Precision Cancer Prevention: Hereditary Polyposis Syndromes

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1 Precision Cancer Prevention: Hereditary Polyposis Syndromes N. Jewel Samadder, MD, MSC, FRCPC HUNTSMAN CANCER INSTITUTE UNIVERSITY OF UTAH

2 Familial Adenomatous Polyposis Familial Adenomatous Polyposis (FAP) Genetic disorder, autosomal dominant Germ line mutation in APC s of colorectal adenomas: 100% risk of CRC Prophylactic colectomy standard of care

3 FAP: Duodenal Neoplasia Duodenal cancer is major cause of death in FAP Duodenal Neolplasia in FAP Duodenal adenomas >50% Dudoenal carcinoma ~12% Management: Endoscopic Surveillance, Duodenectomy or Whipple are suboptimal

4 Chemoprevention in FAP COX Inhibition sulindac and celecoxib inhibits colorectal adenomas 1,2 Non-significant decrease in duodenal adenomas 3 celecoxib associated with cardiac toxicity celecoxib not FDA approved for chemoprevention in FAP 1 Steinbach NEJM, 2 Giardiello NEJM, 3 Phillips Gut.

5 Key Sporadic Adenoma Trials FAP Chemoprevention Trials (% reduction in Adenomas compared to Placebo) Celecoxib 400 mg BID 31%, p=0.001 N=77 FAP Colorectal polyps Steinbach NEJM Colorectal Adenomas Sulindac 150 mg BID 35%, p=0.001 N=22 FAP Colorectal polyps Giardiello NEJM Celecoxib 400 mg BID 4%, p=0.44 Duodenal Adenomas N=83 FAP Duodenal polyps Phillips Gut

6 Cellular Signaling Preclinical murine models suggest synergistic chemoprevention with sulindac and EGFR inhibition 1,2 1 Phelps et al Cell, 2 Roberts et al PNAS.

7 Hypothesis Combination COX and EGFR inhibition sulindac 150mg po BID and erlotinib 75 mg po day Inhibit duodenal adenoma formation in FAP

8 Study Design and Patients Double blind, randomized, placebo-controlled Single academic cancer center June 2010 to June 2014 Inclusion Criteria yo with FAP Genetic Dx: APC mutation (including all AFAP) or Clinical Dx: >100 adenomas & known FAP family Baseline endoscopy (month 0) polyps measured in first 10cm segment of duodenun > 5mm sum of diameters duodenal polyp burden Endpoint endoscopy at 6 months

9 Study Design and Patients Screened: 156 Exclusion criteria: Insufficient duodenal polyps: 40 Advanced disease requiring surgery: 14 Advanced duodenal disease: 1 Abnormal lab values: 4 Gastric erosions: 1 Potential lung disease: 1 Screened in but declined: 3

10 Study Design and Patients Screened: 156 Randomized: 92 Exclusion criteria: Insufficient duodenal polyps: 40 Advanced disease requiring surgery: 14 Advanced duodenal disease: 1 Abnormal lab values: 4 Gastric erosions: 1 Potential lung disease: 1 Screened in but declined: 3 Sulindac-Erlotinib Group N=46 Placebo Group N=46

11 Study Design and Patients Screened: 156 Randomized: 92 Exclusion criteria: Insufficient duodenal polyps: 40 Advanced disease requiring surgery: 14 Advanced duodenal disease: 1 Abnormal lab values: 4 Gastric erosions: 1 Potential lung disease: 1 Screened in but declined: 3 Sulindac-Erlotinib Group N=46 46 Intention to Treat 37 Per Protocol Analysis Placebo Group N=46 46 Intention to Treat 36 Per Protocol Analysis Withdrawn: 19 No endpoint due to study halt: 5 Pregnancy: 2 (both on placebo) Drug intolerance/adverse Rxn: 3 Suspected allergic reaction:2 Unrelated health reasons: 3 Lost to follow-up: 3 Non-compliant: 1

12 Statistical Analysis Statistical Analysis Primary (ITT): Change in duodenal polyp burden Change in sum of polyp diameters in 10 cm segment Secondary: Change in duodenal polyp number Wilcoxon (Mann-Whitney) test to compare groups Interim Analysis: DSMB 2 nd interim analysis: trial stopped early due to statistical significance

13 Demographics Characteristic Sulindac-Erlotinib (n=46) Placebo (n=46) Mean Age (SD) 42 (14) 41 (14) Sex Female 61% 61% Alcohol Yes 37% 37% FAP Status Genetic Diagnosis 85% 91% Classic FAP Attenuated FAP 70% 30% 70% 30% Baseline number of polyps Baseline sum diameters (mm) 29 23

14 Demographics Characteristic Sulindac-Erlotinib (n=46) Placebo (n=46) Mean Age (SD) 42 (14) 41 (14) Sex Female 61% 61% Alcohol Yes 37% 37% FAP Status Genetic Diagnosis 85% 91% Classic FAP Attenuated FAP 70% 30% 70% 30% Baseline number of polyps Baseline sum diameters (mm) 29 23

15 Demographics Characteristic Sulindac-Erlotinib (n=46) Placebo (n=46) Mean Age (SD) 42 (14) 41 (14) Sex Female 61% 61% Alcohol Yes 37% 37% FAP Status Genetic Diagnosis 85% 91% Classic FAP Attenuated FAP 70% 30% 70% 30% Baseline number of polyps Baseline sum diameters (mm) 29 23

16 Demographics Characteristic Sulindac-Erlotinib (n=46) Placebo (n=46) Mean Age (SD) 42 (14) 41 (14) Sex Female 61% 61% Alcohol Yes 37% 37% FAP Status Genetic Diagnosis 85% 91% Classic FAP Attenuated FAP 70% 30% 70% 30% Baseline number of polyps Baseline sum diameters (mm) 29 23

17 Duodenal Polyp Burden Median Change in sum diameter (mm) of duodenal polyps Baseline 6 months Change Percent Change P Intention to Treat Analysis Sulindac- Erlotinib (-9.5, -7) -37.9% 4.2 x 10-9 Placebo (5, 9.5) 30.6%

18 Duodenal Polyp Burden Baseline: Month 0 Endpoint: Month 6

19 Duodenal Polyp Burden: Waterfall Plot

20 Secondary Outcomes Outcome Sulindac-Erlotinib Placebo P Change in Duodenal Polyp Burden Per Protocol Analysis -9 mm 6 mm <0.001 Genetic Diagnosis of FAP -9 mm 9 mm <0.001 Classic FAP 8.5 mm 8.5 mm <0.001 Change in Duodenal Polyp number All Patients <0.001

21 Secondary Outcomes Outcome Sulindac-Erlotinib Placebo P Change in Duodenal Polyp Burden Per Protocol Analysis -9 mm 6 mm <0.001 Genetic Diagnosis of FAP -9 mm 9 mm <0.001 Classic FAP 8.5 mm 8.5 mm <0.001 Change in Duodenal Polyp number All Patients <0.001

22 Secondary Outcomes Outcome Sulindac-Erlotinib Placebo P Change in Duodenal Polyp Burden Per Protocol Analysis -9 mm 6 mm <0.001 Genetic Diagnosis of FAP -9 mm 9 mm <0.001 Classic FAP 8.5 mm 8.5 mm <0.001 Change in Duodenal Polyp number All Patients <0.001

23 Secondary Outcomes Outcome Sulindac-Erlotinib Placebo P Change in Duodenal Polyp Burden Per Protocol Analysis -9 mm 6 mm <0.001 Genetic Diagnosis of FAP -9 mm 9 mm <0.001 Classic FAP 8.5 mm 8.5 mm <0.001 Change in Duodenal Polyp number All Patients <0.001

24 Study Safety: Adverse Events Adverse Events Sulindac-Erlotinib (n=46) Placebo (n=46) Acneiform rash 40 (86%) 9 (20%) Oral mucositis 18 (39%) 5 (11%) Diarrhea 12 (26%) 6 (13%) Nausea 11 (24%) 6 (13%) Adverse Events: No AE above Grade 2 toxicity

25 Discussion Double-blind, placebo controlled randomized trial Combination sulindac and erlotinib therapy vs placebo Reduction in duodenal polyp burden and number in patients with FAP Effect evident after only 6 months therapy In both classic and attenuated FAP

26 Discussion First study to show significant chemoprevention effect in FAP patients for duodenal neoplasia Dual COX-EGFR inhibition therapy Supports future studies to examine: Colorectal polyp regression in FAP* Long term efficacy of COX-EGFR inhibition Dose ranging studies to reduce side effects* Single agent inhibition of EGFR* Polyp burden as surrogate endpoint vs cancer incidence

27 Thank You FAP Patients Funding/Support NCI: PO1-CA NCI: CCSG P30CA Huntsman Cancer Foundation Gastroenterology University of Utah N. Jewel Samadder Randall W. Burt Priyanka Kanth Kathryn Byrne Cancer Biostatistics Core Ken Boucher Tom Greene Lisa Pappas Hereditary GI Cancer Registry Deb Neklason Michelle Done Laurel Smith Therese Berry Danielle Sample Megan Keener Genetic Counseling Resource Wendy Kohlmann Amanda Gammon Kory Jasperson Marjan Champine Data Safety Monitoring Board Paul Limburg David Weinberg Sonia Kupfer William Grady Richard Holubkov Patient Referrals Elena Strait Patrick Lynch Wendy McKinnon