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

An Open-Label, Phase 1/2 Study of Melflufen and Dexamethasone for Patients With AL Amyloidosis Following at Least One Prior Line of Therapy

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.

Study Overview

• Status: Terminated
• Conditions: AL Amyloidosis
• Intervention / Treatment: Drug: Melphalan-Flufenamide (Melflufen); Drug: Dexamethasone

Detailed Description

This is a clinical trial of melphalan flufenamide (melflufen), a peptide-conjugated alkylator which belongs to an novel class of drugs called peptidase-enhanced compounds, and targets the transformation process of tumor cells with a unique mechanism of action, as potential treatment option of AL amyloidosis.

AL amyloidosis is a rare progressive disease caused by proteotoxic light chain protein produced by small plasma cell clone. This plasma cell dyscrasia is characterized by monoclonal plasma cell's excessive production of monoclonal immunoglobulin light-chains that tends to misfold and subsequently deposit as amyloid fibrils in visceral organs. The plasma cell dyscrasia in AL amyloidosis is similar to that in multiple myeloma (MM) and therapies that are effective in MM are often used to treat AL amyloidosis.

Melphalan flufenamide is currently been evaluated in several ongoing clinical trials in patients with multiple myeloma, with observed efficacy. There are currently no therapies approved for treatment of AL amyloidosis and based on the efficacy of melphalan flufenamide and the demonstrated efficacy of melphalan (and other alkylators), it is anticipated that patients with AL amyloidosis may receive benefit from treatment with melphalan flufenamide.

This study consist of a screening period (up to 28 days), a treatment period (up to 8 cycles) and a follow-up period (up to 24 months).

Phase 1: Approximately 8-30 participants will be screened to achieve 7-23 enrolled participants.

Phase 2: Approximately 30 participants will be screened to achieve 23 enrolled participants.

The study was intended to be a Phase 1/2 trial but was early terminated and study never moved forward to Phase 2.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• Czechia
  • Ostrava - Poruba, Czechia, 70852
    • Fakultni nemocnice Ostrava
• France
  • Limoges, France, 87000
    • Centre Hospitalier Universitaire de Limoges
• Germany
  • Heidelberg, Germany, 69120
    • Universitätsklinikum Heidelberg
• Greece
  • Athen, Greece, 11528
    • Alexandra General Hospital of Athens
• Israel
  • Jerusalem, Israel, 9112001
    • Hadassah University Hospital Ein Kerem
• Norway
  • Oslo, Norway, 0372
    • Oslo University Hospital - Rikshospitalet
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic De Barcelona
• United Kingdom
  • London, United Kingdom, NW1 2BU
    • University College London Hospitals NHS Foundation Trust
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Boston University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria: (For full list of inclusion criteria, see study protocol)

• 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

Exclusion Criteria: (For full list of exclusion criteria, see study protocol)

• 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
• Prior major surgical procedure or radiation therapy within 4 weeks of the first dose of study treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Melflufen and dexamethasone in combination; 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); Treatment consist of i.v. melflufen on Day 1 of each 28-day cycle.; Drug: Dexamethasone; Dexamethasone 40 mg (20 mg at investigator's discretion) administered on Days 1 and 2 of each 28-day cycle.; Other Names: Dexamethason JENAPHARM

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess pharmacokinetic profile of melflufen in this patient population	Melphalan plasma concentration post melflufen administration at 3 time points	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	Proportion of patients with each outcome (Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), No Response (NR) or Progressive Disease (PD))	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	Median time (Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), No Response (NR) or Progressive Disease (PD))	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	Proportion of participants with kidney, cardiac or liver response, respectively	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	Duration of organ responses separately for each organ	Throughout the study treatment period of up to 8 cycles (approx 8 months) per patient
To assess hematologic ORR (overall response rate)	Proportion of participants who achieve a hematologic CR, VGPR or PR	During phase 1 for up to 8 cycles of treatment of 28 days each (approx. up to 8 months)
To assess time to next AL amyloidosis treatment	Time to next AL amyloidosis treatment	Throughout the study, covering up to 8 cycles (approx. 8 months) of treatment and 24 months of follow up
To assess Overall Survival (OS)	Overall survival	Throughout the study, covering up to 8 cycles (approx. 8 months) of treatment and up to 24 months of follow up

Collaborators and Investigators

• Sponsor: Oncopeptides AB
• Collaborators: PRA Health Sciences
• Investigators: Principal Investigator: Giovanni Palladini, MD, University Hospital San Matteo in Pavia

Study record dates

Study Major Dates

• Study Start (Actual): August 6, 2020
• Primary Completion (Actual): January 5, 2022
• Study Completion (Actual): January 5, 2022

Study Registration Dates

• First Submitted: August 29, 2019
• First Submitted That Met QC Criteria: October 2, 2019
• First Posted (Actual): October 4, 2019

Study Record Updates

• Last Update Posted (Actual): March 28, 2022
• Last Update Submitted That Met QC Criteria: March 10, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Paraproteinemias; Proteostasis Deficiencies; Neoplasms, Plasma Cell; Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dexamethasone; Melphalan
• Other Study ID Numbers: OP201

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No