Statistics for Clinical Trials in Cancer Research Greg Yothers, Ph.D. Head of Statistics Core, NRG Oncology SDMC Research Assoc. Prof., Univ. of Pittsburgh, Department of Biostatistics NRG Oncology Semi-annual Meeting Philadelphia, PA, July, 2019

Outline Phases of Cancer Research Endpoints for Cancer Trials Basic Statistics Phase II Trial Designs Single Arm vs. Randomized Types of Randomized Designs Adaptive Phase II Designs Adaptive Phase II-III Designs Phase III Designs Questions References 2

Phases of Cancer Research Preclinical Nonhuman studies (laboratory and animal) Efficacy, toxicity and pharmacokinetic information Objective is to determine the feasibility of the investigational agent for possible human testing 3

Phases of Cancer Research Sub-therapeutic dose 10-15 patients All patients get investigational agent Objective is to determine the consistency of pharmacokinetics and pharmacodynamics in humans compared to laboratory and animal models 3

Phases of Cancer Research Phase I Dose finding study 20-100 patients Patients receive escalating doses of the investigational agent Trial usually ends with dose limiting toxicity Objective is to find a modality for delivery and a tolerable dose 4

Phases of Cancer Research Phase II Proof of principle Usually 40-400 patients Compare patients treated with investigational agent to historical control (single arm) or to patients concurrently randomized (multi-arm, preferred) May be open label or single or double blind Objective is to verify the safety of the chosen dose and show activity of the investigational agent in a defined disease population 5

Phases of Cancer Research Phase III Definitive proof of efficacy May involve several hundred to several thousand patients Nearly always a randomized trial May be open label or single or double blind Objective is to conclusively demonstrate safety and effectiveness of the investigational agent and usually obtain regulatory approval 6

Phases of Cancer Research Phase IV Post-Marketing surveillance Look for rare or slow developing adverse events Look for subgroups of the population who may not benefit Refine the risk/benefit profile for the agent 7

Endpoints for Phase II/III Cancer Trials Response Rate (RR) Proportion with partial and/or complete shrinkage of target lesion prior to progression (or at specific time or at surgery) Disease Stabilization Rate Proportion free of progression at a specific time Disease-Free Survival (DFS) Time to recurrence, second primary (type under study) or death Time to Recurrence (TTR) Time to disease recurrence, censor death without recurrence Co-primary endpoints becoming more common e.g. Response Rate and Disease Stabilization 8

Endpoints for Phase II/III Cancer Trials Progression-Free Survival (PFS) Time to progression or death Time to Progression (TTP) Time to progression, censor death without progression Overall Survival (OS) Time to death from any cause, censor last follow-up Co-primary endpoints becoming more common e.g. Response Rate and Disease Stabilization 8

Basic Statistics Alpha, type I error, size of the statistical test, these are all synonymous for the probability of a false finding of efficacy when the agent under study is not active. Can be one or two sided. Beta and type II error are synonymous for the probability of falsely finding an agent inactive when the agent truly has a specified level of activity Power is the probability of a true finding of efficacy when the agent under study has a specified level of activity Power = 1 – Beta 9

Basic Statistics Sample size calculations Require some consensus on what level of activity is clinically meaningful and worth finding – power (and type II error or beta) is always relative to a specific level of activity Level of activity may be difference in rates (for Response or Disease Stabilization) or hazard ratio (for PFS or TTP) Depends on the type I & II error rates (alpha & beta) Depends on the rate of events (or proportion) for the control group 10

Basic Statistics Statistical Conventions in Phase II Research Alpha or type I error may be 10% one-sided in phase II trials while it is never higher than 5% two-sided in phase III trials – we are willing to tolerate a higher level of false positive findings in phase II Power may be 80% in phase II trials while we usually have power of 90% in phase III – we are willing to tolerate a higher level of false negative findings in phase II 11

Phase II Trial Designs Single arm Compare outcome of treated patients with historical results of similar patients treated with standard therapy (historical control) Problems Patients in the study may not be completely similar to the historical controls The outcomes of the historical controls may not be the same as patients receiving control therapy today (drift) Pros: few patients, inexpensive, fast Cons: can make non-statistical errors (type 3) because of inappropriate choice of historical control or patient selection bias 12

Phase II Trial Designs Multi-arm Many types of designs, all are randomized Randomization reduces selection bias Randomization ensures treatment arms are “comparable” Comparison may be formal or informal Randomized phase II trials are encouraged by NCI when feasible 13

Phase II Trial Designs Concurrent control – Informal comparison Add a control group but don’t power the study for a formal comparison Investigational agent is formally compared to a pre-specified criteria (perhaps from a historic control group) and informally compared to control Control group is informally compared to the pre-specified criteria or historical control to check consistency Requires about twice the patients of single arm 14

Phase II Trial Designs Concurrent control – Formal comparison Add a control group and power the study for a formal comparison Requires about 4 times the patients of single arm Multiple agents or multiple doses of 1 agent with or without control Find the best investigational group to carry forward or eliminate poorly performing groups To allow formal comparison, each group would have roughly twice the patients of a typical single arm study 15

Phase II Trial Designs Adaptive Phase II Designs Adaptive means the observed data may alter the conduct of the study Begin the study with multiple investigational agents or multiple doses of single agent Drop less promising groups along the way Results in more patients accrued to the promising groups Study more groups with fewer patients 16

Phase II Trial Designs Single arm trials are being used less frequently today than in the past Multi-arm randomized trials are becoming the gold standard for phase II cancer research Use of co-primary endpoints can be efficient if the method of action of the investigational agent is unclear (cytotoxic vs. cytostatic) 17

Adaptive Phase II-III Designs This design allows for a seamless transition from phase II to phase III If the phase II trial meets pre-defined success criteria accrual continues in the phase III portion of the trial Patients from the phase II trial are included in the phase III analysis (recycling) Phase II and III portions of the trial may have different endpoints (RR and PFS) 18

Phase III Trial Designs Usually a more definitive endpoint than phase II trials (e.g. DFS, PFS, or OS) Tighter control of the type I error (alpha), normally 0.05 two-sided or 0.025 one-sided Sufficient power to avoid inadvertent rejection of an active agent. Normally 90% or higher power 17

Questions

References Guidance for Industry, Investigators, and Reviewers. Food and Drug Administration. January 2006. Retrieved October 31, 2012 from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078933.pdf International Conference on Harmonization, General considerations for clinical trials. Retrieved October 31, 2012, from http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E8/Step4/E8_Guideline.pdf Sill, M. W., Rubinstein, L., Litwin, S., & Yothers, G. (2012, July 18). A method for utilizing co-primary efficacy outcome measures to screen regimens for activity in two-stage Phase II clinical trials. Clinical trials (London, England), 11. PMID: 22811448. Yothers, G., Wieand, S., & Freireich, E. J. (2006, October). Randomization in Phase II Clinical Trials. Clinical Advances in Hematology & Oncology, 4(10), 776-8. PMID: 17111561 18