A Multicenter, Open-label, Phase 1b Study of Carfilzomib, Cyclophosphamide and Dexamethasone in Newly Diagnosed Multiple Myeloma Subjects

Study Overview
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Brief Summary
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The primary objective was to determine the maximum tolerated dose of carfilzomib given twice weekly in combination with cyclophosphamide and dexamethasone for patients with newly diagnosed multiple myeloma.

Official Title
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A Multicenter, Open-label, Phase 1b Study of Carfilzomib, Cyclophosphamide and Dexamethasone in Newly Diagnosed Multiple Myeloma Subjects

Conditions
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Multiple Myeloma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed multiple myeloma Measurable disease, as defined by 1 or more of the following Serum M-protein ≥ 0.5 g/dL, or Urine M-protein ≥ 200 mg/24 hours, or In subjects without detectable serum or urine M-protein, serum free light chain (SFLC) > 100 mg/L (involved light chain) and an abnormal kappa lambda ( κ/λ) ratio Males and females ≥ 18 years of age Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Adequate hepatic function Left ventricular ejection fraction (LVEF) ≥ 40% Absolute neutrophil count (ANC) ≥ 1.0 × 10^9/L Platelet count ≥ 50 × 10^9/L Calculated or measured creatinine clearance (CrCl) of ≥ 15 mL/min Exclusion Criteria: Planned autologous hematopoietic stem cell transplantation (HSCT) for the initial therapy of newly diagnosed multiple myeloma Multiple myeloma of immunoglobulin M (IgM) subtype Prior systemic treatment for multiple myeloma Glucocorticoid therapy within 14 days prior to enrollment that equals or exceeds the equivalent of dexamethasone 160 mg Known amyloidosis Active congestive heart failure (New York Heart Association [NYHA] Class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within 6 months prior to enrollment. Known human immunodeficiency virus (HIV) seropositive, hepatitis C infection, and/or hepatitis B (subjects with hepatitis B surface antigen [SAg] or core antibody receiving and responding to antiviral therapy directed at hepatitis B are allowed) Significant neuropathy (Grades ≥ 2) within 14 days prior to enrollment Any other clinically significant medical disease or condition that, in the investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carfilzomib, Cyclophosphamide and Dexamethasone (CCd)<br>Participants received carfilzomib, cyclophosphamide and dexamethasone for up to eight 28-day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. | Drug: Carfilzomib<br>* Carfilzomib administered as a 30-minute intravenous (IV) infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. On Days 1 and 2 of Cycle 1, all participants received carfilzomib at 20 mg/m².<br>* Other names: Kyprolis® (carfilzomib) for Injection;Drug: Cyclophosphamide<br>* Cyclophosphamide administered orally (PO) at the dose of 300 mg/m² on Days 1, 8, and 15 of each 28-day cycle.<br>Drug: Dexamethasone<br>* Dexamethasone administered PO or IV at 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicities (DLTs) | The MTD is defined as the highest carfilzomib dose at which fewer than 33% of participants experience a treatment-related dose-limiting toxicity (DLT) during the first 28-day cycle. The number of participants who experienced a DLT is reported. Dose-limiting toxicities are defined as any of the following carfilzomib-related adverse events: Nonhematologic: ≥ Grade 3 non-hematological toxicity ≥ Grade 3 acute kidney injury (creatinine > 3 × baseline or > 4.0 mg/dL) lasting > 72 hours Hematologic: Grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 10^9/L) lasting for > 7 days Febrile neutropenia (ANC < 1.0 × 10^9/L with a fever ≥ 38.3ºC) of any duration Grade 4 thrombocytopenia (< 25 × 10^9/L) that persists for > 14 days, despite holding treatment Grade 3 or 4 thrombocytopenia associated with > Grade 1 bleeding | First cycle treatment over 28-days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Participants were evaluated for disease response and progression by the investigator according to the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). Disease response and progression assessments included serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), serum immunofixation, serum free light chain (SFLC), bone marrow sample (including fluorescent in situ hybridization [FISH]), plasmacytoma evaluation, and skeletal survey. Overall response rate is defined as the percentage of participants with a best response of stringent complete response, complete response, very good partial response (VGPR), or partial response. | Disease response was assessed at the end of each cycle and 30 days after the last treatment; maximum treatment duration was 32 weeks. | 
| Time To Response (TTR) | Time to response is defined as months from treatment start to first documentation of response of partial response or better. Summary of time to response includes confirmed responders of PR or better only. | Disease response was assessed at the end of each cycle and 30 days after the last treatment; maximum treatment duration was 32 weeks. | 
| Number of Participants With Adverse Events | Adverse events (AEs) were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 and using the following scale: Grade 1 = Mild, Grade 3 = Moderate; Grade 3 = Severe, Grade 4 = Life-threatening; Grade 5 = Fatal. | From first dose of study drug until 30 days after last dose; median duration of treatment was 31 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple myeloma