Clinical trial NCT02963493: A Study of Melphalan Flufenamide (Melflufen) Plus Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma
Official title: A Single Arm, Open-Label, Phase 2 Study of Melflufen in Combination With Dexamethasone in Patients With Relapsed Refractory Multiple Myeloma Who Are Refractory to Pomalidomide and/or an Anti-CD38 Monoclonal Antibody
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: relapsed refractory multiple myeloma
Lead sponsor: Oncopeptides AB
Sponsor class: INDUSTRY
Collaborators: name: Precision For Medicine
First posted: 2016-11-15
Enrollment: 157
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: Patients were followed until documented progression, unacceptable toxicity, patient/physician decision to withdraw or date of death, whichever came first. Longest time to response in study recorded as 15.3 months. Longest time on treatment 35 months.
Secondary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Patients were followed until documented progression, unacceptable toxicity, patient/physician decision to withdraw or date of death, whichever came first. Longest follow-up time for PFS recorded as 37.2 months at study end.
measure: Duration of Response
timeFrame: From date of response until the date of first documented progression or date of death from any cause, whichever came first. Longest time of response recorded as 36.2 months at study end.
measure: Overall Survival
timeFrame: From date of first dose of study medication until the date of death from any cause, assessed up to 24 months after study drug discontinuation.
measure: Functional Status and Well-being: EORTC QLQ-C30
timeFrame: To be assessed prior to dosing at Cycle 1, 2, 4, 6, 8, and End of Treatment. 23 patients were ongoing for QoL assessments at data cutoff. QoL was added in Protocol Amendment 4 beginning in Oct. 2018.
measure: Functional Status and Well-being: EQ-5D-3L
timeFrame: To be assessed prior to dosing at Cycle 1, 2, 4, 6, 8, and End of Treatment. 23 patients were ongoing for QoL assessments at data cutoff. QoL was added in Protocol Amendment 4 beginning in Oct. 2018.
measure: Clinical Benefit Rate
timeFrame: Patients were followed until documented progression, unacceptable toxicity, patient/physician decision to withdraw or date of death, whichever came first. Longest time on study treatment recorded as 35.0 months at study end.
measure: Time to Response
timeFrame: From start of treatment to first confirmed response. Longest time to response in study recorded as 15.3 months.
measure: Time to Progression
timeFrame: From start of treatment to first evidence of disease progression or date of death from any cause, whichever came first. Longest time to progression recorded was 37.2 months at study end.
Other outcomes:
Locations:
city: Whittier
country: United States
facility: Innovative Clinical Research Institute (ICRI)
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Chicago
country: United States
facility: RUSH
state: Illinois
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Center
state: Michigan
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Poughkeepsie
country: United States
facility: Hudson Valley Hematology Oncology
state: New York
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Insitute
state: Pennsylvania
city: Dallas
country: United States
facility: Baylor
state: Texas
city: Nantes
country: France
facility: CHU de Nantes
city: Poitiers
country: France
facility: CHU de Poitiers
city: Bologna
country: Italy
facility: Universita di Bolognia
city: Turin
country: Italy
facility: Turin Hospital Myeloma Unit
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona
city: Barcelona
country: Spain
facility: Institut Català d'Oncología (ICO) Badalona
city: Madrid
country: Spain
facility: Hospital Universitario de La Princesa
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
city: Pamplona
country: Spain
facility: Clínica Universidad de Navarra
city: Salamanca
country: Spain
facility: Complejo Hospitalario de Salamanca
city: Valencia
country: Spain
facility: Hospital Universitario Doctor Peset
Study officials:
affiliation: Oncopeptides AB
name: Johan Harmenberg, MD, PhD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.