Olaparib in Subjects With Advanced Pancreatic Acinar Cell Carcinoma

Background:

• Pancreatic Acinar Cell Carcinoma (PACC) is a rare pancreatic tumor, representing 0.5-1% of all pancreatic malignancies.
• PACC is commonly advanced at presentation and median overall survival in this population is poor.
• PACC is pathologically and biochemically distinct from pancreatic adenocarcinoma.
• No clinical trials for PACC have ever been reported.
• Patients are most commonly treated with combination regimens used for either pancreatic or colon adenocarcinoma with poor (approximately 30%) response rates in the first line setting.
• PACC pathological specimens demonstrate evidence of high chromosomal instability, a hallmark of deoxyribonucleic acid (DNA) repair deficiency.
• Data derived from ovarian and prostate cancer patients has demonstrated that mutations in DNA repair genes can define subgroups of cancer patients with distinct vulnerabilities to DNA damage response inhibitors.
• Olaparib is a Poly-ADP ribose polymerase (PARP)-1 inhibitor that has been Food and Drug Administration (FDA) approved for the treatment of BReast CAncer genes 1 and 2 (BRCA)-mutant homologous recombination repair (HRR) deficient cancers.
• As PACC has multiple hallmarks of homologous recombination repair (HRR) deficiency, we hypothesize that PACC will be sensitive to PARP inhibition with olaparib.
• Pre-clinical modeling of PACC has been very limited with no currently available animal models or cell lines, which precludes testing this hypothesis in the laboratory setting.

Objective:

• To assess the anti-tumor activity of single agent olaparib, a PARP inhibitor, in participants with advanced pancreatic acinar cell carcinoma (PACC)

Eligibility:

• Participants must have advanced previously treated PACC
• Age >=18 years
• Adequate organ and bone marrow function

Design:

• This is a phase II, single arm, single center study of olaparib in participants with advanced previously treated PACC.
• All participants will take olaparib by mouth twice daily for up to two years or until disease progression or intolerable side effects.
• Participants will be assessed for safety (continuously) and efficacy (every 8 weeks).
• Up to 13 evaluable participants will be enrolled.

-INCLUSION CRITERIA:

• Histological or cytological diagnosis of pancreatic acinar cell carcinoma (PACC) as confirmed by National Institutes of Health (NIH) Laboratory of Pathology (LP).
• Participants must have received one prior line of combination chemotherapy (or be ineligible to receive combination chemotherapy) with tumor still not amenable for potentially curative resection or be ineligible to receive combination chemotherapy. There is no limit on the number of prior therapies.
• Access to medical records from past treatment
• Measurable disease, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• Age >=18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status <=1.
• At least 3 weeks from previous chemotherapy or radiation therapy prior to planned start of treatment.
• At least 30 days or 5 half-lives (whichever is greater) since receipt of any investigational therapy prior to planned start of treatment.
• Fully recovered from all reversible sequelae and >=2 weeks from major surgery or from minor surgical procedure such as biliary or duodenal stenting prior to planned start of treatment.
• At least 2 weeks since last use of known strong cytochrome P450 (CYP) (CYP3A) inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil).
• At least 5 weeks since last use of phenobarbital, enzalutamide, and at least 3 weeks since last use of other strong (e.g., phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate (e.g., bosentan, efavirenz, modafinil) CYP3A inducers.
• Adequate organ and marrow function as measured within 28 days prior to study treatment as defined below:

• leukocytes >=3,000/mcL
• absolute neutrophil count >=1,500/mcL
• hemoglobin >= 10 g/dL with no blood transfusion within the last 28 days
• platelets >=100,000/mcL
• total bilirubin within 1.5x normal institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) <= institutional ULN unless liver metastases are present in which case they may be <=5x ULN
• Creatinine must be within normal range, OR >=51 mL/min per the formula below* or measured by 24-hour urine test

• Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F) serum/ creatinine (mg/dL) x 72^a, where F=0.85 for females and F=1 for males

This list includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.

• The effects of olaparib on the developing human fetus are unknown. For this reason and because PARP inhibitor agents are known to be teratogenic, individuals of child-bearing potential (IOCBP) and individual able to father a child must agree to use adequate contraception prior to study entry and for the duration of study participation.
• Participants must agree to abstain from consuming grapefruit juice throughout the duration of study treatment with olaparib.
• Ability of participant to understand and the willingness to sign a written informed consent document.

Exclusion criteria

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib.
• Participants unable to swallow orally administered medication or suffering from gastrointestinal (GI) disorders likely to interfere with absorption of study medication.
• Participants with human immunodeficiency virus (HIV) are excluded even if viral load is undetectable
• Active hepatitis B (HBV) or hepatitis C virus (HCV)
• Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QT corrected by Fridericia's formula (QTcF) prolongation >500 ms, electrolyte disturbances, etc.), or participants with congenital long QT syndrome.
• Recent (within 3 months) myocardial infarction
• Unstable angina pectoris.
• Symptomatic congestive heart failure
• Uncontrolled major seizure disorder
• Superior vena cava syndrome
• Extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan
• Psychiatric illness/social situations (within the last 3 months) that would limit compliance with study requirements or prohibits obtaining informed consent
• Uncontrolled intercurrent illness or participants considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active uncontrolled infection as documented in prior records or suggested by medical history, physical examination or standard clinical assessments such as imaging and laboratory studies
• Myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML.
• Solid or liquid malignancy other than PACC unless curatively treated with no evidence of disease for >=5 years, except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma.
• Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
• Participants who are nursing and unwilling to stop.
• Symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. Brain metastases are considered uncontrolled if the dose of corticosteroid being provided for control of brain metastases has been titrated in the 4 weeks prior to start of treatment.
• Participants with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for >=28 days. Participants with unstable spinal cord compression are ineligible even if previously treated.
• Participants with large volume ascites, serum albumin < 2.5 mg/dL, or having received paracentesis within the last 4 weeks
• Participants with persistent toxicities > Grade 2 or with new Grade 2 events within the last 2 weeks per Common Terminology Criteria for Adverse Event (CTCAE) version 5 caused by previous cancer therapy.