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

Study Overview
=================
Brief Summary
-----------------
JAVELIN Ovarian PARP 100 (B9991030) is an open-label, randomized study designed to evaluate the efficacy and safety of avelumab in combination with chemotherapy followed by maintenance therapy of avelumab in combination with talazoparib versus an active comparator in treatment-naïve patients with locally advanced or metastatic ovarian cancer (Stage III or Stage IV). On March 19, 2019, Sponsors alliance announced the discontinuation of the ongoing Phase III study, and the decision was based on several factors, including previous announced interim results from JAVELIN Ovarian 100 study (B9991010). Patients who remain in B9991030 study will continue receiving their randomized treatment assigned and will be monitored for appropriate safety assessments until treatment discontinuation.

Detailed Description
-----------------
JAVELIN Ovarian PARP 100 (B9991030) is an open-label, international, multi-center, randomized study designed to evaluate the efficacy and safety of avelumab in combination with chemotherapy followed by maintenance therapy of avelumab in combination with talazoparib versus an active comparator in treatment-naïve patients with locally advanced or metastatic ovarian cancer (Stage III or Stage IV). The primary endpoint is progression-free survival (PFS) as determined based on blinded independent central review (BICR) assessment per RECIST v1.1. On March 19, 2019, Sponsors alliance announced the discontinuation of the ongoing Phase III JAVELIN Ovarian PARP 100 study. The alliance has notified health authorities and trial investigators of the decision to discontinue the trial. The decision was based on several emerging factors since the trial's initiation, including the previously announced interim results from JAVELIN Ovarian 100 study (B9991010), which was stopped due to futility of efficacy at a planned interim analysis on 21 December 2018. The alliance determined that the degree of benefit observed with avelumab in frontline ovarian cancer in that study does not support continuation of the JAVELIN Ovarian PARP 100 trial in an unselected patient population and emphasizes the need to better understand the role of immunotherapy in ovarian cancer. Additional factors include the rapidly changing treatment landscape and the approval of a PARP inhibitor in the frontline maintenance setting. The decision to discontinue the JAVELIN Ovarian PARP 100 trial was not made for safety reasons. Patients who remain in the study will continue receiving investigational products according to their randomized treatment assignment and will be monitored for appropriate safety assessments until treatment discontinuation.

Official Title
-----------------
A RANDOMIZED, OPEN-LABEL, MULTICENTER, PHASE 3 STUDY TO EVALUATE THE EFFICACY AND SAFETY OF AVELUMAB IN COMBINATION WITH CHEMOTHERAPY FOLLOWED BY MAINTENANCE THERAPY OF AVELUMAB IN COMBINATION WITH THE POLY (ADENOSINE DIPHOSPHATE [ADP]-RIBOSE) POLYMERASE (PARP) INHIBITOR TALAZOPARIB IN PATIENTS WITH PREVIOUSLY UNTREATED ADVANCED OVARIAN CANCER (JAVELIN OVARIAN PARP100)

Conditions
-----------------
Ovarian Cancer

Intervention / Treatment
-----------------
* Drug: Chemotherapy + avelumab followed by avelumab + talazoparib
* Drug: Chemotherapy followed by talazoparib maintenance
* Drug: Chemotherapy + bevacizumab followed by bevacizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
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. 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. 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-α), 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: chemotherapy, avelumab and talazoparib<br>Platinum-based chemotherapy + avelumab followed by avelumab + talazoparib maintenance | Drug: Chemotherapy + avelumab followed by avelumab + talazoparib<br>* Chemotherapy Period Paclitaxel Carboplatin Avelumab Maintenance Period Avelumab Talazoparib<br>|
| Experimental: chemotherapy, and talazoparib<br>Platinum-based chemotherapy followed by talazoparib maintenance | Drug: Chemotherapy followed by talazoparib maintenance<br>* Chemotherapy Period Paclitaxel Carboplatin Maintenance Period Talazoparib<br>|
| Active Comparator: chemotherapy and bevacizumab<br>Platinum-based chemotherapy + bevacizumab followed by bevacizumab maintenance | Drug: Chemotherapy + bevacizumab followed by bevacizumab<br>* Chemotherapy Period Paclitaxel Carboplatin Bevacizumab Maintenance Period Bevacizumab<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (Participants With Newly Diagnosed Advanced Ovarian Cancer With Defects in DDR+） | Progression-free survival (PFS) was defined as the time from randomization to the date of the first documentation of objective progressive disease (PD) or death due to any cause, whichever occurred first. PD: >=20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5mm, appearance of one or more new lesions was considered PD. | At screening, 9 and 18 weeks after date of randomization, then every 12 weeks thereafter until PD by Blinded Independent Central Review (BICR) regardless of initiation of new anti-cancer therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (On-Treatment Period) | An adverse event (AE) was any untoward medical occurrence in a study participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death, was lifethreatening (immediate risk of death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions), resulted in congenital anomaly/birth defect or considered to be an important medical event. AEs included SAEs and non-serious AEs. On-treatment period was defined as the time from the first dose of study treatment through up to 30 days after minimum last dose of study treatment or start day of new anti-cancer drug therapy minus 1 day. | From the first dose of study treatment through up to 30 days after minimum last dose of study treatment or start day of new anti-cancer drug therapy minus 1 day (maximum up to 3.5 years approximately) | 
| Number of Participants With ADA Against Avelumab by Never and Ever Positive Status | Predose Anti-drug antibodies (ADA) samples were collected within 2 hours prior to avelumab dosing and drawn from the contralateral arm of the avelumab infusion. | Day 1 pre-dose of Cycles 1, 2, 3, and 4 in the chemotherapy period and Days 1 and 29 of Cycle 1 and Day 1 of Cycles 2, 4, 6, and 10 in the maintenance period and at the end of treatment/withdrawal, up to 27 months. | 
| Pre-dose/Trough Concentration (Ctrough) for Avelumab (Chemotherapy Period) | Ctrough was defined as predose concentration during multiple dosing and it was observed directly from data | Day 1 of Cycles 1, 2, 3, and 4 in the chemotherapy period (1 cycle = 3 weeks) | 
| Pre-dose/Trough Concentration (Ctrough) for Avelumab (Maintenance Period) | Ctrough was defined as predose concentration during multiple dosing and it was observed directly from data | Pre-dose on Days 1 and 29 of Cycle 1 and Day 1 of Cycles 2, 4, 6, and 10 in the maintenance period (1 cycle = 6 weeks) and at the end of treatment, up to 27 months. | 
| Cmax for Avelumab (Chemotherapy Period) | Cmax was defined as maximum observed plasma concentration and it was observed directly from data | Day 1 of Cycles 1, 2, 3, and 4 in the chemotherapy period (1 cycle = 3 weeks) | 
| Cmax for Avelumab (Maintenance Period) | Cmax was defined as maximum observed plasma concentration and it was observed directly from data | Day 1 pre-dose of Cycles 1, 2, 3, and 4 in the chemotherapy period and Days 1 and 29 of Cycle 1 and Day 1 of Cycles 2, 4, 6, and 10 in the maintenance period and at the end of treatment/withdrawal, up to 27 months. | 
| Ctrough for Talazoprib (Maintenance Period) | Ctrough was defined as predose concentration during multiple dosing and it was observed directly from data. | Pre-dose on Days 1, 15 and 29 of Cycle 1 | 
| Overall Survival (Participants of Both DDR+ and Unselected DDR Status) | OS was defined as the time from the date of randomization to the date of death due to any cause. | From 9 weeks up to approximately 3.5 years | 
| Progression-free Survival (Participants of Unselected DDR Status) | PFS was defined as the time from the date of randomization to the date of the first documentation of PD or death due to any cause, whichever occured first. | At screening, 9 and 18 weeks after date of randomization, then every 12 weeks thereafter until PD by BICR regardless of initiation of new anti-cancer therapy, up to approximately 3.5 years. | 
| Progression-free Survival (Participants of Both DDR+ and Unselected DDR Status) | PFS was defined as the time from randomization to the date of the first documentation of objective progressive disease(PD) or death due to any cause, whichever occured first. Participants was defined as having defective DDR (DDR+) or having intact DDR (DDR ) using a next generation sequencing based assay method. | At screening, 9 and 18 weeks after date of randomization, then every 12 weeks thereafter until PD by BICR regardless of initiation of new anti-cancer therapy, up to approximately 3.5 years. | 
| Progression-free Survival on Next-line Therapy. (Participants of Both DDR+ and Unselected DDR Status) | Progression-free survival on next-line therapy (PFS2) was defined as time from the date of randomization to the start of second subsequent treatment after first documentation of PD, or death from any cause, whichever occured first. Participants was defined as having defective DDR (DDR+) or having intact DDR (DDR ) using a next generation sequencing based assay method | From screening until the participant had objective PD on or prior to start of next-line anti-cancer treatment, and started a second subsequent anti-cancer treatment or the participant died, up to approximately 3.5 years. | 
| PFS Per Gynecological Cancer Intergroup Criteria (Participants of Both DDR+ and Unselected DDR Status) | PFS based on investigator assessment per Gynecological Cancer Intergroup criteria (GCIG) would be assessed incorporating both Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and CA 125. Participants was defined as having defective DDR (DDR+) or having intact DDR (DDR ) using a next generation sequencing based assay method. | From screening until death, end of study, or participant withdrawal of consent, whichever occurred first, up to approximately 3.5 years. | 
| Functional Assessment of Ovarian Symptom Index-18 (FOSI-18) Score | NFOSI-18 was an ovarian cancer-specific symptom index comprised of symptoms rated as highest priority by both oncology clinical experts and women with advanced ovarian cancer. It was specifically designed to be a stand-alone instrument to measure disease-related symptoms, treatment side effects and function/well-being in participants with ovarian cancer. The NFOSI-18 has several subscales: disease-related symptoms physical subscale(9 items), disease-related symptoms emotional subscale(1 item), treatment-related side effect subscale (5 items) and functional well-being (3 items). A high score was good. A score of 0 was a severely symptomatic participant and the highest possible score was an asymptomatic participant. | 3 years | 
| Programmed Death Receptor-1 Ligand-1 (PD-L1) Biomarker Expression in Tumor and Immune Cells as Assessed by Immunohistochemistry (IHC) at Baseline | The number of PD-L1 positive cells and/or qualitative assessment of PD-L1 staining on tumor and inflammatory cells in regions of interest that were defined by tumor cell morphology and the presence or absence of inflammatory cells | Baseline | 
| Number of Participants With Mutations in Key Oncogenes at Baseline | Determination/estimation of the frequency of mutations (total and non-synonymous) present in baseline tumor derived nucleic acid samples and in baseline circulating tumor DNA. | Baseline | 
| EuroQol Group 5-Dimension 5-Level (EQ-5D-5L) Score | The EuroQol EQ-5D-5L was a 6 item participant-completed questionnaire designed to assess health status in terms of a single index value or utility score. There are 2 components to the EQ-5D-5L, a Health State Profile which had individuals rate their level of problems (none, slight, moderate, severe, extreme/unable) in 5 areas (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), and a Visual Analogue Scale (VAS) in which participants rate their overall health status from 0 (worst imaginable) to 100 (best imaginable). Published weights were available that allow for imputation of the index score. Overall index scores ranged from 0 to 1, with low scores representing a higher level of dysfunction. | 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
untreated epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer