Pancreatic Acinar Cell Carcinoma
Conditions
Keywords
Poly-Adp Ribose Polymerase (Parp)-1 Inhibitor, Homologous Recombination Repair, Platinum-Sensitive
Brief summary
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 28-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.
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 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.
Interventions
DRUGOlaparib
Administered orally (300 mg) twice daily continuously for 28-day cycles as clinically indicated.
DIAGNOSTIC_TESTECG
Screening.
DIAGNOSTIC_TESTCT CAP
Screening. Baseline Cycle 1, Day 1 (≤7 days), and subsequent Cycles, Day 1 (+/- 7 days) every 8 weeks.
PROCEDURETumor Biopsy
Optional. Baseline Cycle 1, Day 1 (≤7 days), subsequent Cycles, Day 1 (+/- 7 days; once only, Cycle 2 preferred), and end of treatment (14-30 days after last treatment)
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
-INCLUSION CRITERIA: 1. Histological or cytological diagnosis of pancreatic acinar cell carcinoma (PACC) as confirmed by National Institutes of Health (NIH) Laboratory of Pathology (LP). 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 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. 5. Age \>=18 years. 6. Eastern Cooperative Oncology Group (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 sequelae 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 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). 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) * 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. 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, 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. 14. Participants must agree to abstain from consuming grapefruit juice throughout the duration of study treatment with olaparib. 15. Ability of participant 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 gastrointestinal (GI) disorders likely to interfere with absorption of study medication. 3. Participants with human immunodeficiency virus (HIV) are excluded even if viral load is undetectable 4. Active hepatitis B (HBV) or hepatitis C virus (HCV) 5. 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. 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. Myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) 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. Participants who are nursing and unwilling to stop. 18. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Partial Response (PR) or Complete Response (CR) Reported Along With a 95% Two-sided Confidence Interval | 1-year | Objective response rate (ORR) is defined as the proportion of participants with partial response or complete response reported along with a 95% two-sided confidence interval. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. |
| Proportion of Participants With Partial Response or Complete Response Reported Along With a 80% Two-sided Confidence Interval | 1-year | Objective response rate (ORR) is defined as the proportion of participants with partial response or complete response reported along with an 80% two-sided confidence interval. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Partial Response, Complete Response, and/or Stable Disease Reported Along With a 95% Confidence Interval | 1-year | Disease control rate is defined as the percentage of participants with partial response, complete response, and/or stable disease. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Stable Disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum of diameters while on study. Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions. |
| Number of Treatment-related Serious Adverse Events by Grade and Type as Defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | From start of treatment to 30 days after last treatment, up to an average of 30 days | Here is the number of treatment-related serious adverse events as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse events. |
| Median Duration of Treatment Response | 1-year after response noted | Median duration of treatment responses will be reported using the Kaplan-Meier method from the date a response is identified until the date a response ends (by progression or other reason), or the response is continuing, in which case the duration will be censored. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Complete Response is disappearance of all target lesions. Stable Disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum of diameters while on study. Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions. |
| Median Progression-free Survival (PFS) Reported Along With a 95% Confidence Interval | Calculated from on-study date until the date of progression or death without progression as events with participants censored if they do not have an event by the date of last known follow-up, an average of 1.6 months. | PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. PFS will be determined using the Kaplan-Meier method and will be reported along with a 95% confidence interval. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions. |
| Median Overall Survival (OS) Reported Along With a 95% Confidence Interval | Calculated from the on-study date until the date of death, an average of 11 months. | Overall survival (OS) is defined as the length of time from start of treatment until death from any cause estimated using the Kaplan-Meier method. |
| Months to Best Response in Participants Assessed Using Serum Lipase (Tumor Marker in Pancreatic Acinar Cell Carcinoma) | Calculated at baseline and assessed every 28 days for an average of 0.158 months. | Best response in serum lipase (tumor marker in pancreatic acinar cell carcinoma) was assessed for each treated participant (defined as greatest decrease from baseline measurement during the treatment course) tested for statistical significance of the change by a Wilcoxon signed rank test with a two-tailed p-value, and the median and full range was calculated. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORChen Zhao, M.D.
National Cancer Institute (NCI)
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 65.25 years STANDARD_DEVIATION 6.18 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 4 |
| other Total, other adverse events | 4 / 4 |
| serious Total, serious adverse events | 0 / 4 |
Outcome results
None listed