Milademetan in Advanced/Metastatic Solid Tumors

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