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

Primary Purpose

AL Amyloidosis

Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Melphalan-Flufenamide (Melflufen)
Dexamethasone
Sponsored by
Oncopeptides AB
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for AL Amyloidosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Boston University Medical Center
  • Fakultní Nemocnice Ostrava
  • Centre Hospitalier Universitaire de Limoges
  • Universitätsklinikum Heidelberg
  • Alexandra General Hospital of Athens
  • Hadassah University Hospital Ein Kerem
  • Oslo University Hospital - Rikshospitalet
  • Hospital Clinic de Barcelona
  • University College London Hospitals NHS Foundation Trust

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Melflufen and dexamethasone in combination

Arm Description

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

Outcomes

Primary Outcome Measures

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
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.
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)

Secondary Outcome Measures

To assess pharmacokinetic profile of melflufen in this patient population
Melphalan plasma concentration post melflufen administration at 3 time points
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))
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))
To assess the proportion of organ system responses
Proportion of participants with kidney, cardiac or liver response, respectively
To assess duration of organ system responses
Duration of organ responses separately for each organ
To assess hematologic ORR (overall response rate)
Proportion of participants who achieve a hematologic CR, VGPR or PR
To assess time to next AL amyloidosis treatment
Time to next AL amyloidosis treatment
To assess Overall Survival (OS)
Overall survival

Full Information

First Posted
August 29, 2019
Last Updated
March 10, 2022
Sponsor
Oncopeptides AB
Collaborators
PRA Health Sciences
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1. Study Identification

Unique Protocol Identification Number
NCT04115956
Brief Title
A Clinical Study of Melphalan Flufenamide (Melflufen) and Dexamethasone for Patients With Immunoglobulin Light Chain (AL) Amyloidosis
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
Study Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Terminated
Why Stopped
The sponsor decided to terminate the study following an FDA request of a partial clinical hold.
Study Start Date
August 6, 2020 (Actual)
Primary Completion Date
January 5, 2022 (Actual)
Study Completion Date
January 5, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Oncopeptides AB
Collaborators
PRA Health Sciences

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
AL Amyloidosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Model Description
Melflufen + Dexamethasone
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Melflufen and dexamethasone in combination
Arm Type
Experimental
Arm Description
Intravenous infusion of melflufen Day 1 of 28 day cycles, in combination of dexamethasone on Days 1 and 2 of each 28-day cycle.
Intervention Type
Drug
Intervention Name(s)
Melphalan-Flufenamide (Melflufen)
Intervention Description
Treatment consist of i.v. melflufen on Day 1 of each 28-day cycle.
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Other Intervention Name(s)
Dexamethason JENAPHARM
Intervention Description
Dexamethasone 40 mg (20 mg at investigator's discretion) administered on Days 1 and 2 of each 28-day cycle.
Primary Outcome Measure Information:
Title
The primary objective in Phase 1 is to explore safety and tolerability of melflufen
Description
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
Time Frame
During phase 1 for up to 8 cycles of treatment of 28 days each (approx. up to 8 months)
Title
The primary objective in Phase 1 is to identify recommended Phase 2 dose (RP2D)
Description
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.
Time Frame
During phase 1 for up to 8 cycles of 28 days each (approx. up to 8 months)
Title
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
Description
The proportion of participants who achieve a hematologic Complete Response (CR), Very Good Partial Response (VGPR) or Partial Response (PR)
Time Frame
During phase 2 after 4 cycles of treatment ( approx. 4 months)
Secondary Outcome Measure Information:
Title
To assess pharmacokinetic profile of melflufen in this patient population
Description
Melphalan plasma concentration post melflufen administration at 3 time points
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.
Title
To assess best hematologic response
Description
Proportion of patients with each outcome (Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), No Response (NR) or Progressive Disease (PD))
Time Frame
Throughout the study treatment of up to 8 cycles of 28 days each (approx. 8 months) per patient
Title
To assess the duration of hematologic response
Description
Median time (Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), No Response (NR) or Progressive Disease (PD))
Time Frame
Throughout the study treatment period of up to 8 cycles of 28 days each (approx 8 months) per patient
Title
To assess the proportion of organ system responses
Description
Proportion of participants with kidney, cardiac or liver response, respectively
Time Frame
Throughout the study treatment period of up to 8 cycles of 28 days each (approx 8 months) per patient
Title
To assess duration of organ system responses
Description
Duration of organ responses separately for each organ
Time Frame
Throughout the study treatment period of up to 8 cycles (approx 8 months) per patient
Title
To assess hematologic ORR (overall response rate)
Description
Proportion of participants who achieve a hematologic CR, VGPR or PR
Time Frame
During phase 1 for up to 8 cycles of treatment of 28 days each (approx. up to 8 months)
Title
To assess time to next AL amyloidosis treatment
Description
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
Title
To assess Overall Survival (OS)
Description
Overall survival
Time Frame
Throughout the study, covering up to 8 cycles (approx. 8 months) of treatment and up to 24 months of follow up

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Giovanni Palladini, MD
Organizational Affiliation
University Hospital San Matteo in Pavia
Official's Role
Principal Investigator
Facility Information:
Facility Name
Boston University Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02111
Country
United States
Facility Name
Fakultní Nemocnice Ostrava
City
Ostrava - Poruba
ZIP/Postal Code
70852
Country
Czechia
Facility Name
Centre Hospitalier Universitaire de Limoges
City
Limoges
ZIP/Postal Code
87000
Country
France
Facility Name
Universitätsklinikum Heidelberg
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
Facility Name
Alexandra General Hospital of Athens
City
Athen
ZIP/Postal Code
11528
Country
Greece
Facility Name
Hadassah University Hospital Ein Kerem
City
Jerusalem
ZIP/Postal Code
9112001
Country
Israel
Facility Name
Oslo University Hospital - Rikshospitalet
City
Oslo
ZIP/Postal Code
0372
Country
Norway
Facility Name
Hospital Clinic de Barcelona
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
University College London Hospitals NHS Foundation Trust
City
London
ZIP/Postal Code
NW1 2BU
Country
United Kingdom

12. IPD Sharing Statement

Learn more about this trial

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

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