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Olaparib

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Patients receive olaparib PO BID on days 1-28. Treatment repeats every 28 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan or MRI throughout the trial, and collection of blood and tissue samples on study.

Undergo collection of blood and tissue samples

Biospecimen Collection

Computed Tomography

Magnetic Resonance Imaging

Clinical Trials Referral Office

Daniel H. Ahn, MD

Clinical Trials Referrals Office

Amit Mahipal

Angemael Syldor

Ghassan K. Abou-Alfa

Charles Stava

Milind Javle

Daniel H Ahn

This phase II trial studies how well olaparib works in treating patients with biliary tract cancer that has spread to other places in the body (metastatic) and with aberrant DNA repair gene mutations. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine the efficacy (progression free survival \[PFS\] rate at first scan) of olaparib monotherapy in advanced biliary tract cancer (BTC) with mutations in deoxyribonucleic acid (DNA) repair genes.

SECONDARY OBJECTIVES:

I. To determine the overall survival of patients with advanced biliary tract cancer with mutations in DNA repair genes treated with olaparib.

II. To determine the progression free survival of patients with advanced biliary tract cancer with mutations in DNA repair genes treated with olaparib.

III. To determine the objective response of patients with advanced biliary tract cancer with mutations in DNA repair genes treated with olaparib.

IV. To assess the duration of response for patients with advanced biliary tract cancer with mutations in DNA repair genes treated with olaparib who experience an objective response.

V. To assess the frequency and severity of adverse events in advanced biliary tract cancer patients treated with olaparib.

CORRELATIVE RESEARCH OBJECTIVES:

I. Determine the prevalence of mutations including those targeting DNA repair pathways.

II. Identify mutational signatures associated with pathogenic process in advanced biliary tract cancer samples.

III. Correlate the presence of mutations and mutational signatures linked to mutations in DNA repair genes and homologous recombinant repair with clinical responses to olaparib.

IV. To evaluate putative biomarkers related to:

Iva. De novo sensitivity. IVb. Tumor evolution and resistance, to PARP inhibition from olaparib in BTC.

OUTLINE:

Patients receive olaparib orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) scan or magnetic resonance imaging (MRI) throughout the trial, and collection of blood and tissue samples on study.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 3 years.

Olaparib in Treating Patients With Metastatic Biliary Tract Cancer With Aberrant DNA Repair Gene Mutations

A Phase II Study of Olaparib in Patients With Advanced Biliary Tract Cancer With Aberrant DNA Repair Gene Mutations

Will determine the prevalence of mutations including those targeting DNA repair pathways.

Will identify mutational signatures associated with pathogenic process in advanced biliary tract cancer samples. Genomic analyses will be performed on mandatory blood samples collected from patients at the start of therapy, every 8 weeks, and at progression.

Will correlate the presence of mutations and mutational signatures linked to mutations in DNA repair/HRR with clinical responses.

Will evaluate putative biomarkers related to: (a) de novo sensitivity and (b) tumor evolution and resistance, to PARP inhibition in biliary tract cancer.

related to: (a) de novo sensitivity and (b) tumor evolution and resistance, to PARP inhibition in BTC.

A patient is defined as a success if the patient is progression-free and alive at the first disease evaluation scan. Disease status will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria. The PFS rate will be calculated as the proportion of evaluable patients who are progression-free and alive at the first disease assessment scan. The final PFS rate point estimate and corresponding 95% confidence interval (CIs) will be reported according to the method of Clopper-Pearson.

Patients who are still alive at the time of analysis will be censored at the time of their last study assessment (if still actively on the study) or at the date, the patient was last known to be alive (if in survival follow-up). OS will be estimated using the Kaplan-Meier method. The median OS and corresponding 95% confidence interval (by Brookmeyer and Crowley) will be reported.

Progression free survival is defined as the time from study registration to disease progression or death, whichever occurs first. Disease progression will be determined based on RECIST 1.1 criteria. Patients who do not experience disease progression or death while on the protocol will be censored at their last disease assessment date. PFS will be estimated using the Kaplan-Meier method. Median PFS and corresponding 95% CIs (by Brookmeyer and Crowley) will be reported.

Objective response (unconfirmed) is defined as achieving a complete or partial response while on treatment. The objective response rate (ORR) will be calculated as the proportion of evaluable patients who achieve an objective response. Disease status will be assessed using RECIST v1.1 criteria. Confidence intervals for the true success proportion will be calculated according to the approach of Clopper and Pearson.

Will be defined for all evaluable patients who have achieved an objective response as the date at which the patient's earliest best objective status is first noted to be either a complete response or partial response to the earliest date progression is documented, or death if no prior evidence of disease progression. The distribution of DoR will be estimated using the method of Kaplan-Meier. The median DoR and corresponding 95% confidence interval will be reported.

Adverse events by patients will be summarized by frequencies and severity using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The proportion of patients who experience at least one grade 3+ adverse event (regardless of attribution) will be reported.

National Cancer Institute (NCI)

Academic and Community Cancer Research United

Spots Global Cancer Trial Database for fanconi anemia complementation group gene mutation