Overview

Functional Analysis of BRCAness

Status:
Recruiting
Trial end date:
2023-06-21
Target enrollment:
0
Participant gender:
Female
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.
Phase:
Phase 2
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
Leiden University Medical Center
Collaborators:
Erasmus Medical Center
University Medical Center Groningen
Treatments:
Olaparib
Criteria
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.