Milademetan in Advanced/Metastatic Solid Tumors
Primary Purpose
Solid Tumors, Head and Neck Carcinoma, Cholangiocarcinoma
Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
RAIN-32
Sponsored by
About this trial
This is an interventional treatment trial for Solid Tumors focused on measuring MDM2, Milademetan, Basket Study
Eligibility 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 mouse 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
- QTcF at rest, where the mean QTcF interval is > 480 milliseconds
- Myocardial infarction within 6 months
- Uncontrolled angina pectoris within 6 months
- New York Heart Association Class 3 or 4 congestive heart failure
- Uncontrolled hypertension
Sites / Locations
- Stanford University Medical Center
- Florida Cancer Specialists
- Florida Cancer Specialists
- Massachusetts General Hospital
- Dana-Farber Cancer Institute
- Washington University School of Medicine
- Memorial Sloan-Kettering Cancer Center
- Hematology Oncology Associates of Central NY
- Duke University Medical Center
- University of Cincinnati Medical Center
- Sanford Health
- Tennessee Oncology, PLLC
- MD Anderson Cancer Center
- Northwest Medical Specialities
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Milademetan (RAIN-32)
Arm Description
260 mg once dailly orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle
Outcomes
Primary Outcome Measures
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
Secondary Outcome Measures
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
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
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)
Disease Control Rate (DCR)
DCR defined as the percentage of patients with confirmed CR, PR, or stable disease (SD) for ≥ 16 weeks
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
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT05012397
Brief Title
Milademetan in Advanced/Metastatic Solid Tumors
Official Title
A Phase 2 Basket Study of Milademetan in Advanced/Metastatic Solid Tumors (MANTRA-2)
Study Type
Interventional
2. Study Status
Record Verification Date
August 2023
Overall Recruitment Status
Terminated
Why Stopped
Sponsor Decision
Study Start Date
November 1, 2021 (Actual)
Primary Completion Date
October 15, 2023 (Actual)
Study Completion Date
October 15, 2023 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Rain Oncology Inc
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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
Keywords
MDM2, Milademetan, Basket Study
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
40 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Milademetan (RAIN-32)
Arm Type
Experimental
Arm Description
260 mg once dailly orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle
Intervention Type
Drug
Intervention Name(s)
RAIN-32
Other Intervention Name(s)
Milademetan
Intervention Description
260 mg once daily orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle
Primary Outcome Measure Information:
Title
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 Measure Information:
Title
Duration of Response (DOR)
Description
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
Time Frame
3 years
Title
Progression-free Survival (PFS)
Description
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
Time Frame
3 years
Title
Growth Modulation Index (GMI)
Description
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)
Time Frame
3 years
Title
Disease Control Rate (DCR)
Description
DCR defined as the percentage of patients with confirmed CR, PR, or stable disease (SD) for ≥ 16 weeks
Time Frame
3 years
Title
Overall Survival (OS)
Description
OS as measured from the date of the first dose of the study drug until the date of death due to any cause
Time Frame
3 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
QTcF at rest, where the mean QTcF interval is > 480 milliseconds
Myocardial infarction within 6 months
Uncontrolled angina pectoris within 6 months
New York Heart Association Class 3 or 4 congestive heart failure
Uncontrolled hypertension
Facility Information:
Facility Name
Stanford University Medical Center
City
Palo Alto
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Florida Cancer Specialists
City
Fort Myers
State/Province
Florida
ZIP/Postal Code
33901
Country
United States
Facility Name
Florida Cancer Specialists
City
Saint Petersburg
State/Province
Florida
ZIP/Postal Code
33705
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02214
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Memorial Sloan-Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Hematology Oncology Associates of Central NY
City
Syracuse
State/Province
New York
ZIP/Postal Code
13057
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
University of Cincinnati Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45267
Country
United States
Facility Name
Sanford Health
City
Sioux Falls
State/Province
South Dakota
ZIP/Postal Code
57104
Country
United States
Facility Name
Tennessee Oncology, PLLC
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Northwest Medical Specialities
City
Tacoma
State/Province
Washington
ZIP/Postal Code
77030
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
36669146
Citation
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.
Results Reference
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Milademetan in Advanced/Metastatic Solid Tumors
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