Study of Melphalan Flufenamide (Melflufen) + Dex With Bortezomib or Daratumumab in Patients With RRMM

Study Overview
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Brief Summary
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This is an open-label Phase 1/2a study which will enroll patients that have relapsed or relapsed-refractory multiple myeloma to combination regimens of melflufen with currently approved agents. Patients will receive either melflufen+dexamethasone+bortezomib or melflufen+dexamethasone+daratumumab.

Official Title
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An Open-Label Phase 1/2a Study of the Safety and Efficacy of Melflufen and Dexamethasone in Combination With Either Bortezomib or Daratumumab in Patients With Relapsed or Relapsed-Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Melphalan flufenamide (Melflufen)
* Drug: Dexamethasone
* Drug: Bortezomib
* Drug: Daratumumab


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 in need of treatment at time of screening One to four prior lines of therapy Measurable disease defined as any of the following: Serum monoclonal protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP) ≥ 200 mg/24 hours of monoclonal protein in the urine on 24-hour urine electrophoresis (UPEP) Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal serum kappa to lambda free light chain ratio Life expectancy of ≥ 6 months ECOG performance status ≤ 2. (Patients with lower performance status based solely on bone pain secondary to multiple myeloma may be eligible following consultation and approval of the medical monitor) Patient is a female of childbearing potential (FCBP)* with a negative serum or urine pregnancy test prior to initiation of therapy and agrees to practice appropriate methods of birth control, or the patient is male and agrees to practice appropriate methods of birth control 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 Adequate organ function with the following laboratory results during screening (within 21 days) and immediately before study drug administration on Cycle 1 Day 1: Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 109/L) (Growth factors cannot be used within 10 days (14 days for pegfilgrastim) prior to initiation of therapy) Platelet count ≥ 75,000 cells/mm3 (75 x 109/L) (without required transfusions during the 10 days prior to initiation of therapy) Hemoglobin ≥ 8.0 g/dl (red blood cell (RBC) transfusions are permitted) Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), or patients diagnosed with Gilbert's syndrome, that have been reviewed and approved by the medical monitor AST/SGOT and ALT/SGPT ≤ 3.0 x ULN Renal function: Estimated creatinine clearance by Cockcroft-Gault formula ≥ 45 mL/min and serum creatinine ≤ 2 mg/dL Must have, or be willing to have an acceptable central catheter. (Port a cath, peripherally inserted central catheter [PICC] line, or central venous catheter) Regimen A Must be intolerant or refractory to a prior IMiD; refractory defined as failure to respond (MR or better) or progression while on therapy or within 60 days of last dose. Regimen B Must have had a prior IMiD and a proteasome inhibitor (PI); alone or in combination and must be refractory or intolerant to an IMiD, PI or both. (FCBP) is any sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (not having menstrual cycles due to cancer therapy does not rule out childbearing potential) for at least 24 consecutive months. Exclusion Criteria: Primary refractory disease (i.e. never responded with ≥ MR to any prior therapy) Evidence of mucosal or internal bleeding and/or are platelet transfusion refractory (i.e. platelet count fails to increase by > 10,000 cells/mm3 after transfusion of an appropriate dose of platelets) 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. Examples of such conditions are: a significant history of cardiovascular disease (e.g., myocardial infarction, significant conduction system abnormalities, uncontrolled hypertension, ≥ Grade 3 thromboembolic event in the last 6 months) Known active infection requiring parenteral or oral anti-infective treatment within 14 days of initiation of therapy 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 B or C viral infection Concurrent symptomatic amyloidosis or plasma cell leukemia POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes) Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within 3 weeks (6 weeks for nitrosoureas) prior to initiation of therapy. The use of live vaccines within 30 days before initiation of therapy. IMiDs, PIs and or corticosteroids within 2 weeks prior to initiation of therapy. Other investigational therapies and monoclonal antibodies (mAb) within 4 weeks of initiation of therapy Prednisone up to but no more than 10 mg orally once daily (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 initiation of therapy Residual side effects to previous therapy > Grade 1 prior to initiation of therapy (Alopecia any grade and/or neuropathy Grade 1 without pain are permitted) Prior peripheral stem cell transplant within 12 weeks of initiation of therapy Prior allogeneic stem cell transplantation with active graft-versus-host- disease Prior major surgical procedure or radiation therapy within 4 weeks of initiation of therapy (this does not include limited course of radiation used for management of bone pain within 7 days of initiation of therapy) Known intolerance to the required dose and schedule of steroid therapy as determined by the investigator Prior treatment with melflufen Regimen A Refractory to a PI in the last line of therapy prior to enrollment in this trial; refractory defined as failure to respond (MR or better) or progression while on therapy or within 60 days of last dose History of allergic reaction/hypersensitivity attributed to compounds containing boron, mannitol, polysorbate 80 or sodium citrate dihydrate Regimen B Prior exposure to an antiCD-38 mAb Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) less than 50% of predicted normal Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification ≥ Grade 3 conduction system abnormalities unless patient has a pacemaker Active hepatitis B (defined as HBsAg+) or those at risk for reactivation (HBsAg-, Anti- HBs+, Anti-HBc+) 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 only be enrolled after approval of the sponsor and consideration of risk of reactivation (additional screening and monitoring for reactivation of Hepatitis B and consultation with a liver disease specialist may be required)

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A (melflufen+bortezomib+dex)<br>Melflufen 30 mg and 40 mg or 20 mg i.v. Day 1 of each 28-day cycle in combination with bortezomib at 1.3mg/m² S.Q. on Days 1, 4, 8, 11 and dexamethasone 20 mg (12 mg ≥ 75 years) Days 1, 4, 8, 11 and 40 mg (20 mg ≥ 75 years) on Day 15 and 22 of each 28-day cycle. | Drug: Melphalan flufenamide (Melflufen)<br>* Intravenous infusion<br>Drug: Dexamethasone<br>* Oral tablets<br>* Other names: Decadron;Drug: Bortezomib<br>* Subcutaneous administration<br>* Other names: Velcade;|
| Experimental: B (melflufen+daratumumab+dex)<br>Melflufen 30 mg and 40 mg or 20 mg i.v. Day 1 of each 28-day cycle in combination with daratumumab 16 mg/kg weekly for 8 doses, every other week for 8 doses and then once every 4 weeks. Dexamethasone p.o. 40 mg weekly (20 mg weekly for patients age ≥ 75 years). | Drug: Melphalan flufenamide (Melflufen)<br>* Intravenous infusion<br>Drug: Dexamethasone<br>* Oral tablets<br>* Other names: Decadron;Drug: Daratumumab<br>* Intravenous infusion<br>* Other names: Darzalex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) | Toxicity was graded according to the National Cancer Institute - Common Terminology Criteria for Adverse Events Version 4.03. DLT criteria that apply to Regimens A and B: Grade 3 non-hematologic toxicity preventing the administration of > 1 dose of bortezomib or daratumumab during the 1st cycle. Grade 4 or greater non-hematologic toxicity. Grade 4 thrombocytopenia (platelet count < 25,000 cells/ mm^3) preventing the administration of > 1 dose of bortezomib or daratumumab during the 1st cycle or with clinically significant bleeding during the 1st cycle. Grade 4 neutropenia (ANC < 500 cells/mm^3), lasting more than 7 days during the 1st cycle. Greater than 14 days' delay to meet the criteria for the start of a new cycle (Cycle 2) due to toxicity. | Cycle 1: Day 1 to Day 28 | 
| Phase 2: Overall Response Rate (ORR) | ORR was defined as the percentage of participants who achieved a best confirmed response of Partial Response (PR) or better. | Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Response (BR) | BR defined by International Myeloma Working Group Uniform Response Criteria. BR= Complete Response (CR)/Stringent CR (sCR) defined as below negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow/plus normal free light chain (FLC) ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence, Very Good Partial Response (VGPR)= serum and urine M-protein detectable by immunofixation but not on electrophoresis or > 90% reduction in serum M-protein plus urine M-protein level < 100 mg/24 hours, Partial Response (PR)= a > 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by > 90% or to < 200 mg/24 hours, Minimal Response (MR), Stable Disease (SD)= not meeting the criteria for other response options, Progressive Disease (PD)= increase of > 25% from lowest response value in serum/urine M-component or bone marrow plasma cell percentage, or non-evaluable. | Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks) | 
| Duration of Response (DOR) | DOR is defined for participants with confirmed objective response (PR or better, which includes PR, VGPR, CR and sCR) as the time from the first documentation of objective response to the first documentation of objective progression or to death due to any cause, whichever occurs first. | Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks) | 
| Time to Response (TTR) | Time from Cycle 1 Day 1 to a response of PR or better. | Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks) | 
| Progression-Free Survival (PFS) | PFS was defined as the time in months from date of initiation of therapy to the earlier of confirmed disease progression or death due to any cause. | Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks) | 
| Overall Survival (OS) | Time from the first dose of melflufen to death due to any cause. | Up to 24 months following confirmed disease progression, or initiation of subsequent therapy (a maximum of 198.9 weeks) | 
| Duration of Clinical Benefit (DOCB) | DOCB was defined as time in months from the first evidence of confirmed assessment of sCR, CR, VGPR, PR or MR to first confirmed disease progression, or to death due to any cause. | Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks) | 
| Time to Progression (TTP) | TTP defined as time from first dose to first documented confirmed progression. | Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks) | 
| Clinical Benefit Rate (≥ Minimal Response) | ≥ Minimal response for participants included sCR, CR, VGPR, PR and MR. | Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks) | 
| Time to Next Treatment (TTNT) | Defined as time from date of initiation of therapy to start of next line of therapy. | Until death or initiation of subsequent therapy (a maximum of 194.3 weeks) | 
| Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | TEAEs were defined as adverse events (AEs) that started after the first dose of study medication was administered and within 30 days of the last administration of the study treatment or before start of subsequent anticancer treatment (whichever occurred first) or that worsened after the first dose of study medication was administered. | Cycle 1 Day 1 up to a maximum of 198.9 weeks |