Brief Title: Milademetan in Advanced/Metastatic Solid Tumors

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: To Determine the ORR of Treatment With Milademetan in Patients With Advanced/Metastatic Solid Tumors With MDM2 Gene Amplification.

Primary Outcome 1 - Timeframe: From first dose date to first confirmed complete or partial response or study completion date; up to 23.5 months.

CONDITION

• 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

ELIGIBILITY

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

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

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