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
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 54
- 试验地点
- 2
- 主要终点
- Dose-limiting toxicity (DLT) at the maximum tolerated dose (MTD) for the Safety Run-In Phase
研究概览
简要总结
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.
详细描述
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)
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Eligibility waivers are not permitted. Subjects must meet all of the inclusion and
排除标准
- •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
研究组 & 干预措施
Ovarian cancer Cohort
DEC 3+3 dose expansion of Sacituzumab Govitecan in Combination with Cisplatin
干预措施: Cisplatin (Drug)
Endometrial cancer Cohort
DEC 3+3 dose expansion of Sacituzumab Govitecan in Combination with Cisplatin
干预措施: Cisplatin (Drug)
Endometrial cancer Cohort
DEC 3+3 dose expansion of Sacituzumab Govitecan in Combination with Cisplatin
干预措施: Sacituzumab (Drug)
Ovarian cancer Cohort
DEC 3+3 dose expansion of Sacituzumab Govitecan in Combination with Cisplatin
干预措施: Sacituzumab (Drug)
结局指标
主要结局
Dose-limiting toxicity (DLT) at the maximum tolerated dose (MTD) for the Safety Run-In Phase
时间窗: 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
时间窗: 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)
时间窗: 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.
次要结局
- Clinical Benefit Response (CBR)(6 months)
- Progression free survival (PFS)(6 months)
- Number of adverse events(6 months)
研究者
Amy Tiersten
MD. Professor of Medicine (Hematology and Medical Oncology) Clinical Director, Breast Medical Oncology, Dubin Breast Center
Icahn School of Medicine at Mount Sinai