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1、Question,What 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 Answer,Overview,Objectives&Concept DevelopmentDesignEndpoints Outcomes MeasuresSample Size CalculationExamples,Objectives,To define antitumor activity.To d
2、emonstrate 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 treatment and/or toxicity.,Concept Development,The WhatThe WhoThe How,Simple and fun,Moderate and excitin
3、g,Hard and frustrating,The What,What 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 illustrationSell it to your spouseSell it to a colleage,The Who,Who do you want your concept tested in?D
4、efine 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 member,The How,How will you do it?Come to Vail?Select your trial designSelect your endpoints and
5、outcome measuresSelect your sample size,II.Study Designs,Single ArmTwo or more arms,II.Study Designs,FrequentistGehan 2-StageSimon 2-Stage OptimalSimon 2-Stage MinimaxFleming 1-stageGehan-Simon 3-StageRandomized Phase 2Constant Arc-SineRandomized Discontinuation,BayesianThall-Simon-Estey1-Stage Baye
6、sian2-Stage BayesianTan MachinHeitjanAdaptiveMultiple Outcomes,Two-stage Design,Main objective is to minimize the number of patients treated with ineffective regimensA very commonly used 2 stage design is the Simon,which minimizes sample size based on a pre-specified response rate and an and error r
7、ates.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,1989,Simon,Mini-max,Treat 12-18 patients at 1st stage Determine the“response rate”Less than that projected to in
8、dicate 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),One-stage Design,When time-dependent endpoints are considered e.g.,the proportion of patients free of prog
9、ression 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 incorporated for obvious lack of efficacy or unacceptable toxicity.,Biometrics,1982,One-stage Design,Flemi
10、ng 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 the individual patients failure time or TTP1 observed with their prior regimen.If the TTP2/TTP1 ratio is
11、 greater than 1.33,the regimen is considered effective and worthy of further study.,J Clin Oncol,2001Cont Clin Trials,2000,Randomized Phase II Trials,Patients are randomized to receive one of two(or more)regimens differing by dose level,schedule,or specific agent.It is not powered to make inferentia
12、l 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 al,Cancer Treat Rep,1985Liu et al,Control Clin Trials,1999,Randomized Discontinuation,It incorporates time-depe
13、ndent endpoints with disease response.Stable disease patients are randomized to continuation with the agent or placebo(the discontinuation)Patients subsequently showing progression on placebo are then retreated with the agent to determine if stability can be regained.This design is most appropriate
14、in diseases where tumor growth rates are slow.,Kopec,J Clin Epidemiol,1993Rosner(J Clin Oncol,2002,Examples,Phase II Trial of Gefitinib in Patients With Advanced NSCLC:Efficacy,Median overall survival in the 250 mg/d and 500 mg/d gefitinib groupswere 7 months and 6 months,respectively(P=0.40)Project
15、ed 1-year survival rates were 27%and 24%,respectively(P=0.54),P=0.51,P=0.26,Kris et al.JAMA.2003;290:2149.,Single-Agent Nexavar in 3rd line+NSCLC:Double-blind Phase II,ECOG 2501,Joan Schiller,MD.,B,Second:Randomized patients first evaluated for progression after another 8 weeks,First:Patients evalua
16、ted for SD at 8 weeks,ASCO Abstr 8014.,Endpoint Outcome Measures,RECIST/WHO Response RateCR+PRCR+PR+SDTime to Failure/SurvivalProgression-Free RateDisease-Free Rate,Endpoint Outcome Measures,Biological EndpointsSafety&Adverse EventsMultiple EndpointsQOL,Correlative Studies,Important,hypothesis-gener
17、ating,exploratory studiesHowever,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 S
18、ize Calculation,Prior 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,)
19、(false-negative).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 Calculation,Before going to your stati
20、sticianWhat 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
21、importance?What is a good estimate of the standard deviation in the population?The value of the null hypothesis determines in most cases the standard deviation,From Basic&Clinical Biostatistics Dawson-Saunders and Trapp eds.,Given this complexity of design and outcome alternatives,the selection of a
22、 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 a
23、nd 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 Administe
24、red 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/Docetaxe
25、l in Previously Untreated Advanced NSCLC Patients,Capecitabine 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)
26、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 Discontinuation,Interactive Answer,Our Design,Endpoint RECIST objective response(PR/CR)Simon Two-stage minimax30%no interest,50%interestIf 8
27、or more patients show responses in the first 28,11 additional patients are treated for a total of 39.If 15 show responses,the regimen will not be recommended for further study.If 16 patients show responses in the 39,the regimen will be studied further.,Potential Alternatives?,Fleming 1-stage(yes,if
28、time dependent endpoints were chosen)Randomized Phase 2(yes,if multi-institutional)Mick Design(no,first line treatment)Randomized Discontinuation(no for aggressive malignancy,more appropriate to test durability of efficacy or significance of stability),Phase 2 trial of Sequentially Administered CPT-
29、11 and Mitomycin C in Patients with Advanced Esophageal and Stomach Cancer,Irinotecan(CPT-11)is a topoisomerase 1(Topo 1)interactive agent.Decreased levels of Topo 1 is a mechanism of resistance Preclinical studies showed that mitomycin C upregulate activity of Topo 1,thus modulation of Topo 1 activ
30、ity by MMC may result in increased response to CPT-11Mitomycin C has many side effects,so doctors hate it.A phase I trial established 6 mg/m2 on day 1,followed by CPT-11 125mg/m2 days 2 and 9,every 28 days as safe,and showed 5 responses in refractory esophageal cancer patients,How would you design i
31、t?,Simon 2-stage MinimaxFleming 1-stageRandomized Phase 22-stage BayesianRandomized Discontinuation,Interactive Answer,Two Arms,randomized parallel Simon Mini-MaxMMC 6 mg/m2 on day 1 and irinotecan 125 mg/m2 on days 2 and 9,with cycles repeated every 4 weeks.MMC,3 mg/m2 on days 1 and day 8,prior to
32、irinotecan 125 mg/m2 on days 2 and 9,every 4 weeks.A cap in the dose of MMC of 36 mg/m2 was enforced.,Our Design,Potential Alternatives?,Simon 2-stage Minimax(yes,but historical controls shaky)Fleming 1-stage(no since other interventions may follow,time dependent end-points not reliable).Randomized
33、Phase 22-stage Bayesian(yes,if your stats support is active on this)Randomized Discontinuation(no,as per B),Phase 1/2 Study of Etanercept and Gemcitabine in Patients with Advanced Stage and Chemotherapy-Nave Pancreatic Adenocarcinoma,Pancreatic cancer patients are often cacquectic,have very poor qua
34、lity of life and a dismal survivalGemcitabine is standard of care in metastatic pancreatic cancer mainly due to quality of life improvementsTumor necrosis factor have been shown to play a role in caquexia and to stimulate cancer growth through NF-kBEtanercept is a decoy receptor of TNF and you wonde
35、r if adding it to gemcitabine can result in improvements in quality of life and disease progression.,How would you design it?,Simon 2-stage MinimaxFleming 1-stageRandomized Phase 22-stage BayesianRandomized Discontinuation,Interactive Answer,Our Design,Single Stage FlemingProgression-Free Rate at 6
36、Months(7/25).Median Survival and Survival at 6 and 12 months.Assessment of Clinical Benefit ResponsePain Intensity(MPAC)Analgesic UseWeight ChangeECOG PSQuality of LifeCorrelation of cytokines and Clinical Benefit Response.,Potential Alternatives?,Simon 2-stage Minimax(no,time dependent endpoints an
37、d QOL being considered)Fleming 1-stage 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 definitiveEfficient to exclude inactive therapiesResults 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”decisionRequire confirmation in phase III trials,
