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

Tongji Hospital

Status and phase: Completed; Phase 2

Conditions: Ovarian Cancer

Treatments: Drug: Bevacizumab + Nab paclitaxel (intense dose-dense); Drug: Bevacizumab; Drug: Nab paclitaxel; Drug: Pamiparib; Drug: Tislelizumab

Study type: Interventional

Funder types: Other

Identifiers

NCT05044871

2021-TJ-PROC

Details and patient eligibility

About

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).

Full description

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.

Enrollment: 108 patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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108 participants in 3 patient groups

Arm 1: Pamiparib+ Bevacizumab

Experimental group

Description:

Arm1 (Biomarkers: BRCA 1/2 mutant): Pamiparib 40mg PO. bid. plus Bevacizumab 7.5mg/kg IV. D1 (q3w.).

Treatment:

Drug: Pamiparib

Drug: Bevacizumab

Arm 2: Tislelizumab + Bevacizumab + Nab-paclitaxel

Experimental group

Description:

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).

Treatment:

Drug: Tislelizumab

Drug: Nab paclitaxel

Drug: Bevacizumab

Arm 3: Bevacizumab + Nab-paclitaxel

Experimental group

Description:

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:

Drug: Bevacizumab + Nab paclitaxel (intense dose-dense)