S0820Professional SlidesVersion

S0820 A double blind placebo-controlled trial of Eflornithine and Sulindac to prevent recurrence of high risk adenomas and second primary colorectal cancers in patients with Stage 0-III Colon Cancer, Phase III.

S0820Professional SlidesVersion Jason A. Zell, D.O., M.P.H. (Medical Oncology) UC Irvine Medical Center Powel H. Brown, M.D., Ph.D. (Medical Oncology) M.D. Anderson Cancer Center Study Coordinators

S0820Professional SlidesVersion Assess whether eflornithine (+/- sulindac), sulindac (+/- eflornithine) or the combination are effective in reducing the three-year event rate (high-risk adenomas and second primary colorectal cancers) in patients with previously treated Stage 0-III colon cancer. Primary Objective

S0820Professional SlidesVersion U.S. Cancer statistics, 2013 CA: A Cancer Journal for Clinicians Volume 63, Issue 1, pages 11-30, 17 JAN 2013 DOI: /caac Volume 63, Issue 1,

S0820Professional SlidesVersion Colorectal Cancer Primary Prevention: Screening and early detection result in 5- year survival rates of 90% (colon) and 80% (rectum) for localized disease The problem: 50-60% receive proper screening, and 60% present with advanced stage disease Result: overall survival is 64%* 5-year Survival (%) Survival Estimates Siegal, R, Ca-A Cancer Journal for Clinicians 2013; 63 (1):11-30.

S0820Professional SlidesVersion Second Primary Colorectal Cancers among Stage I-III CRC cases Occur in ~1-4% of treated CRC patients Among 69,809 colon cancer cases in California , 40% increased risk of 2 nd primary CRC among CRC cases compared to the underlying population at risk* Standardized Incidence Ratio = 1.4 (95% CI ) * Raj, KP, et al. Risk of second primary colorectal cancer among colorectal cancer cases: A population-based analysis. J Carcinogenesis 2011;10:6

S0820Professional SlidesVersion

REGISTERREGISTER STRATIFY*STRATIFY* RANDOMIZERANDOMIZE eflornithine + sulindac placebo (n=335) eflornithine placebo + sulindac (n=335) eflornithine + sulindac (n=335) eflornithine placebo + sulindac placebo (n=335) 3-year study intervention Colonoscopy Primary endpoint = 3-year rate of high risk adenomas or 2 nd primary CRCs. End-of-study audiogram, blood collection S0820 Study Design: (n=1488) Baseline data collection, audiogram, blood, CT- scans, & colonoscopy at Year-1 post resection *Stratification by stage FOLLOW-UPFOLLOW-UP 5-year follow -up Activated: March 1, 2013

S0820Professional SlidesVersion Study Drug Information  Eflornithine (DFMO) or Placebo, 250 mg, 2 tablets oral daily x 3 years  Sulindac (NSAID) or Placebo, 150 mg, 1 tablet oral daily x 3 years ~1,488 volunteers assigned randomly to one of four trial arms take 2take 1 Arm 1placebo Arm 2eflornithineplacebo Arm 3placebosulindac Arm 4eflornithinesulindac

S0820Professional SlidesVersion Cardiovascular Risk Amended As of May 1, 2014, the protocol was amended to define specific cardiovascular risk factors and specific blood pressure parameters for eligibility. Patients must NOT have: -uncontrolled high blood pressure -unstable angina -history of documented myocardial infarction -history of document cerebrovascular accident -Class III or IV heart failure as defined by the NY Heart Association -known uncontrolled hyperlipidemia within last 3 years

S0820Professional SlidesVersion Stage 0, I, II or III colon adenocarcinoma treated per standard care with resection alone or in combination with adjuvant chemotherapy Adjuvant chemotherapy must have been completed at least 30 days prior to registration Patients with rectosigmoid cancers are eligible only if their treatment did NOT involve radiation therapy (i.e. neo-adjuvant or adjuvant radiation) (mid-low rectal cancers are not eligible) Patients must be registered between 274 days and 465 days (inclusive) of primary resection Eligibility

S0820Professional SlidesVersion CT scan performed at least 180 days after colon resection Must be at least 18 years of age & no history of familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, or inflammatory bowel disease Must have a pure tone audiometry evaluation to document air conduction Not be expecting to receive radiation or additional chemotherapy Not be receiving or plan to receive concomitant corticosteroids NSAIDs, nor anticoagulants on a regular or predictable intermittent basis Patients must have adequate blood counts Eligibility (continued)

S0820Professional SlidesVersion

Year 1: H & P, CBC & chemistries every 3 months Year 2 & 3: H & P, CBC & chemistries every 6 months PE & chemistries, colonoscopy & pure tone audiogram 3 years after randomization Patients followed annually for 5 years (after completion of 3 years of intervention): H & P Weight and Performance Status Follow-up colonoscopy at 8 years post-registration per NCCN guidelines Follow-up

S0820Professional SlidesVersion

Study drug adherence measured by returned tablet count Unused medication returned to the clinic at each visit Patients document study drug intake on an Intake Calendar Individualized adherence strategies used if adherence is ↓75%: Communicate with patient to define barriers Review patient’s routine for taking study drugs Seek family assistance Consider more frequent contact with patient using phone check-in Adherence

S0820Professional SlidesVersion year event rate after registration among Stage 0-III colon cancer patients Event = high risk adenoma or 2nd primary colorectal cancer High risk adenoma = either advanced adenoma (villous or tubulovillous histology, size ≥ 1 cm, or high grade dysplasia) or multiple adenomas (3 or more each > 0.3 cm) Primary Endpoint

S0820Professional SlidesVersion Total advanced colorectal event rate Recurrence High-grade dysplasia Adenomas with villous features Adenomas ≥ 1 cm Multiple adenomas Adenoma Total colorectal event rate Time to first clinically apparent high-risk adenoma or 2nd primary colorectal cancer Secondary Endpoints

S0820Professional SlidesVersion Submission of blood specimen for nutritional assays and banking: including genotyping and biochemical assays fasting whole blood sample required after registration and prior to beginning treatment Diet and Lifestyle Substudy: completion of Diet & Lifestyle Questionnaires after registration Optional for patients…….

S0820Professional SlidesVersion Pharmacokinetic Study ALL SITES have the option to participate in the population pharmacokinetic sampling: Sampling occurs twice at 3 & 12 months during morning visits Collected only on patients receiving intervention at 3 & 12 months Kits are ordered from Cancer Prevention Pharmaceuticals, Inc. Interested sites should contact: Patricia O’Kane SWOG Operations Office San Antonio, TX

S0820Professional SlidesVersion Please help identify potential patients History of stage 0, I, II or III colon adenocarcinoma Treated with resection alone or in combination with adjuvant chemotherapy NED at one year post-operative assessment Timing: Patients must be registered between 274 and 465 days (inclusive) of primary resection Colonoscopy and CT scans of chest, abdomen and pelvis NED performed at least 274 days after resection date and prior to registration Polyps detected at colonoscopy must be completely removed Adjuvant chemo completed ≥ 30 days prior to registration CT Scan is for high risk patients per NCCN guidelines & at discretion of treating physician

S0820Professional SlidesVersion Materials for the Investigators and Staff include: Webinar FAQs Pocket Protocol Recruitment Materials available: Printable Brochure Promotional Flyers Strategies Professional Slide Set Promotional Letter to Physicians Study Logo and Printing Instructions Thank You letter to Referring Physicians Adherence Strategies Materials for the patient include: Thank You Letter from the PI for Enrolling List of Resources S0820 Web Page

S0820Professional SlidesVersion S0820 Thank You