Treatment of Milademetan Versus Trabectedin in Patient With Dedifferentiated Liposarcoma (MANTRA)

A Randomized Multicenter Phase 3 Study of Milademetan Versus Trabectedin in Patients With Dedifferentiated Liposarcoma

Randomized, multicenter, open-label, Phase 3 registration study designed to evaluate the safety and efficacy of milademetan compared to trabectedin in patients with unresectable (i.e., where resection is deemed to cause unacceptable morbidity or mortality) or metastatic DD liposarcoma that progressed on 1 or more prior systemic therapies, including at least 1 anthracycline-based therapy.

Study Overview

• Status: Terminated
• Conditions: Dedifferentiated Liposarcoma
• Intervention / Treatment: Drug: RAIN-32; Drug: Trabectedin

Detailed Description

Approximately 160 patients will be randomly assigned in a 1:1 ratio to receive milademetan or trabectedin. Randomization will be stratified by the ECOG performance status (0 or 1) and number of prior treatments (≤ 2 or > 2) for the patient's liposarcoma.

Patients will receive study drug (i.e., milademetan or trabectedin) until reaching unequivocal disease progression (RECIST v.1.1) as determined by the Investigator, experiencing unmanageable toxicity, or until other treatment discontinuation criteria are met. Patients may be treated beyond tumor progression if they are experiencing clinical benefit based on the assessment of the Investigator in discussion with the Medical Monitor. All patients will be followed for documentation of disease progression and survival information (i.e., date and cause of death) and subsequent treatment information (i.e., date/duration of treatment, response, and subsequent disease progression). Long-term follow-up will continue every 12 weeks (± 7 days) until the endpoint of death, the patient is lost to follow-up, or for 24 months following the final dose of study drug, whichever comes first.

• Study Type: Interventional
• Enrollment (Actual): 175
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Linz, Austria, 4010
    • Order Hospital Linz - Sisters of Mercy
  • Salzburg, Austria, 5020
    • University Hospital Salzburg
  • Vienna, Austria, 1090
    • Medical University Vienna, Department of Internal Medicine I
• Belgium
  • Ghent, Belgium, 9000
    • Ghent University, Oncology Center
  • Leuven, Belgium, 3000
    • University Hospitals Leuven Campus Gasthuisberg
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1Z5
      • Princess Margaret Cancer Centre
• France
  • Lyon, France, 69003
    • Leon Berard Center
  • Villejuif, France, 94805
    • Gustave Roussy
  • Bourgogne-Franche-Comté
    • Dijon, Bourgogne-Franche-Comté, France, 21079
      • Georges-Francois Leclerc Cancer Research Center
  • Grand Est
    • Strasbourg, Grand Est, France, 67000
      • ICANS
  • Nouvelle Aquitaine
    • Bordeaux, Nouvelle Aquitaine, France, 33076
      • Institut Bergonié
    • Poitiers, Nouvelle Aquitaine, France, 86021
      • Centre Hospitalier de Poitiers
  • Occitanie
    • Toulouse, Occitanie, France, 31059
      • Institute Claudius Regaud
  • Provence-Alpes-Côte d'Azur
    • Nice, Provence-Alpes-Côte d'Azur, France, 06189
      • Centre Antoine Lacassagne
  • Prvence-Alpes-Cote d'Azu
    • Marseille, Prvence-Alpes-Cote d'Azu, France, 13005
      • CHU La Timone - Oncologie medicale
• Georgia
  • Batumi, Georgia, 6000
    • LTD High -Tech Hospital MedCenter
  • Tbilisi, Georgia, 0112
    • LLC Todua Clinica
  • Tbilisi, Georgia, 0144
    • LTD Health House
  • Tbilisi, Georgia, 0172
    • Malkhaz Katsiashvili Multiprofile Emergency Medicin Center LLC
  • Tbilisi, Georgia, 0186
    • LTD Caucasus Medical Centre
• Germany
  • Berlin, Germany, 13125
    • HELIOS Hospital Berlin-Buch
  • Mainz, Germany, 55131
    • University Medical Center-Mainz
  • Mannheim, Germany, 68167
    • University Hospital Mannheim, Mannheim Cancer Center
  • Münster, Germany, 48149
    • Münster University Hospital
  • Ulm, Germany, 89081
    • University Hospital Ulm
  • Bradenburg
    • Bad Saarow, Bradenburg, Germany, 15526
      • Helios Hospital Bad Saarow, Clinic for Hematology, Oncology and Palliative Medicine
• Hong Kong
  • Hong Kong, Hong Kong
    • Department of Clinical Oncology, Prince of Wales Hospital
• Ireland
  • Dublin, Ireland, D04 N2E0
    • St Vincent's University Hospital
• Italy
  • Milan, Italy, 20133
    • National Cancer Institute, IRCCS
  • Naples, Italy, 80131
    • National Cancer Institute-IRCCS "Fondazione G. Pascale"
  • Padova, Italy, 35128
    • Veneto Oncology Institute (IOV), IRCCS
  • Palermo, Italy, 90127
    • University Polyclinic Hospital "Paolo Giaccone" Palermo
  • Prato, Italy, 59100
    • Santo Stefano Hospital of Prato - USL Company Toscana Center
  • Prato, Italy, ASL4
    • Santo Stefano Hospital - ASL 4 Toscana
  • Rome, Italy, 00128
    • University Hospital Campus Bio-Medico
  • Turin, Italy, 10060
    • Institute of Cancer Research and Treatment of Candiolo - IRCCS
• Korea, Republic of
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital, Yonsei University Health System Seoul
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center, Department of Oncology
• Poland
  • Warsaw, Poland, 02-781
    • M. Curie National Research Institute of Oncology, Department of Soft Tissue/Bone Sarcoma and Melanoma
• Spain
  • Barcelona, Spain, 08041
    • Hospital de la Santa Creu i Sant Pau
  • Barcelona, Spain, 08035
    • Passeig de la Vall d'Hebron 119-129
  • Madrid, Spain, 28009
    • University General Hospital Gregorio Maranon
  • Madrid, Spain, 28040
    • University Hospital Foundation Jimenez Diaz
  • Zaragoza, Spain, 50009
    • University Hospital Miguel Servet
• Taiwan
  • Taipei, Taiwan, 112
    • Taipei Veterans General Hospital
  • Taipei, Taiwan, 100225
    • National Taiwan University Hospital
• United Kingdom
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust, Department of Medical Oncology
  • Chelsea
    • London, Chelsea, United Kingdom, SW3 6JJ
      • The Royal Marsden Hospital NHS Foundation Trust
• United States
  • California
    • Palo Alto, California, United States, 94304
      • Stanford Cancer Center
    • Santa Monica, California, United States, 90403
      • Sarcoma Oncology Research Center, LLC
    • Santa Monica, California, United States, 90404
      • UCLA Department of Medicine - Hematology/ Oncology
  • Colorado
    • Aurora, Colorado, United States, 80045
      • CU Anschutz Medical Campus, Anschutz Cancer Pavilion
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida
    • Miami, Florida, United States, 33136
      • University of Miami Hospital & Clinics - Sylvester Comprehensive Cancer Center
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center & Research Institute
  • Illinois
    • Chicago Heights, Illinois, United States, 60611
      • Northwestern Memorial Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215-5450
      • Dana Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University School of Medicine, Duke Cancer Institute
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43210
      • The James Cancer Hospital and Solove Research Institute
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19106
      • Abramson Cancer Center at Pennsylvania Hospital
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Hillman Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically confirmed DD liposarcoma, with or without a WD component (WD/DD liposarcoma). Note: Patient must be willing to provide an archival tumor tissue sample that is ≤ 3 years old and of adequate quality or willing to provide a fresh pretreatment biopsy sample
• Advanced unresectable (i.e., where resection is deemed to cause unacceptable morbidity or mortality) and/or metastatic WD/DD liposarcoma
• Measurable tumor lesion(s) in accordance with RECIST version 1.1
• Received 1 or more systemic cancer therapy regimens, including at least 1 anthracycline-based regimen, and had radiographic progressive disease (per RECIST version 1.1) within 6 months before the Screening Visit
• Resolution of any clinically relevant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy
• ECOG performance status of 0 or 1

• Adequate bone marrow function:

  • Platelet count ≥ 100 × 10^9/L
  • Hemoglobin ≥ 9.0 g/dL
  • Absolute neutrophil count ≥ 1.5 × 10^9/L

• Adequate hepatic function:

  • Alanine aminotransferase and aspartate aminotransferase ≤ 3 × upper limit of normal (ULN) if no liver metastases are present; ≤ 5 × ULN if liver metastases are present
  • Total bilirubin ≤ 1.5 × ULN, or ≤ 3 x ULN in the setting of Gilbert's disease

Exclusion Criteria:

• Prior treatment with any mouse double minute 2 (MDM2) inhibitor or trabectedin
• Other primary malignancies that have required systemic antineoplastic treatment within the previous 2 years, except for localized cancers that have apparently been cured
• Gastrointestinal conditions that could affect the absorption of milademetan, in the opinion of the Investigator
• Uncontrolled infection within the last 7 days requiring IV antibiotics, antivirals, or antifungals
• Known HIV infection or active Hepatitis B or C
• Untreated brain metastases. Note: Patients who require steroids for brain metastases must be on a stable or tapering dose of corticosteroids for at least 2 weeks before randomization. If applicable, patients must complete stereotactic radiosurgery 7 days before and whole brain radiotherapy 21 days before their first dose of study drug.

• Investigational therapy administered within the 28 days or 5 half lives:

  1. Cytochrome P450 3A4 isozyme strong inhibitor: 5 elimination half-lives
  2. CYP3A strong or moderate inducers: 4 weeks
  3. Systemic anticancer therapy or investigational therapy 3 weeks or 5 half-lives,
  4. Immunotherapy with checkpoint inhibitor: 4 weeks
• Curative-intent radiation therapy ≤ 4 weeks or palliative radiation therapy,

• Uncontrolled or significant cardiovascular disease:

  1. QTcF at rest, where the mean QTcF interval is > 480 milliseconds
  2. Myocardial infarction within 6 months
  3. Uncontrolled angina pectoris within 6 months
  4. New York Heart Association Class 3 or 4 congestive heart failure
  5. Uncontrolled hypertension

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RAIN-32 (Milademetan); 260 mg once daily orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle.	Drug: RAIN-32; 260 mg once daily orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle; Other Names: Milademetan
Active Comparator: Trabectedin; 1.5 mg/m2 body surface area as a 24-hour IV infusion, every 3 weeks.	Drug: Trabectedin; 1.5 mg/m2 body surface area as a 24-hour IV infusion, every 3 weeks; Other Names: Yondelis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Compare progression-free survival (PFS) as determined by Blinded Independent Central Review (BICR) between the milademetan treatment arm and trabectedin control arm	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	OS as measured from the date of randomization to date of death by any cause	4 years
Disease control rate (DCR)	DCR defined as the percentage of patients who have achieved CR, PR, or SD for ≥ 8 weeks	4 years
Objective response rate (ORR)	ORR defined as the percentage of patients who achieve a confirmed CR or PR	4 years
Duration of response (DOR)	DOR defined as the time from date of first response to date of disease progression or death	4 years
PFS by Investigator assessments	PFS defined as the time from randomization to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause, based on Investigator assessments	4 years
Number of participants with treatment-emergent adverse events until approximately 30 days after the last study drug		4 years
Evaluate the patient-reported outcomes by using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire, Core 30 (QLQ-C30)		4 years

Collaborators and Investigators

• Sponsor: Rain Oncology Inc

Study record dates

Study Major Dates

• Study Start (Actual): July 14, 2021
• Primary Completion (Actual): October 1, 2023
• Study Completion (Actual): October 1, 2023

Study Registration Dates

• First Submitted: July 6, 2021
• First Submitted That Met QC Criteria: July 16, 2021
• First Posted (Actual): July 28, 2021

Study Record Updates

• Last Update Posted (Actual): October 18, 2023
• Last Update Submitted That Met QC Criteria: October 16, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: sarcoma; MDM2; pleomorphic liposarcoma
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Neoplasms, Adipose Tissue; Liposarcoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Trabectedin
• Other Study ID Numbers: RAIN-3201

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No