CLINICAL TRIALS PROFILE FOR MELPHALAN FLUFENAMIDE HYDROCHLORIDE

All Clinical Trials for Melphalan Flufenamide Hydrochloride

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT01897714 ↗	Safety and Efficacy of Melflufen and Dexamethasone in Relapsed and/or Relapsed-Refractory Multiple Myeloma Patients	Terminated	Oncopeptides AB	Phase 1/Phase 2	2013-07-01	The study will explore escalating doses of melflufen in combination with dexamethasone in small groups of patients to find the maximum tolerated dose of melflufen. That dose will then be used to determine the efficacy and safety profile of melflufen in combination with dexamethasone in a larger group of patients.
NCT02963493 ↗	A Study of Melphalan Flufenamide (Melflufen) in Combination With Dexamethasone in Relapsed Refractory Multiple Myeloma Patients	Active, not recruiting	Precision For Medicine	Phase 2	2016-12-28	This study will evaluate melflufen in combination with dexamethasone in the treatment of relapsed refractory multiple myeloma in adult patients with disease refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. All patients in the study will be treated with melflufen on Day 1 and dexamethasone on Days 1, 8, 15 and 22 of each 28-day cycle.
NCT02963493 ↗	A Study of Melphalan Flufenamide (Melflufen) in Combination With Dexamethasone in Relapsed Refractory Multiple Myeloma Patients	Active, not recruiting	Precision Oncology	Phase 2	2016-12-28	This study will evaluate melflufen in combination with dexamethasone in the treatment of relapsed refractory multiple myeloma in adult patients with disease refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. All patients in the study will be treated with melflufen on Day 1 and dexamethasone on Days 1, 8, 15 and 22 of each 28-day cycle.
NCT02963493 ↗	A Study of Melphalan Flufenamide (Melflufen) in Combination With Dexamethasone in Relapsed Refractory Multiple Myeloma Patients	Active, not recruiting	Oncopeptides AB	Phase 2	2016-12-28	This study will evaluate melflufen in combination with dexamethasone in the treatment of relapsed refractory multiple myeloma in adult patients with disease refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. All patients in the study will be treated with melflufen on Day 1 and dexamethasone on Days 1, 8, 15 and 22 of each 28-day cycle.
NCT03151811 ↗	A Study of Melphalan Flufenamide (Melflufen)-Dex or Pomalidomide-dex for RRMM Patients Refractory to Lenalidomide	Active, not recruiting	Oncopeptides AB	Phase 3	2017-06-12	This is a randomized, controlled, open-label, Phase 3 multicenter study which will enroll patients with RRMM following 2-4 lines of prior therapy and who are refractory to lenalidomide in the last line of therapy as demonstrated by disease progression on or within 60 days of completion of the last dose of lenalidomide. Patients will receive either melflufen+dex or pomalidomide+dex.
NCT03481556 ↗	Study of Melphalan Flufenamide (Melflufen) + Dex With Bortezomib or Daratumumab in Patients With RRMM	Active, not recruiting	Oncopeptides AB	Phase 1/Phase 2	2018-04-16	This is an open-label Phase 1/2a study which will enroll patients that have relapsed or relapsed-refractory multiple myeloma following 1-4 lines of prior therapy. Patients will receive either melflufen+dexamethasone+bortezomib or melflufen+dexamethasone+daratumumab and are required to be IMiD refractory to be enrolled to the bortezomib regimen, and to not have any prior exposure to daratumumab or other antiCD-38 mAb to be enrolled to the daratumumab regimen.
NCT03639610 ↗	A PK Study of Melphalan During Treatment With Melphalan Flufenamide (Melflufen) and Dex in RRMM Pat With Impaired Renal Function	Active, not recruiting	Oncopeptides AB	Phase 2	2018-08-06	This is a multicenter, PK study of Melphalan during treatment with Melflufen and Dexamethasone in patients with RRMM and impaired renal function. Received 2 - 4 prior lines of therapy and a renal function (creatinine clearance by Cockcroft-Gault formula) between ≥30 mL/min to <45 mL/min in Cohort 1,and ≥15 mL/min to <30 mL/min in Cohort 2.

Clinical Trial Conditions for Melphalan Flufenamide Hydrochloride

Condition Name

Condition Name for Melphalan Flufenamide Hydrochloride
Intervention	Trials
Multiple Myeloma	4
RRMM	2
Relapsed and/or Relapsed-refractory Multiple Myeloma	1
Renal Impairment	1

Condition MeSH

Condition MeSH for Melphalan Flufenamide Hydrochloride
Intervention	Trials
Neoplasms, Plasma Cell	5
Multiple Myeloma	5
Immunoglobulin Light-chain Amyloidosis	1
Amyloidosis	1

Clinical Trial Locations for Melphalan Flufenamide Hydrochloride

Trials by Country

Trials by Country for Melphalan Flufenamide Hydrochloride
Location	Trials
United States	37
Czechia	6
Poland	5
Spain	5
France	4

Trials by US State

Trials by US State for Melphalan Flufenamide Hydrochloride
Location	Trials
Massachusetts	5
Ohio	4
California	4
New York	3
Florida	3

Clinical Trial Progress for Melphalan Flufenamide Hydrochloride

Clinical Trial Phase

Clinical Trial Phase for Melphalan Flufenamide Hydrochloride
Clinical Trial Phase	Trials
Phase 3	2
Phase 2	3
Phase 1/Phase 2	3

Clinical Trial Status

Clinical Trial Status for Melphalan Flufenamide Hydrochloride
Clinical Trial Phase	Trials
Active, not recruiting	7
Terminated	1

Clinical Trial Sponsors for Melphalan Flufenamide Hydrochloride

Sponsor Name

Sponsor Name for Melphalan Flufenamide Hydrochloride
Sponsor	Trials
Oncopeptides AB	8
Precision Oncology	1
PRA Health Sciences	1

Sponsor Type

Sponsor Type for Melphalan Flufenamide Hydrochloride
Sponsor	Trials
Industry	10
Other	1

Melphalan Flufenamide: A Comprehensive Review of Clinical Trials, Market Analysis, and Projections

Introduction

Melphalan flufenamide, marketed under the brand names Pepaxto and Pepaxti, is a peptide-conjugated alkylating agent designed to treat relapsed or refractory multiple myeloma. Here, we delve into the clinical trials, market analysis, and the current projections for this drug.

Clinical Trials and Approval History

Accelerated Approval

Melphalan flufenamide received accelerated approval from the FDA on February 26, 2021, for use in combination with dexamethasone in adult patients with relapsed or refractory multiple myeloma. This approval was based on the results of the single-arm, multicenter phase 2 HORIZON trial (NCT02963493), which showed an objective response rate (ORR) of 23.7% and a median duration of response of 4.2 months in a population that had received at least four prior lines of therapy and were refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one CD38-directed monoclonal antibody[1][4][5].

Confirmatory Trials

The accelerated approval was contingent upon the completion of a confirmatory trial, the OCEAN trial (NCT03151811), a randomized phase 3 study comparing melphalan flufenamide with dexamethasone to pomalidomide with dexamethasone. However, the OCEAN trial failed to confirm the clinical benefit of melphalan flufenamide. The trial showed no improvement in overall survival and progression-free survival, and it highlighted significant safety concerns, including higher rates of adverse events and dose modifications in the melphalan flufenamide arm[1][3][4].

FDA Decision to Withdraw Approval

Based on the disappointing results of the OCEAN trial, the FDA requested the withdrawal of melphalan flufenamide's US marketing authorization in December 2022. On February 23, 2024, the FDA confirmed its decision to withdraw the approval, citing the failure of the confirmatory trial to demonstrate clinical benefit and the lack of evidence showing the drug's safety and effectiveness under its conditions of use[1][4].

Mechanism of Action and Pharmacology

Melphalan flufenamide is a prodrug of melphalan, designed to be more readily taken up by cells due to its lipophilic nature. It is hydrolyzed by aminopeptidases, which are upregulated in many malignant cells, leading to increased concentrations of free melphalan within these cells. This results in rapid irreversible DNA damage and apoptosis, making it a potent agent against multiple myeloma cells, even those resistant to conventional melphalan[2][5].

Safety and Adverse Events

The clinical trials highlighted several safety concerns associated with melphalan flufenamide. Common adverse reactions included fatigue, nausea, diarrhea, pyrexia, and respiratory tract infections. Significant laboratory abnormalities were also observed, such as decreased leukocytes, platelets, lymphocytes, neutrophils, and hemoglobin, along with increased creatinine levels. The OCEAN trial further emphasized the high rates of Grade 3 and higher treatment-emergent adverse events and the need for frequent dose modifications and discontinuations[1][3][4].

Market Analysis

The withdrawal of melphalan flufenamide from the US market has significant implications for the treatment landscape of relapsed or refractory multiple myeloma. Patients who were benefiting from this drug will need to be transitioned to alternative therapies, which could include other approved agents like pomalidomide, daratumumab, or carfilzomib.

Impact on Patient Care

The loss of melphalan flufenamide as a treatment option reduces the arsenal of therapies available for a patient population that has limited treatment choices. This underscores the need for continuous innovation and the development of new therapeutic agents that can offer improved efficacy and safety profiles.

Economic Implications

The withdrawal also has economic implications for Oncopeptides AB, the manufacturer of melphalan flufenamide. The company had invested significantly in the development and marketing of this drug, and the withdrawal will likely result in substantial financial losses.

Projections and Future Outlook

Given the FDA's decision to withdraw approval, the future of melphalan flufenamide in the treatment of multiple myeloma appears bleak. Here are some key projections:

Alternative Therapies

The focus will shift to other approved therapies for relapsed or refractory multiple myeloma. Researchers and clinicians will continue to explore combination regimens and novel agents that can offer better outcomes for patients.

Ongoing Research

While melphalan flufenamide itself may not be viable, research into peptide-conjugated alkylating agents and other targeted delivery mechanisms will continue. These approaches hold promise for improving the efficacy and safety of cancer treatments.

Regulatory Lessons

The case of melphalan flufenamide highlights the importance of rigorous confirmatory trials in validating the clinical benefit of drugs granted accelerated approval. Regulatory agencies will likely scrutinize future applications more closely, ensuring that only drugs with robust evidence of safety and efficacy reach the market.

Key Takeaways

• Accelerated Approval and Withdrawal: Melphalan flufenamide received accelerated approval in 2021 but was withdrawn in 2024 due to the failure of the confirmatory OCEAN trial to demonstrate clinical benefit.
• Clinical Trials: The HORIZON trial showed initial promise, but the OCEAN trial revealed significant safety concerns and lack of efficacy.
• Mechanism of Action: Melphalan flufenamide is a prodrug of melphalan with enhanced cellular uptake and potency.
• Safety Concerns: High rates of adverse events and dose modifications were observed in clinical trials.
• Market Impact: The withdrawal reduces treatment options for relapsed or refractory multiple myeloma patients and has economic implications for the manufacturer.

FAQs

What was the basis for the FDA's decision to withdraw melphalan flufenamide's approval?

The FDA decided to withdraw the approval because the confirmatory OCEAN trial did not confirm the clinical benefit of melphalan flufenamide, and the available evidence showed that the drug was not safe or effective under its conditions of use[1][4].

What were the key findings of the OCEAN trial?

The OCEAN trial showed no improvement in overall survival and progression-free survival, and it highlighted significant safety concerns, including higher rates of adverse events and dose modifications in the melphalan flufenamide arm[1][3][4].

How does melphalan flufenamide work?

Melphalan flufenamide is a prodrug of melphalan that is more readily taken up by cells due to its lipophilic nature. It is hydrolyzed by aminopeptidases, leading to increased concentrations of free melphalan within malignant cells, causing DNA damage and apoptosis[2][5].

What are the common adverse reactions associated with melphalan flufenamide?

Common adverse reactions include fatigue, nausea, diarrhea, pyrexia, and respiratory tract infections. Significant laboratory abnormalities such as decreased leukocytes, platelets, lymphocytes, neutrophils, and hemoglobin, along with increased creatinine levels, were also observed[1][3][4].

What are the implications of the withdrawal for patient care?

The withdrawal reduces the treatment options for patients with relapsed or refractory multiple myeloma, necessitating the transition to alternative therapies. This underscores the need for continuous innovation in developing new therapeutic agents[1][4].

What is the future outlook for melphalan flufenamide?

Given the FDA's decision to withdraw approval, the future of melphalan flufenamide in treating multiple myeloma appears bleak. Research will continue into other targeted delivery mechanisms and novel agents[1][4].

Sources

1. FDA Confirms Decision to Withdraw Melphalan Flufenamide Approval in Multiple Myeloma. Onclive.
2. Melphalan flufenamide: Uses, Interactions, Mechanism of Action. DrugBank.
3. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA.
4. FDA grants accelerated approval to melphalan flufenamide for relapsed or refractory multiple myeloma. FDA.
5. Melphalan flufenamide. Wikipedia.