The Prevention of Progression to Pancreatic Cancer Trial (The 3P-C Trial)

• ClinicalTrials.gov Identifier: NCT04207944
• Recruitment Status: Recruiting
• First Posted: December 23, 2019
• Last Update Posted: July 14, 2020
• Sponsor: Duke University
• Collaborators: Johns Hopkins University; Massachusetts General Hospital; Memorial Sloan Kettering Cancer Center; National Cancer Institute (NCI)
• Information provided by (Responsible Party): Duke University

Study Description

Brief Summary:

This is a multi-center randomized double-blind placebo controlled trial of patients with high-risk intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. The primary objective is to evaluate the effect of sulindac on the presence or absence of progression of IPMN after 3 years of treatment.

Patients without contraindications will be considered to be eligible and will be required to have a cross-sectional imaging study of the pancreas (pancreas protocol CT or CT angiogram of the pancreas) within 3 months of study entry to document residual IPMNs and to rule out any evidence of pancreatic cancer. Patients will be randomized to receive either sulindac (200 mg p.o. BID) plus standard radiographic and endoscopic surveillance or placebo plus standard radiographic and endoscopic surveillance. Randomization will be stratified by (1) whether the patient had high-grade dysplasia identified in the initial resection specimen (resected patients only) and (2) whether the patient is taking metformin at the time of randomization.

Condition or disease	Intervention/treatment	Phase
IPMN; IPMN, Pancreatic	Drug: Sulindac 200 MG; Other: Placebo	Phase 2

Detailed Description:

This is a phase 2 multicenter, randomized, double-blind, placebo-controlled clinical trial of patients who have high-risk intraductal papillary mucinous neoplasms (IPMN) of the pancreas. Patients will be randomized in a 1:1 fashion and stratified by whether the patient had high-grade dysplasia (yes vs. no vs. no resection) identified in the initial resection specimen (for resected subjects), and whether or not the patient is taking metformin at the time of randomization. Patients will be required to have undergone a pancreas CT or CT angiogram of the pancreas in accordance with the standard practice at the enrolling institution within 3 months of study entry. The CT imaging study will be used to document baseline IPMN characteristics and to ensure that there is no evidence of a preexisting pancreatic cancer.

Following randomization, patients will take the study drug or placebo BID for 3 years. Both the study drug arm and the placebo arm will undergo standard laboratory, radiographic, and endoscopic assessment for IPMN progression. Every 6 months, patients will undergo assessment of serum CMP, CBC, and CA19-9. EUS will be performed 6 months after randomization (+/- 4 weeks) and then annually. Pancreatic CT will be performed 1 year after randomization (+/- 4 weeks) and then annually. The intent of these timings is to have the EUS and CT be on an alternating 6-month schedule per standard of care.

Patients, nurses, and physicians will be blinded to the randomization. Study drug will be provided to patients in the outpatient clinic. Pill diaries will be provided at the time that the study drugs are given and will be evaluated every 6 months, at the time of routine follow-up.

Safety and efficacy will be assessed throughout the treatment period. Assessment for study drug complications will be made by phone call every other month (in between routine follow-up) and at routine follow-up every 6 months by the attending surgeon or designee, until the end of the study. If a complication is identified, the study drug will be discontinued. Patient evaluations will be scheduled bi-annually for the primary endpoint and off-schedule evaluations may be made to address symptoms or clinical concerns as they arise.

The investigators plan to accrue 200 patients during a period of 2 years and will follow all patients for 3 additional years, for a total trial duration of 5 years.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 200 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: The Prevention of Progression to Pancreatic Cancer Trial (The 3P-C Trial)
• Actual Study Start Date: July 10, 2020
• Estimated Primary Completion Date: January 31, 2025
• Estimated Study Completion Date: January 31, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Sulindac; Patients will be randomized to receive standard radiographic/endoscopic surveillance plus sulindac. The sulindac starting dose is 200 mg by mouth 2x daily. Patients will continue drug for 3 years during follow-up.	Drug: Sulindac 200 MG; Patients will be randomized to receive standard radiographic/endoscopic surveillance plus sulindac. The sulindac starting dose is 200 mg by mouth 2x daily. Randomization will be performed at Duke and stratified by (1) the presence of high-grade dysplasia on the operative pathologic report and (2) the use of metformin at the time of enrollment. Patients will be provided the study drugs by a Duke, MSK, MGH, or JHH pharmacist. Patients will continue drug/placebo for 3 years during follow-up.
Placebo Comparator: Placebo; Patients will be randomized to receive standard radiographic/endoscopic surveillance plus placebo. Patients will continue placebo for 3 years during follow-up.	Other: Placebo; Patients will be randomized to receive standard radiographic/endoscopic surveillance plus sulindac. The sulindac starting dose is 200 mg by mouth 2x daily. Randomization will be performed at Duke and stratified by (1) the presence of high-grade dysplasia on the operative pathologic report and (2) the use of metformin at the time of enrollment. Patients will be provided the study drugs by a Duke, MSK, MGH, or JHH pharmacist. Patients will continue drug/placebo for 3 years during follow-up.

Outcome Measures

Primary Outcome Measures :

1. Percent of patients with IPMN progression as measured by a composite of several indicators [ Time Frame: 3 years ]

   Patients will be determined to have progressed if they have:

   1. New cystic lesion(s) of the pancreas >1 cm in diameter (or initial lesion(s) <5 mm that are now >1cm),
   2. Doubling of the diameter of any preexisting cyst initially measuring ≥5 mm
   3. Increase in diameter of the main pancreatic duct by >3mm
   4. Pancreatic resection
   5. The development of an invasive cancer.

Secondary Outcome Measures :

1. Percent of patients with cyst progression as measured by radiographic images [ Time Frame: 3 years ]
   1. All initial and follow-up CT imaging will be quantitatively assessed for radiographic changes associated with progression. Utilizing a recently described radiomics approach to the evaluation of imaging in patients with IPMN, the investigators will further explore the set of 256 imaging features that broadly describe variation in radiographic enhancement patterns (i.e. heterogeneity). Using image analysis techniques, the investigators will derive quantitative measurements of the cyst wall and will determine the presence and degree of solid enhancing component suggestive of malignancy.

Other Outcome Measures:

1. Percent of patients with Inflammatory Marker Progression [ Time Frame: 3 years ]
   2. Cyst fluid obtained at the time of annual EUS will be used to determine whether cyst fluid inflammatory marker analysis can identify progression. Antibody bead array analysis will be used to assess whether previously developed biomarker models for high-risk IPMN (IL-4/sFASL and MMP-9/CA72-4) can identify patients with an increased risk of radiographic progression.

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Subject is a man or woman between the ages of 21 and 85 years.

• Subject has high-risk IPMN as defined below.

  1. Patient has undergone partial pancreatectomy for non-invasive IPMN AND has residual cyst(s) > 1 cm
  2. Patient has a radiographic lesion of the pancreas consistent with IPMN as documented by: :
  3. Cyst fluid CEA > 192 ng/ml OR MRI confirmation of communication with main pancreatic duct AND has any of the following worrisome features:

  i. Cyst > 3 cm ii. Thickened/enhancing cyst walls iii. Main pancreatic duct > 5mm iv. Abrupt change in caliber of pancreatic duct with distal atrophy

• Subjects has ECOG of 0-2
• Subject is medically fit to undergo EUS.
• Female subjects who are of childbearing potential or are capable of becoming pregnant must be willing to use appropriate methods of contraception for the length of the study.
• Subject is able to provide written informed consent.

Exclusion Criteria:

• Subject has pathologic evidence of pancreatic cancer.
• Subject takes an NSAID 3 or more times per week.
• Subject has a history of or currently has known allergy to NSAIDs or a contraindication to use of NSAIDs in the opinion of the treating investigator.
• Subject has a history of gastric ulcer, non-iatrogenic intestinal perforation, gastrointestinal bleeding from NSAID use for which intervention was required, renal insufficiency (eGFR <60 mL/minute/1.73 m2), venous thromboembolism, cirrhosis, asthma, or any other condition that serves as a contraindication to the use of sulindac.
• Myocardial infarction or coronary artery bypass grafting within six months of study entry.
• Congestive Heart Failure.
• Severe adverse drug reaction to iodinated contrast agents that cannot be managed with routine premedication prior to imaging.
• Prior diagnosis or active treatment for (other) prior malignancy (except in situ cancers) within the previous 3 years.
• History of medical procedure that would prevent an endoscopic ultrasound from being performed (such as gastric bypass, prior total gastrectomy).
• Subject is lactating or pregnant.

Contacts and Locations

Contacts

Contact: Peter Allen, MD; 919-684-6858; peter.allen@duke.edu

Contact: Elizabeth Bronson; 919-668-2382; beth.bronson@duke.edu

Locations

United States, Maryland

Johns Hopkins University; Not yet recruiting

Baltimore, Maryland, United States, 21287

Contact: Christopher Wolfgang, MD 410-502-4194 cwolfga2@jhmi.edu

Contact: Neda Amini namini3@jhmi.edu

United States, Massachusetts

Massachusetts General Hospital; Not yet recruiting

Boston, Massachusetts, United States, 02114

Contact: Carlos Fernandez, MD 617-726-5644 cfernandez@mgh.harvard.edu

Contact: Caitlin Stafford CSTAFFORD2@PARTNERS.ORG

United States, New York

Memorial Sloan Kettering; Not yet recruiting

New York, New York, United States, 10021

Contact: Kevin Soares, MD 212-639-3195 soaresk@mskcc.org

Contact: Cristina Olcese OlceseC@mskcc.org

United States, North Carolina

Duke University Medical Center; Recruiting

Durham, North Carolina, United States, 27710

Contact: Elizabeth Bronson 919-737-4914 elizabeth.bronson@duke.edu

Contact: Stacy Murray 919-684-7983 stacy.murray@duke.edu

Principal Investigator: Peter Allen, MD

Sponsors and Collaborators

Duke University

Johns Hopkins University

Massachusetts General Hospital

Memorial Sloan Kettering Cancer Center

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Peter Allen, MD; Duke University

More Information

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT04207944
• Other Study ID Numbers: Pro00103684; 1R01CA235677-01A1 ( U.S. NIH Grant/Contract )
• First Posted: December 23, 2019
• Last Update Posted: July 14, 2020
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Data will only be shared through publication.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Pancreatic Intraductal Neoplasms; Pancreatic Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Neoplasms, Ductal, Lobular, and Medullary; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Sulindac; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action