Milademetan in Advanced/Metastatic Solid Tumors

Phase 2

Terminated

Conditions: Solid Tumors
Head and Neck Carcinoma
Cholangiocarcinoma
Sarcoma
Lung Adenocarcinoma
Ovarian Carcinoma
Gastric Cancer
Bladder Urothelial Carcinoma
Stomach Adenocarcinoma
Breast Cancer Invasive

Interventions: Drug: RAIN-32

Registration Number: NCT05012397

Lead Sponsor: Rain Oncology Inc

Brief Summary: Phase 2, multicenter, single-arm, open-label basket study designed to evaluate the safety and efficacy of milademetan in patients with advanced or metastatic solid tumors refractory or intolerant to standard-of-care therapy that exhibit wild-type (WT) TP53 and MDM2 copy number (CN) ≥ 8 using prespecified biomarker criteria.

Detailed Description: Approximately 65 patients will be enrolled to receive milademetan.

Patients will receive the study drug until reaching unequivocal disease progression (per Response Evaluation Criteria in Solid Tumors \[RECIST\] version \[v\]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). 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 the study drug, whichever comes first.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 40

Inclusion Criteria

Histologically and/or cytologically confirmed diagnosis of a cancer that is a locally advanced or metastatic solid tumor
Measurable tumor lesion(s) in accordance with RECIST v1.1
Received all standard therapy appropriate for their tumor type and stage of disease or, in the opinion of the Investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard-of-care therapy
Resolution of any clinically relevant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy
Presence of WT TP53 and MDM2 gene amplification by tumor tissue/blood testing, defined as ≥ 8 copies in tumor tissue by central laboratory or ≥ 8 copies or 4-fold increase in tumor tissue or blood by local testing
Prescreening for TP53 and MDM2 at a Central Laboratory:
- MDM2 amplification: CN unknown and where CN cannot be derived for documentation by interpretation of reported results
- MDM2 amplification: CN 6 to 7.9
- MDM2 amplification: 3-3.9-fold increase
- MDM2 amplification with CN ≥ 8 and with equivocal TP53 mutation upon discussion with Sponsor's Medical Monitor
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 renal function
- Creatinine clearance ≥ 30mL/min, as calculated using the modified Cockcroft-Gault equation
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 presence of liver metastases

Exclusion Criteria

Prior treatment with a murine double minute 2 (MDM2) inhibitor
Well-differentiated/dedifferentiated liposarcoma or intimal sarcoma/cardiac sarcoma
Primary malignancies that required systemic antineoplastic treatment within the previous 2 years, except for localized cancers that have apparently been cured
Has a primary malignant brain tumor of any grade or histology
Untreated brain metastases
Gastrointestinal conditions that could affect the absorption of milademetan, in the opinion of the Investigator
Known HIV infection or active hepatitis B or C infection
Major surgery ≤ 3 weeks of the first dose of milademetan
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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Milademetan (RAIN-32)	RAIN-32	260 mg once dailly orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle

Primary Outcome Measures

Name	Time	Method
To Determine the ORR of Treatment With Milademetan in Patients With Advanced/Metastatic Solid Tumors With MDM2 Gene Amplification.	From first dose date to first confirmed complete or partial response or study completion date; up to 23.5 months.	Overall Response Rate (ORR) of treatment with milademetan, as defined as the percentage of patients who have achieved confirmed complete response (CR) or Partial Response (PR) according to RECIST v1.1

Secondary Outcome Measures

Name	Time	Method
Duration of Response (DOR)	From start date of response to first PD or study completion date; up to 23.5 months	DOR defined as the time from the date of first documentation of CR or PR according to RECIST v1.1 to the date of disease progression or death due to any cause according to Investigator assessment
Progression-free Survival (PFS)	From the first dose date to the earliest date of recurrence, progression, death, or study completion; up to 23.5 months	PFS defined as the time from the date of the first dose of the study drug to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause according to Investigator assessment
Growth Modulation Index (GMI)	From the start date of the most recent prior line of therapy to the PD date on the study; up to 23.5 months	GMI defined as the ratio of Time to Progression (TTP) with the nth line of therapy (TTPn; here defined as milademetan) to the most recent prior line of therapy (TTPn-1)
Disease Control Rate (DCR)	From first dose date to first CR, PR, or stable disease (SD) >= 16 weeks, or study completion date; up to 23.5 months	DCR defined as the percentage of patients with confirmed CR, PR, or stable disease (SD) for ≥ 16 weeks

Trial Locations

Locations (13): Massachusetts General Hospital
🇺🇸
Boston, Massachusetts, United States
University of Cincinnati Medical Center
🇺🇸
Cincinnati, Ohio, United States
MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Florida Cancer Specialists
🇺🇸
Saint Petersburg, Florida, United States
Stanford University Medical Center
🇺🇸
Palo Alto, California, United States
Sanford Health
🇺🇸
Sioux Falls, South Dakota, United States
Northwest Medical Specialities
🇺🇸
Tacoma, Washington, United States
Tennessee Oncology, PLLC
🇺🇸
Nashville, Tennessee, United States
Hematology Oncology Associates of Central NY
🇺🇸
Syracuse, New York, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸
New York, New York, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States