1. Novel Trial Designs for Early Phase Drug Development Elizabeth Garrett-Mayer, PhD Associate Professor Director of Biostatistics Hollings Cancer Center Medical University of South Carolina CNIO Frontiers Meeting Molecular Cancer Therapeutics March 8-10, 2010 Madrid

2. Phase I trial goals  Classic Phase I trials: Find the highest dose that is deemed safe: the Maximum Tolerated Dose (MTD) DLT = dose limiting toxicity Goal is to find the highest dose that has a DLT rate of x% or less (usually ranges from 20% to 40%)  Newer Phase I trials: Find the dose that is considered to safe and have optimal biologic/immunologic effect (OBD). Goal is to optimize “biomarker” response within safety constraints.

3. Schematic of Classic Phase I Trial 3 Dose % Toxicity 0 33 100 d1d1 d2d2... mtd

4. Based on Presumption: Efficacy and toxicity both increase with dose DLT = dose- limiting toxicity

5. Classic Phase I approach: Algorithmic Designs  “3+3” or “3 by 3”  Prespecify a set of doses to consider, usually between 3 and 10 doses.  MTD is considered highest dose at which 1 or 0 out of six patients experiences DLT.  Confidence in MTD is usually poor. Treat 3 patients at dose K 1.If 0 patients experience DLT, escalate to dose K+1 2.If 2 or more patients experience DLT, de-escalate to level K-1 3.If 1 patient experiences DLT, treat 3 more patients at dose level K A.If 1 of 6 experiences DLT, escalate to dose level K+1 B.If 2 or more of 6 experiences DLT, de-escalate to level K-1

6. Some properties of the “3+3” What can you learn from 3 patients at a single dose? What is the 95% exact c.i. for the probability of toxicity at a given dose if you observe  0/3 toxicities at that dose? ( 0, 0.64)  1/3 toxicities at that dose? (0.09, 0.91)  2/3 toxicities at that dose? (0.29, 0.99)  3/3 toxicities at that dose? (0.36, 1.00)

7. Even if dose level 5 corresponds exactly to a DLT rate of 0.30, the chance that this particular trial will ever reach it is only 32%. The chance of correctly concluding dose level 5 is the MTD is 16%. Dose LevelActual P(DLT)Chance of being highest tried dose 10.109% 20.1517% 30.2021% 40.2521% 50.3032%

8. “Novel” Phase I approaches  Continual reassessment method (CRM) (O’Quigley et al., Biometrics 1990) Many changes and updates in 20 years Tends to be most preferred by statisticians  Other Bayesian designs (e.g. EWOC) and model-based designs (Cheng et al., JCO, 2004, v 22)  Other improvements in algorithmic designs Accelerated titration design (Simon et al. 1999, JNCI) Up-down design (Storer, 1989, Biometrics)

9. CRM: Bayesian Adaptive Design  Dose for next patient is determined based on toxicity responses of patients previously treated in the trial  After each cohort of patients, posterior distribution is updated to give model prediction of optimal dose for a given level of toxicity (DLT rate)  Find dose that is most consistent with desired DLT rate  Modifications have been both Bayesian and non- Bayesian.

10. Examples: Candidate Models

12. CRM Designs  Underlying mathematical model  Doses can be continuous or discrete  Compared to the ‘3+3’ the CRM is safer: fewer patients treated at toxic doses more accurate: selected MTD is closer to the true MTD more efficient: more patients are treated at doses near the MTD.  Disadvantages: requires intensive involvement of statistician because future doses depend on model prediction need more lead time: statisticians need time (weeks?) to select the appropriate CRM design for a given trial  simulations  need to ensure that it will “behave” in a smart way

13. Long-term toxicities?  CRMs and algorithmic designs take a long time to accrue, even with rapid accrual.  Investigators may be interested in toxicities over a span of one to two years.  For a study with only 15 patients with two year follow-up, “three-at-a-time” designs require 10 years to complete, even with perfect accrual.  Need alternatives!  Example scenario interested in the MTD as the 20%-tile of a toxicity requires 2 years followup (so we now have cohorts of 5, not 3).

14. Prorated Designs (Cheung & Chappell, 2000, Biometrics)  Instead of collecting data on a group of 5 patients for 2 years each,  Collect data on more than 5 patients for a total of 10 patient-years.  One patient measured for one year counts (is “prorated” as) 1/2 of a patient.  A Bayesian version (TIme-To-Event Continual Reassment Method, TITE-CRM, is available). Require more patients than traditional designs, provide more information at study’s conclusion; and Are much quicker than traditional designs (commensurate with the number of extra patients).

15. TITE-CRM: Schematic Example

16. Accelerated Titration Design (Simon et al., 1999, JNCI)  The main distinguishing features (1) a rapid initial escalation phase (2) intra-patient dose escalation (3) analysis of results using a dose-toxicity model that incorporates info regarding toxicity and cumulative toxicity.  “Design 4:”  Begin with single patient cohorts,  double dose steps (i.e., 100% increment) per dose level.  When the first DLT is observed or the second instance of moderate toxicity is observed (in any course), the cohort for the current dose level is expanded to three patients  At that point, the trial reverts to use of the standard phase 1 design for further cohorts.  dose steps are now 40% increments.

17. Accelerated Titration Design  “Rapid intrapatient dose escalation … in order to reduce the number of undertreated patients [in the trials themselves] and provide a substantial increase in the information obtained.”  If a first dose does not induce toxicity, a patient may be escalated to a higher subsequent dose.  Obviously requires toxicities to be acute.  If they are, trial can be shortened.

18. Accelerated Titration Design  After MTD is determined, a final “confirmatory” cohort is treated at a fixed dose.  Jordan, et al. (2003) studied intrapatient escalation of carboplatin in ovarian cancer patients and found “The median MTD documented here using intrapatient dose escalation... is remarkably similar to that derived from conventional phase I studies.” I.e., accelerated titration seems to work. Also, since it gives an MTD for each patient, it provides an idea about how MTDs vary between patients.

19. New paradigm: Targeted Therapy How do targeted therapies change the early phase drug development paradigm?  Not all targeted therapies have toxicity Toxicity may not occur at all Toxicity may not increase with dose  Targeted therapies may not reach the target of interest

20. Implications for Study Design  Previous assumption may not hold Does efficacy increase with dose?  Endpoint may no longer be appropriate Should we be looking for the MTD?  What good is phase I if the agent does not hit the target?

21. Possible Dose-Toxicity & Dose-Efficacy Relationships for Targeted Agent

22. Trinary outcome CRM Y = 0 if no toxicity, no efficacy = 1 if no toxicity, efficacy = 2 if toxicity

23. Adding in a pre-phase I level? Phase 0 trials “Human micro-dosing” First in man Not dose finding Proof-of-principle  Give small dose not expected to be therapeutic  Test that target is modified  Small N (10-15?) Short term: one dose Requires pre and post patient sampling. Usually PD assay. Provides useful info for phase I (or if you should simply abandon agent).

24. Phase 0: Example Parp-inhibitor  ABT-888 administered as a single oral dose of 10, 25, or 50 mg  Goals: determine dose range and time course over which ABT-888 inhibits PARP activity  in tumor samples  in PBMCs To evaluate ABT-888 pharmacokinetics  Blood samples and tumor biopsies obtained pre- and postdrug for evaluation of PARP activity and PK  If patients available, trials are quick.  Exploratory Investigational New Drug (EIND) Kummar S, Kinders R, Gutierrez ME, et al.. Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. J Clin Oncol 2009; 27.

25. Study Schema

26. Phase 0: Example Parp-inhibitor  N = 13 patients with advanced malignancies  N = 9 had paired tumor biopsies

27. Clin Cancer Res June 15, 2008 14  Designing Phase 0 Cancer Clinical Trials  Oncologic Phase 0 Trials Incorporating Clinical Pharmacodynamics: from Concept to Patient  A Phase 0 Trial of Riluzole in Patients with Resectable Stage III and IV Melanoma  Preclinical Modeling of a Phase 0 Clinical Trial: Qualification of a Pharmacodynamic Assay of Poly (ADP-Ribose) Polymerase in Tumor Biopsies of Mouse Xenografts  Phase 0 Trials: An Industry Perspective  The Ethics of Phase 0 Oncology Trials  Patient Perspectives on Phase 0 Clinical Trials  The Development of Phase I Cancer Trial Methodologies: the Use of Pharmacokinetic and Pharmacodynamic End Points Sets the Scene for Phase 0 Cancer Clinical Trials  Phase 0 Trials: Are They Ethically Challenged?

28. Article Coming out March 15 In Clinical Cancer Research Approaches to Phase 1 Clinical Trial Design Focused on Safety, Efficiency, and Selected Patient Populations: A Report from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee. S. Percy Ivy, Lillian L. Siu, Elizabeth Garrett- Mayer, and Larry Rubinstein

29. Questions and Comments? garrettm@musc.edu