1. Clinical Research Design & Methodology: Phase II and III Trials
Ian Tannock, MD, PhD, DSc
Princess Margaret Cancer Centre & University of Toronto,
Toronto, Canada

2. Learning Objectives To understand:
The sequence of clinical trials that is necessary to develop an agent showing preclinical activity to become an approved anti-cancer drug
The hierarchy of evidence from clinical trials
Basic principles underlying the design of Phase 3 clinical trials
Common problems relating to the design, analysis and interpretation of Phase 3 clinical trials
How the results of related clinical trials are combined in a meta-analysis
Dr. Tannock

3. Anticancer Drug Development: Clinical Phases
Phase 1: Evaluate toxicity
Study drug disposition (pharmacokinetics)
Determine dose for Phase 2
Phase 2: Estimate antitumor efficacy
Further define toxicity
Phase 3: Compare outcomes with usual standard of care
Phase 4 (after registration):
Additional post-marketing safety assessment
Confirm results from fast-track approval trials
Dr. Tannock

4. So Your Phase 1 Trial is Finished…
Miraculin is reasonably safe with manageable dose limiting toxicity
Miraculin achieves serum (or tissue) levels that are sufficient to achieve effects in pre-clinical studies
Worldwide, a total of patients have now been treated with Miraculin ; 4-8 at the dose you plan to use in phase 2
Only two partial responses (PR) noted in phase 1 – one with bladder cancer, one with heavily-treated breast cancer
No biomarkers used for patient selection in phase 1 although samples were obtained for further study…
Dr. Tannock

5. How will you design these trials?
MiraPharma Decides That They will Support Two Phase 2 Trials of miraculin – In Patients with Metastatic Bladder and Metastatic Breast Cancer
For bladder cancer they elect to support a single arm study of patients who have progressed after one line of cisplatin-based chemotherapy
For breast cancer they will support a randomized phase 2 trial in women with metastatic disease who have had disease progression after receiving both anthracyclene and taxane-based chemotherapy. They will compare miraculin with capecitabine
How will you design these trials?
Dr. Tannock

6. Phase 2 Trials
Phase 2 trials have the major goal of determining whether a new treatment has sufficient evidence of anti-cancer activity to warrant further testing in a phase 3 trial:
Phase 2 trials generally include people with a single type of cancer, for whom there is limited “standard” treatment available.
The new agent can be tested alone, or in combination with standard treatment.
Phase 2 trials are relatively small, and can be single-arm or randomized.
The primary endpoint (outcome measure) is a measure of anticancer activity (e.g. tumor response) and does not imply clinical benefit to patients.
Dr. Tannock

7. Single Arm Phase 2 Trial
For people with metastatic urothelial cancer, cisplatin-based chemotherapy is known to prolong survival and gives response rates (RR = CR + PR) of ~ 50%.
Second-line chemotherapy (e.g. with taxanes) is associated with RR of < 20% with no known effects to improve survival.
MiraPharma executives decide that they would be interested in studying miraculin further if data were consistent with RR ≥ 30%.
They plan a phase 2 trial that accepts all fit patients with urothelial TCC that have received one line of prior platin-based chemotherapy with a maximum sample size of 40 patients.
Dr. Tannock

8. Single-arm Phase 2 Trial of Miraculin for Patients with Metastatic Urothelial TCC
Eligible subjects have adequate performance status (ECOG PS 0-2) and organ function and have progressed on one line of cisplatin or carboplatin-containing chemotherapy
They have measurable disease (RR, is primary endpoint)
Trial should only continue if there is reasonable probability that true RR ≥ 30%)
Hence abandon trial if ≤1 response in first 10 patients (RR = 10% with 95% confidence interval [CI] = 0% - 29%)
Otherwise continue to 40 patients
There will be uncertainty. For example if 10/40 patients respond RR = 25% with CI = 12% - 38%
Dr. Tannock

9. Randomized Phase 2 Trial of Miraculin for Women with Metastatic Breast Cancer
Eligible women will have metastatic breast cancer that has progressed on prior treatment.
They must have had prior chemotherapy with an anthracyclene and a taxane with at least one prior regimen for metastatic disease. They may have had multiple hormone treatments.
The plan is to randomize 80 women, as follows:
The primary endpoint will be progression-free survival (PFS), and Mira-Pharma will mount a phase 3 study if median PFS appears >3 months longer with miraculin
Capecitabine orally in standard dose
80 eligible
women
Miraculin 70mg/m2 IV every three weeks
Dr. Tannock

10. Adaptive Designs in Phase 2 Trials
You might wish to test several new drugs against standard treatment and “pick the winners” to continue in a phase 3 trial.
Patients are randomized to several treatment arms, those with promising results are retained, and new arms can be added.
An example is
the STAMPEDE
trial for men
with prostate
cancer.
© 2012 Sydes et al.; licensee BioMed Central Ltd.
Sydes et al: Trials 2012:13, 168
Dr. Tannock

11. Biomarker-based Clinical Trial Design
Many new agents are designed to act only against tumors that express a “biomarker”.
Examples are trastuzumab (for HER2+ breast cancer), vemurafenib (BRAF-expressing melanoma) and crizotinib (ALK rearranged NSCLC).
These agents would have minimal activity against unselected patients with these diseases.
Hence phase 2 trials are undertaken only in patients whose cancer expresses the appropriate biomarker.
In other phase 2 trials it is appropriate to evaluate potential biomarkers to determine if they correlate with the activity of the new drug.
Dr. Tannock

12. Common Errors in Design, Analysis and Interpretation of Phase 2 Trials
Phase 2 trials are seeking signals of activity that would warrant the huge expense and other resources needed to mount a phase 3 study
Their results are inexact and subject to uncertainty
Their primary endpoint is usually a measure of anti-tumor activity (e.g. tumor response or delay in progression) and NOT a measure of benefit to patients
There are many examples where encouraging phase 2 trials are followed by negative phase 3 trials
Randomized phase 2 trials are NOT small phase 3 studies – although it is possible to design phase 2 trials that transition to phase 3 (e.g. STAMPEDE)
Dr. Tannock

13. Phase 1 & 2 Trials: Ethical Guideposts
Scientific goals should never take precedence over the patient’s best interest
Patients eligible for Phase 1 trials are those for whom no effective therapy exists.
Patients eligible for Phase 2 trials have usually received all therapies known to have a beneficial effect.
Informed consent is obtained from every patient
No new agent can proceed through development without going through Phase I clinical evaluation.
Phase 2 trials are important to detect sufficient evidence of activity before committing the resources necessary for a phase 3 trial
Dr. Tannock

14. Phase 3 Trials
Phase 3 trials have the goal of determining whether a new treatment provides sufficient benefit to patients that it should replace (or add to) current standard treatments.
Phase 3 trials generally include people with a single type of cancer, with randomization between the new treatment and an accepted “standard” treatment.
The new agent can be tested alone (i.e. standard vs. new treatment) or in combination with standard treatment (i.e. standard + new treatment vs. standard treatment).
They may be double-blind (e.g. standard + new treatment vs. standard treatment + placebo)
Dr. Tannock

15. Hierarchy of Evidence Used to Decide if Results of Clinical Trials Should Influence Clinical Practice
High quality randomized phase 3 trials, or meta- analyses
Small randomized trials
Non-randomized trials with concurrent controls
Non-randomized trials with historical controls
Expert committee review, case reports, retrospective studies
Not included are large population-based outcome studies that can assess the influence of a new strategy on a less selected population.
Dr. Tannock

16. Asking a Good Question
Phase 3 trials require huge resources (collaborators, patients, $$$$)
It is therefore important that:
They address a clinically important question
There is substantial evidence for effectiveness of a new treatment in preclinical models
There is evidence that the new treatment is safe and tolerated (phase I)
There is good preliminary evidence of anti-tumor activity (phase II)
Dr. Tannock

17. Phase 3 Trials
The primary endpoint (outcome measure) should be a measure of patient benefit (e.g. overall survival [OS] or QL)
If other endpoints are used they should be shown to be surrogates for OS or QL
Phase 3 trials are large (several hundred patients)
Entry criteria should be as broad as possible so that the results will apply to the general population of patients with the type of cancer under investigation
Dr. Tannock

18. DFS and PFS as Surrogate Endpoints in Phase 3 Trials
When phase III trials show large early increases in PFS, and there are few alternative treatments, ethical considerations may require the new treatment be given to patients randomized to the control arm. This may make it difficult to detect an influence on survival.
Examples include sunitinib for renal cell carcinoma and vemurafenib for BRAF-mutated melanoma
This does not apply to treatments for (e.g.) metastatic breast or ovarian cancer
Dr. Tannock

19. Evaluation of Toxicity
Therapeutic benefit of a new treatment depends on a balance of efficacy and toxicity
All new agents add toxicity
Toxicity is usually reported and graded as per NCI CTC criteria, with rigid requirements for reporting serious (grade 3-4) toxicity
However toxicity is both under-recognized and under- reported in phase III trials – and chronic toxicity associated with many targeted agents may only become apparent after the trial is completed
Dr. Tannock

20. Principles of Design of Phase 3 Trials
Sample size depends on ....
The expected level of survival in the control arm
The difference in survival (δ) between arms that you wish to detect or rule out
α or type 1 error is the probability that a difference ≥ δ is a false positive result (usually α = 0.05)
β or type 2 error is the probability of failing to detect a real difference ≥ δ, i.e. of a false negative result (usually β = 0.1 or 0.2)
The “power of the study” is then 1- β or 0.9 or 0.8
Dr. Tannock

21. Phase 3 Trials: How to Determine Sample Size
Sample size for trials can be estimated from on-line calculators. e.g.
Roughly 300 patients will be needed to detect or rule out a 15% absolute difference in survival & about 1,000 patients for a 10% difference!
Thus phase 3 trials require a large sample size to detect or rule out differences in outcome that might reasonably be expected
They require collaboration between multiple sites and are usually organized either by cooperative groups or companies
For company-organized trials it is essential that there be safeguards to ensure the validity of the data
Dr. Tannock

22. Phase 3 Trial: An Example
A phase 1 trial indicates that a new drug, miraculin at 50mg/m2 IV every three weeks, can be added safely to standard gemcitabine/cisplatin
A phase 2 trial suggests that miraculin is active as second-line therapy for people with metastatic urothelial cancer (TCC)
MiraPharma agree to sponsor the following randomized phase 3 trial to determine if miraculin will become part of first-line treatment for this disease:
Gemcitabine + cisplatin + miraculin
Primary endpoint is overall survival
450 patients with metastatic TCC and no prior chemotherapy
Gemcitabine + cisplatin + matched placebo
Dr. Tannock

23. Survival Curves and Hazard Ratios
Patients are recruited to clinical trials at different times and have different length of follow up.
In actuarial survival curves patients alive at last follow-up are “censored”. The tail of the curve may depend on few patients (given as numbers under curves) and is subject to error.
Proportional hazards applies when the ratio of ‘events’ (e.g. deaths) in the experimental and control arms remains roughly the same over the time of observation.
Dr. Tannock

24. Survival Curves and Hazard Ratios
The Hazard Ratio (HR) is ratio of events in experimental to control arm in any given time interval.
HR < 1 with 95% confidence interval excluding 1.0 implies statistical benefit of experimental treatment.
Note that statistical significance is not the same as clinical significance
Dr. Tannock

25. Survival Curves and Hazard Ratios – An Example
$24.50
Baselga J, et al. N Engl J Med 2012; 366:
Dr. Tannock

26. Common Errors in Design, Analysis and Interpretation of Phase 3 Trials
Control arm is not an accepted standard treatment
The primary endpoint has not been shown to convey benefit to patients (i.e. not a surrogate for survival or its quality)
Sample size too small to detect or rule out a reasonable difference in outcome (failing to find a difference is not the same as proving no difference)
Sample size so large that difference in clinical outcome is statistically significant but not clinically meaningful
Making conclusions on the basis of secondary endpoints
Failure to provide detailed report of toxicity
Dr. Tannock

27. Post-marketing (Phase 4) Studies…
...evaluate a wider population of patients treated with a new therapy.
They can help to better define its tolerance and side effects in a wider population.
Often the unstated purpose of such studies is to encourage oncologists to become familiar with the new treatment (sometimes with financial reward) so that they will continue to use it when it is marketed.
Dr. Tannock

28. Meta-Analyses
Similar (but not necessarily identical) trials are combined (e.g. any adjuvant chemotherapy vs. none for women with primary breast cancer).
In a patient-based meta-analysis (preferred) the data are analyzed like one large trial to produce survival curves.
Date of randomization and death (or last follow-up alive) are known for all patients on multiple trials.
Data are displayed as a Forest plot: individual trials are represented by a square proportional to sample size, with whiskers showing confidence interval for Hazard or Odds Ratio.
Literature based meta-analysis combines published survival curves from reports of individual trials but is subject to error.
Dr. Tannock

29. Meta-Analyses: Example of a Forest Plot
Meta-Analysis of Aromatase Inhibitors vs. Tamoxifen
Dowsett M, et al. J Clin Oncol 2009; 28:
Dr. Tannock