A PK, Safety and Tolerability Study of Peripheral and Central Infusion of Melflufen in RRMM Patients

NCT04412707 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: OP-109
• Study Type: interventional
• Target: 27
• Locations: 5 countries
• Sites: 10

Brief Summary

This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy.

Conditions

RRMM

Keywords

central intravenous administration; peripheral intravenous administration; central venous catheter (CVC); peripheral venous catheter (PVC)

Outcome Measures

Primary Outcomes (4)

• Peak Plasma Concentration for Melphalan

  To evaluate and compare the pharmacokinetic (PK) variable Cmax of melphalan after central and peripheral intravenous infusion of melflufen.

  Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.

• Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melphalan

  To evaluate and compare the pharmacokinetic (PK) variable AUC(0-t) of melphalan after central and peripheral intravenous infusion of melflufen.

  Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.

• Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melphalan

  To evaluate and compare the pharmacokinetic (PK) variable AUC(0-inf) of melphalan after central and peripheral intravenous infusion of melflufen

  Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.

• Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration

  Assessment of the local tolerability of peripheral intravenous administration of melflufen using the Visual Infusion Phlebitis (VIP) scale. The VIP scale provides a score from 0 to 5, noting an ascending order of severity of inflammation. A score of 0 is the lowest possible score, meaning no inflammation detected, and 5 is the highest score, indicating the most severe reaction.

  15 minutes and 4 hours after peripheral intravenous administration, pre- and post-infusion on Day 1 and Day 8

Secondary Outcomes (16)

• Peak Plasma Concentration for Melflufen and Desethyl-melflufen

  Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle)

• Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melflufen and Desethyl-melflufen

  Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle)

• Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melflufen and Desethyl-melflufen

  Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle)

• Elimination Half-life (t1/2) of Melflufen, Melphalan and Desethyl-melflufen

  Cycle 1 Day 1 and Cycle 2 Day 1 - 13 measurements during and post infusion (28 days cycle)

• Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT

  Median treatment durations for Arm A and Arm B were 29.14 weeks and 12.14 weeks, respectively. The AE reporting period is estimated to be 30 days longer.

Study Arms (2)

Arm A

ACTIVE COMPARATOR

Melflufen 40 mg iv Day 1 of each 28 day cycle. Dexamethasone 40 mg po Day 1,8, 15 and 22 of each 28 day cycle, if \> 75 years of age 20 mg. Cycle 1 will be administered via a Peripheral Venous Catheter (PVC) and cycle 2 and onwards melflufen will be administered via a Central Venous Catheter (CVC).

Drug: Melphalan; Drug: Dexamethasone

Arm B

ACTIVE COMPARATOR

Melflufen 40 mg iv Day 1 of each 28 day cycle. Dexamethasone 40 mg po Day 1,8, 15 and 22 of each 28 day cycle, if \> 75 years of age 20 mg. Cycle 1 will be administered via a Central Venous Catheter (CVC) and cycle 2 will be administered via a Peripheral Venous Catheter (PVC). From cycle 3 and onwards melflufen will be administered via CVC.

Drug: Melphalan; Drug: Dexamethasone

Interventions

Melphalan DRUG

Peripheral versus central administration

Also known as: melflufen flufenamide

Arm A; Arm B

Dexamethasone DRUG

Oral tablets

Arm A; Arm B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female, age 18 years or older
• Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol;
• A prior diagnosis of multiple myeloma (MM) with documented disease progression in need of treatment at time of screening;
• Measurable disease defined as any of the following:
• Serum monoclonal protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP)
• ≥ 200 mg/24hr of monoclonal protein in the 24hour urine collection by electrophoresis (UPEP)
• Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal serum kappa to lambda free light chain (FLC) ratio
• Received at least 2 prior lines of therapy and is refractory to an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI). The definition of refractory includes intolerance to an IMiD/PI after at least two 28-day cycles of therapy, see Appendix 10 and Appendix 8.
• Adequate peripheral arm veins for repeated intravenous infusions
• Life expectancy of ≥ 6 months;
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, see Appendix 6. Patients with ECOG performance status \> 2 solely based on bone pain secondary to MM may be eligible following consultation and approval of medical monitor;
• lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of ≤ 470 msec, see Appendix 11;
• Adequate organ function with the following laboratory results during screening (within 21 days) and immediately before study treatment administration on Cycle 1 Day 1:
• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm³ (1.0 x 10⁹/L) (Growth factors cannot be used within 10 days (14 days for pegfilgrastim) prior to initiation of study treatment)
• Platelet count ≥ 75,000 cells/ mm³ (75 x 10⁹/L) (without transfusions during the 10 days prior to initiation of therapy)

You may not qualify if:

• Primary refractory disease (i.e. never responded with at least minimal response \[MR\] to any prior therapy);
• Evidence of mucosal and/or internal bleeding or platelet transfusion refractory (platelet count fails to increase by \> 10,000 cells/mm³ after a transfusion of an appropriate dose of platelets);
• 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. Examples of such conditions are: a significant history of cardiovascular disease (e.g., myocardial infarction, significant cardiac conduction system abnormalities, uncontrolled hypertension, ≥ Grade 3 thromboembolic event in the last 6 months);
• Known active infection that is uncontrolled or has required intravenous systemic therapy within 14 days of randomization. Patients that have required oral anti-infective treatment within 14 days of randomization should be discussed with the Medical Monitor;
• Other malignancy diagnosed or requiring treatment within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in active surveillance;
• Pregnant or breast-feeding females;
• Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation;
• Human immunodeficiency virus (HIV) or active hepatitis B or C viral infection;
• Concurrent known or suspected amyloidosis or plasma cell leukemia;
• POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes);
• Known central nervous system (CNS) or meningeal involvement of myeloma
• Any of the following treatments, within the specified timeframe
• Previous cytotoxic therapies, including cytotoxic investigational agents, for MM within 3 weeks (6 weeks for nitrosoureas) prior to initiation of therapy.
• The use of live vaccines within 30 days before initiation of therapy.
• IMiDs, PIs and or corticosteroids within 2 weeks prior to initiation of therapy.

Sponsors & Collaborators

• Oncopeptides AB: lead

Study Sites (10)

The Oncology Institute of Hope & Innovation - Glendale

Glendale, California, 91204, United States

Location

Specialized Hospital for Active Treatment of Hematological Diseases, Sofia

Sofia, Bulgaria

Location

Multiprofile Hospital for Active Treatment "Sveta Marina", Varna

Varna, Bulgaria

Location

University Hospital Brno, Clinic of Internal Medicine - Hematology and Oncology

Brno, 62500, Czechia

Location

University Hospital Olomouc, Clinic of Hemato-Oncology

Olomouc, 77900, Czechia

Location

Central Hospital of Southern Pest National Institute of Hematology and Infectious Diseases, Department of Hematology and Stem Cell Transplantation

Budapest, Hungary

Location

Semmelweis University, 3rd Department of Internal Medicine

Budapest, Hungary

Location

Public Non-Profit Enterprise "City Clinical Hospital #4" under Dnipro City Council, Regional Hematology Center

Dnipro, Ukraine

Location

Public Non-Profit Enterprise "Kyiv City Clinical Hospital #9" under the Executive Body of Kyiv City Council, Hematology Department #1

Kyiv, Ukraine

Location

Institute of Blood Pathology and Transfusion Medicine, Department of Hematology with Laboratory Group

Lviv, Ukraine

Location

MeSH Terms

Interventions

Melphalan; melflufen; Dexamethasone

Intervention Hierarchy (Ancestors)

Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Results Point of Contact

• Title: VP Chief Operating Officer
• Organization: Oncopeptides AB

trials@oncopeptides.com

+46 8 615 20 40

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 18, 2020
• First Posted: June 2, 2020
• Study Start: August 4, 2020
• Primary Completion: June 2, 2021
• Study Completion: January 10, 2022
• Last Updated: March 9, 2023
• Results First Posted: August 16, 2022

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1); CZ (2); BU (2); HU (2); UA (3)