Sponsor Decision

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.

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.

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