Genetic Landscape in Women with Metastatic Ovarian Cancer Before and During Treatment with PARP Inhibitors

NCT06785077 | Recruiting

• 1 other identifier: IEO 1353
• Study Type: interventional
• Target: 157
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Leukemia, Myeloid, Acute; Myeloid Dysplasia; Ovarian Epithelial Cancer

Keywords

PARP inhibitors (PARPi) Treatment; gene panels; clonal hematopoiesis of indeterminate potential (CHIP); Analysis on peripheral blood; Analysis on bone marrow; Genetic analysis

Outcome Measures

Primary Outcomes (1)

• Identification of the events and determination of their incidence in study patient's population:

  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.

  8 years

Secondary Outcomes (1)

• Survival data evaluation

  8 years

Study Arms (1)

advanced ovarian cancer patient

EXPERIMENTAL

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.

Procedure: buccal cells; Procedure: bone marrow cells; Procedure: peripheral blood cells; Procedure: bone marrow biopsy

Interventions

buccal cells PROCEDURE

custom myeloid gene panel (Myelo-Panel) to identify germline mutations predisposing to cancer development (Thermo Fisher Scientific)

advanced ovarian cancer patient

bone marrow cells PROCEDURE

Bone marrow cells (optional, for comparison, only in a limited number of patients): * morphological analysis * immunophenotype * cytogenetics/FISH * analysis of CHIP by custom gene panel and high sensitivity NGS

advanced ovarian cancer patient

peripheral blood cells PROCEDURE

analysis of CHIP by custom gene panel and high sensitivity NGS

advanced ovarian cancer patient

bone marrow biopsy PROCEDURE

Bone marrow biopsy (optional, for comparison, only in a limited number of patients): * histology * immunohistochemistry

advanced ovarian cancer patient

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• Presence of blood cell count abnormalities before PARP inhibitor treatment;
• Bone marrow infiltration by EOC cells.

Sponsors & Collaborators

• European Institute of Oncology: lead

Study Sites (1)

Istituto Europeo di Oncologia

Milan, 20141, Italy

RECRUITING

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Anemia, Refractory, with Excess of Blasts; Carcinoma, Ovarian Epithelial

Interventions

SLC25A33 protein, human

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Anemia, Refractory; Anemia; Myelodysplastic Syndromes; Bone Marrow Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders

Study Officials

• Federica Gigli

  Istituto Europeo di Oncologia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Federica Gigli

CONTACT

+390257489538; federica.gigli@ieo.it

Fulvia Fusar

CONTACT

+390257489538; fulvia.fusarimperatore@ieo.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 5, 2024
• First Posted: January 20, 2025
• Study Start: October 2, 2020
• Primary Completion (Estimated): April 30, 2028
• Study Completion (Estimated): April 30, 2028
• Last Updated: January 20, 2025

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)