PK of Melphalan During Treatment With Melflufen and Dexamethasone in Patients With RRMM and Impaired Renal Function

Study Overview
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Brief Summary
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This was a multicenter study of the pharmacokinetics (PK) of melphalan during treatment with melflufen and dexamethasone in patients with relapsed refractory multiple myeloma (RRMM) and impaired renal function.

Detailed Description
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This was a multicenter study assessing the safety, tolerability, and efficacy of melflufen given on Day 1 of a 28-day cycle, together with weekly dexamethasone, in patients with relapsed multiple myeloma or RRMM and impaired renal function, as well as the relationship between renal function and PK parameters for the active metabolite melphalan.

Official Title
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A Study of the Pharmacokinetics of Melphalan During Treatment With Melflufen and Dexamethasone in Patients With Relapsed Refractory Multiple Myeloma and Impaired Renal Function

Conditions
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Renal Impairment, 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, at the time of signing the informed consent; A prior diagnosis of multiple myeloma (MM) with documented disease progression in need of treatment at time of screening; Received at least 2 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; Eastern Cooperative Oncology Group (ECOG) performance status ≤2. (Patients with lower performance status based solely on bone pain secondary to MM 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; Renal function: Estimated glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula on 2 consecutive screening evaluations. Patients meeting criteria for Screening 1, must also meet criteria for Screening 2 following optimal hydration (as determined by the investigator). Screening 2 must be on or as close as possible to treatment start date (preferably <24-48 hours) but cannot exceed 72 hours. • Cohort 1 (a and b): Screening 1: eGFR between ≥25 mL/min/1.73m² to <45 mL/min/1.73m². Screening 2: eGFR between ≥30 mL/min/1.73m² to <45 mL/min/1.73m². • Cohort 2 (a and b): Screening 1: eGFR between ≥10 mL/min/1.73m² to <35 mL/min/1.73m². Screening 2: eGFR between ≥15 mL/min/1.73m² to <30 mL/min/1.73m². Cohort 2b will only be enrolled following approval of Data Safety Monitoring Committee (DSMC) after evaluating data from Cohort 1a, 1b and 2a. Patients with fluctuating values of eGFR may be eligible following consideration of additional assessments in consultation with the medical monitor. The following laboratory results must be met 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 higher in patients diagnosed with Gilbert's syndrome, that have been reviewed and approved by the medical monitor Aspartate transaminase / serum glutamic oxaloacetic transaminase (AST / SGOT) and alanine transaminase / serum glutamic pyruvic transaminase (ALT / SGPT) ≤3.0 x ULN; Must have, or be willing to have, an acceptable central catheter. (Port a cath, peripherally inserted central catheter [PICC] line, or central venous catheter). Footnote *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 ≥ minimal response [MR] to any prior therapy); Evidence of mucosal or internal bleeding and/or platelet transfusion refractory (platelet count fails to increase by >10,000 cells/mm³ [10.0 x 10⁹/L] after a 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 MM within 3 weeks (6 weeks for nitrosoureas) prior to initiation of therapy. The use of live vaccines within 30 days before initiation of therapy. Immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs) 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 2 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 study therapy (this does not include limited course of radiation used for management of bone pain to be completed within 7 days of initiation of study therapy). Plasmapheresis is not permitted within 14 days of initiation of therapy; Known intolerance to steroid therapy; Prior renal transplant; Currently in need of renal dialysis.

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
Interventional Model Description: Arms differed based on patients' level of renal function (moderate or severe impairment) and starting dose of melflufen.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1a<br>Patients with moderate renal impairment (eGFR ≥30 to <45 mL/min/1.73m²) and a starting dose of melflufen of 40 mg | Drug: Melflufen<br>* Melflufen was distributed in the European Union (EU) as a powder for concentrate for solution for infusion; in the US, it was distributed as a powder for injection. Melflufen was administered as a 30-minute intravenous infusion on Day 1 of every 28-day cycle via a central catheter.<br>* Other names: Melphalan flufenamide;Drug: Dexamethasone<br>* Tablets. Administered orally on Days 1, 8, 15, and 22 of each 28-day cycle. Dose of 40 mg for patients aged <75 years. Dose of 20 mg for patients aged ≥75 years.<br>|
| Experimental: Cohort 1b<br>Patients with moderate renal impairment (eGFR ≥30 to <45 mL/min/1.73m²) and a starting dose of melflufen of 30 mg | Drug: Melflufen<br>* Melflufen was distributed in the European Union (EU) as a powder for concentrate for solution for infusion; in the US, it was distributed as a powder for injection. Melflufen was administered as a 30-minute intravenous infusion on Day 1 of every 28-day cycle via a central catheter.<br>* Other names: Melphalan flufenamide;Drug: Dexamethasone<br>* Tablets. Administered orally on Days 1, 8, 15, and 22 of each 28-day cycle. Dose of 40 mg for patients aged <75 years. Dose of 20 mg for patients aged ≥75 years.<br>|
| Experimental: Cohort 2a<br>Patients with severe renal impairment (eGFR ≥15 to <30 mL/min/1.73m²) and a starting dose of melflufen of 20 mg | Drug: Melflufen<br>* Melflufen was distributed in the European Union (EU) as a powder for concentrate for solution for infusion; in the US, it was distributed as a powder for injection. Melflufen was administered as a 30-minute intravenous infusion on Day 1 of every 28-day cycle via a central catheter.<br>* Other names: Melphalan flufenamide;Drug: Dexamethasone<br>* Tablets. Administered orally on Days 1, 8, 15, and 22 of each 28-day cycle. Dose of 40 mg for patients aged <75 years. Dose of 20 mg for patients aged ≥75 years.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of Melphalan | Maximum observed concentration (Cmax) | Samples were drawn 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion. | 
| Tmax of Melphalan | Time of maximum observed concentration (Tmax) | Samples were drawn 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion. | 
| Area Under the Curve (0-t) of Melphalan | Area under the concentration-time curve (AUC) from 0h to the last measurable concentration. | Samples were drawn 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion. | 
| Area Under the Curve (Inf) of Melphalan | Area under the concentration-time curve (AUC) from 0 hours to infinity | Samples were drawn 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion. | 
| T1/2 of Melphalan | Elimination half-life of melphalan | Samples were drawn 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Confirmed Response | Best confirmed response required 2 consecutive assessments with the same response result made at any time. In case at the second consecutive assessment (made at any time) the response is higher than the previous one, then confirmed response (linked to the first assessment visit) will be the first one (e.g., PR - VGPR consecutive pair will lead to a PR confirmed response at the first visit). In case the second consecutive response is lower than the first one, then confirmed response (linked to the first assessment visit) will be the second one (e.g. CR-VGPR consecutive pair will lead to a VGPR confirmed response at the first visit). | Patients were assessed for response after each cycle. After discontinuation of therapy, patients continued to be assessed until documented progression (confirmed on 2 consecutive assessments) or initiation of subsequent therapy (max duration 127.1 weeks). | 
| Overall Response Rate | Overall response rate (ORR) is the percentage of patients who achieved a confirmed response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) as best response, as assessed by the Investigator. | Patients were assessed for response after each cycle. After discontinuation of therapy, patients continued to be assessed until disease progression (confirmed on 2 consecutive assessments) (maximum duration 127.1 weeks). | 
| Clinical Benefit Rate | Clinical benefit rate (CBR) is the proportion of patients who achieved a confirmed minimal response (MR) or better (stringent complete response [sCR], complete response [CR], very good partial response [VGPR], partial response [PR], and MR) as their best response, as assessed by the Investigator. | Patients were assessed for response after each cycle (maximum duration 127.1 weeks). | 
| Progression-free Survival | Progression-free survival (PFS) was defined as the time from the date of first study drug (the earliest of melflufen and dexamethasone start date) initiation to the date of first documentation of confirmed PD or death due to any cause, whichever occurred first. Participants were deemed 'progressed' in case of i) unconfirmed progressive disease (PD) as the final response assessment, ii) death after at least one response assessment or PD based on at least two consecutive response assessments at any time, or iii) death before the first response assessment. The distribution of PFS was summarized using the Kaplan-Meier (K-M) method. The median PFS was estimated from the 50th percentile of the corresponding K-M estimates. The 95% confidence interval for median PFS was constructed using the method of Brookmeyer (Brookmeyer, 1982). | Patients were assessed from the initiation of therapy until documented disease progression or initiation of new therapy (maximum duration 127.1 weeks). | 
| Duration of Response | Duration of response (DOR) is defined as the time from the first evidence of confirmed assessment of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) to first confirmed disease progression, or to death due to any cause. The distribution of DOR was summarized using the Kaplan-Meier (K-M) method. The median DOR was estimated from the 50th percentile of the corresponding K-M estimates. The 95% confidence interval for median DOR was constructed using the method of Brookmeyer (Brookmeyer, 1982). | Patients were assessed for response from the first measure of a confirmed response (PR or better) until confirmed progression, death, or initiation of subsequent therapy (maximum duration 127.1 weeks). | 
| Duration of Clinical Benefit | Duration of clinical benefit (DOCB) was calculated as time in months from the first evidence of confirmed assessment of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), or minimal response (MR) to first confirmed disease progression, or to death due to any cause. DOCB was defined only for patients with a confirmed MR or better. DOCB was summarized using the Kaplan-Meier (K-M) method. The median DOCB was estimated from the 50th percentile of the corresponding K-M estimates. The 95% confidence interval for median DOCB was constructed using the method of Brookmeyer (Brookmeyer, 1982). | Patients were assessed from the first measure of a confirmed MR or better until confirmed progression, death, or initiation of subsequent therapy (maximum duration 127.1 weeks). | 
| Time to Response | Time from first dose of therapy to first documented confirmed response of partial response (PR) or better. | From initiation of therapy until documented disease response (maximum duration 127.1 weeks). | 
| Time to Clinical Benefit | Time to clinical benefit was defined as the time from first dose of therapy to first documented confirmed response of minimal response (MR) or better. | Patients were assessed for response after each cycle. After discontinuation of therapy, patients continued to be assessed until documented progression (confirmed on 2 consecutive assessments) or initiation of subsequent therapy (max duration 127.1 weeks). | 
| Overall Survival | Overall survival was defined as the time in months from initiation of therapy to death due to any cause. Patients still alive at the end of the study, or lost to follow up, were censored at last day known alive. | Patients were followed for overall survival until death or until the last patient in the study had documented progression (confirmed on 2 consecutive assessments) or initiation of subsequent therapy (maximum of 39.2 months). |