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

NCT ID: NCT03639610

Last Updated: 2023-03-10

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 35 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-08-28
• Study Completion Date: 2021-12-22

Brief Summary

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

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.

Conditions

Renal Impairment; Multiple Myeloma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cohort 1a

Patients with moderate renal impairment (eGFR ≥30 to \<45 mL/min/1.73m²) and a starting dose of melflufen of 40 mg

Group Type: EXPERIMENTAL

Melflufen

Intervention Type: DRUG

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.

Dexamethasone

Intervention Type: DRUG

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.

Cohort 1b

Patients with moderate renal impairment (eGFR ≥30 to \<45 mL/min/1.73m²) and a starting dose of melflufen of 30 mg

Group Type: EXPERIMENTAL

Melflufen

Intervention Type: DRUG

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.

Dexamethasone

Intervention Type: DRUG

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.

Cohort 2a

Patients with severe renal impairment (eGFR ≥15 to \<30 mL/min/1.73m²) and a starting dose of melflufen of 20 mg

Group Type: EXPERIMENTAL

Melflufen

Intervention Type: DRUG

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.

Dexamethasone

Intervention Type: DRUG

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.

Interventions

Melflufen

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.

Intervention Type: DRUG

Dexamethasone

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.

Intervention Type: DRUG

Other Intervention Names

Melphalan flufenamide

Eligibility Criteria

Inclusion Criteria

1. Male or female, age 18 years or older, at the time of signing the informed consent;

2. A prior diagnosis of multiple myeloma (MM) with documented disease progression in need of treatment at time of screening;

3. Received at least 2 prior lines of therapy;

4. 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

5. Life expectancy of ≥6 months;

6. 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);

7. 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;

8. Ability to understand the purpose and risks of the study and provide signed and dated informed consent;

9. 12-lead electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of ≤470 msec;

10. 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.

11. 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;

12. 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

1. Primary refractory disease (i.e., never responded with ≥ minimal response [MR] to any prior therapy);

2. 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);

3. 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);

4. Known active infection requiring parenteral or oral anti-infective treatment within 14 days of initiation of therapy;

5. 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;

6. Pregnant or breast-feeding females;

7. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation;

8. Known human immunodeficiency virus or active hepatitis B or C viral infection;

9. Concurrent symptomatic amyloidosis or plasma cell leukemia;

10. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes);

11. 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;

12. 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);

13. Prior peripheral stem cell transplant within 12 weeks of initiation of therapy;

14. Prior allogeneic stem cell transplantation with active graft-versus-host-disease;

15. 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;

16. Known intolerance to steroid therapy;

17. Prior renal transplant;

18. Currently in need of renal dialysis.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Oncopeptides AB

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

University Hospital Brno, Clinic of Internal Medicine - Hematology and Oncology

Brno, , Czechia

University Hospital Olomouc, Clinic of Hemato-Oncology

Olomouc, , Czechia

General University Hospital in Prague, 1st Internal Clinic - Clinic of Hematology

Prague, , Czechia

General Hospital of Athens "Evangelismos"

Athens, , Greece

General Hospital of Athens Alexandra, Therapeutic Clinic

Athens, , Greece

University General Hospital of Patras

Pátrai, , Greece

Nasz Lekarz Medical Outpatient Clinics Slawomir Jeka

Torun, Torun, Poland

Maria Sklodowska-Curie Institute of Oncology, Branch in Gliwice, Department of Bone Marrow Transplantation and Hematologic Oncology

Gliwice, , Poland

Independent Public Healthcare Facility Municipal Hospitals, Department of Hematology

Katowice, , Poland

Independent Public Teaching Hospital No.1 in Lublin, Department of Hematooncology, Bone Marrow Transplantation and Chemotherapy

Lublin, , Poland

Countries

Czechia; Greece; Poland

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2018-000478-31

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

OP-107

Identifier Type: -

Identifier Source: org_study_id