Milademetan in Advanced/Metastatic Solid Tumors

• ClinicalTrials.gov Identifier: NCT05012397
• Recruitment Status: Terminated
• First Posted: August 19, 2021
• Last Update Posted: October 18, 2023
• Sponsor: Rain Oncology Inc
• Information provided by (Responsible Party): Rain Oncology Inc

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Solid Tumors; Head and Neck Carcinoma; Cholangiocarcinoma; Sarcoma; Lung Adenocarcinoma; Bladder Urothelial Carcinoma; Stomach Adenocarcinoma; Breast Cancer Invasive; Ovarian Carcinoma; Cervical Cancer; Non Small Cell Lung Cancer; Gastric Cancer; Biliary Tract Cancer; Melanoma; Pancreas Cancer; MDM2 Gene Amplification; Testicular Germ Cell Tumor; Adrenocortical Carcinoma	Drug: RAIN-32	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Basket Study of Milademetan in Advanced/Metastatic Solid Tumors (MANTRA-2)
• Actual Study Start Date: November 1, 2021
• Actual Primary Completion Date: October 15, 2023
• Actual Study Completion Date: October 15, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Milademetan (RAIN-32); 260 mg once dailly 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 Name: Milademetan

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: 3 years ]

Secondary Outcome Measures :

1. Duration of Response (DOR) [ Time Frame: 3 years ]
   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
2. Progression-free Survival (PFS) [ Time Frame: 3 years ]
   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. Growth Modulation Index (GMI) [ Time Frame: 3 years ]
   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)
4. Disease Control Rate (DCR) [ Time Frame: 3 years ]
   DCR defined as the percentage of patients with confirmed CR, PR, or stable disease (SD) for ≥ 16 weeks
5. Overall Survival (OS) [ Time Frame: 3 years ]
   OS as measured from the date of the first dose of the study drug until the date of death due to any cause

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, California

Stanford University Medical Center

Palo Alto, California, United States, 94305

United States, Florida

Florida Cancer Specialists

Fort Myers, Florida, United States, 33901

Florida Cancer Specialists

Saint Petersburg, Florida, United States, 33705

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02214

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, New York

Memorial Sloan-Kettering Cancer Center

New York, New York, United States, 10065

Hematology Oncology Associates of Central NY

Syracuse, New York, United States, 13057

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27710

United States, Ohio

University of Cincinnati Medical Center

Cincinnati, Ohio, United States, 45267

United States, South Dakota

Sanford Health

Sioux Falls, South Dakota, United States, 57104

United States, Tennessee

Tennessee Oncology, PLLC

Nashville, Tennessee, United States, 37203

United States, Texas

MD Anderson Cancer Center

Houston, Texas, United States, 77030

United States, Washington

Northwest Medical Specialities

Tacoma, Washington, United States, 77030

Sponsors and Collaborators

Rain Oncology Inc

More Information

Publications:

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.

• Responsible Party: Rain Oncology Inc
• ClinicalTrials.gov Identifier: NCT05012397
• Other Study ID Numbers: RAIN-3202
• First Posted: August 19, 2021
• Last Update Posted: October 18, 2023
• Last Verified: August 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Rain Oncology Inc:

MDM2; Milademetan; Basket Study

Additional relevant MeSH terms:

Carcinoma; Neoplasms; Adenocarcinoma; Cholangiocarcinoma; Biliary Tract Neoplasms; Pancreatic Neoplasms; Adenocarcinoma of Lung; Adrenocortical Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Digestive System Diseases; Biliary Tract Diseases; Endocrine Gland Neoplasms; Endocrine System Diseases; Pancreatic Diseases; Adrenal Cortex Neoplasms; Adrenal Gland Neoplasms; Adrenal Cortex Diseases; Adrenal Gland Diseases