Status of HRD That Lead to a Benefit From Olaparib in Combination With Bevacizumab (STROBE Trial)

Non-Randomized, Open-Label, Prospective Phase II Trial to Better Characterize the Status of HRD Leading to a Benefit From Olaparib in Combination With Bevacizumab in Patients With Advanced FIGO Stage III-IV High Grade Serous or Endometrioid Ovarian, Fallopian Tube, or Peritoneal Cancer After Standard First-Line Treatment

Background:

The study aims to address the challenge of accurately identifying patients with ovarian cancer who would benefit from poly-ADP ribose inhibitors (PARPi) as first-line maintenance therapy. While BRCA1/2-mutated epithelial ovarian cancer (EOC) patients have shown significant benefits from PARPi treatment, the efficacy in homologous recombination deficient (HRD) patients remains inconclusive. Current assays used to estimate HR status do not effectively differentiate between patients who benefit most from PARPi and those who do not, making it inefficient to treat all patients. There is a need for a more accurate HR status testing method to optimize PARPi benefit. This study aims to assess the performance of the VHIO-CARD-300 test in determining HR status compared to SOPHiA DDM™ Dx HRD Solution.

Summary:

The study is a prospective, non-randomized trial designed to evaluate the concordance of the VHIO-CARD-300 test in establishing HR status compared to SOPHiA DDM™ Dx HRD Solution. Additionally, it aims to assess the association between HRD status determined by the VHIO-CARD-300 test and treatment efficacy. Patients with advanced FIGO stage III-IV high grade serous or endometrioid ovarian, fallopian tube, or peritoneal cancer will be invited to participate. Those eligible will undergo testing with both VHIO-CARD-300 and SOPHiA DDM™ Dx HRD Solution. Patients classified as HRD positive will receive olaparib in combination with bevacizumab, while others will receive bevacizumab alone. Treatment will be administered according to approved doses, with follow-up evaluations conducted until RECIST progression.

This non-randomized, open-label phase II trial seeks to enhance our understanding of HRD status in patients with advanced ovarian, fallopian tube, or peritoneal cancer. Following standard first-line treatment, participants will be assessed for HRD status using the VHIO-CARD-300 test and SOPHiA DDM™ Dx HRD Solution. Those identified as HRD-positive will receive olaparib in combination with bevacizumab, while others will receive bevacizumab alone as per standard care. The study aims to determine the concordance between the two HRD tests, evaluate the efficacy of the olaparib-bevacizumab combination, and assess safety and tolerability. Efficacy outcomes will be evaluated using RECIST criteria, with a minimum follow-up of 30 months post-enrollment. Secondary objectives include examining treatment accuracy, association with efficacy outcomes, and analyzing discrepant cases. Overall, this trial aims to provide valuable insights into personalized treatment approaches for patients with advanced ovarian cancer.

Inclusion Criteria:

1. Patient with newly diagnosed high- grade serous or endometrioid Ovarian cancer, primary peritoneal cancer and/or fallopian-tube cancer. I-3-3 At an advanced stage: FIGO stage IIIB, IIIC, or IV of the 1988 FIGO classification (see appendix 1).

2. Patient who has completed prior to enrollment first line platinum-taxane chemotherapy:

   1. Platinum-taxane based regimen must have consisted of
   2. minimum of 6 treatment cycles and a maximum of 8. However, if platinum-based therapy must be discontinued early as a result of non-hematological toxicityspecificallyrelated to the platinum regimen, (i.e. neurotoxicity, hypersensitivity etc.), patient must have received a minimum of 4 cycles of the platinum regimen.
   3. Patient must have received prior to enrollment a minimum of 3 cycles of bevacizumab in combination with the 3 last cycles of platinum-based chemotherapy. Only in case of interval debulking surgery, it is allowed to realize only 2 cycles of bevacizumab in combination with the last 3 cycles of platinum-based chemotherapy.

3. Patient must be prior to enrollment without evidence of disease (NED) or in complete response (CR) or partial response (PR) from the first line treatment. There should be no clinical evidence of disease progression (physical exam, imagery, CA 125) throughout he first line treatment and prior to study enrollment.

4. Patient must be randomized at least 4 weeks and no more than 8 weeks after her last dose of chemotherapy (last dose is the day of the last infusion) and all major toxicities from theprevious chemotherapy must have resolved to CTCAE grade 1 or better (except alopecia and peripheral neuropathy).

5. Patient must have normal organ and bone marrow function:

6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (see appendix 3)

7. Formalin fixed, paraffin embedded (FFPE) tumor sample from the primary cancer must be available for central BRCA testing and test result must be available for stratification.

Exclusion Criteria:

1. Non-epithelial origin of the ovary, the fallopian tube or the peritoneum (i.e. germ cell tumors).

2. Ovarian tumors of low malignant potential (e.g. borderline tumors) or mucinous carcinoma.

3. Other malignancy within the last 5 years except:

4. Patient with myelodysplastic syndrome/acute myeloid leukemia history.

5. Major surgery within 4 weeks of starting study treatment and patient must have recovered from any effects of any major surgery.

6. Any previous treatment with PARP inhibitor, including olaparib.

7. Concomitant use of known potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.

8. Prior history of hypertensive crisis (CTC-AE grade 4) or hypertensive encephalopathy.

9. Clinically significant (e.g. active) cardiovascular disease, including:

   1. Myocardial infarction or unstable angina within ≤ 6 months of enrollment,
   2. New York Heart Association (NYHA) ≥ grade 2 congestive heart failure (CHF) (see appendix 5).
   3. Poorly controlled cardiac arrhythmia despite medication (patient with rate controlled atrial fibrillation are eligible), or any clinically significant abnormal finding on resting ECG,
   4. Peripheral vascular disease grade ≥ 3 (e.g. symptomatic and interfering with activities of daily living [ADL] requiring repair or revision)

10. Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or Sub-Arachnoids Hemorrhage (SAH) within 6 months prior to enrollment.

11. History or evidence of hemorrhagic disorders within 6 months prior to enrollment.

12. History or clinical suspicion of brain metastases or spinal cord compression.

13. Significant traumatic injury during 4 weeks prior to enrollment.

14. Non-healing wound, active ulcer or bone fracture.

15. History of VEGF therapy related abdominal fistula or gastrointestinal perforation or active gastrointestinal bleeding within 6 months prior to the first study treatment.

16. Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease.

17. Patient with evidence of abdominal free air not explained by paracentesis or recent surgical procedure.