A Clinical Study of Melphalan Flufenamide (Melflufen) and Dexamethasone for Patients With Immunoglobulin Light Chain (AL) Amyloidosis

NCT04115956 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: OP201
• Study Type: interventional
• Target: 6
• Locations: 9 countries
• Sites: 9

Brief Summary

This is a phase 1/2 open label study of melphalan flufenamide (melflufen) in combination with dexamethasone for participants with Al amyloidosis following at least one prior line of therapy. Melflufen will be administered on Day 1 of each 28-day cycle in combination with dexamethasone on days 1 and 2. In both phases, treatment of each individual participant will continue for up to 8 cycles or until any stopping events occur. Approximately 46 participants will be enrolled. The study was intended to be a Phase 1/2 trial but was early terminated and never moved forward to Phase 2.

Conditions

AL Amyloidosis

Outcome Measures

Primary Outcomes (3)

• The primary objective in Phase 1 is to explore safety and tolerability of melflufen

  Endpoints: * Frequency and grade of Adverse Events. The maximum grade for each type of AE will be recorded for each participant and frequency tables will be presented and reviewed to determine patterns * Laboratory values (laboratory abnormalities) for hematology, coagulation, blood chemistry, urinalysis

  During phase 1 for up to 8 cycles of treatment of 28 days each (approx. up to 8 months)

• The primary objective in Phase 1 is to identify recommended Phase 2 dose (RP2D)

  Endpoint: Dose-Limiting Toxicity (DLT) during Cycle 1 up to maximum dose of melflufen of 40 mg. A DLT event is defined as thrombocytopenia, neutropenia, non-hematologic toxicity and/or inability to receive Cycle 2 Day 1 dose within 14 days from planned Cycle 2 Day 2 due to continued melflufen-related toxicity from Cycle 1.

  During phase 1 for up to 8 cycles of 28 days each (approx. up to 8 months)

• The primary endpoint in Phase 2 is to evaluate the hematologic overall response rate (ORR) after 4 cycles at the RP2D determined in Phase 1

  The proportion of participants who achieve a hematologic Complete Response (CR), Very Good Partial Response (VGPR) or Partial Response (PR)

  During phase 2 after 4 cycles of treatment ( approx. 4 months)

Secondary Outcomes (8)

• To assess pharmacokinetic profile of melflufen in this patient population

  At Cycle 1 Day 1 and Cycle 2 Day 1 at time points 5-10 minutes, 1-2 hours and 3-8 hours after end of infusion. Each cycle length is 28 days.

• To assess best hematologic response

  Throughout the study treatment of up to 8 cycles of 28 days each (approx. 8 months) per patient

• To assess the duration of hematologic response

  Throughout the study treatment period of up to 8 cycles of 28 days each (approx 8 months) per patient

• To assess the proportion of organ system responses

  Throughout the study treatment period of up to 8 cycles of 28 days each (approx 8 months) per patient

• To assess duration of organ system responses

  Throughout the study treatment period of up to 8 cycles (approx 8 months) per patient

Study Arms (1)

Melflufen and dexamethasone in combination

EXPERIMENTAL

Intravenous infusion of melflufen Day 1 of 28 day cycles, in combination of dexamethasone on Days 1 and 2 of each 28-day cycle.

Drug: Melphalan-Flufenamide (Melflufen); Drug: Dexamethasone

Interventions

Melphalan-Flufenamide (Melflufen) DRUG

Treatment consist of i.v. melflufen on Day 1 of each 28-day cycle.

Melflufen and dexamethasone in combination

Dexamethasone DRUG

Dexamethasone 40 mg (20 mg at investigator's discretion) administered on Days 1 and 2 of each 28-day cycle.

Also known as: Dexamethason JENAPHARM

Melflufen and dexamethasone in combination

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
• Proven histochemical diagnosis of AL amyloidosis based on tissue specimens with Congo red staining
• At least one prior line of therapy, defined as either one non-transplant regimen, one ASCT (autologous stem cell transplantation), or one regimen of induction therapy followed by a single ASCT. No more that 4 cycles of melphalan containing chemotherapy is allowed.
• Measurable hematologic disease
• Objectively measurable organ amyloid involvement
• ECOG performance status ≤ 2 (ECOG = Eastern cooperative oncology group)
• Women of child bearing potential must have a negative serum or urine pregnancy test
• Less than 30% plasma cells in bone marrow aspirate or biopsy
• Acceptable laboratory results met (absolute neutrophil count (ANC), platelet count, hemoglobin, total bilirubin,alkaline phosphatase, AST (aspartate aminotransferase) and ALT (alanine aminotransferase), renal function)
• Male participant agrees to use contraception during treatment and 90 days after last dose of melflufen

You may not qualify if:

• Amyloidosis due to known mutations of the transthyretin gene or presence of another non-AL amyloidosis
• Evidence of gastro-intestinal bleeding
• Cardiac risk stage 3
• Low platelets value with evidence of mucosal or internal bleeding
• Medical documented cardiac syncope, NYHA Class 3 or 4 congestive heart failure, myocardial infarction, unstable angina pectoris, clinically significant ventricular arrhythmias (NYHA=New York Heart Association Functional Classification)
• Clinically significant finding on 24 h Holter recording
• Severe orthostatic hypotension
• Clinically significant factor X deficiency
• Clinically significant autonomic disease
• Any medical condition that would impose excessive risk to the patient
• Serious psychiatric illness, active alcoholism or drug addiction that may hinder or confuse compliance
• Known HIV or active hepatitis B or C viral infections
• Previous cytotoxic therapies, including cytotoxic investigational agents within 3 weeks prior to start of study treatment. Monoclonal antibodies within 4 weeks. Concomitant immunotherapy, investigational therapy and anticoagulation therapy are not permitted
• Prior autologous or allogenic stem cell transplant within 12 weeks of initiation of therapy
• Prior allogeneic stem cell transplant with active graft-host-disease

Sponsors & Collaborators

• Oncopeptides AB: lead
• PRA Health Sciences: collaborator

Study Sites (9)

Boston University Medical Center

Boston, Massachusetts, 02111, United States

Location

Fakultní Nemocnice Ostrava

Ostrava - Poruba, 70852, Czechia

Location

Centre Hospitalier Universitaire de Limoges

Limoges, 87000, France

Location

Universitätsklinikum Heidelberg

Heidelberg, 69120, Germany

Location

Alexandra General Hospital of Athens

Athens, 11528, Greece

Location

Hadassah University Hospital Ein Kerem

Jerusalem, 9112001, Israel

Location

Oslo University Hospital - Rikshospitalet

Oslo, 0372, Norway

Location

Hospital Clinic de Barcelona

Barcelona, 08036, Spain

Location

University College London Hospitals NHS Foundation Trust

London, NW1 2BU, United Kingdom

Location

MeSH Terms

Conditions

Immunoglobulin Light-chain Amyloidosis

Interventions

melflufen; Dexamethasone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Amyloidosis; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Paraproteinemias

Intervention Hierarchy (Ancestors)

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

Study Officials

• Giovanni Palladini, MD

  University Hospital San Matteo in Pavia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Melflufen + Dexamethasone

Study Record Dates

• First Submitted: August 29, 2019
• First Posted: October 4, 2019
• Study Start: August 6, 2020
• Primary Completion: January 5, 2022
• Study Completion: January 5, 2022
• Last Updated: March 28, 2022

Record last verified: 2022-02

Locations

FR (1); GB (1); US (1); DE (1); ES (1); GR (1); NO (1); CZ (1); IL (1)