Mutational Landscape of Women Suffering from Metastatic Ovarian Cancer Before Poly (ADP-ribose) Polymerase Inhibitors Maintenance Treatment and During Treatment. Incidence of Therapy-related Hematological Neoplasms.
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 157
- 试验地点
- 2
- 主要终点
- Identification of the events and determination of their incidence in study patient's population:
研究概览
简要总结
Therapy related acute myeloid leukemia and myelodysplasia (t-MN) is a potential late complication of cytotoxic therapy, and it is of particular concern in the treatment of patients with epithelial ovarian carcinoma (EOC) exposed to multiple cycles of platinum-based chemotherapy during the course of their disease. An epidemiological analysis published in 2011 (Gynecologic Oncology) showed that the overall incidence of t-AML is 0.17%, with a median latency to development of leukemia of 4 years (range 0-27 years).
Inhibition of PARP is a potential synthetic lethal therapeutic strategy for the treatment of cancers characterized by specific DNA repair defects, such as those that harbor a BRCA1 or BRCA2 (BRCA1/2) mutation and are therefore deficient in homologous recombination repair. In homologous recombination-deficient tumors, PARP inhibition eliminates an alternative DNA repair pathway essential for maintaining viability, leading to tumor cell death. The estimated prevalence of BRCA1/2 mutations in V2 03/06/2021 2 patients with newly diagnosed high-grade serous ovarian cancer is 20-25% and it might be higher in patients with platinum-sensitive, relapsed ovarian cancer. Early studies have shown significant efficacy for PARP inhibitors in patients with germline BRCA1/2 mutations.
Our hypothesis is that these patients are carriers of clonal hematopoiesis of indeterminate potential (CHIP) before treatment with PARPi. CHIP refers to the presence of clonal population(s) of hematopoietic cells with somatic mutations in genes associated with hematological malignancies (e.g. DNMT3A, ASXL1, TET2, TP53 and others), in the absence of morphological evidence of disease.
The proposed study will address the hypothesis that platinum-based chemotherapy may promote the onset of newly developed mutated clones and clonal selection of hematopoietic stem cells harboring somatic mutations.
Moreover, the concomitant presence of germline mutations in cancer predisposing genes might increase the pool of pre-existing hematopoietic clones and/or favor the accumulation of subsequent somatic mutations.
In this context, the inhibition of PARP-mediated repair of DNA lesions created by chemo or radiotherapy can further favor t-MN development.
详细描述
Analysis on peripheral blood
After withdrawal, the following analysis will be performed on the peripheral blood samples:
- morphological evaluation with potential identification of dysplastic changes involving one or more hematopoietic lineage suggesting or not myelodysplastic syndrome or acute leukemias;
- cytofluorimetric analysis of mononuclear cell phenotype to identify possible abnormalities in the differentiation pathway and the presence of blasts.
Immune phenotyping will be performed by 10 colors multiparametric FACS analysis (Navios, Beckman Coulter). Myeloid cell maturation and presence of progenitors/blasts will be assessed in blood samples with the following markers:
- CD66b, CD11b, CD16, CD38, CD34, CD13, CD14, CD33, CD45, HLA-DR
- CD34, CD117, CD45, CD10, CD19, CD13, CD33, CD64, CD36, CD71 The rest of the analyses will be performed on thawed mononuclear cells. For each staining, a marker of cell viability will be used (Live/Dead, Thermo Fisher Scientific). Parameters will be chosen based on previous results obtained from genome and phenotype analysis.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 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
- •Women with advanced ovarian cancer in complete or partial remission after surgery and eligible to oral PARP inhibitors as first line in association to chemotherapy or as maintenance therapy.
排除标准
- •Presence of blood cell count abnormalities before PARP inhibitor treatment;
- •Bone marrow infiltration by EOC cells.
结局指标
主要结局
Identification of the events and determination of their incidence in study patient's population:
时间窗: 8 years
The study is descriptive in nature and no formal statistical testing is necessary or applicable. * Cell blood count abnormalities * Morphological alterations allowing a diagnosis of myelodysplastic syndrome or acute myeloid leukemia * Chromosomal abnormalities * Clonal hematopoiesis and extent of the expansion and evolution of the CHIP clones induced by PARP inhibitors. One of the primary objectives is to estimate the proportion of patients with stable abnormalities in hematologic counts. A patient is defined as having stable abnormalities in hematologic counts if the status "CTCAE grade ≥ 2 and/or platelets \<100,000/mmc" persists for at least two weeks.The 90% confidence interval of the proportion of patients with stable abnormalities in hematologic counts will be calculated using the exact one-sided binomial test.
次要结局
- Survival data evaluation(8 years)