1. Efficient Designs for Phase II and Phase III Trials Jim Paul CRUK Clinical Trials Unit Glasgow

2. Efficient Efficient  Maximising the probability of getting the right answer as quickly as possible  Very easy to get the wrong “answer”  Finding effective treatments  Dismissing ineffective  Miss effective treatments at phase II, because of poor study design  Wasting resource on phase III studies of ineffective regimens

3. Getting it wrong:- Getting it wrong:-  Found 43 phase III studies fulfilling this criteria (1998- 2003) Comparison of Outcome in Phase II Studies and Subsequent Randomized Control Studies Using Identical Chemotherapeutic Regimens Zia et al JCO 2005  Only 28% of subsequent phase III studies were positive  Mean size of phase II :- 52 patients  Some evidence that bigger phase II studies gave better predictions of phase III success  96% single arm phase II

4. Efficient design for phase II trials Phase II is the foundation on which we build – needs to be sound Phase II is the foundation on which we build – needs to be sound Reliably quantify/indicate the risk of success/failure in a subsequent phase III study Reliably quantify/indicate the risk of success/failure in a subsequent phase III study Best way to do this is to randomise between the experimental and control arms in the phase II setting Best way to do this is to randomise between the experimental and control arms in the phase II setting

5. Randomisation in Phase II studies Van Glabbeke M, Steward W, Armand JP. Non-randomised phase II trials of drug combinations: often meaningless, sometimes misleading. Are there alternative strategies? EJC (2002) Recommended changes to oncology clinical trial design: Revolution or evolution?, Ratain et al EJC, Jan 2008 “ We strongly recommend that randomised comparative phase II trials become a standard approach in oncology, especially for the development of drug combinations” Optimising the design of phase II oncology trials: The importance of randomisation. Mark Ratain and Dan Sargent EJC (2009) “…fundamental need for randomisation in phase II oncology trials….ideally with blinding and dose ranging.”

6. Single arm studies prone to selection bias (clinician selection/patient preference) – therefore comparisons with historical benchmarks are intrinsically an unreliable basis for decision making Major problems in studies where the new drug is combined with active standard treatment and the additional benefit is likely to be “modest” and could easily be lost in study bias or in the imprecision of the estimated historical effect Need for randomisation: - Need for randomisation: - No real allowance for imprecision in the historical estimate of response used as the basis for single arm phase II design

7. Randomised Phase II Trial Design in Ovarian Cancer Role of randomisation Role of randomisation What size of benefit can be expected from new agents in ovarian cancer? Introduction of taxanes into first line (GOG111/OV10) – 25% reduction in hazard for pfs Addition of taxane in relapse (ICON4) – 25% reduction in hazard for pfs 25% reduction in hazard (HR=.75) corresponds to an absolute increase in pfs of only approximately 10% at a given time-point (e.g. 50% to 60% or 20% to 30%)

8. Randomised Phase II Trial Design Screening design (Rubinstein Screening design (Rubinstein J Clin Oncol 23:7199-7206 (2005)) Use a permissive 1-sided significance level (10% or 20%) to decide whether there is sufficient activity to go to phase III Set realistic bar for efficacy

9. Randomised Phase II Trial Design Any way to reduce these numbers? Early stopping for futility in a randomised phase II:- Early stopping for futility in a randomised phase II:- Sin-Ho Jung Statist. Med. 2008; 27:568–583 Three outcome design:- Three outcome design:- A Three Outcome Design for Randomised Comparative phase II Clinical Trials. Hong and Wang. Statistics in Medicine (2006) A Three Outcome Design for Randomised Comparative phase II Clinical Trials. Hong and Wang. Statistics in Medicine (2006)

10. Randomised Phase II Trial Design Three outcome design Three outcome design Statistically significant at 10%:- Clear indication from study data to proceed to phase III Clear indication from study data to proceed to phase III Not statistically significant at 20%:- Clear indication from study data NOT to proceed to phase III Clear indication from study data NOT to proceed to phase III Three possible outcomes e.g.:- Three possible outcomes e.g.:- Statistically significant at 20%, but not 10%:- Uncertain outcome – decision based on other information (changes in relevant biomarkers, clinical judgement)

11. Randomised Phase II Trial Design Three outcome design Three outcome design Allows the sample size requirements for screening designs to be lowered ( Allows the sample size requirements for screening designs to be lowered (20–30% less than that of the corresponding two-outcome screening design) The price paid is the introduction of an area of uncertainty The price paid is the introduction of an area of uncertainty Avoids the “discomfort” of a go/no-go decision resting potentially on a single response Avoids the “discomfort” of a go/no-go decision resting potentially on a single response

12. Estimated HR from phase II A Better Estimate of Success at Phase III  Weighted average probability of success over range of plausible estimates of HR from phase II (Christy Chuang-Stein Sample size and the probability of a successful trial Pharmaceut. Statist. 2006; 5: 305–309)

13. Moving from Phase II to Phase III For fixed phase III sample size estimated probability of success depends on – For fixed phase III sample size estimated probability of success depends on – Estimated phase II hazard ratio (bigger difference -> bigger probability of success) Estimated phase II hazard ratio (bigger difference -> bigger probability of success) Precision of estimate (higher precision of estimate -> higher probability of success ) Precision of estimate (higher precision of estimate -> higher probability of success ) Use these probabilities to prioritise your phase III effort Use these probabilities to prioritise your phase III effort

14. Seamless Phase II/III Trial Design - To make efficient use of the patients involved in phase II - desirable to incorporate their information into subsequent phase III – seamless phase II/III Reliable randomised Phase II designs tend to be relatively large Reliable randomised Phase II designs tend to be relatively large - To make efficient use of control patients involved - incorporate multiple experimental arms – not all of which will go on to phase III stage

15. Seamless Phase II/III Trial Design - Multi-Arm/Multi-Stage (MAMS) Designs – Parmar et a JNCI 2008 GOG182 -ICON 5 prime example (4 experimental arms/ 2 stages) GOG182 -ICON 5 prime example (4 experimental arms/ 2 stages) - Used intermediate phase II outcome (pfs) to decide whether to continue experimental arms to phase III Phase III bit Phase II bit

16. Seamless Phase II/III Trial Design - Multi-Arm/Multi-Stage (MAMS) Design – MRC STAMPEDE study in prostate cancer MRC STAMPEDE study in prostate cancer (1 control, 5 experimental arms – randomisation ratio (2:1:1:1:1:1) Phase II bit Phase III bit

17. Seamless Phase II/III Trial Design - Multi-Arm/Multi-Stage (MAMS) Design – Advantages Advantages -Rapid and reliable way to assess a large number of promising new combinations simultaneously – ICON5 (3.5 years to assess 4 new treatments) Disadvantages Disadvantages -Time consuming and complex to set up -Potentially very large studies requiring large inter-group collaboration

18. Seamless Phase II/III Trial Design - Sequential Bayesian Phase II/III - Inoue, LYT; Thall, PF; Berry, DA BIOMETRICS (2002 ) - Randomised design - Decision to switch from phase II to phase III can take place at several times during a defined phase II period if there is enough favourable data - Uses the impact of experimental treatment on the phase II end-point (6 months pfs) to predict impact of experimental treatment on phase III end- point (survival) 6 months pfs Survival Experimental treatment Observed Predicted - Two arms only – experimental and contol

19. Seamless Phase II/III Trial Design - Sequential Bayesian Phase II/III - Inoue, LYT; Thall, PF; Berry, DA BIOMETRICS (2002 ) - Not tried in practice - Sample size may be much smaller than “conventional” sequential or multi-stage designs - Issues of using phase II end-point information in reaching definitive phase III conclusions -Smaller sample size due to use of phase II end-point to predict effect of new treatment on actual outcome (OS)