Phase II trial designs and endpoints

Transcription

1 Eti Estimating anti-tumour tit activity it Phase II trial designs and endpoints Margaret Hutka MD PhD The Royal Marsden Hospital GI & Lymphoma Unit London, UK

2 Overview Role of phase II trials Elements of a phase 2 trial Endpoints Single arm vs randomised design Types of randomised phase II designs

3 Role of phase II trials To define antitumour activity To demonstrate safety To better understand the pharmacokinetics, pharmacodynamics and metabolism of therapeutic agents To evaluate biologic correlates which may predict response or resistance to treatment and/or toxicity

4 A critical component of drug development Phase 2 studies act as screening tools to assess whether treatment has sufficient activity to warrant further investigation in large, costly phase 3 trials Go / no go decision Minimise the number of patients exposed to ineffective treatment Enroll as few patients as necessary to show presence or lack of benefit

5 Phase 2/3 status quo On average 8 years in phase I III spent on development of new drugs 1 Only 5% of oncology drugs make it from early clinical trials to registration 2 60% failure rate in phase III trials 2..are we making inappropriate go/no go decisions at the end of phase 2 trials? 1. Adams CP, Brantner VV. Estimating the cost of new drug development: is it really 802 million dollars? Health Aff (Millwood). 2006;25(2): Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov. 2004;3(8):

6 Questions What patient population should be targeted? What are the appropriate endpoints? What is the appropriate trial design? Single arm? Randomised? Upfront randomisation Randomised discontinuation

7 Aspects of phase 2 clinical trial design Endpoints (response vs progression free survival) Randomisation (single arm vs randomisation) Inclusion of biomarkers Biomarker based patient enrichment p strategies

8 Essential elements Why? Who? What? How?

9 Essential elements WHY? Objective and hypothesis One primary, hypothesis testing, objective and a limited number of secondary objectives

10 Essential elements WHO? Patient selection Inclusion/exclusion criteria Clearly defined patient population (specific histology subtype); Expression of target marker (enrichment of patient population); Feasibility bl of turnaround time for screening); Baseline characteristics (prior therapy, organ function, PS)

11 Essential elements WHAT? Treatment plan Drug/intervention, Dose, schedule, dose modification Specification of permitted supportive therapy, Route of administration, pre medication, infusion details), if pt is fasting, what happens at missed dose.

12 Essential elements HOW? Endpoints and design: Measurable tumour mass reduction Combined clinical benefit rates Progression based endpoints PFS, TTP Serologic response criteria: Ca125, PSA Survival Biomarker studies

13 Endpoints

14 Endpoints RECIST/WHO Response Rate CR + PR CR + PR + SD Confirmed vs. Unconfirmed Biological Endpoints Safety & Adverse Events Multiple Endpoints QOL Time to Failure / Survival Poge Progression-Free ionfeerate Disease-Free Rate

15 Endpoints: Measurable tumour mass reduction Proves antitumour activity and permits of early yield of data BUT May not be applicable to all cancer types, may not be a good surrogate for important clinical effect (survival), may be difficult to assess in some cancers, may no be appropriate for some group of agents

16 Survival Easy to measure BUT Can be influenced by subsequent therapies and requires time

17 Progression based endpoints More clinically meaningful than RR for some agents Reflect biologic activity BUT Are influenced by frequency of observation and variable ibl dfiit definitons

18 Serologic response Easy to measure and quantitate, generally reflects tumour biology BUT Not always a validated surrogate for survival and secretion may be influenced by other factors than cell death or reduced tumour growth

19 Correlative studies aspects Prognostic markers: correlate with disease outcome Predictive i markers: predict outcome with ih specific therapy Ph d i k fi bi l i l Pharmacodynamic markers: confirm biological activity

20 Design: To randomise or not to randomise?

21 Single arm trial design Results of single arm trials are typically interpreted relative to data from historical control subjects, past study participants with similar characteristics The validity of conclusions from single arm trials based on historical control subjects is limited by selection bias and confounding Appropriateness is dependent on the endpoint that is being used, and patient population, for ex: in a diseasesetting setting for which there areno active therapy

22 Single arm trial design Comparison is fixed constant Binaryendpoint (clinical response vs. no response RR or rate of PFS at a certain time point) Appropriate when testing a targeted agent in tumour types for which robust historical databases exist (pancreatic cancer, glioblastoma) When hypothesis of the study is to demonstrate t target effect Appropriate in late disease/ salvage settings

23 Phase II randomised design Continuous response endpoints: Time to event endpoints PFS, time to progression, overall survival (not possible in single arm trials because of absence of continuous historical data) Ability to study biomarkers that may reflect pharmacodynamic effects or correlate with findings regarding tumour response and time to event endpoints compared with samples from patients t not receiving the study drug

24 Randomised phase 2 design Reduces selection bias Improves patient comparability Simplicity of assessment of non survival endpoint BUT Requires more patients than a single arm Requires more patients than a single arm phase II trial

25 To randomise or not to randomise? Single arm trials only screen out very ineffective drugs (h (those with ihrr lower than certain threshold) h R d i d h II ti l i t ti ll Randomised phase II trials screen in potentially effective drugs

26 Randomised phase 2 design Primary endpoint is tumour response Monotherapy trials single arm designs are acceptable but randomisation should be encouraged to optimise dose and schedule or to benchmark activity against known active therapies Combination trials randomisation is usually required for trials testing combinations of agents to establish efficacy Seymour L et al Clin Cancer Res March 15; 16(6):

27 Randomised phase 2 design Primary endpoint is progression free survival Randomisation i is required and blinded d designs are encouraged in both monotherapy or combination trials Seymour L et al Clin Cancer Res March 15; 16(6):

28 Biomarker considerations

29 Patient selection and enrichment strategies In an unselected trial (patients not defined by a biomarker) the patient population of primary interest (ie cohort defined by a biomarker) should be predefined and the study powered accordingly to dt detect tan effect in that t subset If the objective is to test a biomarker focused hypothesis, multi disease phase II designs should be considered d

30 Patient selection and enrichment strategies Molecular biomarkers should be explored in order to identify subsets of patients of interest for future study Enrollment should not be limited by biomarker status unless there is strong confirmatory and supportive clinical data justifying enrichment strategy. Adaptive statistical designs may be used to allow modification of enrollment if data suggest a biomarker is predictive Seymour L et al Clin Cancer Res March 15; 16(6):

31 Prospective designs Can improve efficiency i of drug development and provide greater precision Adaptations include: Stopping early Continuing longer than anticipated Dropping arms (or doses) Adding arms Seamlessly l moving from phase I to phase II or phase II to phase III Seymour L et al Clin Cancer Res March 15; 16(6):

32 Types of randomised phase II trials Simplest design is a two arm trial with upfront randomisation to the new drug or combination vs existing standard of care (or placebo) Variations include the use of multiple arms to allow for dose ranging of the investigational drug or the use of an unbalanced randomisation (2:1 or 3:1) to boost accrual with only a modest reduction in statistical power Sharma M et al J Natl Cancer Inst 2011;103:

33 5 types of randomised phase II trials Randomised discontinuation design Delayed start design Adaptive (Bayesian) design Selection design Phase II/III design Sharma M et al J Natl Cancer Inst 2011;103:

34 Randomised discontinuation design Mi Mainobjective is tominimize i i thenumber of patients t treated with ineffective regimens A very commonly used 2 stage design is the Simon, which minimizes sample size based on a pre specified response rate and an α and β 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. Sharma M et al J Natl Cancer Inst 2011;103:

35 Randomised discontinuation design Sharma M et al J Natl Cancer Inst 2011;103:

36 Summary Phase II studies estimate clinical activity and provide further safety information, effective to exclude inactive therapies Remain an important screeningtool in drug development and require thoughtful design appropriate for each individual agent Badlydesignedphase2 designed trialmay allow more ineffective drugs enter phase 3, are a waste of patients, time and money and may prevent effective drugs from entering phase 3 Phase II trials are exploratory studies, rarely are definitive and rapid screening phase II trials asaeesse are essential for efficient ce tand dcost effective ect e development of a new intervention/agent

37 Summary Molecularenrichment enrichment isnot essential but the identification, piloting and validation of putative predictive markers is an importantendpoint ofphase IItrials. Clinical validation of surrogate biomarkers of efficacy through serial iltissue collection may be best after clinical i l benefit fithas been demonstrated in phase II Single arm phase II studies continue to be appropriate when the possible outcomes in studied population are well described d

38 Summary Tumour growth kinetic assessments, biomarker or functional imaging endpoints are generally not sufficiently validated to be considered primary endpoints BUT continued assessment and validation i is encouraged Results must be interpreted cautiously, in the context of the availability of other therapies Require confirmation in phase III trial Complete reporting to include negative studies/ studies prematurely terminated Publications to include all relevant information, patient characteristics, design, endpoints, and predefined go/no go criteria

39 References Sharma M et al Randomised Phase II Trials: A long term Investment With peromising Returns J Natl Cancer Inst 2011;103: Booth C et al Design and conduct of Phase II studies of targeted anticancer therapy: Recommendations from the task force of methodology for the development of innovative cancer therapies (MDICT) EJC 44 (2008) Royall R. Statistical Evidence:A Likelihood Paradigm, London, Chapman & Hall, Schaid DJ, Ingle JN, Wieand S, Ahmann DL.A design for phase II testing of anticancer agents within a phase III clinical trial. Control Clin Trials Jun;9(2): Scher HI, Heller G. Picking the winners in a sea of plenty. Clin Cancer Res Feb;8(2): Simon R, Wittes RE, Ellenberg SS. Randomized phase II clinical trials. Cancer Treat Rep Dec;69(12): Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials Mar;10(1):1-10.