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 testing, defined as ≥ 12 copies by central diagnostic laboratory or ≥ 12 copies or 6-fold increase by local testing modalities 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 setting of Gilbert's disease  Exclusion Criteria:  Prior treatment with a mouse double minute 2 (MDM2) inhibitor Well-differentiated/dedifferentiated liposarcoma or intimal sarcoma Primary malignancies that required systemic antineoplastic treatment within the previous 2 years, except for localized cancers that have apparently been cured Primary brain tumor (e.g., glioma) 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