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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04115956
Recruitment Status : Recruiting
First Posted : October 4, 2019
Last Update Posted : August 11, 2020
Sponsor:
Collaborator:
PRA Health Sciences
Information provided by (Responsible Party):
Oncopeptides AB

Tracking Information
First Submitted Date  ICMJE August 29, 2019
First Posted Date  ICMJE October 4, 2019
Last Update Posted Date August 11, 2020
Actual Study Start Date  ICMJE August 6, 2020
Estimated Primary Completion Date February 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 2, 2019)
  • 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
  • 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.
  • 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)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 4, 2019)
  • 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
  • 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))
  • 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))
  • 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
  • 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
  • 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
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: October 2, 2019)
  • To assess pharmacokinetic profile of melflufen in this patient population [ Time Frame: At Cycle 1 Day 1 and Cycle 2 Day 1, 5-10 min, 1-2 h and 3-8 h after end of infusion ]
    Melphalan plasma concentration post melflufen administration at 3 time points
  • 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))
  • 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))
  • 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
  • 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
  • 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
  • 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
  • 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Clinical Study of Melphalan Flufenamide (Melflufen) and Dexamethasone for Patients With Immunoglobulin Light Chain (AL) Amyloidosis
Official Title  ICMJE An Open-Label, Phase 1/2 Study of Melflufen and Dexamethasone for Patients With AL Amyloidosis Following at Least One Prior Line of Therapy
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.

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
Melflufen + Dexamethasone
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE AL Amyloidosis
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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.
Interventions:
  • Drug: Melphalan-Flufenamide (Melflufen)
  • Drug: Dexamethasone
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 2, 2019)
46
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 2024
Estimated Primary Completion Date February 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 involvment
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Head of Clinical Development +46 8 615 20 40 trials@oncopeptides.se
Contact: Clinical Operations Director +46 8 615 20 40 trials@oncopeptides.se
Listed Location Countries  ICMJE Czechia,   France,   Germany,   Greece,   Israel,   Italy,   Norway,   Poland,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04115956
Other Study ID Numbers  ICMJE OP201
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Oncopeptides AB
Study Sponsor  ICMJE Oncopeptides AB
Collaborators  ICMJE PRA Health Sciences
Investigators  ICMJE
Principal Investigator: Giovanni Palladini, MD University Hospital San Matteo in Pavia
PRS Account Oncopeptides AB
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP