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

Study Overview
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Brief Summary
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This is an open-label, Phase 1 study with a dose expansion cohort of Sacituzumab Govitecan in Combination with Cisplatin in Platinum Sensitive Recurrent Ovarian and Endometrial Cancer. The goal 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.

Detailed Description
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This is an open-label, Phase 1 study with a dose expansion cohort, 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 10 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 7.5-10 mg/kg IV (depending on phase I result) + Cisplatin 70 mg/m2 IV. Drug product administration will continue until PD, unacceptable toxicity, or death. 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 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.

Official Title
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A Single-Center, Open-Label, Single-Arm, Phase I Study With Dose Expansion Cohort of Sacituzumab Govitecan in Combination With Cisplatin in Platinum Sensitive Recurrent Ovarian and Endometrial Cancer

Conditions
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Ovarian Cancer, Malignant Neoplasm of Uterus

Intervention / Treatment
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* Drug: Sacituzumab
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: * must provide value Expand 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 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 child-bearing potential must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 90 days 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. 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 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. History of allergic reactions attributed to compounds of similar chemical or biologic composition to sacituzumab govitecan, cisplatin or irinotecan. 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 4-week 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, 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ovarian cancer arm<br>DEC 3+3 dose expansion of Sacituzumab Govitecan in Combination with Cisplatin | Drug: Sacituzumab<br>* Dose 0: Sacituzumab govitecan 10 mg/kg Dose 1: Sacituzumab govitecan 7.5 mg/kg<br>* Other names: Sacituzumab Govitecan;Drug: Cisplatin<br>* Cisplatin 70 mg/m2 IV<br>|
| Experimental: endometrial cancer arm<br>DEC 3+3 dose expansion of Sacituzumab Govitecan in Combination with Cisplatin | Drug: Sacituzumab<br>* Dose 0: Sacituzumab govitecan 10 mg/kg Dose 1: Sacituzumab govitecan 7.5 mg/kg<br>* Other names: Sacituzumab Govitecan;Drug: Cisplatin<br>* Cisplatin 70 mg/m2 IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) for the Safety Run-In Phase | Safety Run-In Phase: Dose-limiting toxicity (DLT) and the recommended Dose Expansion Cohort (DEC) dose of sacituzumab govitecan in combination with a fixed schedule of cisplatin in patients with ovarian and endometrial cancers. DLT is defined as any therapy-attributable adverse event (AE) requiring discontinuation of therapy within one cycle of combined therapy; specifically grade 3 or 4 non-hematologic toxicity and grade 4 hematologic toxicity events. These will be assessed via NCI's CTCAE v 5.0 toxicity criteria. DEC dose is defined as the highest dose at which no more than 1 out of 6 patients experience a DLT. | within the first cycle of therapy (each cycle = 21 days) | 
| Dose limiting toxicity (DLT) for the DEC Phase | Dose Expansion Cohort Phase: DLT is defined as any therapy-attributable adverse event (AE) requiring discontinuation of therapy within one cycle of combined therapy; specifically grade 3 or 4 non-hematologic toxicity and grade 4 hematologic toxicity events. These will be assessed via NCI's CTCAE v 5.0 toxicity criteria. The DLT rate for the DEC cohort is define as the proportion of patients in the safety population and DEC phase of the study that experience at least 1 DLT within the first cycle of sacituzumab in combination with cisplatin treated at the maximum tolerated dose (MTD) | within 1 cycle of therapy (each cycle = 21 days) | 
| Overall Response Rate (ORR) | Overall Response Rate ORR will be measured by the percentage of patients whose cancer decreases in size on assessment. This will be measured as the sum of complete response and partial response by RECISIT 1.1 criteria. | every 3 cycles (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Response (CBR) | CBR will be measured by the percentage of patients whose cancer shrinks or remains stable over the duration of the study. This will be measured as the sum of complete response (CR), partial response (PR), and stable disease (SD) for greater than or equal to 6 months. | 6 months | 
| Progression free survival (PFS) | 6 month progression free survival (PFS) as defined as the time from the start of treatment until confirmed disease progression or death from any cause, whichever occurs first. Disease status (i.e., SD, PR, PR, CR or progressive disease (PD)) will be assessed based on RECIST 1.1 criteria for measurable and non-measurable disease. | 6 months |