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 14, 2021
• Sponsor: Tongji Hospital
• Collaborators: Qilu Hospital of Shandong University; Hubei Cancer Hospital; Hunan Cancer Hospital; Beijing Cancer Hospital; 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

Tracking Information

• First Submitted Date: September 9, 2021
• First Posted Date: September 16, 2021
• Last Update Posted Date: October 14, 2021
• Estimated Study Start Date: January 1, 2022
• Estimated Primary Completion Date: June 1, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 9, 2021)

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 6, 2021)

• 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.
• 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.
• 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.
• 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.
• 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.

Original Secondary Outcome Measures (submitted: September 9, 2021)

• 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.
• 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.
• 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.
• 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.
• Safety of therapies [ 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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 Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Ovarian Cancer

Intervention

• Drug: Pamiparib
  40mg PO. bid.
• Drug: Bevacizumab
  7.5mg/kg IV. D1 (q3w.)
• Drug: Tislelizumab
  200mg IV. D1
• Drug: Nab paclitaxel
  125mg / m2 IV. D1, 8 (q3w).
• Drug: Bevacizumab + Nab paclitaxel (intense dose-dense)
  Bevacizumab 7.5mg/kg IV. D1, 15 (Q4w). + Nab paclitaxel 100mg / m2 IV. D1, 8, 15 (Q4w).

Study Arms

• 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.).
  Interventions:

  • Drug: Pamiparib
  • Drug: Bevacizumab
• 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).
  Interventions:

  • Drug: Bevacizumab
  • Drug: Tislelizumab
  • Drug: Nab paclitaxel
• 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).
  Intervention: Drug: Bevacizumab + Nab paclitaxel (intense dose-dense)
• 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).
  Interventions:

  • Drug: Bevacizumab
  • Drug: Tislelizumab
  • Drug: Nab paclitaxel
• 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).
  Intervention: Drug: Bevacizumab + Nab paclitaxel (intense dose-dense)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: September 9, 2021): 160
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 1, 2027
• Estimated Primary Completion Date: June 1, 2024 (Final data collection date for primary outcome measure)

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 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.

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: China

Administrative Information

• NCT Number: NCT05044871
• Other Study ID Numbers: 2021-TJ-PROC
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Responsible Party: Qinglei Gao, Tongji Hospital
• Study Sponsor: Tongji Hospital

Collaborators

• Qilu Hospital of Shandong University
• Hubei Cancer Hospital
• Hunan Cancer Hospital
• Beijing Cancer Hospital
• 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

• PRS Account: Tongji Hospital
• Verification Date: October 2021