Ovarian Cancer, Malignant Neoplasm of Uterus
Conditions
Brief summary
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
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.
Interventions
DRUGSacituzumab
Dose 0: Sacituzumab govitecan 7.5 mg/kg Dose -1: Sacituzumab govitecan 5 mg/kg
DRUGCisplatin
Cisplatin 70 mg/m2 IV
Sponsors
Icahn School of Medicine at Mount Sinai
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-limiting toxicity (DLT) at the maximum tolerated dose (MTD) for the Safety Run-In Phase | within the first cycle of therapy (each cycle = 21 days) | Safety Run-In Phase: The primary endpoint of the safety run-in phase is to determine DLT and the recommended 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. All primary endpoints will be reported separately for each of the ovarian and endometrial cohorts. |
| Dose limiting toxicity (DLT) for the DEC Phase | within 1 cycle of therapy (each cycle = 21 days) | A primary endpoint for the dose expansion cohort (DEC) phase of this study will be the DLT rate evaluated within 1 cycle of sacituzumab in combination with cisplatin. The DLT rate is defined as the proportion of patients in the safety population of the phase 1 and dose expansion cohort (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). 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. All primary endpoints will be reported separately for each of the ovarian and endometrial cohorts. |
| Overall Response Rate (ORR) | every 3 cycles (each cycle is 21 days) | A primary endpoint for the dose expansion cohort (DEC) phase will be the ORR evaluated within 3 cycles of sacituzumab in combination with cisplatin in patients with platinum-sensitive recurrent epithelial ovarian cancer and endometrial cancer. This will be measured every 3 cycles (12 weeks +/- 1 week). The overall response rate is defined as the proportion of patients in the full analysis (FA) population treated at the MTD, in both the phase 1 and DEC phases of the study, whose cancer decreases in size on assessment (as measured by the sum of complete response (CR) and partial response (PR)). Disease status will be assessed based on RECIST 1.1 criteria for measurable and non-measurable disease. The Full Analysis (FA) population includes all patients who received at least one cycle of all study medications and had at least one valid post-baseline efficacy assessment. All primary endpoints will be reported separately for each of the ovarian and endometrial cohorts. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Response (CBR) | 6 months | For the entire cohort (Safety Run-In and Dose Expansion Cohort), 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. Disease status will be assessed based on RECIST 1.1 criteria for measurable and non-measurable disease. The analysis plan for all secondary endpoints will be conducted separately for each disease cohort (ovarian and endometrial). |
| Progression free survival (PFS) | 6 months | For the entire cohort (Safety Run-In and Dose Expansion Cohort), 6-month progression free survival (PFS) is as defined as the time from the start of treatment until confirmed disease progression or death from any cause, whichever occurs first. Disease status will be assessed with comprehensive radiographic studies every 3 treatment cycles (12 weeks +/- 1 week), but the development of new signs or symptoms of disease in between scheduled evaluations may prompt off-schedule radiographic or non-radiographic evaluations. Disease status will be assessed based on RECIST 1.1 criteria for measurable and non-measurable disease. The analysis plan for all secondary endpoints will be conducted separately for each disease cohort (ovarian and endometrial). |
| Number of adverse events | 6 months | For the entire cohort (Safety Run-In and Dose Expansion Cohort), the type, incidence, severity (as graded by the National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] v5.0), seriousness and relationship to study medications of Adverse Events will be determined. |
Countries
United States
Contacts
Primary ContactAmy Tiersten, MD
Backup ContactMelanie Kier, MD
Outcome results
None listed