Milademetan in Advanced/Metastatic Solid Tumors

Gastric Cancer Clinical Trial

Official title:

A Phase 2 Basket Study of Milademetan in Advanced/Metastatic Solid Tumors (MANTRA-2)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT05012397
• Other study ID #: RAIN-3202
• Status: Terminated
• Phase: Phase 2
• Start date: November 1, 2021
• Est. completion date: October 15, 2023

Study information

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

Clinical Trial 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 40
• Est. completion date: October 15, 2023
• Est. primary completion date: October 15, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Adenocarcinoma
• Adenocarcinoma of Lung
• Adrenocortical Carcinoma
• Biliary Tract Cancer
• Biliary Tract Neoplasms
• Bladder Urothelial Carcinoma
• Breast Cancer Invasive
• Carcinoma
• Cervical Cancer
• Cholangiocarcinoma
• Gastric Cancer
• Head and Neck Carcinoma
• Lung Adenocarcinoma
• Melanoma
• Neoplasms
• Non Small Cell Lung Cancer
• Ovarian Carcinoma
• Pancreas Cancer
• Pancreatic Neoplasms
• Sarcoma
• Solid Tumors
• Stomach Adenocarcinoma
• Testicular Germ Cell Tumor

Intervention

Drug:
• RAIN-32
260 mg once daily orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Rain Oncology Inc

Country where clinical trial is conducted

United States, 

References & Publications (1)

Gounder MM, Bauer TM, Schwartz GK, Weise AM, LoRusso P, Kumar P, Tao B, Hong Y, Patel P, Lu Y, Lesegretain A, Tirunagaru VG, Xu F, Doebele RC, Hong DS. A First-in-Human Phase I Study of Milademetan, an MDM2 Inhibitor, in Patients With Advanced Liposarcoma, Solid Tumors, or Lymphomas. J Clin Oncol. 2023 Mar 20;41(9):1714-1724. doi: 10.1200/JCO.22.01285. Epub 2023 Jan 20. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 criteria		3 years
Secondary	Duration of Response (DOR)	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	3 years
Secondary	Progression-free Survival (PFS)	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	3 years
Secondary	Growth Modulation Index (GMI)	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)	3 years
Secondary	Disease Control Rate (DCR)	DCR defined as the percentage of patients with confirmed CR, PR, or stable disease (SD) for = 16 weeks	3 years
Secondary	Overall Survival (OS)	OS as measured from the date of the first dose of the study drug until the date of death due to any cause	3 years