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

• ClinicalTrials.gov Identifier: NCT05044871
• Recruitment Status: Not yet recruiting
• First Posted: September 16, 2021
• Last Update Posted: October 20, 2022
• Sponsor: Tongji Hospital
• Collaborators: Qilu Hospital of Shandong University; Hubei Cancer Hospital; Hunan Cancer Hospital; Peking University Cancer Hospital & Institute; Obstetrics and Gynecology Hospital of Zhejiang University; Sun Yat-sen University; Anhui Provincial Cancer Hospital; Jilin Provincial Tumor Hospital; First Affiliated Hospital, Sun Yat-Sen University; Affiliated Hospital of Jiangnan University
• Information provided by (Responsible Party): Qinglei Gao, Tongji Hospital

Study Description

Brief 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).

Condition or disease	Intervention/treatment	Phase
Ovarian Cancer	Drug: Pamiparib; Drug: Bevacizumab; Drug: Tislelizumab; Drug: Nab paclitaxel; Drug: Bevacizumab + Nab paclitaxel (intense dose-dense)	Phase 2

Detailed 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 (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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 160 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Efficiency of Biomarker-driven Targeted Therapy in Patients With Recurrent Platinum-resistant Epithelial Ovarian Cancer (PROC): An Umbrella Study
• Estimated Study Start Date: January 1, 2023
• Estimated Primary Completion Date: June 1, 2024
• Estimated Study Completion Date: December 1, 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm 1: Pamiparib+ Bevacizumab; 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; 40mg PO. bid.; Drug: Bevacizumab; 7.5mg/kg IV. D1 (q3w.)
Experimental: Arm 2: Tislelizumab + Bevacizumab + Nab-paclitaxel; 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; 7.5mg/kg IV. D1 (q3w.); Drug: Tislelizumab; 200mg IV. D1; Drug: Nab paclitaxel; 125mg / m2 IV. D1, 8 (q3w).
Experimental: Arm 3: Bevacizumab + Nab-paclitaxel; 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); Bevacizumab 7.5mg/kg IV. D1, 15 (Q4w). + Nab paclitaxel 100mg / m2 IV. D1, 8, 15 (Q4w).
Experimental: Arm 4: Tislelizumab + Bevacizumab + Nab-paclitaxel; 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; 7.5mg/kg IV. D1 (q3w.); Drug: Tislelizumab; 200mg IV. D1; Drug: Nab paclitaxel; 125mg / m2 IV. D1, 8 (q3w).
Experimental: Arm 5: Bevacizumab + Nab-paclitaxel; 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); Bevacizumab 7.5mg/kg IV. D1, 15 (Q4w). + Nab paclitaxel 100mg / m2 IV. D1, 8, 15 (Q4w).

Outcome Measures

Primary Outcome Measures :

1. Objective response rate (ORR) [ Time Frame: 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.

Secondary Outcome Measures :

1. Progression-free survival (PFS) [ Time Frame: Up to 3 years ]
   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.
2. Overall survival (OS) [ Time Frame: Up to 5 years ]
   OS is defined as the time between enrollment and the patient's death due to any cause.
3. Disease control rate (DCR) [ Time Frame: Up to 5 years ]
   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.
4. Duration of remission (DOR) [ Time Frame: Up to 3 years ]
   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.
5. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: Up to 5 years ]
   Safety includes the adverse event profile of all drugs included according to the Common Terminology Criteria for Adverse Events version 5.0.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Accepts Healthy Volunteers: No

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 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

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, but the proportion of these patients would not exceed 20%;
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.

Contacts and Locations

Contacts

Contact: Qinglei Gao, MD. PhD; 15391566981; qingleigao@hotmail.com

Locations

China, Hubei

Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology

Wuhan, Hubei, China, 430030

Sponsors and Collaborators

Tongji Hospital

Qilu Hospital of Shandong University

Hubei Cancer Hospital

Hunan Cancer Hospital

Peking University Cancer Hospital & Institute

Obstetrics and Gynecology Hospital of Zhejiang University

Sun Yat-sen University

Anhui Provincial Cancer Hospital

Jilin Provincial Tumor Hospital

First Affiliated Hospital, Sun Yat-Sen University

Affiliated Hospital of Jiangnan University

Investigators

• Principal Investigator: Qinglei Gao, MD. PhD; Tongji Hospital

More Information

• Responsible Party: Qinglei Gao, Professor, Tongji Hospital
• ClinicalTrials.gov Identifier: NCT05044871
• Other Study ID Numbers: 2021-TJ-PROC
• First Posted: September 16, 2021
• Last Update Posted: October 20, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Qinglei Gao, Tongji Hospital:

Biomarker-driven; Targeted therapy; Immunotherapy

Additional relevant MeSH terms:

Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Endocrine System Diseases; Gonadal Disorders; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Paclitaxel; Albumin-Bound Paclitaxel; Bevacizumab; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors