Avelumab and Talazoparib in Untreated Advanced Ovarian Cancer (JAVELIN OVARIAN PARP 100)

This is a Phase 3, randomized, open-label, multicenter study to evaluate the efficacy and safety of avelumab in combination with chemotherapy followed by maintenance therapy of avelumab in combination with the PARP inhibitor talazoparib in patients with previously untreated advanced ovarian cancer. Eligible patients must have previously untreated histologically confirmed Stage III IV epithelial ovarian, fallopian tube, or primary peritoneal cancer and must be candidates for bevacizumab in combination with platinum based chemotherapy.

The primary purpose of the study is to demonstrate that avelumab in combination with platinum-based chemotherapy followed by avelumab plus talazoparib maintenance is superior to platinum-based chemotherapy plus bevacizumab followed by bevacizumab maintenance in prolonging PFS in patients with advanced ovarian cancer.

• Drug: Chemotherapy + avelumab followed by avelumab + talazoparib
  

  Chemotherapy Period Paclitaxel Carboplatin Avelumab

  Maintenance Period Avelumab Talazoparib

• Drug: Chemotherapy followed by talazoparib maintenance
  

  Chemotherapy Period Paclitaxel Carboplatin

  Maintenance Period Talazoparib

• Drug: Chemotherapy + bevacizumab followed by bevacizumab
  

  Chemotherapy Period Paclitaxel Carboplatin Bevacizumab

  Maintenance Period Bevacizumab

• Experimental: chemotherapy, avelumab and talazoparib
  
  Platinum-based chemotherapy + avelumab followed by avelumab + talazoparib maintenance
  Intervention: Drug: Chemotherapy + avelumab followed by avelumab + talazoparib
• Experimental: chemotherapy, and talazoparib
  
  Platinum-based chemotherapy followed by talazoparib maintenance
  Intervention: Drug: Chemotherapy followed by talazoparib maintenance
• Active Comparator: chemotherapy and bevacizumab
  
  Platinum-based chemotherapy + bevacizumab followed by bevacizumab maintenance
  Intervention: Drug: Chemotherapy + bevacizumab followed by bevacizumab

Inclusion Criteria:

• Histologically confirmed Stage III IV epithelial ovarian, fallopian tube, or primary peritoneal cancer including carcinosarcoma with high-grade serous component.
• Patients must be candidates for bevacizumab in combination with platinum based chemotherapy and previously untreated.

• Must have completed a primary surgical debulking procedure, or be candidates for neoadjuvant chemotherapy with planned interval debulking surgery.

  1. Patients who completed primary debulking must have had incompletely resected disease that is macroscopically/grossly visible and at least with lesions >1 mm and be randomized at a maximum of 8 weeks after surgery.

  2. For patients who are candidates for neoadjuvant chemotherapy, the diagnoses must have been confirmed by:

     • Core tissue (not fine-needle aspiration) biopsy is required for diagnosis.
     • Stage IIIC-IV documented via imaging or surgery (without attempt at cytoreduction).
     • Serum CA-125/CEA ratio >25. If the serum CA-125/CEA ratio is <25, then workup should be negative for the presence of a primary gastrointestinal or breast malignancy (<6 weeks before start of neoadjuvant treatment).
     • Randomization must occur within 8 weeks after diagnosis.
• Availability of an archival FFPE tumor tissue block or a minimum of 25 slides, together with an accompanying original H&E slide. If archived FFPE tissue is not available, a de novo (ie, fresh) tumor sample must be obtained in accordance with local institutional practice for tumor biopsies. Tumor tissue must contain 40% or greater tumor nuclei per central laboratory assessment.
• ECOG performance status 0-1
• Age >=18 years (or >=20 years in Japan).
• Adequate bone marrow, hepatic, and renal function and blood coagulation

Exclusion Criteria:

• Non-epithelial tumors or ovarian tumors with low malignant potential (ie, borderline tumors) or mucinous tumors.
• Patients for whom intraperitoneal cytotoxic chemotherapy is planned.
• Prior exposure to immunotherapy with interleukin (IL)-2, interferon alpha (IFN-?), or an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte associated antigen 4 (anti-CTLA4) antibody (including ipilimumab), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, excluding therapeutic anticancer vaccines.
• Prior treatment with a PARP inhibitor.
• Prior treatment with any anti-vascular endothelial growth factor (VEGF) drug, including bevacizumab.
• Major surgery (other than debulking or exploratory surgery for ovarian cancer) for any reason within 4 weeks prior to randomization and/or incomplete recovery from surgery.
• Prior radiotherapy to any portion of the abdominal cavity or pelvis. Prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease.
• Prior targeted therapy (including but not limited to vaccines, antibodies, tyrosine kinase inhibitors) or hormonal therapy for management of their ovarian, peritoneal primary or fallopian tube carcinoma.
• Prior organ transplantation including allogenic stem cell transplantation.
• Diagnosis of Myelodysplastic Syndrome (MDS).
• Known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study enrollment, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable.