biomarker-driven targeted therapy in patients with recurrent platinum-resistant epithelial ovarian cancer

Conditions: Ovarian Cancer

Summary: 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).

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.

Eligibility criteria:
inclusion criteria: 1. voluntary participation and signing of informed consent 2. age ≥ 18 years; 3. the eastern united states cancer cooperation group (ecog) score 0-1; 4. 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; 5. 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; 6. 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 7. 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 8. patients must have lesions that can be measured according to recist v1.1 standard; 9. participants were allowed to have previously vegf / vegfr inhibitors treatment; 10. 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; 11. life expectancy ≥ 3 months; exclusion criteria: 1. 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; 2. 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; 3. 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; 4. major surgery within 30 days before the first administration of study treatment; patients expected to have invasive surgery during treatment; 5. patients with other malignant tumors; 6. 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 \[tumor necrosis factor receptor superfamily member 9 (tnfrsf9)\]; 7. active autoimmune diseases requiring systemic treatment in the past 2 years; 8. 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; 9. known history of human immunodeficiency virus (hiv) infection; 10. 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; 11. history of interstitial lung disease, noninfectious pneumonia, or uncontrolled diseases, including pulmonary fibrosis, acute lung disease, etc; 12. previous heterologous stem cell transplantation or organ transplantation; 13. peripheral neuropathy ≥ grade 2; 14. foods or drugs that are expected to use cyp3a4 strong inducers or strong inhibitors within 28 days before the use of the study drug; 15. 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; 16. 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. 17. other conditions judged by the researcher that do not meet the enrollment requirements.

Keywords: biomarker-driven targeted therapy immunotherapy