Phase-II-Trials-Methods-in-Clinical-Cancer-ResearchII期试验方法在临床癌症的研究课件.ppt

1、Phase II Clinical TrialsMiguel Villalona-Calero,MD.,FACPThe Ohio State University2019 AACR/ASCO WorkshopQuestionWhat percentage of the concepts submitted by you are Phase 2 trials or the Phase 2 trial is its main component?20%40%50%a.60%Interactive AnswerOverviewObjectives&Concept DevelopmentDesignE

2、ndpoints Outcomes MeasuresSample Size CalculationExamplesObjectivesTo define antitumor activity.To demonstrate safety.To gain new insights into the pharmacokinetics,pharmacodynamics and metabolism of therapeutic agents.To evaluate biologic correlates which may predict response or resistance to treat

3、ment and/or toxicity.Concept Development The WhatThe WhoThe HowSimple and funModerate and excitingHard and frustratingThe What What is your hypothesis?Is it sound?Do a background check What has been written?What is being tested at present?Review your preclinical and phase I data well Draw an illustr

4、ation Sell it to your spouse Sell it to a colleageThe Who Who do you want your concept tested in?Define your population Define the standard of care Define historical outcomes with standard of care Decide on dose and schedule Prior treatment allowed Discuss with your mentor and with an experienced fa

5、culty memberThe How How will you do it?Come to Vail?Select your trial design Select your endpoints and outcome measures Select your sample sizeII.Study Designs Single Arm Two or more armsII.Study Designs Frequentist Gehan 2-Stage Simon 2-Stage Optimal Simon 2-Stage Minimax Fleming 1-stage Gehan-Simo

6、n 3-Stage Randomized Phase 2 Constant Arc-Sine Randomized Discontinuation Bayesian Thall-Simon-Estey 1-Stage Bayesian 2-Stage Bayesian Tan Machin Heitjan Adaptive Multiple OutcomesTwo-stage Design Main objective is to minimize the number of patients treated with ineffective regimens A very commonly

7、used 2 stage design is the Simon,which minimizes sample size based on a pre-specified response rate and an and error rates.Optimal:minimizes the#of pts treated if the regimen is ineffective Minimax:minimizes the whole sample size Recist Response CR+PR+SD is generally utilized.Simon et al,Cont Clin T

8、rials,1989Simon,Mini-max Treat 12-18 patients at 1st stage Determine the“response rate”Less than that projected to indicate activity(p0):STOP!Sufficiently great to indicate activity:CONTINUE At the end of 2nd stage,declare drug/intervention worthy of further evaluation if x number of“responses”are o

9、bserved(p1)One-stage Design When time-dependent endpoints are considered e.g.,the proportion of patients free of progression at one year following initiation of treatment.Given the time period from initiation of treatment to the endpoint,two-stage designs are often impractical.Early stopping rules a

10、re usually incorporated for obvious lack of efficacy or unacceptable toxicity.Biometrics,1982One-stage Design Fleming is the most commonly utilized one-stage design.You need to have a good grip on historical control data.Mick Design:Compare time to treatment failure or progression on the new regimen

11、 TTP2 with the individual patients failure time or TTP1 observed with their prior regimen.If the TTP2/TTP1 ratio is greater than 1.33,the regimen is considered effective and worthy of further study.J Clin Oncol,2019Cont Clin Trials,2000Randomized Phase II Trials Patients are randomized to receive on

12、e of two(or more)regimens differing by dose level,schedule,or specific agent.It is not powered to make inferential comparisons between the treatment arms.Pick the winner approach.If both arms incorporate two-stage designs,you would have four specific decision points for determining efficacy.Simon et

13、 al,Cancer Treat Rep,1985Liu et al,Control Clin Trials,2019Randomized Discontinuation It incorporates time-dependent endpoints with disease response.Stable disease patients are randomized to continuation with the agent or placebo(the discontinuation)Patients subsequently showing progression on place

14、bo are then retreated with the agent to determine if stability can be regained.This design is most appropriate in diseases where tumor growth rates are slow.Kopec,J Clin Epidemiol,1993Rosner(J Clin Oncol,2019ExamplesPhase II Trial of Gefitinib in Patients With Advanced NSCLC:Efficacy Median overall

15、survival in the 250 mg/d and 500 mg/d gefitinib groupswere 7 months and 6 months,respectively(P=0.40)Projected 1-year survival rates were 27%and 24%,respectively(P=0.54)P=0.51P=0.26Kris et al.JAMA.2019;290:2149.Single-Agent Nexavar in 3rd line+NSCLC:Double-blind Phase IIECOG 2501,Joan Schiller,MD.A

16、Stable DiseasePDDiscontinueProtocol TreatmentPRContinueNexavar protocol treatmentArm 1Nexavarpo bidArm 2Placebopo bidSCANRANDOMIZENexavar po bid X 2 cycles(8 weeks)PDPopulationStage IIIB and IV2 or more prior chemotherapy regimens 18 years of ageECOG PS 01Asymptomatic brain metastases allowedSample

17、SizeN=330 accrued,98 randomizedEndpoints1st endpoint:SD or response after 2 courses of treatment post randomization2nd endpoint:PFS,RR,SurvivalBSecond:Randomized patients first evaluated for progression after another 8 weeksFirst:Patients evaluated for SD at 8 weeksASCO Abstr 8014.Endpoint Outcome M

18、easures RECIST/WHO Response Rate CR+PR CR+PR+SD Time to Failure/Survival Progression-Free Rate Disease-Free RateEndpoint Outcome Measures Biological Endpoints Safety&Adverse Events Multiple Endpoints QOLCorrelative Studies Important,hypothesis-generating,exploratory studies However,dont do them beca

19、use everyone else is.BUT during course of study:Validation of targets and assays may occur New markers and pathways may be identified Consider collecting specimens to evaluate only if activity signals are seen in stage I(for 2-stage designs)Sample Size Calculation Prior determination of the sample s

20、ize that is needed to show an important difference is essential.Two errors can be made in a test of a hypothesis:rejecting the null hypothesis when it is true(Type I Error,)(false-positive)not rejecting the null hypothesis when it is false(Type II,)(false-negative).Another important consideration is

21、 Power;the probability of rejecting the null hypothesis when it is false,or of concluding the alternative hypothesis when it is true.From Basic&Clinical Biostatistics Dawson-Saunders and Trapp eds.Sample Size Calculation Before going to your statistician What is the desired level of significance of

22、the null hypothesis(0)?What chance should there be of detecting an actual difference(what power)associated with the alternative hypothesis(1)is desired?How large should the difference between the proportions(1-0)be in order for it to have clinical importance?What is a good estimate of the standard d

23、eviation in the population?The value of the null hypothesis determines in most cases the standard deviationFrom Basic&Clinical Biostatistics Dawson-Saunders and Trapp eds.N=Z 0(1-0)-Z 1(1-1)1 -02SYSTAT,MINITAB,STATISTIXPASS Given this complexity of design and outcome alternatives,the selection of a

24、trial design requires close collaboration between the study investigator and clinical biostatisticians to clearly define study objectives,to select appropriate endpoints,to select a trial design,and to compute the required number of patients to be enrolled.We should individualize the trial design an

25、d outcome measures to the particular agent(or combination)and disease or subset of disease to be evaluated.My Examples Phase 2 Study of Capecitabine and Docetaxel in Previously Untreated advanced Non-Small Cell Lung Cancer Patients(OSU-0356).NCI R21 CA108157 Phase 2 trial of Sequentially Administere

26、d CPT-11 and Mitomycin C in Patients with Advanced Esophageal and Stomach Cancer(OSU-0151).NCI R21 CA92956 Phase 1/2 Study of Etanercept and Gemcitabine in Patients with Advanced Stage and Chemotherapy-Nave Pancreatic Adenocarcinoma(OSU-0041).NCI R21 CA101360 Phase 2 Study of Capecitabine/Docetaxel

27、in Previously Untreated Advanced NSCLC Patients Capecitabine last conversion step is mediated by thymidine phosphorylase(TF),which is preferentially expressed in tumors Preclinical studies suggest that paclitaxel/docetaxel increase expression of TF A previous trial in pretreated NSCLC patients(n=31)

28、showed a 26%RR,25%26-wks PFS,MS 9.1 m,1-year survival 37%How would you design it?Simon 2-stage MinimaxFleming 1-stageRandomized Phase 2Mick DesignRandomized DiscontinuationInteractive AnswerOur Design Endpoint RECIST objective response(PR/CR)Simon Two-stage minimax 7/25).Median Survival and Survival

29、 at 6 and 12 months.Assessment of Clinical Benefit Response Pain Intensity(MPAC)Analgesic Use Weight Change ECOG PS Quality of Life Correlation of cytokines and Clinical Benefit Response.Potential Alternatives?Simon 2-stage Minimax(no,time dependent endpoints and QOL being considered)Fleming 1-stage

30、 Randomized Phase 2(yes,if both arms fleming and multi-institutional)2-stage Bayesian(yes,if your stats support is active on this)Randomized Discontinuation(too aggressive)Conclusions Phase II trials are exploratory studies and rarely are definitive Efficient to exclude inactive therapies Results must be interpreted cautiously,in the context of the availability of other therapies Estimate clinical activity and provide further safety information important in the“go/no go”decision Require confirmation in phase III trials