Adrenocortical Carcinoma, Biliary Tract Cancer, Bladder Urothelial Carcinoma, Breast Cancer Invasive, Cervical Cancer, Cholangiocarcinoma, Gastric Cancer, Head and Neck Carcinoma, Lung Adenocarcinoma, MDM2 Gene Amplification, Melanoma, Non Small Cell Lung Cancer, Ovarian Carcinoma, Pancreas Cancer, Sarcoma, Solid Tumors, Stomach Adenocarcinoma, Testicular Germ Cell Tumor
Conditions
Keywords
MDM2, Milademetan, Basket Study
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.
Interventions
DRUGRAIN-32
260 mg once daily orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle
Sponsors
Rain Oncology Inc
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Pre-assignment details
All enrolled participants (40 participants) received the study medication. Twenty-eight (28) discontinued treatment. Fourteen (14) completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Milademetan (RAIN-32) 260 mg once daily (QD) orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 10 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Physician Decision | 9 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Milademetan (RAIN-32) |
|---|---|
| Age, Continuous | 56.5 years STANDARD_DEVIATION 13.3 |
| BMI | 24.8 kg/m2 STANDARD_DEVIATION 5.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 32 Participants |
| Region of Enrollment United States | 40 participants |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 10 / 40 |
| other Total, other adverse events | 40 / 40 |
| serious Total, serious adverse events | 11 / 40 |
Outcome results
Primary
To Determine the ORR of Treatment With Milademetan in Patients With Advanced/Metastatic Solid Tumors With MDM2 Gene Amplification.
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
Time frame: From first dose date to first confirmed complete or partial response or study completion date; up to 23.5 months.
Population: This analysis is conducted in all participants within the Centrally confirmed population (CCP) which is defined as all participants who had at least one dose of study treatment and also have WT TP53 and MDM2 amplification with CN ≥ 8 by central testing.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Milademetan (RAIN-32) | To Determine the ORR of Treatment With Milademetan in Patients With Advanced/Metastatic Solid Tumors With MDM2 Gene Amplification. | 3.2 percentage of participants |
Secondary
Disease Control Rate (DCR)
DCR defined as the percentage of patients with confirmed CR, PR, or stable disease (SD) for ≥ 16 weeks
Time frame: From first dose date to first CR, PR, or stable disease (SD) >= 16 weeks, or study completion date; up to 23.5 months
Population: The efficacy analysis is conducted in all participants within the Centrally confirmed population (CCP).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Milademetan (RAIN-32) | Disease Control Rate (DCR) | 22.6 percentage of participants |
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
Time frame: From start date of response to first PD or study completion date; up to 23.5 months
Population: This analysis is conducted in all participants within the Centrally confirmed population (CCP) who had a confirmed CR or PR.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Milademetan (RAIN-32) | Duration of Response (DOR) | 3.84 months |
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)
Time frame: From the start date of the most recent prior line of therapy to the PD date on the study; up to 23.5 months
Population: The efficacy analysis is conducted in all participants within the Centrally confirmed population (CCP).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Milademetan (RAIN-32) | Growth Modulation Index (GMI) | 0.76 months |
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
Time frame: From the first dose date to the earliest date of recurrence, progression, death, or study completion; up to 23.5 months
Population: The efficacy analysis is conducted in all participants within the Centrally confirmed population (CCP).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Milademetan (RAIN-32) | Progression-free Survival (PFS) | 3.5 months |