Olaparib in Subjects With Advanced Pancreatic Acinar Cell Carcinoma

Phase II Study of Olaparib in Subjects With Advanced Pancreatic Acinar Cell Carcinoma

Background:

Pancreatic Acinar Cell Carcinoma (PACC) is a rare pancreatic tumor. People with PACC usually present with advanced disease, and their prognosis is poor. Researchers want to learn if a cancer drug called olaparib can help.

Objective:

To see if olaparib is an effective treatment for PACC.

Eligibility:

People aged 18 and older with PACC whose cancer did not respond to previous treatments or is not eligible for surgery.

Design:

Participants will be screened with the following:

Medical history

Physical exam

Blood and urine tests

Electrocardiogram (to test heart function)

Computed tomography (CT) scans

Pregnancy test (if needed)

Tumor biopsy (if a sample is not available)

Treatment will be given in 21-day cycles. Participants will take olaparib by mouth twice daily for each cycle. They will keep a medicine diary. They will receive treatment for up to 2 years. They may stop treatment early if their cancer gets worse or they have serious side effects.

Participants will have study visits at the beginning of each cycle. At visits, they will repeat some screening tests. They will be asked about any changes in medicines they are taking and how they are feeling. They will have CT scans every 8 weeks starting in cycle 2.

Participants will give blood samples for research. They may have optional tumor biopsies.

Participants will have 2 follow-up visits in the 30 days after treatment ends or before they begin a new anti-cancer treatment. Then they will be contacted every 3 months by phone for 1 year.

Participation will last for up to 3 years.

Study Overview

• Status: Recruiting
• Conditions: Pancreatic Acinar Cell Carcinoma
• Intervention / Treatment: Drug: Olaparib

Detailed Description

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 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 FDA approved for the treatment of BRCA-mutant homologous recombination repair (HRR) deficient cancers.
• As PACC has multiple hallmarks of 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 subjects with advanced previously treated PACC.
• All subjects will take olaparib by mouth twice daily for up to two years or until disease progression or intolerable side effects.
• Subjects will be assessed for safety (continuously) and efficacy (every 8 weeks).
• Up to 13 evaluable participants will be enrolled.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Christine C Alewine, M.D.; Phone Number: (240) 760-6146; Email: alewinecc@mail.nih.gov
• Study Contact Backup: Name: NCI Medical Oncology Referral Office; Phone Number: (888) 624-1937; Email: ncimo_referrals@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR); Phone Number: TTY dial 711 800-411-1222; Email: ccopr@nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

-INCLUSION CRITERIA:

1. Histological or cytological diagnosis of Pancreatic Acinar Cell Carcinoma (PACC) as confirmed by NIH Laboratory of Pathology.
2. 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.
3. Access to medical records from past treatment
4. Measurable disease, per RECIST 1.1.
5. Age >=18 years.
6. ECOG performance status <=1.
7. At least 3 weeks from previous chemotherapy or radiation therapy prior to planned start of treatment.
8. At least 30 days or 5 half-lives (whichever is greater) since receipt of any investigational therapy prior to planned start of treatment.
9. Fully recovered from all reversible sequalae and >=2 weeks from major surgery or from minor surgical procedure such as biliary or duodenal stenting prior to planned start of treatment.
10. At least 2 weeks since last use of known strong 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).
11. 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.

12. 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)
    • AST(SGOT)/ALT(SGPT) <= institutional ULN unless liver metastases are present in which case they may be <=5x ULN

    • Creatinine clearance must be >51 mL/min as estimated using the Cockroft-Gault equation* 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.

13. The effects of olaparib on the developing human fetus are unknown. For this reason and because PARP inhibitor agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation.
14. Participants must agree to abstain from consuming grapefruit juice throughout the duration of study treatment with olaparib.
15. Ability of subject to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

1. History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib.
2. Participants unable to swallow orally administered medication or suffering from GI disorders likely to interfere with absorption of study medication.
3. Participants with HIV are excluded even if viral load is undetectable
4. Active hepatitis B or C
5. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or participants with congenital long QT syndrome.
6. Recent (within 3 months) myocardial infarction
7. Unstable angina pectoris.
8. Symptomatic congestive heart failure
9. Uncontrolled major seizure disorder
10. Superior vena cava syndrome
11. Extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan
12. Psychiatric illness/social situations (within the last 3 months) that would limit compliance with study requirements or prohibits obtaining informed consent
13. 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
14. Participants with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML.
15. 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.
16. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
17. Women who are breastfeeding and unwilling to stop.
18. Participants with 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.
19. 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.
20. Participants with large volume ascites, serum albumin < 2.5 mg/dL, or having received paracentesis within the last 4 weeks
21. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; Olaparib, taken orally, twice daily	Drug: Olaparib; Administered orally (300 mg) twice daily continuously for 21-day cycles for up to 2 years.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
antitumor activity	Objective response rate (ORR, CR+PR)	1 year post-last dose of olaparib

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
anti-tumor efficacy	Disease control rate, median duration of treatment response, median progression-free survival (PFS) and median overall survival (OS)	1 year after last olaparib treatment
safety	AEs and SAEs of olaparib	from start of treatment to 30 days after last treatment

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Christine C Alewine, M.D., National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2023
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: March 12, 2022
• First Submitted That Met QC Criteria: March 17, 2022
• First Posted (Actual): March 18, 2022

Study Record Updates

• Last Update Posted (Actual): January 22, 2024
• Last Update Submitted That Met QC Criteria: January 19, 2024
• Last Verified: January 11, 2024

More Information

Terms related to this study

• Keywords: Poly-Adp Ribose Polymerase (Parp)-1 Inhibitor; Homologous Recombination Repair; Platinum-Sensitive
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Acinar Cell; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Olaparib
• Other Study ID Numbers: 10000596; 000596-C

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request.@@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.
• IPD Sharing Time Frame: Clinical data available during the study and indefinitely. @@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.@@@@@@Genomic data are made available via dbGaP through requests to the data custodians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No