Functional Analysis of BRCAness

  • STATUS
    Recruiting
  • End date
    Jun 21, 2023
  • participants needed
    55
  • sponsor
    Leiden University Medical Center
Updated on 9 April 2021

Summary

PARP inhibitors are most effective in homologous recombinant (HR) deficient tumors. There are clear indications that besides BRCA1 or BRCA2 mutated EOC, there is an additional group of EOC having deficiencies in HR (i.e. BRCAness) that might benefit from treatment with PARP inhibitors. Assessment of HR in high grade EOC might therefore serve as a better predictive biomarker and allow the identification of a larger group of patients that could benefit most from platinum based chemotherapy and maintenance treatment with a PARP inhibitor. We recently developed a robust ex vivo functional assay (RAD51 assay;) to test HR in viable tumor tissue. In the proposed study, we will evaluate whether the RAD51 assay predicts sensitivity to therapy with olaparib, in patients with recurrent EOC. With the RAD51 assay we aim to identify a larger number of patients who will benefit from treatment with the PARP inhibitor olaparib than patients with a germline or somatic BRCA mutation only. Furthermore, we aim to identify molecular markers (including genomic markers) that are associated with the outcome of the RAD51 assay. Finally, we will explore whether these molecular markers can be measured in liquid biopsies by analysing ctDNA.

Description

Epithelial ovarian cancer (EOC) often presents at an advanced stage, and harbours an unfavourable prognosis. Standard of care includes complete or optimal debulking surgery and chemotherapy, however, most patients experience recurrent disease. Recurrences are often treated with additional chemotherapy, and for selected patients, treatment with PARP inhibitors may be an option. Patients with platinum sensitive recurrent epithelial ovarian cancer (EOC) and a germ-line or somatic BRCA1 or BRCA2 mutation, who are in response to platinum based chemotherapy are currently eligible for maintenance treatment with the Poly (ADP-ribose) polymerase (PARP) inhibitor olaparib after chemotherapy. Germline (11-15%) or somatically acquired (6-7%) BRCA1 and BRCA2 mutations lead to deficiency in homologous recombination (HR) and subsequent less effective DNA repair. PARP inhibitors are most effective in HR deficient tumors. There are clear indications that besides BRCA1 or BRCA2 mutated EOC, there is an additional group of EOC (~15-30%) having deficiencies in HR (i.e. BRCAness) that might benefit from treatment with PARP inhibitors (Mukhopadhyay, Cancer Res 2012; Konstantinopolos, Cancer Discovery 2015; Telli, Clin Cancer Res 2016). Assessment of HR in high grade EOC might therefore serve as a better predictive biomarker and allow the identification of a larger group of patients that could benefit most from platinum based chemotherapy and maintenance treatment with a PARP inhibitor. We recently developed a robust ex vivo functional assay (RAD51 assay;) to test HR in viable tumor tissue (Naipal, Clin. Cancer Res., 2014). It is still unknown however, whether the outcome of the RAD51 assay reliably predicts the sensitivity to platinum-based chemotherapy or PARP inhibitors. In the proposed study, we will therefore evaluate whether the RAD51 assay predicts sensitivity to therapy with olaparib, in patients with recurrent EOC. With the RAD51 assay we aim to identify a larger number of patients who will benefit from treatment with the PARP inhibitor olaparib than patients with a germline or somatic BRCA mutation only. Furthermore, we aim to identify molecular markers (including genomic markers) that are associated with the outcome of the RAD51 assay. Finally, we will explore whether these molecular markers can be measured in liquid biopsies by analysing ctDNA.

Details
Condition BRCA1 Mutation, BRCA2 Mutation, Ovarian Neoplasm Epithelial, Homologous Recombination Deficiency
Treatment Olaparib Oral Product, Functional RAD51 assay
Clinical Study IdentifierNCT04780945
SponsorLeiden University Medical Center
Last Modified on9 April 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Patients with recurrent high grade serous or endometrioid EOC (more than 3 months after platinum containing chemotherapy and unwilling or ineligible for platinum based therapy) with a tumor lesion that is amendable for biopsy or who can undergo ascites drainage prior to treatment
Diagnosis of high grade serous or endometrioid EOC confirmed by histology
Provision of informed consent prior to any study specific procedures
Female aged equal or above 18 years
Patients must have normal organ and bone marrow function measured within 28 days prior to administration olaparib
Eastern Cooperative Oncology Group performance status 0 to 2
Patients must have a life expectancy equal or above 16 weeks
Postmenopausal or evidence of nonchildbearing 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
Patients willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
Evaluable disease, measurable and, or nonmeasurable, that can be accurately assessed at baseline using RECIST by CT or MRI and is suitable for repeated assessment
For inclusion in the optional exploratory genetic research and the optional biomarker research, patients must fulfil informed consent for genetic research and informed consent for biomarker research

Exclusion Criteria

Participation in another clinical study with an investigational product during the last month
Any previous treatment with PARP inhibitor, including olaparib
Other malignancy within the last 5 years, except, adequately treated nonmelanoma skin cancer, curatively treated in situ cancer, stage 1 and grade 1 endometrial carcinoma, or other solid tumours including breast cancer and lymphomas curatively treated with no evidence of disease for equal or above 3 years
Patients receiving radiotherapy within 3 weeks prior to study treatment
Concomitant use of known strong CYP3A inhibitors or moderate CYP3A inhibitors
Concomitant use of known strong or moderate CYP3A inducers
Persistent toxicities , Common Terminology Criteria for Adverse Event equal or above grade 2, caused by previous cancer therapy, excluding alopecia
Patients with symptomatic uncontrolled brain metastases. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days
Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery
Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease or active, uncontrolled infection
Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
Breast feeding women
Immunocompromised patients, for example, patients who are known to be serologically positive for human immunodeficiency virus
Patients with a known hypersensitivity to olaparib or any of the excipients of the product
Patients with known active hepatitis due to risk of transmitting the infection through blood or other body fluids
Previous allogenic bone marrow transplant or double umbilical cord blood transplantation
Patients with myelodysplastic syndrome, acute myeloid leukaemia or with features suggestive of MDS, AML
Whole blood transfusions in the last 120 days prior to entry to the study
Resting ECG with QTc equal or above 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
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