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

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%60%Interactive AnswerOverviewObjectives & Concept DevelopmentDesig

2、nEndpoints 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 tr

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

4、rationSell it to your spouseSell it to a colleageThe WhoWho do you want your concept tested in?Define your populationDefine the standard of careDefine historical outcomes with standard of careDecide on dose and schedulePrior treatment allowedDiscuss with your mentor and with an experienced faculty m

5、emberThe HowHow will you do it?Come to Vail?Select your trial designSelect your endpoints and outcome measuresSelect your sample sizeII. Study DesignsSingle ArmTwo or more armsII. Study DesignsFrequentistGehan 2-StageSimon 2-Stage OptimalSimon 2-Stage MinimaxFleming 1-stageGehan-Simon 3-StageRandomi

6、zed Phase 2Constant Arc-SineRandomized DiscontinuationBayesianThall-Simon-Estey1-Stage Bayesian2-Stage BayesianTan MachinHeitjanAdaptiveMultiple OutcomesTwo-stage Design Main objective is to minimize the number of patients treated with ineffective regimensA very commonly used 2 stage design is the S

7、imon, 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 ineffectiveMinimax: minimizes the whole sample size Recist Response CR+PR+SD is generally utilized.Simon et al, Cont Clin Trials, 1989Simon, Mini-

8、maxTreat 12-18 patients at 1st stage Determine the “response rate”Less than that projected to indicate activity (p0): STOP!Sufficiently great to indicate activity: CONTINUEAt the end of 2nd stage, declare drug / intervention worthy of further evaluation if x number of “responses” are observed (p1)On

9、e-stage DesignWhen 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 are usually

10、incorporated for obvious lack of efficacy or unacceptable toxicity.Biometrics,1982One-stage DesignFleming 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 TTP2 with

11、 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 TrialsPatients are randomized to receive one of tw

12、o (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

13、et al, Cancer Treat Rep,1985Liu et al, Control Clin Trials,2019Randomized DiscontinuationIt 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

14、placebo 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: EfficacyMedian

15、 overall 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,

16、Joan Schiller, MD.A 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 metas

17、tases allowedSample 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 Ab

18、str 8014. Endpoint Outcome MeasuresRECIST/WHO Response RateCR + PRCR + PR + SDTime to Failure / SurvivalProgression-Free RateDisease-Free RateEndpoint Outcome MeasuresBiological EndpointsSafety & Adverse EventsMultiple EndpointsQOLCorrelative StudiesImportant, hypothesis-generating, exploratory stud

19、iesHowever, dont do them because 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 CalculationPrior

20、determination of the sample size 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-negati

21、ve). Another important consideration is 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 CalculationBefore going to your statisticianWha

22、t is the desired level of significance of 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 im

23、portance?What is a good estimate of the standard deviation 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, STATISTIXPASSGiven this comp

24、lexity of design and outcome alternatives, the selection of a 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 pa

25、tients to be enrolled. We should individualize the trial design and outcome measures to the particular agent (or combination) and disease or subset of disease to be evaluated. My ExamplesPhase 2 Study of Capecitabine and Docetaxel in Previously Untreated advanced Non-Small Cell Lung Cancer Patients

26、(OSU-0356). NCI R21 CA108157 Phase 2 trial of Sequentially Administered 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 Adenocarci

27、noma (OSU-0041). NCI R21 CA101360 Phase 2 Study of Capecitabine/Docetaxel in Previously Untreated Advanced NSCLC PatientsCapecitabine last conversion step is mediated by thymidine phosphorylase (TF), which is preferentially expressed in tumorsPreclinical studies suggest that paclitaxel/docetaxel increase expression of TFA previous trial in pretreated NSCLC patients (n=31) 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 D