Phase 2 Study of Carfilzomib in Relapsed and Refractory Multiple Myeloma

Study Overview
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Brief Summary
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To evaluate the overall response rate and safety and tolerability of carfilzomib in subjects with relapsed and refractory multiple myeloma. Patients must have received prior treatment with bortezomib and either thalidomide or lenalidomide and be refractory to their last treatment.

Official Title
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An Open-label, Single-arm, Phase 2 Study of Carfilzomib in Patients With Relapsed and Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: carfilzomib
* Drug: carfilzomib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Disease Related Multiple myeloma Subjects must have measurable disease defined as one of the following: Serum M-protein ≥ 1 g/dL Urine M-protein ≥ 200 mg/24 hours Serum FLC ≥ 10 mg/dL with abnormal ratio (A0 Only) Quantitative immunoglobulin levels using nephelometry or turbidometry (only if protein electrophoresis was felt to be unreliable for M-protein measurement) (A0 Only) Subjects must have been responsive (i.e., achieved an MR or better) to first-line, standard of care therapy Refractory to the most recently received therapy. Refractory disease is defined as ≤ 25% response or progression during therapy or within 60 days after completion of therapy. Subjects must have received ≥ 2 prior regimens for relapsed disease. Induction therapy and stem cell transplant will be considered as one regimen (A1 Only) Subjects must have received prior treatment with bortezomib, and either thalidomide or lenalidomide Subjects must have received an alkylating agent either alone or in combination with other myeloma treatments (history of stem cell transplant is acceptable) (A1 Only) Subjects must have received an anthracycline either alone or in combination with other myeloma treatments, unless not clinically indicated (A1 Only) Demographic Males and females > 18 years of age Life expectancy of more than three months Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 Laboratory Adequate hepatic function, with bilirubin less than 2.0 times the upper limit of normal, and AST and ALT of less than 3.0 times the upper limit of normal Uric acid within normal range (A0 Only) Total white blood cell (WBC) count ≥ 2.0 × 109/L, absolute neutrophil count (ANC) ≥ 1.0 × 109/L, hemoglobin ≥ 8.0 g/dL, and platelet count ≥ 50.0 × 109/L (A0 Only) Absolute neutrophil count > 1,000/mm3, hemoglobin > 8.0 g/dL, and platelet count > 50,000/mm3 (A1 Only) Subjects should be platelet transfusion independent Screening ANC should be independent of G-CSF or GM-CSF support for ≥ 1 week and of pegylated G-CSF for ≥ 2 weeks Subjects may receive red blood cell (RBC) or platelet transfusions or receive supportive care such as erythropoietin and darbepoetin in accordance with institutional guidelines Calculated and measured creatinine clearance of ≥ 30 mL/minute, calculated using the formula of Cockcroft and Gault [(140 - Age) X Mass (kg) / (72 X Creatinine mg/dL)]. Multiply result by 0.85 if female. Ethical / Other Written informed consent in accordance with federal, local, and institutional guidelines Female subjects of child-bearing potential must have a negative serum pregnancy test within seven days of the first dose and agree to use dual methods of contraception during and for 3 months following last dose of drug. Post menopausal females (> 45 years old and without menses for > 1 year) and surgically sterilized females are exempt from a pregnancy test. Male subjects must use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with a female of child-bearing potential. Exclusion Criteria: Disease Related Multiple Myeloma IgM (A1 Only) Subjects who failed to achieve at least a confirmed MR(≥ 25% reduction in M-protein for ≥ 6 weeks) (A1 Only) Subjects with non-secretory multiple myeloma, defined as < 1 g/dL M-protein in serum and < 200 mg/24 hr M-protein in urine Subjects with disease measurable only by serum free light chain (SFLC) analysis (A1 Only) Glucocorticoid therapy (prednisone > 10 mg/day orally or equivalent) within the last three weeks POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) Plasma cell leukemia Chemotherapy with approved or investigative anticancer therapeutics including steroid therapy within the three weeks prior to first dose Radiation therapy or immunotherapy in the previous four weeks; localized radiation therapy within 1 week prior to first dose Participation in an investigational therapeutic study within three weeks or within five drug half-lives (t1/2) prior to Day 1, whichever time is greater Prior treatment with carfilzomib Concurrent Conditions Major surgery within three weeks before Day 1 Congestive heart failure (New York Heart Association class III to IV), symptomatic cardiac ischemia, cardiomyopathy, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction in the previous six months, LVEF < 40 Acute active infection requiring systemic antibiotics, antivirals or antifungals within 2 weeks prior to first dose Known or suspected HIV infection or subjects who are HIV seropositive Active hepatitis A,B,or C infection Non-hematologic malignancy within the past three years except a) adequately treated basal cell or squamous cell skin cancer, b) carcinoma in situ of the cervix, or c) prostate cancer <Gleason Grade 6 with stable PSA Subjects with treatment related myelodysplastic syndrome Significant neuropathy (Grade 3, 4 or Grade 2 with pain) at the time of study initiation Subjects in whom the required program of oral and intravenous fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, cardiac or renal impairment (A1 Only) Subjects with known or suspected amyloidosis (A1 Only) Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis (A1 Only) Any 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 (A1 Only) Ethical / Other Female subjects who are pregnant or lactating Serious psychiatric or medical conditions that could interfere with treatment

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: carfilzomib (A0)<br> | Drug: carfilzomib<br>* Subjects will receive carfilzomib 20 mg/m2 as an intravenous bolus over 2 minutes on Days 1, 2, 8, 9, 15, and 16 of 28 day cycles. A maximum of 12 cycles will be administered.<br>* Other names: Kyprolis® (carfilzomib) for Injection;|
| Experimental: carfilzomib (A1)<br> | Drug: carfilzomib<br>* Subjects will receive carfilzomib intravenously over up to 10 minutes on Days 1, 2, 8, 9, 15, and 16 of 28 day cycles. In cycle 1, the dose is 20 mg/m2. If all doses are administered and well-tolerated over Cycle 1, beginning with Cycle 2 the dose will escalate to 27 mg/m2 cycle. A maximum of 12 cycles will be administered.<br>* Other names: Kyprolis® (carfilzomib) for Injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response Rate (ORR) | For both A0 and A1, to evaluate the best overall response rate (stringent complete response [sCR]+ complete response [CR]+ very good partial response [VGPR]+ partial response [PR]) in patients with multiple myeloma who had previously received bortezomib and either thalidomide or lenalidomide, had relapsed after two or more therapies, and were refractory to the most recently received therapy | A0: Subjects evaluated for disease response on Day 24 of Cycles 2, 4, 6, 9, and 12. Onset of response measured on Day 15 of Cycle 1. A1: Subjects evaluated for disease response on Day 15 of Cycle 1, Day 1 of Cycles 2 through 12 and at End of Study. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Response (CBR) (A0 Only) | sCR, CR, VGPR, PR, and minimal response (MR) | Response assessments same as described in primary outcome measure | 
| Clinical Benefit Response (CBR) (A1 Only) | sCR, CR, VGPR, PR, and minimal response (MR) | Response assessments same as described in primary outcome measure | 
| Duration of Response (A0 Only) | Duration of response (DOR) was calculated separately for subjects with clinical benefit response or overall response. DOR is defined as the time from first evidence of PR or better (for overall response) and MR or better (for clinical benefit response) to start of disease progression or death. | Response assessments same as described in primary outcome measure | 
| Duration of Response (A1 Only) | Duration of response (DOR) was calculated separately for subjects with clinical benefit response or overall response. DOR is defined as the time from first evidence of PR or better (for overall response) and MR or better (for clinical benefit response) to start of disease progression or death. | Response assessments same as described in primary outcome measure | 
| Time to Progression (A0 Only) | Time to progression (TTP) is defined as the time from the study entry (first dose of carfilzomib) to disease progression. | Response assessments same as described in primary outcome measure | 
| Time to Progression (A1 Only) | Time to progression (TTP) is defined as the time from the study entry (first dose of carfilzomib) to disease progression. | Response assessments same as described in primary outcome measure | 
| Progression-free Survival (A0 Only) | The PFS was defined as the time from the start of treatment to progressive disease (PD) determined by PI or until death. | Response assessments same as described in primary outcome measure | 
| Progression-free Survival (A1 Only) | The PFS was defined as the time from the start of treatment to progressive disease (PD) determined by PI or until death. | Response assessments same as described in primary outcome measure | 
| Overall Survival (A1 Only) | The time from start of treatment to death due to any cause OS was to be censored on the date the subject was last known to be alive for those who were alive or lost to follow-up as of a data analysis cutoff date. | Patients were to be followed by telephone contact for disease progression and OS every 3 months after study discontinuation for the first year and every 6 months thereafter for up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Onyx, PR171, carfilzomib, multiple myeloma, relapsed, refractory