Testing the Safety of the Anti-Cancer Drugs Durvalumab and Olaparib During Radiation Therapy for Locally Advanced Unresectable Pancreatic Cancer

Brief summary public domain (ClinicalTrials.gov)

This phase I trial tests the safety and tolerability of olaparib in combination with durvalumab and radiation therapy in patients with pancreatic cancer that has spread to nearby tissue or lymph nodes (locally advanced) and cannot be removed by surgery (unresectable). Olaparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. The combination of targeted therapy with olaparib, immunotherapy with durvalumab and radiation therapy may stimulate an anti-tumor immune response and promote tumor control in locally advanced unresectable pancreatic cancer.

Detailed description public domain (ClinicalTrials.gov)

PRIMARY OBJECTIVE: I. Determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of olaparib in combination with durvalumab and radiation therapy (RT). SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. Correlate response with the circulating frequency and diversity of T cells within the peripheral blood. III. Evaluate the safety and toxicity of olaparib in combination with durvalumab and RT. EXPLORATORY OBJECTIVES: I. Evaluate the genetic and clinicopathologic markers of response and resistance including prior receipt of platinum therapy. II. To correlate response with baseline tumoral immune infiltrate. OUTLINE: This is a dose-escalation study of olaparib in combination with fixed dose durvalumab and radiation therapy. Patients receive olaparib orally (PO) twice daily (BID) on days 1-28 and durvalumab intravenously (IV) over 55-65 minutes on day 1 of each cycle. Beginning cycle 2, patients also undergo radiation therapy daily on weekdays for 3 weeks. Chemotherapy and immunotherapy cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan with or without magnetic resonance imaging (MRI) and collection of blood samples throughout the study. Patients may undergo optional collection of buccal samples and optional biopsy at screening and/or on study. After completion of study treatment, patients are followed up at 90 days and every 12 weeks thereafter for two years on until death, whichever occurs first.

Intervention public domain (ClinicalTrials.gov)

Procedure: Biopsy Procedure. Undergo biopsy

Intervention public domain (ClinicalTrials.gov)

Procedure: Biospecimen Collection. Undergo collection of blood and buccal samples

Intervention public domain (ClinicalTrials.gov)

Procedure: Computed Tomography. Undergo CT scan

Intervention public domain (ClinicalTrials.gov)

Biological: Durvalumab. Given IV

Intervention public domain (ClinicalTrials.gov)

Procedure: Magnetic Resonance Imaging. Undergo MRI

Intervention public domain (ClinicalTrials.gov)

Drug: Olaparib. Given PO

Arm public domain (ClinicalTrials.gov)

Treatment (olaparib, durvalumab, radiation therapy) (experimental): Patients receive olaparib PO BID on days 1-28 and durvalumab IV over 55-65 minutes on day 1 of each cycle. Beginning cycle 2, patients also undergo radiation therapy daily on weekdays for 3 weeks. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo Patients undergo CT scan with or without MRI and collection of blood samples throughout the study. Patients may undergo optional collection of buccal samples and optional biopsy at screening and/or on study.

Primary outcome public domain (ClinicalTrials.gov)

Dose-limiting toxicities (DLTs) for olaparib in combination with durvalumab and radiation. The numbers of subjects treated at each dose level and DLT incidence in both components will be summarized. Will report the estimate probability of DLT with 95% Bayesian Credible Intervals for each dose level as estimated by the TiTE-CRM algorithm at the completion of the phase IB Part 2. Time frame: From start of radiation therapy for up to 6 weeks.

Secondary outcome public domain (ClinicalTrials.gov)

Progression-free survival. Time frame: From date of treatment to date of radiological or clinical progression, or death from any cause, whichever comes first, assessed up to 4 years.

Secondary outcome public domain (ClinicalTrials.gov)

Relapse free survival. Time frame: Up to 4 years.

Secondary outcome public domain (ClinicalTrials.gov)

Overall survival. Time frame: Up to 4 years.

Secondary outcome public domain (ClinicalTrials.gov)

Overall response rate (ORR). Time frame: Up to 4 years.

Secondary outcome public domain (ClinicalTrials.gov)

Incidence of adverse events. Time frame: Up to 90 days after last dose.

Secondary outcome public domain (ClinicalTrials.gov)

Number and diversity of T cells. Time frame: Up to 4 years.

Eligibility public domain (ClinicalTrials.gov)

Inclusion Criteria: * Patients must have histologically confirmed pancreatic cancer (excluding islets) (not otherwise specified \[NOS\]) (Medical Dictionary for Regulatory Activities \[MEDDRA\] code: 10033612). * Patients must have unresectable locally advanced pancreatic cancer as determined by a multidisciplinary tumor board applying National Comprehensive Cancer Network (NCCN) version (v)2.2021 criteria or as surgically determined during failed resection attempt. * Patients must have had prior first-line chemotherapy for this cancer for at least 16 weeks without clinical, biochemical, or radiologic progression. There should be a washout of at least 2 weeks from first-line chemotherapy and start of therapy on clinical trial. * Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of durvalumab and olaparib in combination with radiation in patients \< 18 years of age, children are excluded from this study. * Body weight \> 30 kg. * Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%). * Hemoglobin \>= 9.0 g/dL without blood transfusion in last 4 weeks (within 2 weeks of enrollment). * Absolute neutrophil count \>= 1,500/mcL (within 2 weeks of enrollment). * Platelets \>= 100,000/mcL (within 2 weeks of enrollment). * Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (within 2 weeks of enrollment). * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine transferase (ALT) (serum glutamic pyruvic transaminase) \[SGPT\]) =\< 2.5 x institutional ULN (within 2 weeks of enrollment). * Creatinine =\< 1.5 x institutional ULN (within 2 weeks of enrollment). * Measured creatinine clearance \> 60 mL/min/1.73 m\^2 (within 2 weeks of enrollment). * Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: * Women \< 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). * Women \>= 50 years of age would be considered …

Enrollment public domain (ClinicalTrials.gov)

Enrollment: 18 participants (estimated).