Treatment of Milademetan Versus Trabectedin in Patient With Dedifferentiated Liposarcoma

Dedifferentiated Liposarcoma Clinical Trial

— MANTRA  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04979442
• Other study ID #: RAIN-3201
• Status: Terminated
• Phase: Phase 3
• Start date: July 14, 2021
• Est. completion date: October 1, 2023

Study information

• Verified date: October 2023
• Source: Rain Oncology Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 175
• Est. completion date: October 1, 2023
• Est. primary completion date: October 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Dedifferentiated Liposarcoma
• Liposarcoma

Intervention

Drug:
• RAIN-32
260 mg once daily orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle
• Trabectedin
1.5 mg/m2 body surface area as a 24-hour IV infusion, every 3 weeks

Locations

Country	Name	City	State
Austria	Order Hospital Linz - Sisters of Mercy	Linz
Austria	University Hospital Salzburg	Salzburg
Austria	Medical University Vienna, Department of Internal Medicine I	Vienna
Belgium	Ghent University, Oncology Center	Ghent
Belgium	University Hospitals Leuven Campus Gasthuisberg	Leuven
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
France	Institut Bergonie	Bordeaux	Nouvelle Aquitaine
France	Georges-Francois Leclerc Cancer Research Center	Dijon	Bourgogne-Franche-Comté
France	Leon Berard Center	Lyon
France	CHU La Timone - Oncologie medicale	Marseille	Prvence-Alpes-Cote d'Azu
France	Centre Antoine Lacassagne	Nice	Provence-Alpes-Côte d'Azur
France	Centre Hospitalier de Poitiers	Poitiers	Nouvelle Aquitaine
France	ICANS	Strasbourg	Grand Est
France	Institute Claudius Regaud	Toulouse	Occitanie
France	Gustave Roussy	Villejuif
Georgia	LTD High -Tech Hospital MedCenter	Batumi
Georgia	LLC Todua Clinica	Tbilisi
Georgia	LTD Caucasus Medical Centre	Tbilisi
Georgia	LTD Health House	Tbilisi
Georgia	Malkhaz Katsiashvili Multiprofile Emergency Medicin Center LLC	Tbilisi
Germany	Helios Hospital Bad Saarow, Clinic for Hematology, Oncology and Palliative Medicine	Bad Saarow	Bradenburg
Germany	HELIOS Hospital Berlin-Buch	Berlin
Germany	University Medical Center-Mainz	Mainz
Germany	University Hospital Mannheim, Mannheim Cancer Center	Mannheim
Germany	Münster University Hospital	Münster
Germany	University Hospital Ulm	Ulm
Hong Kong	Department of Clinical Oncology, Prince of Wales Hospital	Hong Kong
Ireland	St Vincent's University Hospital	Dublin
Italy	National Cancer Institute, IRCCS	Milan
Italy	National Cancer Institute-IRCCS "Fondazione G. Pascale"	Naples
Italy	Veneto Oncology Institute (IOV), IRCCS	Padova
Italy	University Polyclinic Hospital "Paolo Giaccone" Palermo	Palermo
Italy	Santo Stefano Hospital - ASL 4 Toscana	Prato
Italy	Santo Stefano Hospital of Prato - USL Company Toscana Center	Prato
Italy	University Hospital Campus Bio-Medico	Rome
Italy	Institute of Cancer Research and Treatment of Candiolo - IRCCS	Turin
Korea, Republic of	Asan Medical Center, Department of Oncology	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System Seoul	Seoul
Poland	M. Curie National Research Institute of Oncology, Department of Soft Tissue/Bone Sarcoma and Melanoma	Warsaw
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Passeig de la Vall d'Hebron 119-129	Barcelona
Spain	University General Hospital Gregorio Marañon	Madrid
Spain	University Hospital Foundation Jimenez Diaz	Madrid
Spain	University Hospital Miguel Servet	Zaragoza
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
United Kingdom	The Royal Marsden Hospital NHS Foundation Trust	London	Chelsea
United Kingdom	The Christie NHS Foundation Trust, Department of Medical Oncology	Manchester
United States	University of Michigan	Ann Arbor	Michigan
United States	CU Anschutz Medical Campus, Anschutz Cancer Pavilion	Aurora	Colorado
United States	Johns Hopkins Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Northwestern Memorial Hospital	Chicago Heights	Illinois
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	The James Cancer Hospital and Solove Research Institute	Columbus	Ohio
United States	Duke University School of Medicine, Duke Cancer Institute	Durham	North Carolina
United States	MD Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic Florida	Jacksonville	Florida
United States	University of Miami Hospital & Clinics - Sylvester Comprehensive Cancer Center	Miami	Florida
United States	Columbia University Medical Center	New York	New York
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Stanford Cancer Center	Palo Alto	California
United States	Abramson Cancer Center at Pennsylvania Hospital	Philadelphia	Pennsylvania
United States	UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Sarcoma Oncology Research Center, LLC	Santa Monica	California
United States	UCLA Department of Medicine - Hematology/ Oncology	Santa Monica	California
United States	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Rain Oncology Inc

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Canada,  France,  Georgia,  Germany,  Hong Kong,  Ireland,  Italy,  Korea, Republic of,  Poland,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Overall survival (OS)	OS as measured from the date of randomization to date of death by any cause	4 years
Secondary	Disease control rate (DCR)	DCR defined as the percentage of patients who have achieved CR, PR, or SD for = 8 weeks	4 years
Secondary	Objective response rate (ORR)	ORR defined as the percentage of patients who achieve a confirmed CR or PR	4 years
Secondary	Duration of response (DOR)	DOR defined as the time from date of first response to date of disease progression or death	4 years
Secondary	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
Secondary	Number of participants with treatment-emergent adverse events until approximately 30 days after the last study drug		4 years
Secondary	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