Clinical trial NCT04979442: Treatment of Milademetan Versus Trabectedin in Patient With Dedifferentiated Liposarcoma
Official title: A Randomized Multicenter Phase 3 Study of Milademetan Versus Trabectedin in Patients With Dedifferentiated Liposarcoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Dedifferentiated Liposarcoma
Keywords: sarcoma
MDM2
pleomorphic liposarcoma
Lead sponsor: Rain Oncology Inc
Sponsor class: INDUSTRY
First posted: 2021-07-28
Enrollment: 175
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Compare Progression-free Survival (PFS) as Determined by Blinded Independent Central Review (BICR) Between the Milademetan Treatment Arm and Trabectedin Control Arm
timeFrame: from the randomization date to date of documented progression or death, up to 13 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: From randomization date to death. The result is based on primary analysis data cut.
measure: Disease Control Rate (DCR)
timeFrame: From the randomization date to first CR, PR or SD >= 16 weeks or the primary study completion date; up to 26.6 months.
measure: Objective Response Rate (ORR)
timeFrame: From randomization date to the first confirmed complete or partial response, or study completion date; up to 26.6 months.
measure: PFS by Investigator Assessments
timeFrame: disease progression or death
measure: Number of Participants With Treatment-emergent Adverse Events Until Approximately 30 Days After the Last Study Drug
timeFrame: From first dose date to 30 days after the last dose date or the primary study completion date whichever came first; up to 26.6 months.
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford Cancer Center
state: California
city: Santa Monica
country: United States
facility: Sarcoma Oncology Research Center, LLC
state: California
city: Santa Monica
country: United States
facility: UCLA Department of Medicine - Hematology/ Oncology
state: California
city: Aurora
country: United States
facility: CU Anschutz Medical Campus, Anschutz Cancer Pavilion
state: Colorado
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Miami
country: United States
facility: University of Miami Hospital & Clinics - Sylvester Comprehensive Cancer Center
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center & Research Institute
state: Florida
city: Chicago Heights
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University School of Medicine, Duke Cancer Institute
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: The James Cancer Hospital and Solove Research Institute
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: Abramson Cancer Center at Pennsylvania Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Linz
country: Austria
facility: Order Hospital Linz - Sisters of Mercy
city: Salzburg
country: Austria
facility: University Hospital Salzburg
city: Vienna
country: Austria
facility: Medical University Vienna, Department of Internal Medicine I
city: Ghent
country: Belgium
facility: Ghent University, Oncology Center
city: Leuven
country: Belgium
facility: University Hospitals Leuven Campus Gasthuisberg
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Dijon
country: France
facility: Georges-Francois Leclerc Cancer Research Center
state: Bourgogne-Franche-Comté
city: Strasbourg
country: France
facility: ICANS
state: Grand Est
city: Bordeaux
country: France
facility: Institut Bergonie
state: Nouvelle Aquitaine
city: Poitiers
country: France
facility: Centre Hospitalier de Poitiers
state: Nouvelle Aquitaine
city: Toulouse
country: France
facility: Institute Claudius Regaud
state: Occitanie
city: Nice
country: France
facility: Centre Antoine Lacassagne
state: Provence-Alpes-Côte d'Azur
city: Marseille
country: France
facility: CHU La Timone - Oncologie medicale
state: Prvence-Alpes-Cote d'Azu
city: Lyon
country: France
facility: Leon Berard Center
city: Villejuif
country: France
facility: Gustave Roussy
city: Batumi
country: Georgia
facility: LTD High -Tech Hospital MedCenter
city: Tbilisi
country: Georgia
facility: LLC Todua Clinica
city: Tbilisi
country: Georgia
facility: LTD Health House
city: Tbilisi
country: Georgia
facility: Malkhaz Katsiashvili Multiprofile Emergency Medicin Center LLC
city: Tbilisi
country: Georgia
facility: LTD Caucasus Medical Centre
city: Bad Saarow
country: Germany
facility: Helios Hospital Bad Saarow, Clinic for Hematology, Oncology and Palliative Medicine
state: Bradenburg
city: Berlin
country: Germany
facility: HELIOS Hospital Berlin-Buch
city: Mainz
country: Germany
facility: University Medical Center-Mainz
city: Mannheim
country: Germany
facility: University Hospital Mannheim, Mannheim Cancer Center
city: Münster
country: Germany
facility: Münster University Hospital
city: Ulm
country: Germany
facility: University Hospital Ulm
city: Hong Kong
country: Hong Kong
facility: Department of Clinical Oncology, Prince of Wales Hospital
city: Dublin
country: Ireland
facility: St Vincent's University Hospital
city: Milan
country: Italy
facility: National Cancer Institute, IRCCS
city: Naples
country: Italy
facility: National Cancer Institute-IRCCS "Fondazione G. Pascale"
city: Padova
country: Italy
facility: Veneto Oncology Institute (IOV), IRCCS
city: Palermo
country: Italy
facility: University Polyclinic Hospital "Paolo Giaccone" Palermo
city: Prato
country: Italy
facility: Santo Stefano Hospital of Prato - USL Company Toscana Center
city: Prato
country: Italy
facility: Santo Stefano Hospital - ASL 4 Toscana
city: Rome
country: Italy
facility: University Hospital Campus Bio-Medico
city: Turin
country: Italy
facility: Institute of Cancer Research and Treatment of Candiolo - IRCCS
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System Seoul
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center, Department of Oncology
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Warsaw
country: Poland
facility: M. Curie National Research Institute of Oncology, Department of Soft Tissue/Bone Sarcoma and Melanoma
city: Barcelona
country: Spain
facility: Passeig de la Vall d'Hebron 119-129
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Madrid
country: Spain
facility: University General Hospital Gregorio Marañon
city: Madrid
country: Spain
facility: University Hospital Foundation Jimenez Diaz
city: Zaragoza
country: Spain
facility: University Hospital Miguel Servet
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: London
country: United Kingdom
facility: The Royal Marsden Hospital NHS Foundation Trust
state: Chelsea
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust, Department of Medical Oncology
Study officials:
References: