1. Keynote lecture 5: Priorities for clinical research in GI cancer Daniel G. Haller, MD Professor of Medicine Abramson Cancer Center and the Perelman School of Medicine at the University of Pennsylvania

2. Establishing a Balance of Priorities Clinical trials are designed to ultimately benefit patients with cancer, but motivations are varied and frequently contradictory – Patients: want better treatment, but <10% participate in trials – Investigators: same as above plus career-building – Pharma: same as above plus $$$ – Government: same as above plus bureaucracy

3. Research hurdles faced by investigators Regulatory hurdles Access to new drugs Funding Independence Registration of academic trials International collaborations Publication bias

4. Rational vs. personal(ized) medicine Clinicians have been practicing personal, individualized oncology for years, based on – Clinicopathologic factors, frequently qualitative – Demographics – Patient and physician preference Rational (personalized) oncology practice identifies unique, quantifiable and validated tumors biology (targets) with interventions that relate to targets, identifiable MOA and proven efficacy in specific subsets of patients

5. Biomarker Research Type of marker:IdentificationValidation PrognosticEasy, but often flawed Frequent, but often disappointing PredictiveHard, needs randomized trial Very rare, needs large randomized trial SurrogateHard, needs meta- analysis or large randomized trial Very rare, needs large randomized trial In GI cancer are there predictive biomarkers beyond KRAS in mCRC, MSI in Stage II colon cancer and HER2 in metastatic gastric cancer?

7. Endpoints in Clinical Trials: the need for innovative and validated endpoints Endpoint EventDFSRFSTTRTTFCSSOS Locoregional recurrence  Distant metastases  Second primary, same cancer  Second primary, other cancer  Death from same cancer  Death from other cancer  Non-cancer death  Treatment-related death  Loss to follow- up   = failure  = censored observation

8. Endpoints in Clinical Trials: the need for innovative and validated endpoints WGIC Barcelona 2012: Friday, June 29 th 08:00 Session X: Clinical trials for GI oncologists – Trials and endpoints in GI cancer Chairs: Fortunato Ciardiello, MD, PhD and Alberto Sobrero, MD Is DFS, RR or survival the best endpoint in colorectal cancer? Marc Buyse, ScD Which difference should we target? Alberto Sobrero, MD Pharmacodynamic endpoints Fortunato Ciardiello, MD, PhD

9. ARCAD Principles and Goals ARCAD Clinical Trials Program: International group of oncologists, statisticians, and trialists, formed with the goal of accelerating the development of new drugs and treatment strategies in gastrointestinal oncology by helping establish guidelines for smaller, faster, and less expensive clinical trials Ongoing program of original research and consensus discussions, focused on endpoints, biomarkers, and clinical trials design. Free academic collaboration—members receive no remuneration for attending meetings/participating in consensus discussions Sponsorship will be sought to meet general running costs and costs of specific research initiatives ARCAD Database Project is the Main research initiative of the program—a database of large clinical trials in advanced colorectal cancer. Initial goal will be clarifying/standardizing PFS and related end points

10. ARCAD Publications Update Toward Efficient Trials in Colorectal Cancer: The ARCAD Clinical Trials Program Journal of Clinical Oncology, Vol 28, No 4 (February 1), 2010: pp. 527-530

11. International collaboration Pros: – GI cancers taken together constitute a large proportion of the burden of cancer – Large studies may accrue more rapidly Cons: – Tumor biology and host factors may vary from region to region, introducing heterogeneity of clinical effects and toxicity – Bureaucracy in establishing and maintaining individual trials and ongoing relationships

12. U.S. NCI GI Intergroup To coordinate the clinical research of the 8 (now 4) adult cooperative groups in the US Ideas and protocols are developed with the Groups for randomized phase II/III trials Vetted and approved protocol concepts are discussed in each of the organ site Task Forces Task Force concept proposals are submitted to the GI Steering Committee for review and approval

13. U.S. NCI GI Intergroup Within a month of submission protocol concepts are externally reviewed and CTEP reviewed, queries raised and one hour of teleconference with investigators dedicated to proposal. Votes: Approve, Reject, Pending response/revision Decisions of GISC NOT made on NCI budget constraints ; GISC and ultimate CTEP decisions based on science Current approval ~50%

14. U.S. NCI GI Intergroup Issues: – Rejections after long incubation times in cooperative groups and Task Forces Most common cause of rejection – Statistics and endpoints not optimal – Accrual goals overly optimistic – For cytotoxic biologic combinations, insufficient data available to move forward to randomized phase II/III trials – No integrated biologic correlative studies ? Possibility of GISC concept pre-review

15. U.S. NCI Intergroup Clinical Trials Planning Meetings Goal of CTPMs: to design clinical trials in GI cancer that can be successfully performed in the US Cooperative Group system CTPMs – Hepatocellular – NET – Pancreas – Colorectal

16. NCI Intergroup Colorectal Clinical Trials Planning Meeting (2011): Conclusions Advances in understanding molecular characterization of tumors and germline variations requires a national infrastructure to provide real-time clinical testing of patient specimens for treatment assignment. Integral marker studies are a high priority. Existing tissue banks should be exploited for predictive classifier discovery; treatment-classifier-response relationships defined in banked tissue are necessary to design prospective validation studies. Banking of patient tumors and germline DNA for future research is an imperative. High-priority therapeutic targets include signaling kinases, stem cells, DNA damage response, host response.

17. NCI Intergroup Colorectal Clinical Trials Planning Meeting (2011): Conclusions Early Stage Adjuvant Therapy There is not currently a new agent of sufficient promise to warrant testing in a phase III adjuvant study. A triple drug combination regimen, FOLFOXIRI should be tested against standard FOLFOX as adjuvant therapy in high-risk stage III colon cancers. Neoadjuvant approaches in early stage colon cancer should be considered to establish a model for evaluation of agents potentially active in the adjuvant setting. Discovery efforts should continue to focus on identification of populations at particularly high risk of recurrence, as a setting for testing new agents in early stage disease.

18. NCI Intergroup Colorectal Clinical Trials Planning Meeting (2011): Conclusions Resectable liver-confined metastatic disease Preoperative treatment with a new agent will permit in vivo pharmacodynamic assessment of treatment effect. “Adjuvant” treatment after potentially curative resection will allow testing of new approaches in this high-risk setting using resected stage IV disease as a model for micrometastatic disease. Oligometatatic disease with extrahepatic component A common clinical setting is liver metastasis with intraabdominal extrahepatic disease. A study is suggested to test the combination of surgical (resection/ablation) plus systemic approach in the setting where minimal residual disease can be accomplished with surgical treatment.

19. NCI Intergroup Colorectal Clinical Trials Planning Meeting (2011): Conclusions Unresectable metastatic disease Tumors with BRAF mutations have a poor prognosis. A first-line randomized phase II study involving new agents, with or without conventional cytotoxics is suggested in this population. Patients often have a period of stable disease after initial treatment response. This “window” after response is an opportunity to test targeted approaches in molecularly-defined patient groups. A randomized phase II study of combinations of signaling inhibitors is suggested. Irinotecan is commonly administered as a component of second- line treatment. A phase II trial of irinotecan plus novel agent(s) with treatment assignment based on tumor molecular characterization is suggested. “Last-line”, salvage settings present a patient population of high clinical need with opportunities for drug development.

20. NCI Intergroup Colorectal Clinical Trials Planning Meeting (2011): Conclusions Rectal Cancer Current treatment algorithms typically involve trimodality therapy in a “one-size fits all” approach. Future trials should tailor treatment to patient risk of local and distant recurrence. For upper rectal cancer, studies should explore the selective use of radiotherapy. For lower rectal cancer or upper rectal cancer at high risk for local recurrence, studies should explore novel agents in addition to a backbone of neoadjuvant fluoropyrimidine plus radiation. Explore the role of 5 x 5 radiation therapy in high risk rectal cancer. Examine/identify appropriate early end-points/prognostic markers for neoadjuvant clinical trials that can subsequently be integrated into future trials. These endpoints and classifiers will correlate with local recurrence and overall, and include pathological assessment, imaging biomarkers, and molecular classifiers.

21. Less is more in adjuvant therapy, does everyone need radiation? For patients at lowest risk of locoregional failure – Pancreas (RTOG): Head of pancreas, R0. Gemcitabine ± erlotinib, if relapse free at 13 weeks, ± radiation – Gastric (Dutch) CT vs. CT/XRT – Rectal (Alliance): High T3, N0-1 Neoadjuvant CT » if no PD, CT ± XRT

22. Less is More : Part II Intermittent Rx and Maintenance Premise: in mCRC, continuous therapy may result in excessive toxicity, patient/physician burnout, excess cost Treatment “holidays” may ameliorate this clinical conundrum Induction-maintenance therapy

23. Treatment-Free Intervals Rationale – Decrease intensity of therapy – Reduce toxicity – Prevent discontinuation of therapy – Preserve ability to administer later therapy – Maximize time on treatment – Increase QOL Recognize drug toxicities – Proactively determine therapeutic strategy – Assess acute and cumulative toxicity – Develop strategies to avoid or minimize toxicity

24. Treatment-Free Intervals Types of treatment breaks – Treatment break with maintenance regimen OPTIMOX-1 CONcePT – Complete chemotherapy-free intervals (CFI) OPTIMOX-2 When to interrupt/restart therapy – After pre-planned number of cycles – When toxicity reaches a certain grade – When tumor progresses – Planned reintroduction Stop 1 drug (e.g. oxaliplatin) or all? Optimal maintenance: biologics, cytotoxics or both

25. Raising the Bar: Can we surpass PFS/OS benefits of 1-2 months? ASCO 2012 – DREAM: biologic maintenance in mCRC – TML: bevacizumab in 2 nd line beyond progression – VELOUR: aflibercept (VEGF-TRAP) in 2 nd line, w/wo bevacizumab in 1 st line – CORRECT: regorafenib in last-line therapy

26. OPTIMOX3 – DREAM protocol mFOLFOX7 + bevacizumab a XELOX2 + bevacizumab b FOLFIRI + bevacizumab c a Oxaliplatin 100 mg/m² d1 (6 cycles), 5-FU 2.4 g/m² d1–2, FA 400 mg/m² d1, bev 5 mg/kg d1, q2w, 6–12 cycles b Oxaliplatin 100 mg/m² d1 (6 cycles), capecitabine 1.25–1.5 g/m² bid d1–d8, bev 5 mg/kg d1 q2w, 6–12 cycles c Irinotecan 180 mg/m² d1, 5-FU 2.4 mg/m² d1–2, FA 400 mg/m² d1, bev 5 mg/kg d1, q2w, 12 cycles Bevacizumab (7.5 mg/kg q3w) + erlotinib (150 mg/d) until PD Bevacizumab (7.5 mg/kg q3w) + erlotinib (150 mg/d) until PD R A N D O M I S A T IO N No PD n=222 n=224 4 Jan 2007 – 13 Oct 2011 INDUCTION (N=700)MAINTENANCE (N=446) Bevacizumab (7.5 mg/kg q3w) until PD Bevacizumab (7.5 mg/kg q3w) until PD REREGGIISSTTRRAATTIIOONNREREGGIISSTTRRAATTIIOONNGISTRATION

27. Summary Randomized patients Bevacizumab (N=224) Bevacizumab + erlotinib (N=222) HR [95% CI]p-value Maintenance PFS (from randomisation) 4.57 [4.11–5.52] 5.75 [4.50–6.20] 0.73 [0.59--0.91] 0.0050 PFS (from registration) 9.23 [8.54–10.05] 10.22 [9.63–11.10] 0.73 [0.59--0.91] 0.0045 Overall survival (all patients):25.44 months [95% CI 22.96–28.19]

28. CAIRO3 CKTO 2006-17 MTD chemotherapy 6 cycles of Oxaliplatin + Capecitabine + Bevacizumb SD PR CR PD observation LD capecitabine + bevacizumab not eligible RANDOMIZERANDOMIZE PROGRESSIONPROGRESSION MTD chemotherapy + bevacizumab PFS1 PFS2 PROGRESSIONPROGRESSION

29. VEGF = vascular endothelial growth factor. Continuation of Bevacizumab Beyond Progression: Pros Decreased intratumoral interstitial pressure leads to higher concentrations of chemotherapeutic agents Normalization of vasculature and better oxygenation Cytotoxic effects of all chemotherapeutics, regardless of “line of therapy” enhanced In experimental models, rapid regrowth of blood vessels after withdrawal of VEGF- inhibitors

30. FGF = fibroblast growth factor; PDGF = platelet-derived growth factor; GIP = gastrointestinal perforations; RPLS = reversible posterior leukoencephalopathy syndrome. Continuation of Bevacizumab Beyond Progression: Cons Potential alternative pathways to activate angiogenesis apart from VEGF Bevacizumab is not nontoxic (ATE, HTN, RPLS, etc.) Treatment alternatives exist most of the time Cost

31. Bevacizumab beyond progression (BBP) BRiTE* study design BRiTE* – total n=1,953 – 1,445 patients with first PD – 932 deaths (21 January 2007 cut-off) – median follow-up 19.6 months Primary endpoint: survival beyond first progression Secondary endpoints: safety, OS Grothey, et al. JCO 2008 PD = disease progression * Non-randomised, observational cohort study Bevacizumab post- PD (n=642) No post-PD treatment (n=253) No bevacizumab post-PD (n=531) Physician decision (no randomization) Unresectable mCRC treated with first-line chemotherapy + bevacizumab (n=1,953) First progression (n=1,445)

32. BRiTE Registry: Bevacizumab Regimens: Investigation Treatment Effects Grothey et al, ASCO, 2007

33. BEV + standard first- line CT (either oxaliplatin or irinotecan-based) (n=820) Randomise 1:1 Standard second-line CT (oxaliplatin or irinotecan-based) until PD BEV (2.5 mg/kg/wk) + standard second-line CT (oxaliplatin or irinotecan-based) until PD PD ML18147 study design (phase III) CT switch: Oxaliplatin → Irinotecan Irinotecan → Oxaliplatin CT switch: Oxaliplatin → Irinotecan Irinotecan → Oxaliplatin Study conducted in 220 centres in Europe and Saudi Arabia Primary endpointOverall survival (OS) from randomisation Secondary endpoints included Progression-free survival (PFS) Best overall response rate Safety Stratification factors First-line CT (oxaliplatin-based, irinotecan-based) First-line PFS (≤9 months, >9 months) Time from last BEV dose (≤42 days, >42 days) ECOG PS at baseline (0/1, 2)

34. OS: ITT population OS estimate Time (months) 1.0 0.8 0.6 0.4 0.2 0 0612182430364248 No. at risk CT41029316251247320 BEV + CT409328188642913410 CT (n=410) BEV + CT (n=409) 9.8 mo11.2 mo Unstratified a HR: 0.81 (95% CI: 0.69–0.94) p=0.0062 (log-rank test) Stratified b HR: 0.83 (95% CI: 0.71–0.97) p=0.0211 (log-rank test) a Primary analysis method; b Stratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1) Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0)

35. VELOUR Study Design Primary endpoint: overall survival Sample size: HR=0.8, 90% power, 2-sided type I error 0.05 Final analysis of OS: analyzed at 863 rd death event using a 2-sided nominal significance level of 0.0466 (α spending function) Metastatic Colorectal Cancer RANDOMIZERANDOMIZE Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks Placebo IV, day 1 + FOLFIRI q2 weeks Placebo IV, day 1 + FOLFIRI q2 weeks 1:1 Disease Progression Death 600 600 600 Stratification factors: ECOG PS (0 vs 1 vs 2) Prior bevacizumab (Y/N)

36. VELOUR Study Overall results – Adding aflibercept to FOLFIRI in mCRC patients previously treated with an oxaliplatin-based regimen resulted in significant OS and PFS benefits Van Cutsem E et al. ESMO/WCGC 2011, Barcelona, Abstract O-0024. OS PFS

37. CORRECT: Patients with metastatic colorectal cancer treated with regorafenib or placebo after failure of standard therapy Multicenter, randomized, double-blind, placebo-controlled, phase III – Stratification: prior anti-VEGF therapy, time from diagnosis of metastatic disease, geographical region Global trial: 16 countries, 114 centers Recruitment: May 2010 to March 2011 2:1 Evaluation with CT scan of abdomen and chest every 8 weeks

38. Overall survival (primary endpoint) Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p<0.009279 at approximately 74% of events required for final analysis) Eligibility: survival ≥ 90 days

39. Medical Publishing Misadventures: Authorship An author must meet all three of the following criteria: 1)Contribute to the study in one of three ways: a)Conception and Design b)Acquisition of Data c)Analysis and Interpretation of Data 2)Draft or revise the article for important intellectual content. 3)Approve the final version.

40. Medical Publishing Misadventures: Conflict of Interest: – A conflict of interest exists if you have financial or personal relationships or academic affiliations that may bias your judgment and influence your work. – Disclose all relationships that are potential conflicts. – If you are unsure whether a conflict exists, it is better to include the relationship.

41. Medical Publishing Misadventures: Author Misconduct Author misconduct may include, but is not limited to: Fabrication or falsification of data Plagiarism (including self-plagiary) Redundant publication of content Electronic journals allow for reader access to the literature, thereby eliminating need for republication in separate journals. Duplicate submission NY Times April 16, 2102: marked rise of retractions for fraud, fabrication, scientific mistakes. the rate of retractions in 17 journals from 2001 to 2010 and compared it with the journals’ “impact factor,” a score based on how often their papers are cited by scientists. The higher a journal’s impact factor, the two editors found, the higher its retraction rate.