1. 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

2. 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

3. 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

4. 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

5. Phases of Cancer Research
Phase I
Dose finding study
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

6. Phases of Cancer Research
Phase II
Proof of principle
Usually 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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 one-sided
Sufficient power to avoid inadvertent rejection of an active agent. Normally 90% or higher power 17

22. Questions

23. References
Guidance for Industry, Investigators, and Reviewers. Food and Drug Administration. January Retrieved October 31, 2012 from
International Conference on Harmonization, General considerations for clinical trials. Retrieved October 31, 2012, from
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:
Yothers, G., Wieand, S., & Freireich, E. J. (2006, October). Randomization in Phase II Clinical Trials. Clinical Advances in Hematology & Oncology, 4(10), PMID: 18