Wendy Parulekar MD FRCPC Wei Tu PhD Objectives To review the classification of randomized phase II trial designs To propose and critique potential randomized phase II trials designs for a concept in head and neck cancer case scenario to be presented ID: 1034301
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1. Randomized Phase II WorkshopWendy Parulekar MD, FRCP(C)Wei Tu PhD
2. ObjectivesTo review the classification of randomized phase II trial designsTo propose and critique potential randomized phase II trials designs for a concept in head and neck cancer (case scenario to be presented)To classify and describe the randomized phase II trial design utilized in the ongoing CCTG HN.9 study (NCT03410615)2
3. Defining CharacteristicsObjective(s)estimate activity w/wo benchmarking against a concurrent controlselect the most promising novel therapy(ies) based on activityestimate activity of a novel therapy in the initial phase of a phase III RCTEndpointsMeasure of activity informed by mechanism of action of novel therapy e.g. objective response rate (ORR); lack of progressionStatistical FrameworkH0, HA, α (Type 1 error), β (Type II error); comparative measures eg. hazard ratio (hazard ratio)…3
4. Classification of Randomized Phase II Designs4
5. Intermediate Risk HPV Related Oropharyngeal Carcinoma5Standard of care:chemoradiotherapy: 70Gy/35fr + platinumEvent free survival* 83% at 3 yearshigh burden of treatment related morbidityCan we harness the immune system to improve outcomes and replace cisplatin using immune checkpoint inhibitors?
6. Propose a Randomized Phase II Trial Design6Patient population: Intermediate risk, HPV+ oropharyngeal carcinomaGoal: Evaluate novel therapeutics durvalumab (anti PDL1 antibody) +/- tremelimumab (anti CTLA4 antibody) Statistical framework: Standard of care: RT + platinum – EFS 83% at 3 years Target EFS: 91% at 3 years Type 1 error: 0.1 (one sided) Type II error: 0.2
7. 7CCTG HN.9 (NCT03410615)Randomized Phase II Study of Cisplatin plus Radiotherapy versus Durvalumab plus Radiotherapy followed by Adjuvant Durvalumab versus Durvalumab plus Radiotherapy followed by Adjuvant Tremelimumab and Durvalumab in Intermediate Risk HPV-Positive Locoregionally Advanced Oropharyngeal Squamous Cell Cancer (LA-OSCC) Study Chairs: Anna Spreafico Khalil Sultanem Senior Investigator (SI): Wendy Parulekar Senior Biostatistician: Bingshu Chen Study Coordinator (SC): Kate Whelan Supported by: AstraZeneca
8. HN.9 Study Design8Non-comparativeRandomizedPhase II studyN = 240 (1:1:1, 80 pts per arm)Arm A:Radiation/CisplatinArm B:Radiation/Durvalumab + Maintenance Durvalumab RANDOMIZELA-Oropharyngeal SCCp16 positiveIntermediate Risk:T1-2 N2b (smokers)T3 N0-N2b (smokers)T1-3 N2c (any smoking hx)Arm C:Radiation/Durvalumab + Maintenance Durvalumab/Tremelimumab
9. Sample Size Considerations 9Design: randomized non-comparativePrimary endpoint: EFSSample size: 80 patients each arm (total = 240 patients)Null hypothesis (H0): to exclude a 3-year PFS of 83% or lessAlternative hypothesis (H1): new treatment will improve 8% of 3-years PFS to 91%.One-side type I error of 0.1If the treatment is effective, the power of rejecting the null hypothesis is greater than 80%Duration of study, 2.5 years of accrual and 2.5 years of follow-upNull hypothesis (H0) will be rejected if a total of 11 PFS events or less is observed with 267.3 person-year of follow-up at the final analysis, which is equivalent to observed a 3-year FFS rate of 88.4% or higher to ensure the lower bound of one-side 90% CI is greater than 83%
10. CCTG HN.9 Study Design10
11. Statistical Design This is a randomized non-comparative trial with 3-year EFS rate as the primary endpoint. A sample size of approximately 240 patients total (i.e. 80 patients per group) is anticipated, accounting for a 2.5% lost to follow-up patients. The duration of study will be 5.5 years with 2.5 years of accrual and 3 years of follow-up for each of Arm A, Arm B and Arm C.Update as per Amendment #1: This is a randomized non-comparative trial with 3-year EFS rate as the primary endpoint. A sample size of approximately 180 patients total (i.e. 60 patients in Arm A and 120 patients in Arm B is anticipated), accounting for a 2.5% lost to follow-up patients. Enrollment of 60 patients and 120 patients to Arms A and B respectively would enable the ability to reject the null hypothesis of 3 year EFS 83% or lower with 90% power and one-sided alpha of 0.10 when the expected 3-year EFS in Arm B is 91% or higher.11
12. Classification of Randomized Phase II Designs12
13. Objectives√ To review the classification of randomized phase II trial designs√ To propose and critique potential randomized phase II trials designs for a concept in head and neck cancer (case scenario to be presented)√ To classify and describe the randomized phase II trial design utilized in the ongoing CCTG HN.9 study (NCT03410615)13