site
    • Memphis, Tennessee, United States
      • The West Clinic, PC
    • Nashville, Tennessee, United States, 37203
      • Research Site
    • Nashville, Tennessee, United States, 37232
      • Research Site
    • Nashville, Tennessee, United States
      • Vanderbilt University Medical Center
    • Nashville, Tennessee, United States
      • Tennessee Oncology, PLLC / The Sarah Cannon Research lnstitute
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Research Site
    • Salt Lake City, Utah, United States
      • Huntsman Cancer Institute
  • Washington
    • Seattle, Washington, United States, 98104
      • Research Site
    • Seattle, Washington, United States
      • Swedish Cancer Institute
  • Wisconsin
    • Milwaukee, Wisconsin, United States
      • Aurora Health Care, Aurora Cancer Care
    • Wauwatosa, Wisconsin, United States, 53226
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

1. Newly diagnosed or relapsed multiple myeloma
2. Measureable disease by serum M protein, or urine M protein, or serum free light chain (SFLC) and an abnormal serum kappa lambda ratio (for subjects without detectable serum or urine M-protein), or serum quantitative immunoglobulin A (glgA) (for immunoglobulin (Ig) A subjects whose disease can only be reliable measured by qlgA).
3. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2
4. Left ventricular ejection fraction (LVEF) ≥ 40%

Key Exclusion Criteria:

1. Waldenström macroglobulinemia
2. For newly diagnosed multiple myeloma: multiple myeloma of IgM subtype

3. For relapsed disease:

   1. If treated with a lenalidomide and dexamethasone combination, progression during the first 3 months after initiating treatment.
   2. Any progression during treatment if the lenalidomide and dexamethasone regimen was the most recent line of therapy.
   3. Any prior treatment with carfilzomib
4. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
5. Plasma cell leukemia (> 2.0 × 10^9/L circulating plasma cells by standard differential)
6. Myelodysplastic syndrome
7. Amyloidosis
8. Prior treatment with carfilzomib or oprozomib

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RRMM Dose-evaluation: Carfilzomib 56 mg/m²; Participants with relapsed or refractory multiple myeloma (RRMM) received treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) for up to eighteen 28-day cycles, or until disease progression, patient withdrawal, stem cell transplant, or death. Participants received carfilzomib on days 1, 8, and 15 of each cycle. The dose was 20 mg/m² on cycle 1, day 1, and 56 mg/m² thereafter. Participants also received lenalidomide 25 mg once daily on days 1-21 and dexamethasone 40 mg (oral or IV) on days 1, 8, and 15 of each cycle, and on day 22 of cycles 1 to 8.	Drug: Carfilzomib; Administered once weekly by 30-minute intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle.; Other Names: PR-171; PR171; Kyprolis® (carfilzomib) for Injection; Drug: Lenalidomide; Administered orally once daily on days 1-21 of each 28-day cycle.; Other Names: Revlimid®; Drug: Dexamethasone; Administered by mouth or IV at 40 mg on days 1, 8, and 15 of each 28-day cycle and on day 22 of cycles 1 to 8.
Experimental: RRMM Dose-evaluation: Carfilzomib 70 mg/m²; Participants with RRMM received treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) for up to eighteen 28-day cycles, or until disease progression, patient withdrawal, stem cell transplant, or death. Participants received carfilzomib on days 1, 8, and 15 of each cycle. The dose was 20 mg/m² on cycle 1, day 1, and 70 mg/m² thereafter. Participants also received lenalidomide 25 mg once daily on days 1-21 and dexamethasone 40 mg (oral or IV) on days 1, 8, and 15 of each cycle, and on day 22 of cycles 1 to 8.	Drug: Carfilzomib; Administered once weekly by 30-minute intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle.; Other Names: PR-171; PR171; Kyprolis® (carfilzomib) for Injection; Drug: Lenalidomide; Administered orally once daily on days 1-21 of each 28-day cycle.; Other Names: Revlimid®; Drug: Dexamethasone; Administered by mouth or IV at 40 mg on days 1, 8, and 15 of each 28-day cycle and on day 22 of cycles 1 to 8.
Experimental: RRMM Dose-expansion: Carfilzomib 70 mg/m²; Participants with RRMM received treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) for up to eighteen 28-day cycles, or until disease progression, patient withdrawal, stem cell transplant, or death. Participants received carfilzomib on days 1, 8, and 15 of each cycle. The dose was 20 mg/m² on cycle 1, day 1, and 70 mg/m² thereafter. Participants also received lenalidomide 25 mg once daily on days 1-21 and dexamethasone 40 mg (oral or IV) on days 1, 8, and 15 of each cycle, and on day 22 of cycles 1 to 8.	Drug: Carfilzomib; Administered once weekly by 30-minute intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle.; Other Names: PR-171; PR171; Kyprolis® (carfilzomib) for Injection; Drug: Lenalidomide; Administered orally once daily on days 1-21 of each 28-day cycle.; Other Names: Revlimid®; Drug: Dexamethasone; Administered by mouth or IV at 40 mg on days 1, 8, and 15 of each 28-day cycle and on day 22 of cycles 1 to 8.
Experimental: NDMM Dose-evaluation: Carfilzomib 56/70 mg/m²; Participants with newly diagnosed multiple myeloma (NDMM) received treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) for up to eighteen 28-day cycles, or until disease progression, patient withdrawal, stem cell transplant, or death. Participants received carfilzomib on days 1, 8, and 15 of each cycle. The dose was 20 mg/m² on cycle 1 day 1, 56 mg/m² on cycle 1 days 8 and 15, and then 70 mg/m² thereafter. Participants also received lenalidomide 25 mg once daily on days 1-21 and dexamethasone 40 mg (oral or IV) on days 1, 8, and 15 of each cycle, and on day 22 of cycles 1 to 8.	Drug: Carfilzomib; Administered once weekly by 30-minute intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle.; Other Names: PR-171; PR171; Kyprolis® (carfilzomib) for Injection; Drug: Lenalidomide; Administered orally once daily on days 1-21 of each 28-day cycle.; Other Names: Revlimid®; Drug: Dexamethasone; Administered by mouth or IV at 40 mg on days 1, 8, and 15 of each 28-day cycle and on day 22 of cycles 1 to 8.
Experimental: NDMM Dose-expansion: Carfilzomib 70 mg/m²; Participants with NDMM received treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) for up to eighteen 28-day cycles, or until disease progression, patient withdrawal, stem cell transplant, or death. Participants received carfilzomib on days 1, 8, and 15 of each cycle. The dose was 20 mg/m² on cycle 1, day 1, and 70 mg/m² thereafter. Participants also received lenalidomide 25 mg once daily on days 1-21 and dexamethasone 40 mg (oral or IV) on days 1, 8, and 15 of each cycle, and on day 22 of cycles 1 to 8.	Drug: Carfilzomib; Administered once weekly by 30-minute intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle.; Other Names: PR-171; PR171; Kyprolis® (carfilzomib) for Injection; Drug: Lenalidomide; Administered orally once daily on days 1-21 of each 28-day cycle.; Other Names: Revlimid®; Drug: Dexamethasone; Administered by mouth or IV at 40 mg on days 1, 8, and 15 of each 28-day cycle and on day 22 of cycles 1 to 8.
Experimental: NDMM Dose-expansion: Carfilzomib 56 mg/m²; Participants with NDMM received treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) for up to eighteen 28-day cycles, or until disease progression, patient withdrawal, stem cell transplant, or death. Participants received carfilzomib on days 1, 8, and 15 of each cycle. The dose was 20 mg/m² on cycle 1, day 1, and 56 mg/m² thereafter. Participants also received lenalidomide 25 mg once daily on days 1-21 and dexamethasone 40 mg (oral or IV) on days 1, 8, and 15 of each cycle, and on day 22 of cycles 1 to 8.	Drug: Carfilzomib; Administered once weekly by 30-minute intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle.; Other Names: PR-171; PR171; Kyprolis® (carfilzomib) for Injection; Drug: Lenalidomide; Administered orally once daily on days 1-21 of each 28-day cycle.; Other Names: Revlimid®; Drug: Dexamethasone; Administered by mouth or IV at 40 mg on days 1, 8, and 15 of each 28-day cycle and on day 22 of cycles 1 to 8.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs)	Safety and tolerability were evaluated according to the type, incidence, and severity of adverse events. An AE is defined as any untoward medical occurrence in a clinical trial subject. The event does not necessarily have a causal relationship with study treatment. A serious adverse event is defined as an AE that meets at least 1 of the following serious criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event The severity of each AE was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening, and Grade 5 = Death.	From the first dose of any study drug up to 30 days after the last dose of any study drug; median (range) duration of treatment with carfilzomib was 32 (1.1, 76.7) weeks in RRMM participants and 26 (1.0, 94.4) weeks in NDMM participants.
Change From Baseline in Hemoglobin Levels		Baseline and Cycle 1, days 8 and 15 and Cycle 2 days 1, 8, and 15
Change From Baseline in Platelet Count		Baseline and Cycle 1, days 8 and 15 and Cycle 2 days 1, 8, and 15
Change From Baseline in Neutrophil Count		Baseline and Cycle 1, days 8 and 15 and Cycle 2 days 1, 8, and 15
Change From Baseline in Bilirubin		Baseline and Cycle 2 day 1
Change From Baseline in Creatinine		Baseline and Cycle 1, days 8 and 15 and Cycle 2 days 1, 8, and 15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Plasma Concentration of Carfilzomib on Day 8 of Cycle 1 by Dose Group		Day 8 of Cycle 1 at predose, 15 minutes after the start of infusion, at the end of infusion, and 15 and 60 minutes after the end of infusion
Time to Maximum Plasma Concentration of Carfilzomib on Day 8 of Cycle 1 by Dose Group		Day 8 of Cycle 1 at predose, 15 minutes after the start of infusion, at the end of infusion, and 15 and 60 minutes after the end of infusion
Area Under the Curve From Time Zero to Time of Last Quantifiable Concentration of Carfilzomib on Day 8 of Cycle 1 by Dose Group		Day 8 of Cycle 1 at predose, 15 minutes after the start of infusion, at the end of infusion, and 15 and 60 minutes after the end of infusion
Overall Response Rate (ORR)	Response was determined by the investigator based on the International Myeloma Working Group Uniform Response Criteria (IMWG URC). ORR was defined as the percentage of participants who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR). Responses must have been confirmed in 2 consecutive assessments at any time prior to initiation of any new therapy. Disease assessments included serum protein electrophoresis (SPEP) with immunofixation, urine protein electrophoresis (UPEP; 24-hour assessment) with immunofixation, serum free light chain (SFLC), quantitative immunoglobulins, bone marrow aspirates to determine percent plasma cell involvement, and skeletal imaging for plasmacytoma evaluation.	Response assessments were performed on day 1 of each treatment cycle from cycle 2 and then every 8 weeks during follow-up until disease progression. Median time on follow-up was 10.6 months in RRMM participants and 6.9 months in NDMM participants.
Complete Response Rate (CRR)	Complete Response Rate (CRR) is defined as the percentage of participants who achieved a best overall response of either stringent complete response (sCR) or complete response (CR) in accordance with International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). sCR: As for CR, and absence of clonal plasma cells in bone marrow (BM) CR: Negative serum and urine immunofixation, disappearance of any soft tissue plasmacytomas, < 5% plasma cells in BM, and normal SFLC ratio in participants with measurable disease only by SFLC.	Response assessments were performed on day 1 of each treatment cycle from cycle 2 and then every 8 weeks during follow-up until disease progression. Median time on follow-up was 10.6 months in RRMM participants and 6.9 months in NDMM participants.
Progression-free Survival (PFS)	PFS is defined as the time from the first day of study treatment to the earlier of disease progression or death due to any cause. Disease progression was determined by the investigator according to IMWG-URC. Progressive Disease (PD): Increase of 25% from lowest value in serum M-component (absolute increase ≥ 0.5 g/dL), urine M-component (absolute increase ≥ 200 mg per 24 hours) and/or the difference between involved and uninvolved FLC levels (absolute increase >10 mg/dL) in patients without measurable serum and urine M-protein levels, and/or any new or increase in size of bone lesions or soft tissue plasmacytomas, or development of hypercalcemia. PFS was analyzed using Kaplan-Meier methods. Participants who were alive with no documented PD, started new anticancer therapy before documentation of PD or death, had death or PD immediately after > 1 consecutively missed assessment visit, were lost to follow-up or withdrew consent were censored at the date of last disease assessment.	From first dose of study drug until the end of follow-up; Median time on follow-up was 10.6 months in RRMM participants and 6.9 months in NDMM participants.
Duration of Response (DOR)	Duration of response (DOR) was calculated for participants who achieved a confirmed PR or better based on Investigator assessment and according to the IMWG URC. Duration of overall response is defined as the time from first documentation of response to disease progression or death due to any cause. DOR was analyzed using Kaplan-Meier methods. Participants who were alive with no documented PD, started new anticancer therapy before documentation of PD or death, had death or PD immediately after > 1 consecutively missed disease assessment visit, were lost to follow-up, or withdrew consent were censored at the date of last disease assessment.	From first dose of study drug until the end of follow-up; Median time on follow-up was 10.6 months in RRMM participants and 6.9 months in NDMM participants.

Collaborators and Investigators

• Sponsor: Amgen
• Investigators: Study Director: Amy Kimball, MD, Amgen

Publications and helpful links

General Publications

• Biran N, Siegel D, Berdeja JG, Raje N, Cornell RF, Alsina M, Kovacsovics T, Fang B, Kimball AS, Landgren O. Weekly carfilzomib, lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: A phase 1b study. Am J Hematol. 2019 Jul;94(7):794-802. doi: 10.1002/ajh.25498. Epub 2019 May 13.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2015
• Primary Completion (Actual): October 28, 2019
• Study Completion (Actual): October 28, 2019

Study Registration Dates

• First Submitted: December 23, 2014
• First Submitted That Met QC Criteria: January 7, 2015
• First Posted (Estimate): January 12, 2015

Study Record Updates

• Last Update Posted (Actual): November 6, 2020
• Last Update Submitted That Met QC Criteria: October 15, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Dexamethasone; Lenalidomide
• Other Study ID Numbers: CFZ013

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO