Safety and Efficacy of Melflufen and Dexamethasone in Relapsed and/or Relapsed-Refractory Multiple Myeloma Patients

Study Overview
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Brief Summary
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The study will explore escalating doses of melflufen in combination with dexamethasone in small groups of patients to find the maximum tolerated dose of melflufen. That dose will then be used to determine the efficacy and safety profile of melflufen in combination with dexamethasone in a larger group of patients.

Official Title
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An Open-Label Phase I/IIa Study of the Safety and Efficacy of Melphalan-flufenamide (Melflufen) and Dexamethasone Combination for Patients With Relapsed and/or Relapsed-Refractory Multiple Myeloma

Conditions
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Relapsed and/or Relapsed-refractory Multiple Myeloma

Intervention / Treatment
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* Drug: Melflufen
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, age 18 years or older Patient has a diagnosis of multiple myeloma with documented relapsed and/or relapsed-refractory disease Patient has measurable disease defined as any of the following: Serum monoclonal protein ≥ 0.5 g/dL by protein electrophoresis ≥200 mg of monoclonal protein in the urine on 24-hour electrophoresis Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio If no monoclonal protein is detected, then ≥ 30% monoclonal bone marrow plasma cells Patient has had at least 2 or more prior lines of therapy including lenalidomide and bortezomib and has demonstrated disease progression on or within 60 days of completion of the last therapy Life expectancy of ≥6 months Patient has an ECOG performance status ≤ 2 (Patients with lower performance status based solely on bone pain secondary to multiple myeloma will be eligible) Females of childbearing potential must have a negative serum or urine pregnancy test prior to patient registration Female patients of child bearing potential and non-vasectomized male patients agree to practice appropriate methods of birth control Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information The patient has, or accepts to have, an acceptable infusion device for infusion of melflufen 12 lead ECG with QtcF interval ≤ 470 msec The following laboratory results must be met within 21 days of patient registration: Absolute neutrophil count ≥ 1,000 cells/dL (1.0 x 109/L) Platelet count ≥ 75,000 cells/dL (75 x 109/L) Hemoglobin ≥ 8.0 g/dL Total Bilirubin ≤ 1.5 x upper limit of normal Renal function: Estimated creatinine clearance ≥ 45 ml/min or serum creatinine ≤ 2.5 mg/dL AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN Exclusion Criteria: Patient has evidence of mucosal or internal bleeding and/or is 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 participation in this study Known active infection requiring parenteral or oral anti-infective treatment Other malignancy within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix Other ongoing anti-myeloma therapy. Patients may be receiving concomitant therapy with bisphosphonates and low dose corticosteroids for symptom management and comorbid conditions. Doses of corticosteroid should be stable for at least 7 days prior to patient registration. Pregnant or breast-feeding females Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse follow-up evaluation Known HIV or hepatitis B or C viral infection Patient has 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 start of study treatment. Biologic, novel therapy (including investigational agents in this class) or corticosteroids within 2 weeks prior to patient registration. Patient has side effects of the previous therapy > grade 1 or previous baseline. Prior peripheral stem cell transplant within 12 weeks of patient registration Radiotherapy within 21 days prior to Cycle 1 Day 1. However, if the radiation portal covered ≤ 5% of the bone marrow reserve, the patient may be enrolled irrespective of the end date of radiotherapy 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I: Melflufen 15 mg + Dexamethasone<br>Intravenous (IV) infusion of 15 milligram (mg) melflufen on Day 1 of each 21-day treatment cycle, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycle. | Drug: Melflufen<br> <br> Drug: Dexamethasone<br> <br> |
| Experimental: Phase I: Melflufen 25 mg + Dexamethasone<br>IV infusion of 25 mg melflufen on Day 1 of each 21-day treatment cycle, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycle. | Drug: Melflufen<br> <br> Drug: Dexamethasone<br> <br> |
| Experimental: Phase I: Melflufen 40 mg + Dexamethasone<br>IV infusion of 40 mg melflufen on Day 1 of each 21-day treatment cycle, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycle. | Drug: Melflufen<br> <br> Drug: Dexamethasone<br> <br> |
| Experimental: Phase I: Melflufen 55 mg + Dexamethasone<br>IV infusion of 55 mg melflufen on Day 1 of each 21-day treatment cycle, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycle. | Drug: Melflufen<br> <br> Drug: Dexamethasone<br> <br> |
| Experimental: Phase I + II: Melflufen 40 mg + Dexamethasone<br>IV infusion of 40 mg melflufen on Day 1 of each 21-day or 28-day treatment cycles, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycles. For any patients on the 28-day treatment schedule, an additional dose of 40 mg dexamethasone was administered on Day 22 of each treatment cycle. | Drug: Melflufen<br> <br> Drug: Dexamethasone<br> <br> |
| Experimental: Phase II: Melflufen 40 mg (Single Agent)<br>IV infusion of 40 mg melflufen on Day 1 of each 28-day treatment cycle. | Drug: Melflufen<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Who Achieved Best Overall Disease Response | The best overall disease response on treatment including stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), stable disease (SD) or progressive disease (PD) were evaluated. Starting on completion of Cycle 2, response was assessed according to International Myeloma Working Group (IMWG) criteria based on Investigator's assessment for all patients at every cycle during treatment period. PD was defined as increase of ≥25% from lowest response value in any 1 of the following: serum M-component (absolute increase must be ≥0.5 gram/deciliter) and/or urine M-component (absolute increase must be ≥200 mg/24 hr); development of new bone lesions or soft tissue plasmacytomas or increase in size of existing bone lesions or soft tissue plasmacytomas or development of hypercalcemia that could be attributed solely to plasma cell proliferative disorder. SD was defined as not meeting criteria for CR, VGPR, PR or PD. | Baseline (Cycle 1 Day 1) and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months. | 
| Overall Response Rate (ORR) | ORR was defined as percentage of patients with an overall response (OR), defined as first occurrence of confirmed disease response including PR or better (i.e, PR, VGPR, CR or sCR). Starting on completion of Cycle 2, response was assessed according to IMWG criteria based on Investigator's assessment for all patients at every cycle during treatment period. VGPR was defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum plus urine M-protein level <100 mg/24hr and >90% decrease in difference between involved and uninvolved free light chain (FLC) levels (only in FLC diseased patients). CR was defined as negative immunofixation on serum and urine, loss of any soft tissue plasmacytomas, <5% plasma cells in bone marrow and normal FLC ratio of 0.26 to 1.65 (only in FLC diseased patients). sCR was defined as CR plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or 2 to 4 color flow cytometry. | Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months. | 
| Clinical Benefit Response Rate (CBRR) | The CBRR was defined as the percentage of patients with a clinical benefit response (CBR), defined as the first occurrence of confirmed disease response including MR or better (i.e, MR, PR, VGPR, CR, or sCR). Starting on completion of Cycle 2, response was assessed according to the IMWG criteria based on the Investigator's assessment for all patients at every cycle during the treatment period. MR was defined as ≥25% but <49% reduction of serum M-protein and reduction in 24 hour urine M-protein by 50 to 89%, which still exceeds 200 mg/24 hours. In addition to above; if present at baseline, 25 to 49% reduction in the size of soft tissue plasmacytomas is also required. No increase in size or number of lytic bone lesions (development of compression fractures does not exclude response). PR was defined as 50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by ≥90% or to <200 mg/24 hour. | Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Disease Response (DOR) | The DOR to treatment was defined as time from first response (PR or better) to disease progression or death, or date of last evaluable disease response assessment for those who had not progressed or died. DOR was estimated using Kaplan-Meier statistics. | Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months. | 
| Time to Disease Response in Patients Who Achieved OR and CBR | Time to first OR was defined as the time from the date of the first dose of study drug (overall reference start date) to the date of the first occurrence of PR or better (first of 2 consecutive assessments-confirmed response). Time to first CBR was defined as the time from the date of the first dose of study drug (overall reference start date) to the date of the first occurrence of MR or better (first of 2 consecutive assessments-confirmed response). Time to disease response was estimated using Kaplan-Meier statistics. | Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months. | 
| Time to Disease Progression | Time to disease progression was defined as the time from the date of the first dose of study drug (overall reference start date) to the date of the first occurrence of evaluable PD. Time to disease progression was estimated using Kaplan-Meier statistics. | Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months. | 
| Median Progression-Free Survival (PFS) | The PFS was defined as the time from the date of the first dose of melflufen (overall reference start date) to the date of the first occurrence of any disease response assessment available for PD or death. The PFS was estimated using Kaplan-Meier statistics. | Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months. | 
| Median Overall Survival (OS) | The OS was defined as the time from the date of the first dose of melflufen (overall reference start date) to death. The OS was estimated using Kaplan-Meier statistics. | From baseline until death. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months. | 
| Time to First Subsequent Treatment | Time to first subsequent treatment start was defined as the time from the date of the actual end of treatment to the date of the first subsequent treatment. Time to first subsequent treatment was estimated using Kaplan-Meier statistics. | From baseline until start of first subsequent treatment. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months. | 
| Number of Patients With Treatment Emergent Adverse Events (TEAEs) | An adverse event (AE) was any untoward medical occurrence in a study patient administered an investigational product and that does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was defined as any AE, occurring at any dose, that met any one or more of the following criteria: is fatal or immediately life-threatening; results in persistent or significant disability/incapacity; constitutes a congenital anomaly/birth defect; is medically significant; requires inpatient hospitalization or prolongation of existing hospitalization; or other important medical event. TEAEs were defined as AEs that started or worsened on or after the first dose of study drug (overall reference start date) up to and including the actual EOT date. TESAEs = Treatment emergent serious adverse events. | From the first dose of study drug up to and including the actual EOT date of 29 October 2019; up to a maximum of approximately 76 months. |