Phase 2/3 Study of Navtemadlin as Maintenance Therapy in TP53WT Advanced or Recurrent Endometrial Cancer

Prior treatment

• Clinically significant bacterial, mycobacterial, fungal, parasitic, or viral infection. Intravenous (IV) antibiotics within 2 weeks prior to first dose of study treatment
• Major surgery or planned major surgery within 28 days prior to first dose of study treatment
• Subjects with indwelling surgical drains (e.g., peritoneal, CNS, or pleural)
• Received immune therapy, cytokine therapy, or any investigational therapy within 28 days prior to the first dose of study treatment.
• Subjects with active fever (temperature higher than 38.2°C [100.8°F]) within 14 days prior to the first dose of study treatment
• Participation in another interventional clinical study within 28 days prior to the first dose of study treatment (participation in observational studies is permitted)
• Uncontrolled clinically significant cardiac disease (New York Heart Class III or IV), symptomatic congestive heart failure, unstable angina pectoris, ventricular arrhythmia or history of myocardial infarction within 3 months prior to the first dose of study treatment
• Indwelling surgical drains (eg, peritoneal, central nervous system [CNS], or pleural)
• Active fever (temperature higher than 38.2°C [100.8°F]) within 14 days prior to the first dose of study treatment
• History of bleeding diathesis; major hemorrhage or intracranial hemorrhage within 24 weeks prior to the first dose of study treatment

Other illness

• History of major organ transplant
• Known active hepatitis B or C infection
• Known infection with human immunodeficiency virus
• Known hypersensitivity to or contraindications to the study drug or any of its excipients, or to required prophylaxes
• History of difficult swallowing, gastric or small bowel surgery with history of malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the study treatment
• Medical condition, serious intercurrent illness, psychiatric condition, or other circumstance (ie, committed to an institution by judicial or administrative authority) that, in the investigator's judgment, could jeopardize the subject's safety, or that could interfere with study objectives
• History of another malignancy within the last 3 years, other than curatively treated basal cell or squamous cell skin cancer, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma

Lab values

• Grade 2 or higher QTc prolongation >480 msec per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0

Other

• Has any sarcomas or small-cell carcinomas with neuroendocrine differentiation.
• Women who are pregnant or breastfeeding

• Female ≥18 years of age and able to provide informed consent.
• Histologically or cytologically confirmed diagnosis of endometrial cancer (including endometroid adenocarcinoma, serous carcinoma, papillary serous carcinoma, adeno-squamous carcinoma, clear cell carcinoma, mixed carcinoma, undifferentiated carcinoma, carcinosarcoma, and carcinoma not otherwise specified) documented as TP53WT. In Part 2, TP53WT to be determined by central testing.
• Subjects with advanced or recurrent disease (ie, first relapse) must have completed a single line of up to 6 cycles of taxane-platinum combination chemotherapy (not including adjuvant or neoadjuvant therapy) and achieved a CR or PR per RECIST V1.1. • Primary Stage IV disease, defined as: − had a primary or later debulking surgery during first-line platinum therapy with R0 resection (R0 resection indicates a macroscopic complete resection of all visible tumor), OR − had a primary or later debulking surgery during first-line taxane-platinum therapy with R1 resection (R1 resection indicates incomplete removal of all macroscopic disease), OR − had no surgery. • Subjects at first relapse (ie, relapse after primary therapy including surgery and/or chemotherapy with or without immunotherapy for Stage I-IV disease), defined as: − had Stage I-III disease at diagnosis and received adjuvant chemotherapy with or without immunotherapy at initial diagnosis and relapsed later, OR − had Stage I-III disease at diagnosis and did not receive adjuvant chemotherapy with or without immunotherapy at initial diagnosis and relapsed later, OR − had Stage IV disease at diagnosis and initially received immunotherapy or endocrine therapy/with or without surgery and relapsed later. Note: Subjects that required dose interruption of their current chemotherapy may be considered eligible if they meet the other criteria above and achieve CR or PR per RECIST V1.1.
• Subjects must be able to initiate study treatment within 6 weeks after completion of their final dose of chemotherapy.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
• Adequate hematologic function within 14 days prior to first dose of study treatment and independent of growth factor support for at least 7 days with the exception of pegylated granulocyte-colony stimulating factor (G-CSF) which require at least 14 days, defined as: a. ANC ≥ 1.0 x 10^9/L b. Platelet count ≥ 75 x 10^9/L
• Adequate hepatic function within 14 days prior to the first dose of study treatment defined as: a. Total serum bilirubin within normal limits. If total bilirubin is > upper limit of normal (ULN), then subjects are eligible if the direct bilirubin is ≤ 2.0 x ULN b. Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN. For subjects with liver involvement: AST and ALT ≤ 5 x ULN.
• Adequate renal function within 14 days prior to first dose of study treatment defined as an estimated creatinine clearance ≥30 mL/min by Cockcroft Gault
• Female subjects of childbearing potential and their male partners must both use a highly effective contraception method during the study (Appendix 2 of the protocol). In addition, after the last dose of study drug, female subjects must continue to use a highly effective method of contraception for 1 month and 1 week. A woman is considered of childbearing potential (ie, fertile, following menarche and until becoming post-menopausal) unless permanently sterile (Appendix 2 of the protocol).