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

Study Overview
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Brief Summary
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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.

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

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Carfilzomib
* Drug: Lenalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Newly diagnosed or relapsed multiple myeloma 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). Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2 Left ventricular ejection fraction (LVEF) ≥ 40% Key Exclusion Criteria: Waldenström macroglobulinemia For newly diagnosed multiple myeloma: multiple myeloma of IgM subtype For relapsed disease: If treated with a lenalidomide and dexamethasone combination, progression during the first 3 months after initiating treatment. Any progression during treatment if the lenalidomide and dexamethasone regimen was the most recent line of therapy. Any prior treatment with carfilzomib POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) Plasma cell leukemia (> 2.0 × 10^9/L circulating plasma cells by standard differential) Myelodysplastic syndrome Amyloidosis Prior treatment with carfilzomib or oprozomib

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RRMM Dose-evaluation: Carfilzomib 56 mg/m²<br>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<br>* Administered once weekly by 30-minute intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle.<br>* Other names: Kyprolis® (carfilzomib) for Injection;Drug: Lenalidomide<br>* Administered orally once daily on days 1-21 of each 28-day cycle.<br>* Other names: Revlimid®;Drug: Dexamethasone<br>* 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.<br>|
| Experimental: RRMM Dose-evaluation: Carfilzomib 70 mg/m²<br>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<br>* Administered once weekly by 30-minute intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle.<br>* Other names: Kyprolis® (carfilzomib) for Injection;Drug: Lenalidomide<br>* Administered orally once daily on days 1-21 of each 28-day cycle.<br>* Other names: Revlimid®;Drug: Dexamethasone<br>* 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.<br>|
| Experimental: RRMM Dose-expansion: Carfilzomib 70 mg/m²<br>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<br>* Administered once weekly by 30-minute intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle.<br>* Other names: Kyprolis® (carfilzomib) for Injection;Drug: Lenalidomide<br>* Administered orally once daily on days 1-21 of each 28-day cycle.<br>* Other names: Revlimid®;Drug: Dexamethasone<br>* 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.<br>|
| Experimental: NDMM Dose-evaluation: Carfilzomib 56/70 mg/m²<br>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<br>* Administered once weekly by 30-minute intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle.<br>* Other names: Kyprolis® (carfilzomib) for Injection;Drug: Lenalidomide<br>* Administered orally once daily on days 1-21 of each 28-day cycle.<br>* Other names: Revlimid®;Drug: Dexamethasone<br>* 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.<br>|
| Experimental: NDMM Dose-expansion: Carfilzomib 70 mg/m²<br>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<br>* Administered once weekly by 30-minute intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle.<br>* Other names: Kyprolis® (carfilzomib) for Injection;Drug: Lenalidomide<br>* Administered orally once daily on days 1-21 of each 28-day cycle.<br>* Other names: Revlimid®;Drug: Dexamethasone<br>* 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.<br>|
| Experimental: NDMM Dose-expansion: Carfilzomib 56 mg/m²<br>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<br>* Administered once weekly by 30-minute intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle.<br>* Other names: Kyprolis® (carfilzomib) for Injection;Drug: Lenalidomide<br>* Administered orally once daily on days 1-21 of each 28-day cycle.<br>* Other names: Revlimid®;Drug: Dexamethasone<br>* 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.<br>|

What is the study measuring?
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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. |