1. Phase II Trials in Oncology S. Gail Eckhardt, MD Lillian Siu, MD Brian I. Rini, M.D.

2. Phase II Goal To decipher a ‘signal’ of anti-tumor activity (and risk) that will lead to a successful (positive) phase III trial and change the standard of care in a given disease (a go vs. no-go decision)

3. Key Questions for Phase II Trials What patient population should be targeted? What are the appropriate endpoints of efficacy? –ORR, DCR, TTP, PFS What is the appropriate trial design? –Single arm –Randomized

4. Patient Selection for Phase II Trials Selection of Tumor Types for Phase II Trials When Target Pt Population NOT Identified in Phase I Trials Tumor types in which objective response/prolonged stable disease seen in a small number of pts in phase I Tumor types in which preclinical or laboratory data suggest relevance of specific target inhibition Enrichment based on presence of “unvalidated” biomarker “Big four” – breast, lung, colorectal, prostate Unmet need and/or orphan tumor types

5. Phase II Trial Nuts and Bolts Hypothesis/Objectives Patient selection (Eligibility) Endpoints Practical Stuff –Dose modifications –Scheduling issues –Number of pokes, visits, scans, etc. –Accrual

6. Phase II Hypothesis/Objectives YOU GET ONE GOOD AND REALISTIC QUESTION TO ASK AND ANSWER IN A PHASE II TRIAL

7. Phase II Patient Selection THINK ABOUT EACH AND EVERY ELIGIBILITY POINT – DO NOT CUT AND PASTE! Know the disease (e.g. enrichment strategies like Her2+, Alk+) and what patients walk in your door Be restrictive enough to not increase toxicity but liberal enough to actually enroll the trial before you retire and to mimic the phase III Its OK to adapt eligibility as a trial progresses (a little)

8. Phase II Endpoints The primary endpoint is the answer to the ONE question you are asking. Secondary endpoints are fine but be focused, realistic and limit the number. Remember data collection costs money, so ask yourself if you REALLY need to follow people for overall survival, etc.

9. Randomized phase II trials Inherently underpowered to ‘compare’ arms although that’s what ends up happening Best utility is to provide a concurrent ‘control’ arm so you know that its not just patient selection that is driving your amazing results –i.e. you can always beat historical controls

10. Randomized Phase II Designs 1)Randomized phase II selection design: “Pick-the-winner“, prioritization 2)Randomized phase II design including a reference standard treatment control arm: Non-comparative Standard control arm acts as a check Not to be compared directly with the experimental arm(s) 3)Phase II/III trial design: Randomized phase II trial embedded within phase III trial This design is efficient only if the experimental regimen has a reasonably high likelihood of “success”, otherwise intensive efforts are expended in developing a phase III protocol

11. Single-Arm versus Randomized Phase II Trials DesignSingle-Arm Phase IIRandomized Phase II Advantage Simple and easy to execute Typically smaller sample size Provides a contemporary control Enhances collection of biospecimens to help development of predictive biomarkers Disadvantage Historical control can be unreliable due to pt heterogeneity and changes in outcome based on supportive care and diagnostic techniques Larger sample size Elevated  and  error rates to reduce sample size can lead to false + or - results Gan, Grothey, Pond, Moore, Siu, Sargent. In Press, J Clin Oncol

12. Phase II Trials: Practical Stuff Dose modifications – know when you really need to modify vs. just hold drug Scheduling issues – patients have lives – make them better not worse Number of pokes, visits, scans, etc. Who is paying for all this? Think realistically about how many pts you can accrue, monthly accrual rate – Early stopping rules for toxicity/efficacy are GOOD

13. Conclusions Phase II trials are designed to generate a signal of anti-tumor activity and to inform the phase III decision The ideal phase II trial uses a good PK/PD drug against a validated disease target and shows convincing anti-tumor activity Think carefully about the hypothesis, eligibility, design and endpoints required Be practical and learn from each and every trial