A Study of Melphalan Flufenamide (Melflufen) Plus Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

NCT ID: NCT02963493

Last Updated: 2022-11-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 157 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-12-28
• Study Completion Date: 2021-11-16

Brief Summary

This study will evaluate melflufen in combination with dexamethasone in adult patients with relapsed or refractory multiple myeloma in whose disease is 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.

Detailed Description

Melphalan flufenamide (melflufen) is a peptide-drug conjugate that rapidly delivers an alkylating payload into tumor cells. Peptidases are expressed in several cancers, including solid tumors and hematologic malignancies. Melphalan flufenamide is rapidly taken up by myeloma cells due to its high lipophilicity. Once inside the myeloma cell, the activity of melphalan flufenamide is determined by its immediate cleavage by peptidases into hydrophilic alkylator payloads that are entrapped. Melphalan flufenamide is 50-fold more potent than melphalan in myeloma cells in vitro due to increased intracellular alkylator concentration. It rapidly induces irreversible DNA damage leading to apoptosis of myeloma cells. Melphalan flufenamide displays cytotoxic activity against myeloma cell lines resistant to other treatments, including alkylators, in vitro. Melphalan flufenamide also has demonstrated inhibition of angiogenesis and DNA damage with a lack of functional DNA repair in preclinical studies.

Conditions

Multiple Myeloma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

melphalan flufenamide (melflufen) + dexamethasone

Melphalan flufenamide (melflufen) 40 mg Day 1 and dexamethasone 40 mg (20 mg for patients 75 years or older) on Days 1, 8, 15 and 22 of each 28-day cycle.

Group Type: EXPERIMENTAL

Melphalan flufenamide (Melflufen)

Intervention Type: DRUG

Dexamethasone

Intervention Type: DRUG

IV dexamethasone may be substituted for oral dexamethasone in the US. Oral only in Europe.

Interventions

Melphalan flufenamide (Melflufen)

Intervention Type: DRUG

Dexamethasone

IV dexamethasone may be substituted for oral dexamethasone in the US. Oral only in Europe.

Intervention Type: DRUG

Other Intervention Names

Pepaxto

Eligibility Criteria

Inclusion Criteria

• Male or female, age 18 years or older
• A prior diagnosis of multiple myeloma with documented disease progression
• Measurable disease based on either of a) serum monoclonal protein by protein electrophoresis (SPEP), b) monoclonal protein in the urine on 24-hour urine electrophoresis (UPEP), and/or c) serum immunoglobulin free light chain combined with abnormal serum immunoglobulin kappa to lambda free light chain ratio
• A minimum of 2 prior lines of therapy including an IMiD and a PI and is refractory to pomalidomide and/or daratumumab
• Life expectancy of ≥ 6 months
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Female of child bearing potential (FCBP) and non-vasectomized male agree to practice appropriate methods of birth control
• Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information
• 12-lead ECG with QTc interval within defined limit
• Acceptable laboratory results during screening and prior to first study drug administration of the following parameters: absolute neutrophil count (ANC), platelet count, hemoglobin, total bilirubin, aspartate transaminase (AST/SGOT) and alanine transaminase (ALT/SGPT), renal function based on estimated creatinine clearance
• Must have, or accept to have, an acceptable central catheter for infusion of melflufen

Exclusion Criteria

• Evidence of mucosal or internal bleeding and/or is platelet transfusion refractory
• Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study
• Known active infection requiring parenteral or oral anti-infective treatment within defined period
• Primary refractory disease
• Other malignancy diagnosed or requiring treatment within the defined period with specific exceptions
• Pregnant or breast-feeding females
• Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation
• Known HIV or active hepatitis B or C viral infection
• Concurrent symptomatic amyloidosis or plasma cell leukemia
• POEMS syndrome [plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes]
• Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within defined values prior to start of study treatment
• Residual side effects to previous therapy over specific grade prior to initiation of therapy
• Prior autologous or allogeneic stem cell transplant within defined period of initiation of therapy
• Prior allogeneic stem cell transplant with active graft-versus-host- disease (GVHD).
• Prior major surgical procedure or radiation therapy within specified period of the first dose of study treatment (with defined exception).
• Known intolerance to steroid therapy

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Precision For Medicine

INDUSTRY

Sponsor Role: collaborator

Oncopeptides AB

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Johan Harmenberg, MD, PhD

Role: STUDY_CHAIR

Oncopeptides AB

Locations

Innovative Clinical Research Institute (ICRI)

Whittier, California, United States

University of Florida

Gainesville, Florida, United States

RUSH

Chicago, Illinois, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Karmanos Cancer Center

Detroit, Michigan, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Hudson Valley Hematology Oncology

Poughkeepsie, New York, United States

UPMC Hillman Cancer Insitute

Pittsburgh, Pennsylvania, United States

Baylor

Dallas, Texas, United States

CHU de Nantes

Nantes, , France

CHU de Poitiers

Poitiers, , France

Universita di Bolognia

Bologna, , Italy

Turin Hospital Myeloma Unit

Turin, , Italy

Hospital Clinic i Provincial de Barcelona

Barcelona, , Spain

Institut Català d'Oncología (ICO) Badalona

Barcelona, , Spain

Hospital Universitario de La Princesa

Madrid, , Spain

Hospital Universitario Fundación Jiménez Díaz

Madrid, , Spain

Clínica Universidad de Navarra

Pamplona, , Spain

Complejo Hospitalario de Salamanca

Salamanca, , Spain

Hospital Universitario Doctor Peset

Valencia, , Spain

Countries

United States; France; Italy; Spain

References

Richardson PG, Oriol A, Larocca A, Blade J, Cavo M, Rodriguez-Otero P, Leleu X, Nadeem O, Hiemenz JW, Hassoun H, Touzeau C, Alegre A, Paner A, Maisel C, Mazumder A, Raptis A, Moreb JS, Anderson KC, Laubach JP, Thuresson S, Thuresson M, Byrne C, Harmenberg J, Bakker NA, Mateos MV; HORIZON (OP-106) Investigators. Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma. J Clin Oncol. 2021 Mar 1;39(7):757-767. doi: 10.1200/JCO.20.02259. Epub 2020 Dec 9.

Reference Type: RESULT

PMID: 33296242 (View on PubMed)

Sonneveld P, Richardson PG, Ludwig H, Dimopoulos MA, Schjesvold FH, Hajek R, Abdulhaq H, Thuresson M, Norin S, Bakker NA, Mateos MV. Benefit Versus Risk Assessment of Melflufen and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Analyses From Longer Follow-up of the OCEAN and HORIZON Studies. Clin Lymphoma Myeloma Leuk. 2023 Sep;23(9):687-696. doi: 10.1016/j.clml.2023.05.004. Epub 2023 May 6.

Reference Type: DERIVED

PMID: 37355418 (View on PubMed)

Larocca A, Leleu X, Touzeau C, Blade J, Paner A, Mateos MV, Cavo M, Maisel C, Alegre A, Oriol A, Raptis A, Rodriguez-Otero P, Mazumder A, Laubach J, Nadeem O, Sandberg A, Orre M, Torrang A, Bakker NA, Richardson PG. Patient-reported outcomes in relapsed/refractory multiple myeloma treated with melflufen plus dexamethasone: analyses from the Phase II HORIZON study. Br J Haematol. 2022 Feb;196(3):639-648. doi: 10.1111/bjh.17887. Epub 2021 Oct 21.

Reference Type: DERIVED

PMID: 34671975 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

OP-106

Identifier Type: -

Identifier Source: org_study_id