A Study of Melphalan Flufenamide (Melflufen)-Dex or Pomalidomide-dex for RRMM Patients Refractory to Lenalidomide

Study Overview
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Brief Summary
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This is a randomized, controlled, open-label, Phase 3 multicenter study which will enroll patients with RRMM following 2-4 lines of prior therapy and who are refractory to lenalidomide in the last line of therapy as demonstrated by disease progression on or within 60 days of completion of the last dose of lenalidomide. Patients will receive either melflufen+dex or pomalidomide+dex.

Detailed Description
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This is a randomized, controlled, open-label, Phase 3 multicenter study which will enroll patients with RRMM following 2-4 lines of prior therapy and who are refractory to lenalidomide in the last line of therapy as demonstrated by disease progression on or within 60 days of completion of the last dose of lenalidomide. Patients will be randomized to either one of two arms: Arm A: Melphalan flufenamide (Melflufen) 40 mg on Day 1 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle. Arm B: Pomalidomide 4 mg daily on Days 1 to 21 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle. Patients ≥ 75 years of age will have a reduced dose of dexamethasone of 20 mg on Days 1, 8, 15 and 22 for both Arm A and Arm B. Patients may receive treatment until such time as there is documented disease progression, unacceptable toxicity or the patient/treating physician determines it is not in the patient's best interest to continue. Dose modifications and delays in therapy may be implemented based on patient tolerability as detailed in the protocol. In the event of a cycle delay, unrelated to dexamethasone toxicity, it is recommended to continue dexamethasone weekly.

Official Title
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A Randomized, Controlled, Open-label, Phase 3 Study of Melflufen/Dexamethasone Compared With Pomalidomide/Dexamethasone for Patients With Relapsed Refractory Multiple Myeloma Who Are Refractory to Lenalidomide

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Melflufen
* Drug: Pomalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, age 18 years or older A prior diagnosis of multiple myeloma with documented disease progression requiring further treatment at time of screening Measurable disease defined as any of the following: Serum monoclonal protein ≥ 0.5 g/dL by protein electrophoresis. ≥ 200 mg/24 hours of monoclonal protein in the urine on 24-hour electrophoresis Serum free light chain ≥ 10 mg/dL AND abnormal serum kappa to lambda free light chain ratio Received 2-4 prior lines of therapy, including lenalidomide and a PI, either sequential or in the same line, and is refractory (relapsed and refractory or refractory) to both the last line of therapy and to lenalidomide (≥ 10 mg) administered within 18 months prior to randomization. Refractory to lenalidomide is defined as progression while on lenalidomide therapy or within 60 days of last dose, following at least 2 cycles of lenalidomide with at least 14 doses of lenalidomide per cycle. Life expectancy of ≥ 6 months Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Females of child bearing potential (FCBP) must have a negative serum or urine pregnancy test prior to start of treatment. Participants must agree to ongoing pregnancy testing. All patients must be willing to comply with all requirements of the USA pomalidomide Risk Evaluation and Mitigation Strategy (REMS) program or the pomalidomide Pregnancy Prevention Plan (PPP). Ability to understand the purpose and risks of the study and provide signed and dated informed consent. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of ≤ 470 msec Fridericia Formula. The following laboratory results must be met during screening and also immediately before study drug administration on Cycle 1 Day 1: Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 109/L) Platelet count ≥ 75,000 cells/mm3 (75 x 109/L) Hemoglobin ≥ 8.0 g/dl Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), or patients diagnosed with Gilberts syndrome, that have been reviewed and approved by the medical monitor. Aspartate transaminase (AST /SGOT) and alanine transaminase (ALT/SGPT) ≤ 3.0 x ULN. Renal function: Estimated creatinine clearance by Cockcroft-Gault formula ≥ 45 mL/min. Must be able to take antithrombotic prophylaxis. Must have, or be willing to have an acceptable central catheter. (Port a cath, peripherally inserted central catheter [PICC-line], or central venous catheter) (Insertion only required if randomized to Arm A). Exclusion Criteria: Primary refractory disease (i.e. never responded (≥ MR) to any prior therapy) Evidence of mucosal or internal bleeding or platelet transfusion refractory Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study. Prior exposure to pomalidomide Known intolerance to IMiDs. Known active infection requiring parenteral or oral anti-infective treatment within 14 days of randomization. Other malignancy diagnosed or requiring treatment within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in active surveillance. Pregnant or breast-feeding females Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation Known human immunodeficiency virus or active hepatitis C viral infection Active hepatitis B viral infection (defined as HBsAg+). Patients with prior hepatitis B vaccine are permitted (defined as HBsAg-, Anti-HBs+, Anti-HBc-). Non-active hepatitis B (HBsAg-, Anti-HBs+, Anti-HBc+) may be enrolled at the discretion of the investigator after consideration of risk of reactivation. Concurrent symptomatic amyloidosis or plasma cell leukemia POEMS syndrome Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within 3 weeks (6 weeks for nitrosoureas) prior to randomization. IMiDs, PIs and or corticosteroids within 2 weeks prior to randomization. Other investigational therapies and monoclonal antibodies within 4 weeks of randomization. Prednisone up to but no more than 10 mg orally q.d. or its equivalent for symptom management of comorbid conditions is permitted but dose should be stable for at least 7 days prior to randomization Residual side effects to previous therapy > grade 1 prior to randomization (Alopecia any grade and/or neuropathy grade 2 without pain are permitted) Prior peripheral stem cell transplant within 12 weeks of randomization Prior allogeneic stem cell transplantation with active graft-versus-host-disease. Prior major surgical procedure or radiation therapy within 4 weeks of the randomization Known intolerance to steroid therapy

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: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Melflufen+Dexamethasone<br>Melflufen 40 mg i.v. on Day 1 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle. Patients are to be treated until confirmed progression, unacceptable toxicity or the patient or investigator decides it is not in the patients best interest to continue. | Drug: Melflufen<br>* Intravenous infusion<br>* Other names: Melphalan Flufenamide;Drug: Dexamethasone<br>* Oral tablets<br>* Other names: Decadron;|
| Active Comparator: Arm B: Pomalidomide+Dexamethasone<br>Pomalidomide 4 mg orally daily on Days 1 to 21 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle. Patients are to be treated until confirmed progression, unacceptable toxicity or the patient or investigator decides it is not in the patients best interest to continue. | Drug: Pomalidomide<br>* Oral capsules<br>* Other names: Imnovid;Drug: Dexamethasone<br>* Oral tablets<br>* Other names: Decadron;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Progression Free Survival defined as the duration in months from randomization until first evidence of confirmed disease progression, as assessed by the Independent Review Committee (IRC) according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC) | From randomization to time of progression, or, if no progression, 24 months after end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR defined as the proportion of patients for whom the best overall confirmed response is stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR), as assessed by IRC. | From randomization until best response achieved before confirmed progression, or if no progression up to 24 months after end of treatment. Median time to best response was 2.1 and 2.0 months for Arm A and B, respectively. | 
| Duration of Response (DOR) | DOR defined as the duration in months from first documentation of a confirmed response to first evidence of confirmed disease progression or death due to any cause. | From first evidence of response until confirmed progression, or if no progression, 24 months after end of treatment | 
| Overall Survival (OS) | OS defined as the time in months from randomization to date of death due to any cause. Patients who are alive will be censored at the last follow up visit or data cut-off date for patients still on-study. | From randomization until end of study (2 years after confirmed progression) | 
| Safety and Tolerability: Number of Patients With Treatment-emergent Adverse Events, Including Clinical Laboratory and Vital Signs Abnormalities, as Assessed by CTCAE v4.0 | Number of patients with treatment-emergent adverse events, including clinical laboratory and vital signs abnormalities, as assessed by CTCAE v4.0 will be presented. No formal statistical analysis will be performed for safety endpoints. | From start of dosing until 30 days after the last dose of study treatment, the median time frame for study treatment was 25.1 and 22.1 months for Arm A and B, respectively. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Refractory Multiple Myeloma, Relapsed Multiple Myeloma, Melphalan flufenamide (Melflufen), Pomalidomide, Dexamethasone