Upload
reeves
View
34
Download
0
Tags:
Embed Size (px)
DESCRIPTION
Introduction to Design of Genomic Clinical Trials. Richard Simon, D.Sc. Chief, Biometric Research Branch National Cancer Institute http://brb.nci.nih.gov. Biometric Research Branch Website brb.nci.nih.gov. Powerpoint presentations Reprints & Technical Reports BRB-ArrayTools software - PowerPoint PPT Presentation
Citation preview
Introduction to Introduction to Design of Genomic Design of Genomic
Clinical TrialsClinical TrialsRichard Simon, D.Sc.Richard Simon, D.Sc.
Chief, Biometric Research BranchChief, Biometric Research BranchNational Cancer InstituteNational Cancer Institutehttp://brb.nci.nih.govhttp://brb.nci.nih.gov
Biometric Research Branch Biometric Research Branch WebsiteWebsite
brb.nci.nih.govbrb.nci.nih.gov
Powerpoint presentationsPowerpoint presentations Reprints & Technical ReportsReprints & Technical Reports BRB-ArrayTools softwareBRB-ArrayTools software Web based Sample Size Planning Web based Sample Size Planning
OutlineOutline IntroductionIntroduction
BiomarkersBiomarkers ValidationValidation
Targeted enrichment designTargeted enrichment design Stratification designsStratification designs Prospective-Retrospective DesignsProspective-Retrospective Designs Prognostic biomarkersPrognostic biomarkers Clinical Trial Designs with adaptive Clinical Trial Designs with adaptive
identification of indication for treatmentidentification of indication for treatment Development and Validation of Classifiers Development and Validation of Classifiers
with High Dimensional Datawith High Dimensional Data
Different Kinds of Different Kinds of BiomarkersBiomarkers
Endpoint biomarkerEndpoint biomarker A measurement made on a patient before, during and after A measurement made on a patient before, during and after
treatment to determine whether the treatment is workingtreatment to determine whether the treatment is working Surrogate endpointSurrogate endpoint PharmacodynamicPharmacodynamic Intermediate endpointIntermediate endpoint
Prognostic biomarkersPrognostic biomarkers Measured before treatment to indicate long-term outcome for Measured before treatment to indicate long-term outcome for
patients untreated or receiving standard treatmentpatients untreated or receiving standard treatment Single arm study of patients receiving a particular rx can identify Single arm study of patients receiving a particular rx can identify
patients with good prognosis on that rxpatients with good prognosis on that rx Those patients may not benefit from that rx but they don’t need additional rxThose patients may not benefit from that rx but they don’t need additional rx
Predictive biomarkersPredictive biomarkers Measured before treatment to identify who will benefit from a Measured before treatment to identify who will benefit from a
particular treatmentparticular treatment Single arm study with response endpointSingle arm study with response endpoint RCT with survival or dfs endpointRCT with survival or dfs endpoint
Cardiac Arrhythmia Cardiac Arrhythmia Supression TrialSupression Trial
Ventricular premature beats was Ventricular premature beats was proposed as a surrogate for survivalproposed as a surrogate for survival
Antiarrythmic drugs supressed Antiarrythmic drugs supressed ventricular premature beats but ventricular premature beats but killed patients at approximately 2.5 killed patients at approximately 2.5 times that of placebotimes that of placebo
Surrogate EndpointsSurrogate Endpoints
It is extremely difficult to properly validate a It is extremely difficult to properly validate a biomarker as a surrogate for clinical outcome.biomarker as a surrogate for clinical outcome.
It is not sufficient to demonstrate that the surrogate It is not sufficient to demonstrate that the surrogate is correlated with clinical outcomeis correlated with clinical outcome That responders live longer than non-responders does not That responders live longer than non-responders does not
establish response as a valid surrogate endpoint establish response as a valid surrogate endpoint Proper validation requires a series of randomized Proper validation requires a series of randomized
trials with both the candidate biomarker and trials with both the candidate biomarker and clinical outcome measuredclinical outcome measured Demonstrate that differences between randomized Demonstrate that differences between randomized
treatment arm with regard to the candidate surrogate are treatment arm with regard to the candidate surrogate are consistent with differences with regard to clinical outcomeconsistent with differences with regard to clinical outcome
It is often more difficult and time It is often more difficult and time consuming to properly “validate” an consuming to properly “validate” an endpoint as a surrogate than to use the endpoint as a surrogate than to use the clinical endpoint in phase III trialsclinical endpoint in phase III trials
Using Intermediate Endpoints Not Using Intermediate Endpoints Not Established as Surrogates of Established as Surrogates of
Clinical BenefitClinical Benefit Biomarkers can be useful in phase I/II studies as Biomarkers can be useful in phase I/II studies as
measures of treatment effectmeasures of treatment effect they need not be validated as surrogates for clinical they need not be validated as surrogates for clinical
benefitbenefit Unvalidated surrogates can also be used for Unvalidated surrogates can also be used for
interim “futility analyses” of phase III trials (e.g. interim “futility analyses” of phase III trials (e.g. seamless phase II/III). The trial should continue seamless phase II/III). The trial should continue accrual and follow-up to evaluate true endpoint if accrual and follow-up to evaluate true endpoint if treatment effect on biomarker is sufficienttreatment effect on biomarker is sufficient Conditional surrogate endpointsConditional surrogate endpoints
Can be used for developing predictive biomarkers Can be used for developing predictive biomarkers in phase II studies or in adaptive signature in phase II studies or in adaptive signature designsdesigns
Prognostic & Predictive Prognostic & Predictive BiomarkersBiomarkers
Many cancer treatments benefit only a minority Many cancer treatments benefit only a minority of patients to whom they are administeredof patients to whom they are administered Particularly true for molecularly targeted drugsParticularly true for molecularly targeted drugs
Being able to predict which patients are likely to Being able to predict which patients are likely to benefit would benefit would save patients from unnecessary toxicity, and enhance save patients from unnecessary toxicity, and enhance
their chance of receiving a drug that helps themtheir chance of receiving a drug that helps them Help control medical costs Help control medical costs Improve the success rate of clinical drug developmentImprove the success rate of clinical drug development
Prognostic and Predictive Prognostic and Predictive Biomarkers in OncologyBiomarkers in Oncology
Single gene or protein measurementSingle gene or protein measurement e.g. HER2 protein staining 2+ or 3+e.g. HER2 protein staining 2+ or 3+ HER2 amplificationHER2 amplification KRAS mutationKRAS mutation
Scalar index or classifier that Scalar index or classifier that summarizes contributions of multiple summarizes contributions of multiple genes/proteinsgenes/proteins Empirically determined based on genome-Empirically determined based on genome-
wide correlating gene expression to wide correlating gene expression to patient outcome after treatmentpatient outcome after treatment
Prognostic Factors in OncologyPrognostic Factors in Oncology
Most prognostic factors are not used Most prognostic factors are not used because they are not therapeutically because they are not therapeutically relevantrelevant
Most prognostic factor studies do Most prognostic factor studies do not have a clear medical objectivenot have a clear medical objective They use a convenience sample of They use a convenience sample of
patients for whom tissue is available. patients for whom tissue is available. Generally the patients are too Generally the patients are too
heterogeneous to support heterogeneous to support therapeutically relevant conclusionstherapeutically relevant conclusions
Pusztai et al. The Oncologist 8:252-8, Pusztai et al. The Oncologist 8:252-8, 20032003
939 articles on “prognostic markers” or 939 articles on “prognostic markers” or “prognostic factors” in breast cancer in “prognostic factors” in breast cancer in past 20 yearspast 20 years
ASCO guidelines only recommend routine ASCO guidelines only recommend routine testing for ER, PR and HER-2 in breast testing for ER, PR and HER-2 in breast cancercancer
““With the exception of ER or progesterone With the exception of ER or progesterone receptor expression and HER-2 gene receptor expression and HER-2 gene amplification, there are no clinically amplification, there are no clinically useful molecular predictors of response to useful molecular predictors of response to any form of anticancer therapy.”any form of anticancer therapy.”
Prognostic Biomarkers Can Prognostic Biomarkers Can be Therapeutically Relevantbe Therapeutically Relevant
<10% of node negative ER+ breast <10% of node negative ER+ breast cancer patients require or benefit cancer patients require or benefit from the cytotoxic chemotherapy from the cytotoxic chemotherapy that they receivethat they receive
OncotypeDxOncotypeDx 21 gene RTPCR assay for FFPE tissue21 gene RTPCR assay for FFPE tissue
Key Features of OncotypeDx Key Features of OncotypeDx DevelopmentDevelopment
Identification of important therapeutic decision Identification of important therapeutic decision contextcontext
Prognostic marker development was based on Prognostic marker development was based on patients with node negative ER positive breast cancer patients with node negative ER positive breast cancer receiving tamoxifen as only systemic treatmentreceiving tamoxifen as only systemic treatment Use of patients in NSABP clinical trialsUse of patients in NSABP clinical trials
Staged development and validationStaged development and validation Separation of data used for test development from data used Separation of data used for test development from data used
for test validationfor test validation Development of robust assay with rigorous analytical Development of robust assay with rigorous analytical
validationvalidation 21 gene RTPCR assay for FFPE tissue21 gene RTPCR assay for FFPE tissue Quality assurance by single reference laboratory operationQuality assurance by single reference laboratory operation
B-14 Results—Relapse-Free B-14 Results—Relapse-Free SurvivalSurvival
338 pts
149 pts
181 pts
0 2 4 6 8 10 12 14 16Time (yrs)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Relapse-Free Survival
Low R isk (RS < 18) In termediate R isk (R S 18 - 30) H igh R isk (RS 31)
p<0.0001
Paik et al, SABCS 2003
Predictive BiomarkersPredictive Biomarkers In the past often studied as un-In the past often studied as un-
focused post-hoc subset analyses of focused post-hoc subset analyses of RCTs.RCTs. Numerous subsets examinedNumerous subsets examined Same data used to define subsets for Same data used to define subsets for
analysis and for comparing treatments analysis and for comparing treatments within subsetswithin subsets
No control of type I errorNo control of type I error
Statisticians have taught physicians Statisticians have taught physicians not to trust subset analysis unless the not to trust subset analysis unless the overall treatment effect is significantoverall treatment effect is significant This was good advice for post-hoc data This was good advice for post-hoc data
dredging subset analysisdredging subset analysis For many molecularly targeted cancer For many molecularly targeted cancer
being developed, the subset analysis will being developed, the subset analysis will be an essential component of the primary be an essential component of the primary analysis and analysis of the subsets will analysis and analysis of the subsets will not be contingent on demonstrating that not be contingent on demonstrating that the overall effect is significantthe overall effect is significant
MutationsCopy number changes
TranslocationsExpression profile
Treatment
Types of Validation for Types of Validation for Prognostic and Predictive Prognostic and Predictive
BiomarkersBiomarkers Analytical validationAnalytical validation
Pre-analytical and post-analytical Pre-analytical and post-analytical robustnessrobustness
Clinical validationClinical validation Does the biomarker predict what it’s Does the biomarker predict what it’s
supposed to predict for independent datasupposed to predict for independent data Clinical utilityClinical utility
Does use of the biomarker result in Does use of the biomarker result in patient benefitpatient benefit
Clinical UtilityClinical Utility Benefits patient by improving Benefits patient by improving
treatment decisionstreatment decisions Depends on context of use of the Depends on context of use of the
biomarkerbiomarker Treatment options and practice Treatment options and practice
guidelinesguidelines Other prognostic factorsOther prognostic factors
Clinical Utility of Clinical Utility of Prognostic BiomarkerPrognostic Biomarker
Prognostic biomarker for identifying patientsPrognostic biomarker for identifying patients for whom practice standards imply cytotoxic for whom practice standards imply cytotoxic
chemotherapychemotherapy who have good prognosis without chemotherapywho have good prognosis without chemotherapy
Prospective trial to identify such patients Prospective trial to identify such patients and withhold chemotherapyand withhold chemotherapy
TAILORxTAILORx ““Prospective plan” for analysis of archived Prospective plan” for analysis of archived
specimens from previous clinical trial in specimens from previous clinical trial in which patients did not receive chemotherapywhich patients did not receive chemotherapy OncotypeDx OncotypeDx
Marker Strategy DesignMarker Strategy Design
MINDACT DesignMINDACT Design
Clinical Utility of Predictive Clinical Utility of Predictive BiomarkerBiomarker
Predictive biomarker for identifying the Predictive biomarker for identifying the patients who benefit from a specific patients who benefit from a specific regimen and/or the patients who do notregimen and/or the patients who do not
Prospective RCT of new regimen versus Prospective RCT of new regimen versus control with tissue prospectively collected control with tissue prospectively collected and assayed and patients classified as test and assayed and patients classified as test + or test – + or test – Sample size established to have enough test + Sample size established to have enough test +
patients for separate analysis of new regimen patients for separate analysis of new regimen versus control and enough test – patients for versus control and enough test – patients for separate analysis of new regimen versus controlseparate analysis of new regimen versus control
Focused analysis on a single completely Focused analysis on a single completely prospectively defined biomarker classifierprospectively defined biomarker classifier
Prospective Co-Prospective Co-Development of Drugs and Development of Drugs and
Companion DiagnosticsCompanion Diagnostics1.1. Develop a completely specified genomic Develop a completely specified genomic
classifier of the patients likely to benefit from classifier of the patients likely to benefit from a new druga new drug
• Single gene/proteinSingle gene/protein• Gene expression signatureGene expression signature
• Screen genes using microarraysScreen genes using microarrays• Develop classifier for RT-PCR platformDevelop classifier for RT-PCR platform
• Pre-clinical, phase II data, archived specimens from Pre-clinical, phase II data, archived specimens from previous phase III studiesprevious phase III studies
2.2. Establish analytical validity of the classifierEstablish analytical validity of the classifier3.3. Use the completely specified classifier to Use the completely specified classifier to
design and analyze a new clinical trial to design and analyze a new clinical trial to evaluate effectiveness of the new treatment evaluate effectiveness of the new treatment with a pre-defined analysis plan that preserves with a pre-defined analysis plan that preserves the overall type-I error of the study.the overall type-I error of the study.
Guiding PrincipleGuiding Principle The data used to develop the classifier The data used to develop the classifier
should be distinct from the data used to should be distinct from the data used to test hypotheses about treatment effect test hypotheses about treatment effect in subsets determined by the classifierin subsets determined by the classifier Developmental studies can be exploratoryDevelopmental studies can be exploratory Studies on which treatment effectiveness Studies on which treatment effectiveness
claims are to be based should be definitive claims are to be based should be definitive studies that test a treatment hypothesis in studies that test a treatment hypothesis in a patient population completely pre-a patient population completely pre-specified by the classifierspecified by the classifier
New Drug Developmental New Drug Developmental Strategy I Strategy I
Restrict entry to the phase III trial based Restrict entry to the phase III trial based on the binary predictive classifier, i.e. on the binary predictive classifier, i.e. targeted designtargeted design
Using phase II data, develop predictor of response to new drugDevelop Predictor of Response to New Drug
Patient Predicted Responsive
New Drug Control
Patient Predicted Non-Responsive
Off Study
Developmental Strategy (II)Developmental Strategy (II)
Develop Predictor of Response to New Rx
Predicted Non-responsive to New Rx
Predicted ResponsiveTo New Rx
ControlNew RX Control
New RX