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)
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 发起方
- Pfizer
- 入组人数
- 79
- 试验地点
- 47
- 主要终点
- Progression-free Survival (Participants With Newly Diagnosed Advanced Ovarian Cancer With Defects in DDR+）
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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 >
- •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
排除标准
- •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.
研究组 & 干预措施
chemotherapy, avelumab and talazoparib
Platinum-based chemotherapy + avelumab followed by avelumab + talazoparib maintenance
干预措施: Chemotherapy + avelumab followed by avelumab + talazoparib (Drug)
chemotherapy, and talazoparib
Platinum-based chemotherapy followed by talazoparib maintenance
干预措施: Chemotherapy followed by talazoparib maintenance (Drug)
chemotherapy and bevacizumab
Platinum-based chemotherapy + bevacizumab followed by bevacizumab maintenance
干预措施: Chemotherapy + bevacizumab followed by bevacizumab (Drug)
结局指标
主要结局
Progression-free Survival (Participants With Newly Diagnosed Advanced Ovarian Cancer With Defects in DDR+）
时间窗: 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
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.
次要结局
- Cmax for Avelumab (Chemotherapy Period)(Day 1 of Cycles 1, 2, 3, and 4 in the chemotherapy period (1 cycle = 3 weeks))
- Overall Survival (Participants of Both DDR+ and Unselected DDR Status)(From 9 weeks up to approximately 3.5 years)
- PFS Per Gynecological Cancer Intergroup Criteria (Participants of Both DDR+ and Unselected DDR Status)(From screening until death, end of study, or participant withdrawal of consent, whichever occurred first, up to approximately 3.5 years.)
- Number of Participants With ADA Against Avelumab by Never and Ever Positive Status(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)(Day 1 of Cycles 1, 2, 3, and 4 in the chemotherapy period (1 cycle = 3 weeks))
- Cmax for Avelumab (Maintenance Period)(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 (Maintenance Period)(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.)
- Ctrough for Talazoprib (Maintenance Period)(Pre-dose on Days 1, 15 and 29 of Cycle 1)
- Progression-free Survival on Next-line Therapy. (Participants of Both DDR+ and Unselected DDR Status)(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.)
- Programmed Death Receptor-1 Ligand-1 (PD-L1) Biomarker Expression in Tumor and Immune Cells as Assessed by Immunohistochemistry (IHC) at Baseline(Baseline)
- Number of Participants With Treatment-Emergent Adverse Events (On-Treatment Period)(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))
- Progression-free Survival (Participants of Unselected DDR Status)(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.)
- Number of Participants With Mutations in Key Oncogenes at Baseline(Baseline)
- EuroQol Group 5-Dimension 5-Level (EQ-5D-5L) Score(3 years)
- Progression-free Survival (Participants of Both DDR+ and Unselected DDR Status)(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.)
- Functional Assessment of Ovarian Symptom Index-18 (FOSI-18) Score(3 years)