The Efficiency of Biomarker-driven Targeted Therapy in Patients With Recurrent Platinum-resistant Epithelial Ovarian Cancer (PROC): An Umbrella Study
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 108
- 试验地点
- 1
- 主要终点
- Objective response rate (ORR)
研究概览
简要总结
This study is an open-label, multicenter, umbrella study aimed to evaluate the combined, biomarker-driven, targeted treatment efficiency of Pamiparib, Bevacizumab, Tislelizumab, and Nab-paclitaxel in patients with platinum-resistant recurrent ovarian cancer (PROC).
详细描述
BRCA1/2 gene status and CD8+ tumor-infiltrating T cell count (CD8 + TILs count) were evaluated as biomarkers using archived tumor tissue samples. Treatment arms were arranged according to pathological diagnosis and biomarker detection results.
Arm1 (Biomarkers: BRCA 1/2 mutant): Pamiparib 40mg PO. bid. plus Bevacizumab 7.5mg/kg IV. D1 (q3w.).
Arm2 (Biomarkers: BRCA 1/2 wildtype and ≥3 CD8+ TILs count): Tislelizumab 200mg IV. D1 + Bevacizumab 7.5mg/kg IV. D1 + Nab-paclitaxel 125mg / m2 IV. D1, 8 (q3w).
Arm3 (Biomarkers: BRCA 1/2 wildtype and <3 CD8+ TILs count): Bevacizumab 7.5mg/kg IV D1, 15 + Nab-paclitaxel 100mg / m2 IV D1, 8, 15 (Q4w).
Treatment would continue until disease progression, intolerable toxicity, death, withdrawal of consent, or sponsor termination of the study, whichever occurs first.
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
- •Voluntary participation and signing of informed consent
- •Age ≥ 18 years;
- •the Eastern United States cancer cooperation group (ECoG) score 0-1;
- •Platinum-resistant recurrent ovarian cancer (PROC): the patient was diagnosed with platinum-resistant recurrence for the first time. PROC refers to the disease progression that occurred < 6 months after the last dose of platinum-based chemotherapy. Imaging-based evaluation for the latest recurrence/progression before enrollment was required;
- •Malignant epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer confirmed by histology or cytology, including high-grade serous cancer, low-grade serous cancer, endometrioid cancer, clear cell cancer, mucinous cancer, and carcinosarcoma;
- •Biomarker detection and tumor sample collection meet the following standards:
- •Patients must provide archived tumor tissue samples (formalin-fixed, paraffin-embedded tumor tissue blocks [preferred], or at least 10 unstained tissue sections), except for patients with serous carcinoma, endometrioid carcinoma, clear cell carcinoma and gBRCAm
- •If the patient has been tested for BRCA1 / 2 gene in the past, only the corresponding test report needs to be provided
- •Sufficient organ functions, which is defined as:
- •neutrophil absolute value (ANC) ≥ 1.5 × 109/L
- •platelet count (PLT) ≥ 75 × 10*9/L
- •hemoglobin ≥ 9 g / dl
- •serum creatinine CR < 1.5 × Upper normal value (ULN)
- •total serum bilirubin ≤ 1.5 × Upper normal range (ULN)
- •both aspartate aminotransferase and alanine aminotransferase ≤ 3 × ULN
- •coagulation function: international normalized ratio (INR) ≤ 1.5; Activated partial prothrombin time (APTT) ≤ 1.5 × ULN
- •Patients must have lesions that can be measured according to RECIST v1.1 standard;
- •Participants were allowed to have previously VEGF / VEGFR inhibitors treatment;
- •Participants were allowed to have previously PARP inhibitors treatment. However, for treatment arm 1 (arm1), the exposure time of PARP inhibitors should ≥ 12 months after first-line chemotherapy or ≥ 6 months after second-line and above chemotherapy;
- •Life expectancy ≥ 3 months;
排除标准
- •The exclusion criteria of bevacizumab were clinically significant cardiovascular and cerebrovascular diseases, history of abdominal fistula or gastrointestinal perforation, acute intestinal obstruction or sub obstruction, and active bleeding;
- •Uncontrolled hypertension (systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg) or clinically significant (active) cardiovascular disease: cerebrovascular accident (CVA) / stroke ≤ 6 months from the treatment of the first clinical study; Myocardial infarction ≤ 6 months from the first clinical study treatment; Unstable angina pectoris; Congestive heart failure (CHF) of grade II or above in the cardiac function classification standard of the New York Heart Association (NYHA); Serious arrhythmias requiring treatment;
- •Previous medical history showed newly discovered thrombotic diseases within 6 months before or during the screening period; Patients with severe wound nonunion, ulcer, or fracture;
- •Major surgery within 30 days before the first administration of study treatment; Patients expected to have invasive surgery during treatment;
- •Patients with other malignant tumors;
- •Patients who have previously received anti-programmed cell death protein-1 (anti-PD-1), anti-programmed death ligand-1 (anti-PD-L1) or anti-PD-L2 drugs, or another drug treatment for T cell inhibitory receptors (e.g., cytotoxic T lymphocyte-associated antigen-4 [CTLA-4], OX-40, CD137 [tumor necrosis factor receptor superfamily member 9 (tnfrsf9)];
- •Active autoimmune diseases requiring systemic treatment in the past 2 years;
- •Any case requiring systemic treatment with corticosteroids (prednisone or equivalent > 10 mg/day) or other immunosuppressive drugs ≤ 14 days before the first administration of the study drug;
- •Known history of human immunodeficiency virus (HIV) infection;
- •Untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers (HBV DNA > 500 IU / ml) or active HCV carriers with detectable HCV RNA; Note: inactive hepatitis B surface antigen (HBsAg) carriers and treated and stable hepatitis B patients (HBV DNA < 500 IU / ml) can be included in the group;
- •History of interstitial lung disease, noninfectious pneumonia, or uncontrolled diseases, including pulmonary fibrosis, acute lung disease, etc;
- •Previous heterologous stem cell transplantation or organ transplantation;
- •Peripheral neuropathy ≥ grade 2;
- •Foods or drugs that are expected to use CYP3A4 strong inducers or strong inhibitors within 28 days before the use of the study drug;
- •Participate in another clinical study at the same time, unless it is an observational (non-intervention) clinical study or is in the follow-up period of intervention study;
- •Women of childbearing age who are unwilling or unable to use effective methods for contraception during the whole treatment period of this trial and within 6 months after the last administration of the study drug [women of childbearing age include: any women who have had menarche and have not undergone successful artificial sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or premenopausal], pregnant or lactating women.
- •Other conditions judged by the researcher that do not meet the enrollment requirements.
研究组 & 干预措施
Arm 1: Pamiparib+ Bevacizumab
Arm1 (Biomarkers: BRCA 1/2 mutant): Pamiparib 40mg PO. bid. plus Bevacizumab 7.5mg/kg IV. D1 (q3w.).
干预措施: Pamiparib (Drug)
Arm 1: Pamiparib+ Bevacizumab
Arm1 (Biomarkers: BRCA 1/2 mutant): Pamiparib 40mg PO. bid. plus Bevacizumab 7.5mg/kg IV. D1 (q3w.).
干预措施: Bevacizumab (Drug)
Arm 2: Tislelizumab + Bevacizumab + Nab-paclitaxel
Arm2 (Biomarkers: BRCA 1/2 wildtype and ≥3 CD8+ TILs count): Tislelizumab 200mg IV. D1 + Bevacizumab 7.5mg/kg IV. D1 + Nab-paclitaxel 125mg / m2 IV. D1, 8 (q3w).
干预措施: Bevacizumab (Drug)
Arm 2: Tislelizumab + Bevacizumab + Nab-paclitaxel
Arm2 (Biomarkers: BRCA 1/2 wildtype and ≥3 CD8+ TILs count): Tislelizumab 200mg IV. D1 + Bevacizumab 7.5mg/kg IV. D1 + Nab-paclitaxel 125mg / m2 IV. D1, 8 (q3w).
干预措施: Tislelizumab (Drug)
Arm 2: Tislelizumab + Bevacizumab + Nab-paclitaxel
Arm2 (Biomarkers: BRCA 1/2 wildtype and ≥3 CD8+ TILs count): Tislelizumab 200mg IV. D1 + Bevacizumab 7.5mg/kg IV. D1 + Nab-paclitaxel 125mg / m2 IV. D1, 8 (q3w).
干预措施: Nab paclitaxel (Drug)
Arm 3: Bevacizumab + Nab-paclitaxel
Arm3 (Biomarkers: BRCA 1/2 wildtype and <3 CD8+ TILs count): Bevacizumab 7.5mg/kg IV D1, 15 + Nab-paclitaxel 100mg / m2 IV D1, 8, 15 (Q4w).
干预措施: Bevacizumab + Nab paclitaxel (intense dose-dense) (Drug)
结局指标
主要结局
Objective response rate (ORR)
时间窗: Up to 3 years
ORR is defined as the proportion of patients with complete response(CR) and partial response(PR) assessed by the investigator in accordance with the RECIST 1.1 criteria.
次要结局
- Overall survival (OS)(Up to 5 years)
- Disease control rate (DCR)(Up to 5 years)
- Progression-free survival (PFS)(Up to 3 years)
- Duration of remission (DOR)(Up to 3 years)
- Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability](Up to 5 years)