1. Opportunities and main challenges faced by clinical researchers in LA – a young oncologist investigator’s vision Rachel Riechelmann MD - Assistant Oncologist GI Tumors - Chief of Clinical Research Instituto do Cancer do Estado de Sao Paulo -Scientific Director Brazilian Gastrointestinal Tumors Group

2. LIMITATIONS TO LAUNCH AN ACADEMIC CAREER IN LA

3. Issues and Challenges Regulatory hurdles Funding Non-inferiority trials with cheaper drugs are nearly impossible … 1 Accesss to new drugs – Developing countries are mostly “recruiting fields” – Investigator initiated trials are uncommon in the developing world Time protected for “creating” research Hierarchical environment Mailankody. NEJM 2014

4. So… If you have limited time, little money, shortage of specialized personnel, few people to count on…. ….but you love research What do you do? BE CREATIVE!!!!

5. Opportunities in LA 1.Pragmatic questions 1.Trials of cancers common in LA 2.Trials of rare cancers 2. Testing old (cheap) drugs 3. Patient-reported outcomes 3. When the sujbect is the study: 1.Meta-analyses 2.Critical appraisal Saad ED, Katz A, Riechelmann R. Rev SBOC 2011

6. Pragmatic question: how much are cancer patients at risk of dangerous drug-drug interactions?

7. Pragmatic Trials at ICESP – Phase III adjuvant FLOX vs observation in stage III rectal cancer (NCT01941979) – Phase II surgery vs watch and wait in rectal cancer after complete response with chemorads (NCT02052921) – Phase II trial of dose-reduced first line chemo in ECOG 3/4 (not yet registered) – Phase III trial of adjuvant chemoradiation with 5FU/LV vs observation in billiary cancer (not yet registered)

8. Examples of pending pragmatic questions… Second line treatment for – Biliary cancer – Head and neck – Esophageal cancer First line treatment for metastatic anal cancer Dose escalation of SSA in NETs

9. Dowling et al. J Mol Endocrinol. 2012;48:R31-R43. Metformin: A New-Old Antitumor Agent

10. Trials of old drugs: metformin – Phase II of metformin and 5FU in refractory mCRC (NCT01941953) – Phase II metformin + paclitaxel in gemcitabine- refractory pancreatic cancer (NCT01971034) – Phase II trial of metformin in NET (not yet registered)

11. Old drugs with potential clinical affect against cancer Aspirin Statins Omeprazole

12. Patient-reported outcomes Complex but relatively cheap to perform Ex. of poorly explored issues: – Sexual function – Terminally ill Ex futile meds (Supp Care in Cancer) – Spirituality

13. Chemoholiday or treatment given until progression in mCCR? Pereira A, Rego J, Sasse A, Riechelmann R. ASCO 2014 Under review JNCI

14. Reasons for designing NIF (N=62): 23 (30%): convenience 15 (15%): less toxicity 9 (12%): either above 11 (15%): less dose-intensity 2: cheaper 13 (17%)  me too drugs, … most with drug approval Median noninferiority margin for time-to- event primary endpoints: HR: 1.25 (1.10-1.50)

15. Other examples of critical appraisal of the literature

16. Conclusions Many limitations to develop clinical research in LA – Time protected – Funding – Mindset “difficulty is gasoline on the fire of human creativity”

17. Flowers from greenhouses

18. Cerrado - Brazil