Sacituzumab Govitecan in Combination With Cisplatin in Platinum Sensitive Recurrent Ovarian and Endometrial Cancer

This is an open-label, Phase 1 study with a dose expansion cohort (DEC), conducted in two separate disease groups (ovarian and endometrial cancer). The primary objective of the study is to determine the optimal dose of sacituzumab govitecan for use in combination with cisplatin for treatment of epithelial ovarian and endometrial cancers.

For each disease group, there will be a safety run-in phase utilizing a 3+3 design with a de-escalated dose level if the starting dose shows toxicity and an expansion cohort to evaluate the preliminary efficacy and tolerability of the experimental regimen. The dose expansion cohort will consist of 14 patients in the ovarian cohort and 12 patients in the endometrial cohort with an additional 2 patients in each cohort to account for potential patient replacement. This will yield a total sample size of 22-28 patients in the ovarian cancer cohort and a total sample size of 20-26 patients in the endometrial cancer cohort.

Phase 1, Safety Run-in with Dose De-escalation Scheme:

Dose Level 0, starting level: Sacituzumab govitecan 7.5 mg/kg + Cisplatin 70 mg/m2 IV Dose -1: Sacituzumab govitecan 7.5 mg/kg + Cisplatin 70 mg/m2 IV In this stage, a minimum of 6 patients and a maximum of 12 patients will be required.

The recommended dose expansion cohort (DEC) dose is defined as the highest dose at which no more than 1 out of 6 patients experience a Dose-Limiting Toxicity (DLT)

Phase 2, Dose Expansion Cohort:

Sacituzumab govitecan 5-7.5 mg/kg IV (depending on phase I result) + Cisplatin 70 mg/m2 IV.

Drug product administration will continue until progressive disease (PD), unacceptable toxicity, or death.

The primary endpoint of the safety run-in phase is to determine the recommended DEC dose of Sacituzumab in combination with a fixed schedule of cisplatin in patients with ovarian and endometrial cancers. In the safety run-in phase, the assessment of dose limiting toxicity (DLT) will be performed standard 3 + 3 design rules. The recommended DEC dose is defined as the highest dose of Sacituzumab in combination with Cisplatin at the fixed dose of 70 mg/m2 at which no more than 1 out of 6 patients experience DLT within the first cycle of therapy.

The DEC is designed to indicate proof of concept regarding the overall response rate (ORR) and safety of the combination of sacituzumab with cisplatin at the dose established in the safety run-in phase of the study. Once the recommended DEC dose for sacituzumab and cisplatin combination has been established for each disease cohort, an additional 14 patients will be enrolled for the ovarian group and 12 patients for the endometrial group. An additional 2 patients will be added to each cohort to account for potential patient replacement for a total of 42-54 evaluable patients.

Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria to be registered to the study. Study treatment may not begin until a subject is registered.

Inclusion criteria

• Pathologic (histology or cytology) confirmed diagnosis of epithelial ovarian cancer or endometrial cancer
• Radiographic evidence of recurrent epithelial ovarian cancer (ovarian, fallopian tube, or primary peritoneal cancer) or endometrial cancer that is "platinum-sensitive," defined as progression of disease beyond 6 months from the last dose of platinum-based chemotherapy
• Female, age ≥ 18 years
• World Health Organization (WHO) performance status 0-1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks
• Patient has measurable disease (at least one lesion that can be accurately assessed repeatedly by CT) as evidenced on pre-treatment baseline CT of Chest/Abdomen/Pelvis or PET/CT, or evaluable disease
• Adequate hematologic counts, as defined below, without transfusion or growth factor support within 2 weeks of study drug initiation:

• Hemoglobin ≥ 8.5 g/dL
• Absolute neutrophil count ≥ 1500/mm3
• Platelets ≥ 100,000/μL
• Adequate organ function as defined below:

• Total bilirubin ≤ 1.5 ULN
• AST(SGOT)/ALT(SPGT) ≤ 2.5x ULN or ≤ 5 x ULN if known liver metastases
• Serum albumin > 3 g/dL
• Creatinine clearance ≥ 50 mL/min per the Cockcroft-Gault equation
• Women of childbearing potential must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 6 months following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

o A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
• Ability to understand and the willingness to sign a written informed consent.

Exclusion criteria

Treatment with any of the following:

• Any investigational agents or study drugs from a previous clinical study within 28 days or 5 half-lives (whichever is longer) of the first dose of study treatment
• Any other chemotherapy, immunotherapy or anticancer agents within 14 days of the first dose of study treatment
• Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment
• Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 2 weeks of the first dose of study treatment
• With the exception of alopecia, any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment
• As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses, or uncontrolled infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
• Known or severe (Grade 3 or higher) hypersensitivity to SG and/or cisplatin, their metabolites, or formulation excipients
• Peripheral neuropathy grade 2 or greater
• Refractory nausea and vomiting, chronic gastrointestinal diseases
• Patients must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.
• Women of childbearing potential unwilling to use effective contraception during study until conclusion of 6-month post-treatment evaluation period
• Known history of unstable angina, MI, or CHF present within 6 months of randomization or clinically significant cardiac arrhythmia (other than stable atrial fibrillation) requiring anti-arrhythmia therapy
• Known history of clinically significant active COPD, or other moderate-to-severe chronic respiratory illness present within 6 months of enrollment.
• Prior history of clinically significant bleeding, intestinal obstruction, or GI perforation within 6 months of enrollment.
• Other concurrent medical or psychiatric conditions that, in the Investigator's opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations.
• Prior therapy with sacituzumab govitecan, irinotecan, Trop-2-directed antibody drug conjugate, or any topoisomerase I-containing antibody-drug conjugates at any time for early stage disease
• Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn's disease) or GI perforation within 6 months of enrollment.
• Requirement for ongoing therapy with any prohibited medications
• Have known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they have stable CNS disease for ≥ 4 weeks prior to randomization and all neurologic symptoms have returned to baseline, have no evidence of new or enlarging brain metastases, and are taking 10 mg/day or less of prednisone or its equivalent. All participants with carcinomatous meningitis are excluded regardless of clinical stability.
• Have an active second malignancy. Participants with a history of malignancy that have been completely treated, with no evidence of active cancer for 3 years prior to randomization, or participants with surgically cured tumors with low risk of recurrence (e.g., nonmelanoma skin cancer, histologically confirmed complete excision of carcinoma in situ, or similar) are allowed to enroll.
• Use of any live vaccine against infectious diseases within 30 days of the first dose of study drugs.
• Have an active serious infection requiring systemic antimicrobial therapy