Biomarker-driven Targeted Therapy in Patients With Recurrent Platinum-resistant Epithelial Ovarian Cancer

Study Overview
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Brief Summary
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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).

Detailed Description
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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 (Pathological classification: Serous, Endometrioid, and Clear cell Ovarian cancer; Biomarkers: BRCA 1/2 mutant): Pamiparib 40mg PO. bid. plus Bevacizumab 7.5mg/kg IV. D1 (q3w.). Arm2 (Pathological classification: Serous, Endometrioid, and Clear cell Ovarian cancer; 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 (Pathological classification: Serous, Endometrioid, and Clear cell Ovarian cancer; 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). Arm4 (Pathological classification: Mucinous Ovarian cancer, Ovarian carcinosarcoma; Biomarkers: ≥3 CD8+ TILs count): Tislelizumab 200mg IV D1 + Bevacizumab 7.5mg/kg IV D1 + Nab-paclitaxel 125mg / m2 IV D1, 8 (q3w). Arm5 (Pathological classification: Mucinous Ovarian cancer, Ovarian carcinosarcoma; Biomarkers: <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.

Official Title
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The Efficiency of Biomarker-driven Targeted Therapy in Patients With Recurrent Platinum-resistant Epithelial Ovarian Cancer (PROC): An Umbrella Study

Conditions
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Ovarian Cancer

Intervention / Treatment
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* Drug: Pamiparib
* Drug: Bevacizumab
* Drug: Tislelizumab
* Drug: Nab paclitaxel
* Drug: Bevacizumab + Nab paclitaxel (intense dose-dense)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 about 20 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, but the proportion of these patients would not exceed 20%; 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; Exclusion Criteria: 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.

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: Arm 1: Pamiparib+ Bevacizumab<br>Arm1 (Pathological classification: Serous, Endometrioid, and Clear cell Ovarian cancer; Biomarkers: BRCA 1/2 mutant): Pamiparib 40mg PO. bid. plus Bevacizumab 7.5mg/kg IV. D1 (q3w.). | Drug: Pamiparib<br>* 40mg PO. bid.<br>Drug: Bevacizumab<br>* 7.5mg/kg IV. D1 (q3w.)<br>|
| Experimental: Arm 2: Tislelizumab + Bevacizumab + Nab-paclitaxel<br>Arm2 (Pathological classification: Serous, Endometrioid, and Clear cell Ovarian cancer; 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). | Drug: Bevacizumab<br>* 7.5mg/kg IV. D1 (q3w.)<br>Drug: Tislelizumab<br>* 200mg IV. D1<br>Drug: Nab paclitaxel<br>* 125mg / m2 IV. D1, 8 (q3w).<br>|
| Experimental: Arm 3: Bevacizumab + Nab-paclitaxel<br>Arm3 (Pathological classification: Serous, Endometrioid, and Clear cell Ovarian cancer; 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). | Drug: Bevacizumab + Nab paclitaxel (intense dose-dense)<br>* Bevacizumab 7.5mg/kg IV. D1, 15 (Q4w). + Nab paclitaxel 100mg / m2 IV. D1, 8, 15 (Q4w).<br>|
| Experimental: Arm 4: Tislelizumab + Bevacizumab + Nab-paclitaxel<br>Arm4 (Pathological classification: Mucinous Ovarian cancer, Ovarian carcinosarcoma; Biomarkers: ≥3 CD8+ TILs count): Tislelizumab 200mg IV D1 + Bevacizumab 7.5mg/kg IV D1 + Nab-paclitaxel 125mg / m2 IV D1, 8 (q3w). | Drug: Bevacizumab<br>* 7.5mg/kg IV. D1 (q3w.)<br>Drug: Tislelizumab<br>* 200mg IV. D1<br>Drug: Nab paclitaxel<br>* 125mg / m2 IV. D1, 8 (q3w).<br>|
| Experimental: Arm 5: Bevacizumab + Nab-paclitaxel<br>Arm5 (Pathological classification: Mucinous Ovarian cancer, Ovarian carcinosarcoma; Biomarkers: <3 CD8+ TILs count: Bevacizumab 7.5mg/kg IV. D1, 15 + Nab-paclitaxel 100mg / m2 IV. D1, 8, 15 (Q4w). | Drug: Bevacizumab + Nab paclitaxel (intense dose-dense)<br>* Bevacizumab 7.5mg/kg IV. D1, 15 (Q4w). + Nab paclitaxel 100mg / m2 IV. D1, 8, 15 (Q4w).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | 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. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | PFS is defined as the time from enrollment to the first imaging disease progression or death (whichever occurs first). Assessed according to RECIST v1.1 by investigator. | Up to 3 years | 
| Overall survival (OS) | OS is defined as the time between enrollment and the patient's death due to any cause. | Up to 5 years | 
| Disease control rate (DCR) | DCR is defined as the proportion of the patients with complete response, partial remission, and stable disease after treatment. Assessed according to RECIST v1.1 by investigator. | Up to 5 years | 
| Duration of remission (DOR) | DOR is defined as the time interval from the first record of disease response to disease progression or death (whichever occurs first). Assessed according to RECIST v1.1 by investigator. | Up to 3 years | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Safety includes the adverse event profile of all drugs included according to the Common Terminology Criteria for Adverse Events version 5.0. | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biomarker-driven, Targeted therapy, Immunotherapy