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

• ClinicalTrials.gov Identifier: NCT04115956
• Recruitment Status: Terminated
• First Posted: October 4, 2019
• Last Update Posted: March 28, 2022
• Sponsor: Oncopeptides AB
• Collaborator: PRA Health Sciences
• Information provided by (Responsible Party): Oncopeptides AB

Study Description

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.

Condition or disease	Intervention/treatment	Phase
AL Amyloidosis	Drug: Melphalan-Flufenamide (Melflufen); Drug: Dexamethasone	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Melflufen + Dexamethasone
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Phase 1/2 Study of Melflufen and Dexamethasone for Patients With AL Amyloidosis Following at Least One Prior Line of Therapy
• Actual Study Start Date: August 6, 2020
• Actual Primary Completion Date: January 5, 2022
• Actual Study Completion Date: January 5, 2022

Arms and Interventions

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 Name: Dexamethason JENAPHARM

Outcome Measures

Primary Outcome Measures :

1. The primary objective in Phase 1 is to explore safety and tolerability of melflufen [ Time Frame: During phase 1 for up to 8 cycles of treatment of 28 days each (approx. up to 8 months) ]

   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
2. The primary objective in Phase 1 is to identify recommended Phase 2 dose (RP2D) [ Time Frame: During phase 1 for up to 8 cycles of 28 days each (approx. up to 8 months) ]
   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.
3. 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 [ Time Frame: During phase 2 after 4 cycles of treatment ( approx. 4 months) ]
   The proportion of participants who achieve a hematologic Complete Response (CR), Very Good Partial Response (VGPR) or Partial Response (PR)

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Massachusetts

Boston University Medical Center

Boston, Massachusetts, United States, 02111

Czechia

Fakultní Nemocnice Ostrava

Ostrava - Poruba, Czechia, 70852

France

Centre Hospitalier Universitaire de Limoges

Limoges, France, 87000

Germany

Universitätsklinikum Heidelberg

Heidelberg, Germany, 69120

Greece

Alexandra General Hospital of Athens

Athen, Greece, 11528

Israel

Hadassah University Hospital Ein Kerem

Jerusalem, Israel, 9112001

Norway

Oslo University Hospital - Rikshospitalet

Oslo, Norway, 0372

Spain

Hospital Clinic de Barcelona

Barcelona, Spain, 08036

United Kingdom

University College London Hospitals NHS Foundation Trust

London, United Kingdom, NW1 2BU

Sponsors and Collaborators

Oncopeptides AB

PRA Health Sciences

Investigators

• Principal Investigator: Giovanni Palladini, MD; University Hospital San Matteo in Pavia

More Information

• Responsible Party: Oncopeptides AB
• ClinicalTrials.gov Identifier: NCT04115956
• Other Study ID Numbers: OP201
• First Posted: October 4, 2019
• Last Update Posted: March 28, 2022
• Last Verified: February 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

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