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

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

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

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 15-25 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Phase 3 Trials: How to Determine Sample Size Sample size for trials can be estimated from on-line calculators. e.g. http://www.openepi.com/v37/SampleSize/SSCohort.htm 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

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

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

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

Survival Curves and Hazard Ratios – An Example $24.50 Baselga J, et al. N Engl J Med 2012; 366:109-119 Dr. Tannock

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

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

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

Meta-Analyses: Example of a Forest Plot Meta-Analysis of Aromatase Inhibitors vs. Tamoxifen Dowsett M, et al. J Clin Oncol 2009; 28:509-518 Dr. Tannock