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S0820

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. Study Coordinators. Jason A. Zell, D.O., M.P.H. (Medical Oncology)

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S0820

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  1. 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.

  2. Study Coordinators 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

  3. Primary Objective 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.

  4. U.S. Cancer statistics, 2013 CA: A Cancer Journal for CliniciansVolume 63, Issue 1, pages 11-30, 17 JAN 2013 DOI: 10.3322/caac.21166http://onlinelibrary.wiley.com/doi/10.3322/caac.21166/full#fig1

  5. 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%* Survival Estimates 5-year Survival (%) Siegal, R, Ca-A Cancer Journal for Clinicians 2013; 63 (1):11-30.

  6. Second Primary Colorectal Cancersamong Stage I-III CRC cases Occur in ~1-4% of treated CRC patients Among 69,809 colon cancer cases in California 1990-2005, 40% increased risk of 2nd primary CRC among CRC cases compared to the underlying population at risk* Standardized Incidence Ratio = 1.4 (95% CI 1.3-1.5) * Raj, KP, et al. Risk of second primary colorectal cancer among colorectal cancer cases: A population-based analysis. J Carcinogenesis 2011;10:6

  7. S0820 Study Design: (n=1340) 5-year follow-up 3-year study intervention eflornithine + sulindac placebo (n=335) Colonoscopy Primary endpoint = 3-year rate of high risk adenomas or 2nd primary CRCs. End-of-study audiogram, blood collection FOL LOW-UP RANDOMIZE S TRA T I F Y* REGISTER eflornithine placebo + sulindac (n=335) eflornithine + sulindac (n=335) eflornithine placebo + sulindac placebo (n=335) Baseline data collection, audiogram, blood, CT-scans, & colonoscopy at Year-1 post resection *Stratification by stage Activated: March 1, 2013

  8. 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

  9. Cardiovascular Risk • Defined as a modified version of the criteria originally proposed by Solomon et al • Patients with baseline high cardiovascular risk scores are not eligible for enrollment in S0820 • High cardiovascular risk = one of the following: • diabetes mellitus • prior history of cardiovascular disease • or ≥ 2 of the risk factors used in isolation to define moderate risk • Patients may take daily aspirin for CV prophylaxis if ASA is ≤ 100 mg/day or ≤ two 325 mg tablets/week.

  10. Eligibility • Stage 0, I, II or III colon cancer 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) • Had a primary resection one year previously and had a one-year post-op colonoscopy and CT scans of chest, abdomen and pelvis showing no evidence of disease.

  11. Eligibility (continued) • Must be at least 18 years of age • No history of familial adenomatous polyposis, hereditary nonpolyposiscolorectal 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

  12. Patients will be randomized using a 2x2 factorial design

  13. Follow-up • Year 1: H & P, CBC & chemistries every 3 months • Year 2 & 3: H & P, CBC & chemistries every 6 months • Colonoscopy & 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

  14. Adherence • 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

  15. Primary Endpoint • 3-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)

  16. Secondary Endpoints • 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

  17. Optional for patients……. • 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

  18. Please help identify potential patients • History of stage 0, I, II or III colon cancer • 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

  19. S0820 Web Page 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

  20. S0820 Thank You

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