Preventing Adenomas of the Colon with Eflornithine and Sulindac (PACES)/S0820 is an important phase III National Clinical Trials Network (NCTN)-based colorectal cancer prevention clinical trial, and to ensure the success of PACES/S0820, major changes were instituted in April 2017. These changes affected the study design, the translational aims, as well as the leadership across the NCTN.
PACES launched in March 2013 as a tertiary prevention clinical trial for colorectal cancer survivors (from stage 0-III disease). Its goal was to test whether the rate of high-risk adenomas or second primary colorectal cancers can be reduced by agents called polyamine inhibitors, such as eflornithine and sulindac. Patients in the trial take these agents for three years (postoperative years one to four). Polyamines are molecules that are essential for normal physiology but, when in excess, can act as carcinogens within epithelial tissues (particularly within the colon, breast, and prostate). PACES investigators are testing two polyamine inhibitors for their anti-carcinogenic effects: first, eflornithine (difluoromethylornithine or DFMO) is a suicide inhibitor of ornithine decarboxylase, the rate-limiting step of polyamine synthesis; and second, sulindac (a cyclooxygenase non-specific nonsteroidal anti-inflammatory drug) is known to promote polyamine export from epithelial tissues.
The PACES launch came on the heels of another phase III clinical trial to prevent colorectal adenomas, involving three years of treatment with a combination of eflornithine and sulindac versus combination placebos.1 When compared with placebo, these agents led to a 70 percent decrease in total adenomas and, importantly, a more than 92 percent decrease in high-risk adenomas (large adenomas >1cm, adenomas with high-grade dysplasia and multiple adenomas) and second primary colorectal cancers. The regimen was well-tolerated, with no significant side effects when compared with the placebo group. Due to concerns about eflornithine-associated hearing loss observed in older trials that used up to 40-fold higher doses of eflornithine, detailed audiometry studies were done on patients in the adenoma study.2 No clinical hearing loss was observed, and the observed 8 percent non-significant reduction in audiogram thresholds at end-of-study essentially resolved three to six months after the discontinuation of eflornithine. Given the favorable efficacy versus safety profile, PACES was launched to investigate these polyamine-inhibitor agents in colorectal cancer survivors who remain at risk for high-risk adenomas and secondary colorectal cancers in the surveillance period.
Changes to PACES to enhance accrual
Accrual to PACES was significantly slower than anticipated. Therefore, to enhance accrual and ensure feasibility of this cancer prevention trial, in 2016 investigators worked closely with the NCTN leadership, the National Cancer Institute Division of Cancer Prevention, and the NCTN Accrual to Clinical Trials (NCTN ACT) committee to propose major changes to the Data Safety Monitoring Committee. A revised protocol was approved and formally activated April 15, 2017. The key changes are as follows:
The trial was contracted from a four-arm 2 × 2 factorial design requiring 1,488 patients, to a two-arm phase III design requiring 480 patients. This new design directly compares combination agents (eflornithine/sulindac) with combination placebos. The goal is to reduce the three-year incidence of high-risk adenomas or second primary colorectal cancers by 50 percent. While the single agent/placebo arms were discontinued, all patients previously assigned to them are continuing their therapy. Available data from these patients will be analyzed for efficacy and safety.
PACES has gained the full support and leadership of all the NCTN groups. Y. Nancy You, MD, FACS, a co-author of this column, joins the PACES/S0820 team as lead investigator representing the Alliance for Clinical Trials in Oncology. Other investigators new to the team include Jennifer Dorth, MD, radiation oncologist, Cleveland Clinic, OH, representing the NRG cooperative group, and Raymond Bergan, MD, medical oncologist, Oregon Health Sciences University, Portland, representing the ECOG-ACRIN Research Group. The result of this enhanced representation across the NCTN has resulted in a renewed commitment to PACES/S0820 and improved accrual.
New translational aims were developed with Jason Zell, DO, MPH, principal investigator and a co-author of this article, and Weian Zhao, PhD, associate professor, department of biomedical engineering, University of California, Irvine, based on their prior biomarker analyses in colorectal cancer patients.3 Dr. Zhao’s laboratory recently developed a platform technology called Integrated Comprehensive Droplet Digital Detection (IC 3D) that can selectively detect biomarkers (for example, cells, proteins, and nucleic acids) from milliliters (mLs) of blood samples at single-cell (or single-molecule) sensitivity.4 This system integrates real-time fluorescent sensors, droplet microfluidics, and a high throughput 3D particle counting system. Here, study investigators propose to evaluate and use the IC 3D technology as a complementary tool to predict CRC recurrence in stage 0-III CRC patients enrolled in S0820/PACES.
The IC 3D test will detect a panel of cancer mutations with great sensitivity, including a gene panel that collectively identifies driver mutations in one or more key genes among 90 percent of CRC patients. Investigators will analyze the total DNA isolated from peripheral blood mononucleated cells (PBMCs) for circulating tumor cells and plasma-derived circulating tumor DNA to further increase the clinical sensitivity.
The trial is open for accrual at 550 U.S. sites. At press time, 157 of 480 patients were registered (33 percent of the total accrual target), and accrual over the previous six months averaged six patients per month. The new target is eight patients registered per month. At this rate of accrual, the trial will close in slightly more than three years.
The research team is excited about the changes made to PACES and the opportunity to complete accrual in a more timely fashion. A dynamic group of experts across the NCTN represent the trial on a regular basis, and novel translational endpoints have been developed to provide insight into biomarkers for carcinogenesis and cancer progression. For more information about the trial, search for S0820 on either the SWOG website or ClinicalTrials.gov. These sites will provide location and contact information of investigators participating in the trial. On the SWOG abstract page for S0820, scroll down to the bottom and click on the “Where is this study open?” button. On the ClinicalTrials.gov page, under “Contacts and Locations,” expand the “show study locations” list.
- Meyskens FL Jr., McLaren CE, Pelot D, et al. Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: A randomized placebo-controlled, double-blind trial. Cancer Prev Research (Phila). 2008;1(1):32-38.
- McLaren CE, Fujikawa-Brooks S, Chen WP, et al. Longitudinal assessment of air conduction audiograms in a phase III clinical trial of difluoromethylornithine and sulindac for prevention of sporadic colorectal adenomas. Cancer Prev Research (Phila). 2008;1(7):514-521.
- Zhang K, Kang DK, Ali MM, et al. Digital quantification of miRNA directly in plasma using Integrated Comprehensive Droplet Digital Detection. Lab Chip. 2015;15(21):4217-4226.
- Kang, DK, Ali MM, Zhang K, et al. Rapid detection of single bacteria in unprocessed blood using Integrated Comprehensive Droplet Digital Detection. Nat Commun. 2014;13:5:5427. Available at: www.nature.com/articles/ncomms6427. Accessed September 1, 2017.