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

NCT03639610 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: OP-1072018-000478-31
• Study Type: interventional
• Target: 35
• Locations: 3 countries
• Sites: 10

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.

Conditions

Renal Impairment; Multiple Myeloma

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (9)

• Best Confirmed Response

  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

  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

  Patients were assessed for response after each cycle (maximum duration 127.1 weeks).

• Progression-free Survival

  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

  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).

Study Arms (3)

Cohort 1a

EXPERIMENTAL

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

Drug: Melflufen; Drug: Dexamethasone

Cohort 1b

EXPERIMENTAL

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

Drug: Melflufen; Drug: Dexamethasone

Cohort 2a

EXPERIMENTAL

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

Drug: Melflufen; Drug: Dexamethasone

Interventions

Melflufen 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.

Also known as: Melphalan flufenamide

Cohort 1a; Cohort 1b; Cohort 2a

Dexamethasone 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 1a; Cohort 1b; Cohort 2a

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;
• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• Oncopeptides AB: lead

Study Sites (10)

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

Brno, Czechia

Location

University Hospital Olomouc, Clinic of Hemato-Oncology

Olomouc, Czechia

Location

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

Prague, Czechia

Location

General Hospital of Athens "Evangelismos"

Athens, Greece

Location

General Hospital of Athens Alexandra, Therapeutic Clinic

Athens, Greece

Location

University General Hospital of Patras

Pátrai, Greece

Location

Nasz Lekarz Medical Outpatient Clinics Slawomir Jeka

Torun, Torun, Poland

Location

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

Gliwice, Poland

Location

Independent Public Healthcare Facility Municipal Hospitals, Department of Hematology

Katowice, Poland

Location

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

Lublin, Poland

Location

MeSH Terms

Conditions

Renal Insufficiency; Multiple Myeloma

Interventions

melflufen; L-melphalanyl-p-L-fluorophenylalanine ethyl ester; Dexamethasone

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Limitations and Caveats

Between-group comparisons were not performed in this study due the small number of patients in each cohort, as well as differences with regards to some baseline characteristics.

Results Point of Contact

• Title: VP Chief Operating Officer
• Organization: Oncopeptides AB

trials@oncopeptides.com

+46 8 615 20 40

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Arms differed based on patients' level of renal function (moderate or severe impairment) and starting dose of melflufen.

Study Record Dates

• First Submitted: August 14, 2018
• First Posted: August 21, 2018
• Study Start: August 28, 2018
• Primary Completion: December 22, 2021
• Study Completion: December 22, 2021
• Last Updated: March 10, 2023
• Results First Posted: March 9, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

PL (4); GR (3); CZ (3)