Trial design : who and what

1. Highlights on Non Small Cell Lung Cancer Management Rome, October 29, 2010 Trial design: who and what Maria Carmela Piccirillo Clinical TrialsUnit National CancerInstitute Naples

2. Gli studi di fase 2 randomizzati: • non possono essere formalmente comparativi; • possono prevedere un confronto tra i bracci con criteri statistici rilassati; • possono prevedere un confronto tra i bracci purché preveda gli stessi criteri statistici di un studio di fase 3; • non costituiscono un disegno di studio ottimale per lo sviluppo di farmaci biologici. Cross-tab label 1 / 30

3. Gli studi di fase 3 con agenti biologici: • devono essere condotti con una metodologia analoga a quella prevista per gli studi di chemioterapia; • devono prevedere una valutazione retrospettiva dei fattori predittivi di risposta; • devono prevedere una valutazione prospettica dei fattori predittivi di risposta; • nessuna delle precedenti. Cross-tab label 1 / 30

4. Goals of oncology practice • To recommend the most effective treatment that scientific evidence can support • To tailor systemic treatment to the biologic characteristics of patients’ tumors

5. Classic clinical trial approach • Qualitative treatment by subset interaction is unlikely • If the new treatment is better than control for one type of eligible patient, then it will be better than control for the other subsets of eligible patients, although the degree of the improvement in outcome may differ

6. Modern clinical trial approach • Biologicdrugs are targeted at the proteinproductsofspecificderegulatedgenes • Most of the human cancers have several genetic abnormalities driving tumor growth and survival and there is rarely a single critical target • A biologic targeted drugs might be effective in only a subset of patients in whom the cancer is dependent on the drug target for growth or survival • Qualitative treatment by subset interactionislikely

7. NSCLC heterogeneity Y Bang, ASCO 2010 plenary session

8. Predictive marker • A single trait or signature of traits that separates a population with respect to the outcome of interest in response to a particular (targeted) treatment

9. Ideal scenario • Prospective drug development with a companion diagnostic (predictive biomarker) • Development of a promising genomic classifiers using pre-clinical and early phase clinical studies • Development of an analytically validate test for measurement of that classifier • Use the classifier and the test to design a clinical trial to evaluate the effectiveness of the drug and how the effectiveness relates to the classifier Simon R. Clinical Trials 2010

10. What should be done • Data used to develop the classifier should be distinct from the phase 3 data used to test the hypoteses about treatment effects and subsets determioned by the classifier.

11. What should not be done • To do a trial with everything measured and analyzing it to death

12. Why it has been so difficult? • Weak availability and quantity of tissue that can be studied • Multitude of marker assessment methods and lack of reliability of the assays • Choice of clinical trial design

13. NSCLC: molecularanalysesin phase III trialswith EGFR inhibitors

14. Attritionrates in biomarkeranalysisthe IPASS study Mok, ESMO 2008

15. Why it has been so difficult? • Weak availability and quantity of tissue that can be studied • Multitude of marker assessment methods and lack of reliability of the assays • Choice of clinical trial design

17. Main issues in designingphase 2 trials • Traditionalmeasuresoftumorshrinkage (objectiveresponse rate) mightbeless sensitive for the anticanceractivityoftageteddrugsthat are mainlycytostatic

18. Alternative endpoints • Earlyprogressionrates • Proportion of patients without progressive disease (progression-free rate, PFR) at a given time-point • Proportion of patients alive at a specified time-point (for example, 1 year) • PFS o TTP • GrowthModulationIndex or TTP ratio

19. A phase 2 study of Erlotinibas first-line treatment of advanced NSCLC • Chemotherapy-naive, stage IIIB/IV , PS 0-2 • Study design: • Simon’s two-stage optimal design • Primary end-point: • rate of non-progression of patients (PFR) after 6 weeks of treatment • Results: • Rate of non-progression at 6 weeks: 52.8% • Objective response rate 22.7% Giaccone G, ClinCancerRes 2008

20. A randomized phase 2 study of cetuximab and gemcitabine in the treatment of elderly or unfit patients with advanced NSCLC (CALC1) • Chemotherapy-naive, stage IIIB/IV , PS 2 or elderly • Aim of the study: • To select the most promising modality of association of gemcitabine and cetuximab (concomitant vs sequential) in this special populations • Study design • Two parallel randomized phase 2 trials (CALC1-E for elderly and CALC1-PS2 for adult PS2 patients) • Selection design according to Simon, Wittes and Ellenberg • Primary endpoint: • Proportion of patients alive at 1 year after starting treatment Gridelli C, LungCancer 2010

21. Main limitations for progression-based endpoints • Strictly related to the timing and modalities chosen for the instrumental restaging, thus easily biased • Variability of study assessment between single-arm trials may bias the interpretation of the results • Progression rates at a given time-point are less sensitive than PFS

22. Main issues in designingphase 2 trials • Traditionalmeasuresoftumorshrinkagemightbeless sensitive for the anticanceractivityoftageteddrugsthat are mainlycytostatic • Altrnativeend-points can produce resultsthat are difficulttointerpretwithout a controlgroup

23. “Single armphase II trialsmaynotbe appropriate fortestingcytostaticagents” Freidlin B & Simon R Evaluationofrandomizeddiscontinuation design J ClinOncol 23: 5094-5098, 2005

25. Summary • Single-arm trials • High negative predictive value (effective in discarding inactive treatments) • Low positive predictive value (poorly effective in selecting the best challengers for phase 3 trials) • Randomized, formally comparative, trials • Higher positive predictive value • Could (should) be conducted according to “relaxed” statistical criteria (i.e. one-sided alfa = 0.20 and beta not exceeding 0.80) • If positive, must be followed by a phase 3 trial with adequate statistical criteria

27. Heymach, J Clin Oncol 2008 Heymach, J Clin Oncol 2007

28. Vandetanib in 2nd lineRandomizedphase II trial Heymach, J Clin Oncol 2007

29. Vandetanib in 1st lineRandomizedphase II trial Heymach, J Clin Oncol 2008

30. Experimental drug Placebo Randomized discontinuation design R A N D O M I Z A T I O N On treatment OR Stable disease Experimental drug PD Out of treatment Rosner, Stadler, Ratain. J Clin Oncol 2002; 20:4478-4484

31. Randomized discontinuation design • Discriminate whether a stabilization of disease was simply related to the natural history of the disease or due to treatment activity • Enrich the study population of potentially responsive patients • The discontinuation of a treatment potentially active is ethically problematic • Difficulty related to the use of placebo in cancer patients Rosner, Stadler, Ratain. J Clin Oncol 2002; 20:4478-4484

32. Schiller, ASCO 2008

33. Sorafenib in advanced NSCLC Schiller, ASCO 2008

34. Sorafenib in advanced NSCLC Schiller, ASCO 2008

35. Main issues in designingphase 3 trials • Choiceof the endpoint • Selectionofpatients • Non-inferiority design

36. GuidanceforindustryClinical trialsendpointsfor the approvalofcancerdrugsFDA, May 2007 NSCLC ?

37. GuidanceforindustryClinical trialsendpointsfor the approvalofcancerdrugsFDA, May 2007 Whetheranimprovement in PFS represents a directclinical benefit or a surrogate forclinical benefitdepends on the magnitudeof the effect and the risk-benefitof the new treatment comparedtoavailabletherapies. www.fda.gov

40. The first message • Response rate and timetoprogression are correlatedwithoverallsurvival • But it’s not a demonstrationof treatment effect on survival

43. The finalmessage • Verylargedifferences in response rate or timetoprogression are requiredto anticipate significantsurvival benefit • Suchdifferencesmustbeaslargerassmalleris the sample sizeof the trial

45. Median PFS: 6.7 vs 6.1 mos Median PFS: 6.5 vs 6.1 mos

47. AVAIL-like ?

48. Main issues in designingphase 3 trials • Choiceof the endpoint • Selectionofpatients • Non-inferiority design