A Phase IIIb, Single-arm, Open-label Multicentre Study of Olaparib Maintenance Monotherapy in Platinum Sensitive Relapsed Non-Germline BRCA Mutated Ovarian Cancer Patients Who Are in Complete or Partial Response Following Platinum Based Chemotherapy
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 279
- 试验地点
- 1
- 主要终点
- Progression Free Survival (PFS)
研究概览
简要总结
The purpose of the study is to assess the efficacy and safety of single-agent olaparib as a maintenance treatment in patients with relapsed High Grade Serous Ovarian Cancer (including patients with primary peritoneal and/or fallopian tube cancer) or high grade endometrioid cancer who do not have known deleterious or suspected deleterious germline BRCA mutations (non-gBRCAm) and who had responded following platinum based chemotherapy
详细描述
Maintenance monotherapy with the potent polyadenosine 5'diphosphoribose [Poly (ADP-ribose)] polymerisation (PARP) inhibitor (PARPi) olaparib will significantly prolong progression-free survival (PFS) in platinum sensitive relapsed non-germline breast cancer susceptibility gene (BRCA) mutated ovarian cancer patients who are in complete or partial response following platinum based chemotherapy.
Olaparib is a potent PARPi (PARP-1, -2 and -3) that is being developed as an oral therapy, both as a monotherapy (including maintenance) and for combination with chemotherapy and other anticancer agents. PARP inhibition is a novel approach to targeting tumours with deficiencies in DNA repair mechanisms. PARP enzymes are essential for repairing DNA single strand breaks (SSBs). Inhibiting PARP enzymes leads to the persistence of SSBs, which are then converted to the more serious DNA double strand breaks (DSBs) during the process of DNA replication. During the process of cell division, DSBs can be efficiently repaired in normal cells by homologous recombination (HR) repair. Tumours with HR deficiencies (HRDs), such as ovarian cancers in patients with BRCA1/2 mutations, cannot accurately repair the DNA damage, which may become lethal to cells as it accumulates. In such tumour types, olaparib may offer a potentially efficacious and less toxic cancer treatment compared with currently available chemotherapy regimens.
While multiple randomized controlled trials (RCTs) have demonstrated that platinum sensitive BRCAm patients have profound response to maintenance treatment with PARP inhibitors, PARP inhibitors target cells with homologous recombination deficiency (HRD), of which BRCA mutation is only one type. Consistent with the mechanism of action of PARP inhibition, response has also been seen in multiple RCTs in patients who are platinum sensitive but whose tumours do not harbor BRCA mutations. Presumably these responders have defects in other components of HRR pathways, though currently available diagnostic technology is not adequate to reliably identify the full spectrum of HRR deficiencies. Instead, these data support the hypothesis that platinum sensitivity itself is a clinical selection factor for HRD.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Open
入排标准
- 年龄范围
- 18 Years 至 95 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Female patients with histologically diagnosed relapsed HGSOC (including primary peritoneal and / or fallopian tube cancer) or high grade endometrioid ovarian cancer
- •Documented gBRCA1/2 mutation status
- •Patients must have completed at least 2 previous courses of platinum containing therapy
- •Patients must have normal organ and bone marrow function measured within 28 days of starting study treatment
- •ECOG performance status 0-1 (see Appendix E)
- •Patients must have a life expectancy ≥16 weeks
- •Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1
- •At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline with computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for repeated assessment OR No evidence of disease following a complete response to chemotherapy
- •An appropriately prepared tumour sample from the cancer, of sufficient quantity and quality (as specified in the Central Laboratory Services Manual) must be available for future central testing of tumour genetic status
排除标准
- •Patients receiving any systemic hormonal therapy, chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to start of study treatment
- •Any previous treatment with PARP inhibitor, including olaparib
- •Patients with a germline BRCA mutation that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental / lead to loss of function)
- •Other malignancy unless curatively treated with no evidence of disease for ≥5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma.
- •Concomitant use of known strong CYP3A inhibitors and strong (or moderate CYP3A inducers
- •Persistent toxicities (≥ Grade 2 Common Terminology Criteria for Adverse Event (CTCAE) adverse event) caused by previous cancer therapy, excluding alopecia
- •Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML
- •Patients with symptomatic uncontrolled brain metastases
研究组 & 干预措施
Olaparib
Olaparib will be supplied as film-coated tablets containing 150 mg or 100 mg of olaparib.
Patients will be administered olaparib orally twice daily (bid) at 300 mg.
干预措施: Olaparib (Drug)
结局指标
主要结局
Progression Free Survival (PFS)
时间窗: Up to maximum of 32 months
PFS is defined as the time from date of first dose until the date of objective radiological disease progression. Assessed according to modified Response Evaluation Criteria In Solid Tumours Version 1.1 (RECIST 1.1) or death (by any cause in the absence of progression). Progression was determined by investigator assessment, RECIST 1.1. Calculated using the Kaplan-Meier technique. Confidence intervals (CI) for median PFS was derived based on Brookmeyer-Crowley method.
次要结局
- PFS by Homologous Recombination Deficiency (HRD)/ Breast Cancer Susceptibility Gene Mutation (Mutated) (BRCAm) Status(Up to maximum of 32 months)
- Chemotherapy-free Interval (CT-FI)(Up to a maximum of 43 months)
- Percentage of Patients With Any Improvement From Baseline in Trial Outcome Index (TOI) Score at Any Point During the Treatment Period(Baseline up to a maximum of 32 months)
- Percentage of Patients With a 10-Point Deterioration From Baseline in TOI Score at Any Point During the Treatment Period(Baseline up to a maximum of 32 months)
- Overall Survival (OS)(Up to a maximum of 43 months)
- Time to First Subsequent Therapy or Death (TFST)(Up to a maximum of 43 months)
- Time to Treatment Discontinuation or Death (TDT)(Up to a maximum of 43 months)