Inclusion Criteria:

• Histologically confirmed DD liposarcoma, with or without a WD component (WD/DD liposarcoma).
  • Note: Patient must be willing to provide an archival tumor tissue sample that is ≤ 3 years old and of adequate quality or willing to provide a fresh pretreatment biopsy sample.
• Advanced unresectable (i.e., where resection is deemed to cause unacceptable morbidity or mortality) and/or metastatic WD/DD liposarcoma.
• Measurable tumor lesion(s) in accordance with RECIST version 1.1.
• Received 1 or more systemic cancer therapy regimens, including at least 1 anthracycline-based regimen, and had radiographic progressive disease (per RECIST version 1.1) within 6 months before the Screening Visit.
• Resolution of any clinically relevant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy.
• 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 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 any mouse double minute 2 (MDM2) inhibitor or trabectedin.
• Other primary malignancies that have required systemic antineoplastic treatment within the previous 2 years, except for localized cancers that have apparently been cured.
• Gastrointestinal conditions that could affect the absorption of milademetan, in the opinion of the Investigator.
• Uncontrolled infection within the last 7 days requiring IV antibiotics, antivirals, or antifungals.
• Known HIV infection or active Hepatitis B or C.
• Untreated brain metastases.
  • Note: Patients who require steroids for brain metastases must be on a stable or tapering dose of corticosteroids for at least 2 weeks before randomization. If applicable, patients must complete stereotactic radiosurgery 7 days before and whole brain radiotherapy 21 days before their first dose of study drug.
• Investigational therapy administered within the 28 days or 5 half lives:
  • Cytochrome P450 3A4 isozyme strong inhibitor: 5 elimination half-lives;
  • CYP3A strong or moderate inducers: 4 weeks;
  • Systemic anticancer therapy or investigational therapy 3 weeks or 5 half-lives;
  • Immunotherapy with checkpoint inhibitor: 4 weeks;
  • 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.

Eligibility last updated 8/13/21. Questions regarding updates should be directed to the study team contact.