clinical design phase iii€¦ · clinical endpoints in phase iii trials: overall survival...

CLINICAL DESIGN PHASE IIICLINICAL DESIGN PHASE IIICLINICAL DESIGN PHASE III CLINICAL DESIGN PHASE III CLINICAL TRIALS AND ENPOINTSCLINICAL TRIALS AND ENPOINTS

Evandro de Azambuja, MD, PhDJules Bordet InstituteJules Bordet InstituteBREAST data centerBrussels, Belgium

ESMO Young Oncologist Committee

[email protected] @https://www.br-e-a-s-t.org

I h fli fI h fli fI have no conflict of I have no conflict of interest to declareinterest to declareinterest to declareinterest to declare

OUTLINEOUTLINE

• Oncology drug developmentgy g p

• Why drug development fails in phase III trials?

• Classic Phase III Study Design

• The targeted therapy era and challenges forThe targeted therapy era and challenges for phase III trials

Cli i l d i t i h III t i l• Clinical endpoints in phase III trials

• Surrogate endpoints in phase III oncology trialsg p p gy

• Novel strategies to move forward in drug developmentdevelopment

ONCOLOGY DRUG DEVELOPMENTONCOLOGY DRUG DEVELOPMENT

Oncology Drug DevelopmentOncology Drug DevelopmentTHE GOOD & BAD NEWSTHE GOOD & BAD NEWSTHE GOOD & BAD NEWSTHE GOOD & BAD NEWS

THE GOOD NEWSTHE GOOD NEWS THE BAD NEWSTHE BAD NEWS

• Given priority ratings by the FDA

• Faster review of marketing applications

• Estimated true cost of a drug reaching the market is US$0.8‐1.0 Billion2

• For oncology Drugs:

• The FDA reviewed oncology drugs, on average, 6 months faster than other drugs1

• Longer US clinical development times

• ~1 year longer from of clinical testing to US regulatory approval

M di t iti ti i 7 8 6 3• Median transition time is 7.8 vs 6.3yrs for non oncology drugs

WHYWHY

• Difficulties in recruitment

• Longer times needed to establish efficacy (especially for Overall Survival)

• Targeted era Mean clinical development and regulatory approval times for Targeted era

1. DiMasi, J Clin Oncol 2007; 25(2):2092.Walker, Nature Reviews, Drug Development Jan 2009, 8:15-17

new oncology therapies approved by FDA from 1990 to 2005

Oncology Drug DevelopmentOncology Drug Development

TRANSITION FROM PHASE I TO PHASE IIITRANSITION FROM PHASE I TO PHASE III

• 50% of oncology drugs that entered phase III NEVER make it to US regulatory approval1

• Success rates can be increased by:– Longer development timeframe for drugs1 Clinical phase transition probabilities for investigational

• Longer development time in period 1993 to 1997 meant approximately 1/5 drugs reached regulatory

h d d l6370

se

oncology compounds from the firms by pharmaceutical sales (2005) by period which compound first entered clinical testing

• But shorter drug development time in the period 1993 to 2002 meant approximately only 1/ 4 reached regulatory approval

22

38

30

40

50

60

f Dru

gs in

Pha

str

ials

(%

)

– Higher response rates in earlier stages of development2

• Balance of competing factors

22

0

10

20

<5% 5-10% >10%

Effic

acy

of III t

(%)• Balance of competing factors <5% 5 10% >10%Response Rate in Phase I trials (%)

1. DiMasi, J Clin Oncol 2007; 25(2):2092.Sekine I. et al., Annals of Oncology 2002; 13(8):1306

Why do Drugs fail at Phase III Development?Why do Drugs fail at Phase III Development?Why do Drugs fail at Phase III Development?Why do Drugs fail at Phase III Development?

d d• Wrong study design

• Wrong doseo g dose

• Wrong schedule

• Wrong combination

• Wrong comparatorWrong comparator

• Wrong endpoint

• Wrong tumour type

• Weak phase 2 dataWeak phase 2 data

CLASSIC PHASE III STUDY DESIGNSCLASSIC PHASE III STUDY DESIGNS

Trial Designs: Parallel DesignTrial Designs: Parallel Design

Parallel DesignParallel Design

• Each patient receives one i d f hiPOPULATION treatment in a random fashion

• Simple and easy to implement

l bl d

POPULATION

Assessment & ScreeningAssessment & Screening

Eligible patients consent • Applicable to acute conditions

• The interpretation of the results i t i htf d

g p

Allocation/RandomisationAllocation/Randomisation

TREATMENT A TREATMENT B is straightforward

• Good if inter‐patient variability exists

TREATMENT A TREATMENT B

AssessmentAssessment

existsData AnalysisData Analysis

Trial Designs: Cross OverTrial Designs: Cross Over

• Same patients receive different treatments at different dosing Cross OverCross Over gperiods

• Patients serve as their own l h

POPULATIONPOPULATION

controls: removes the inter‐patient variability from the comparison between treatments

Assessment & ScreeningAssessment & Screening

Eligible patients consent Eligible patients consent

Allocation/Randomisation between treatments

• Typically requires a much smaller sample size than a parallel design

/

TREATMENT ATREATMENT A TREATMENT BTREATMENT B

WASH OUT sample size than a parallel design

• Should only be used for chronic diseases

TREATMENT BTREATMENT B TREATMENT ATREATMENT A

WASH OUT

• Need to be careful with ”carryover” effect and washout


Data AnalysisData Analysis

period

Adapted from Hoering A. et al Clin Can Res 2008; 14:4358

Trial Designs: 2 X 2 Factorial DesignTrial Designs: 2 X 2 Factorial Design

2 x 2 Factorial Design2 x 2 Factorial Design

• Attempts to evaluate two or more treatments in a single experimentll l h• Allows to evaluate the interaction

effect between treatments

M f t i l t i l l k ffi i t

Trt A Control

Trt B a b

Control c d • Many factorial trials lack sufficient power to look at the interaction effecta = A +B effect

• 2x2x2 or more complex design: require large sample size and the

b = B + Control

c = A + Control

d C l C lq g p

results are more difficult to interpret.

d = Control + Control


The Targeted Therapy Era: The Targeted Therapy Era: Challenges in the Development of newChallenges in the Development of newChallenges in the Development of new Challenges in the Development of new

Therapeutic AgentsTherapeutic Agents

• Change in type of cancer therapies developed and the clinical practice associated with these therapies

• Greater than 90% of all new oncology agents in clinical trials are targeted therapies

Th t h h i f ti• These agents have new mechanisms of action

• New agents pose major challenges for drug development– Predominately cytostatic drugs rather than cytotoxic y y g y

– Often produce less toxic side effects than conventional cytotoxic agents and therefore have a broad therapeutic margin

– Continued beyond progression in some casesContinued beyond progression in some cases

• Conventional trial design is a potential reason for the high percentage of drug failure in Phase III clinical trials

• Modification to current trial design needs to take into consideration these challenges

Example of Trial Design FailureExample of Trial Design FailurePhase III Equivalence Study of BAY 12-9566 in advanced pancreatic cancer

GEMCITABINERA

FOLLOW UP AND ASSESSMENT

Patients with Advanced Pancreatic

GEMCITABINEANDOM

First Interim Analysis

SecondInterim Analysis

Trial Terminated

Pancreatic cancer

BAY-12 9566

MISED

Analysis Analysis

TRIAL CONTINUED

TRIAL CONTINUED

• BAY 12‐9566: Metalloproteinase inhibitor with efficacy in pancreatic cancers, SCLC,

D

ovarian and breast• Trials in pancreatic and SCLC prematurely terminated due to methodological problems• First interim analysis: Termination rule: <6/30 patients on BAY 12‐9556 were

i f t 2 thprogression free at 2 months– Analysis failed to demonstrate this

• Second Interim Analysis: Completed after 227 patients enrolledG it bi ffi i ifi tl b tt– Gemcitabine efficacy significantly better

– Immediate trial termination• Trials in lung cancer and ovarian cancer also terminated

Parulekar W.R. et al Annal Oncol 2002; 13(supple 4): 139

Example of Trial Design FailureExample of Trial Design Failure

• What were the problems:What were the problems:– Inadequate number of patients at first interim analysis

Interim analysis conducted too early– Interim analysis conducted too early

– Trial design: consider pilot phase II or integrative Phase II/III designII/III design

– Trial arm design: Gemcitabine vs. Gemcitabine + BAY 12‐95569556

– Wrong study population: may have demonstrated benefit in patients with low tumour burden rather than advanced pdisease as cytostatic

IMPROVEMENTS IN PHASE III DESIGNIMPROVEMENTS IN PHASE III DESIGN

Improvement in Phase III Study DesignImprovement in Phase III Study Design

1. Enriching the patient population– Pre‐screening

– Trial designs based around a pre‐screened population• Example HER‐2 positive patients

2. Testing patients with an earlier stage disease1. Adjuvantj

2. Neo‐adjuvant

3. Cancer chemopreventionp

Novel Strategies in Drug Development: Novel Strategies in Drug Development: Th NTh N Adj t S ttiAdj t S ttiThe NeoThe Neo‐‐Adjuvant SettingAdjuvant Setting

Biological Window pCR

C

LapatinibPaclitaxel

RA S 24.7%

pCR

C PaclitaxelAND

SUR

Invasive Operable HER2+ BC

C

TrastuzumabPaclitaxel

DOM

RGE

29.5%

HER2+ BCT>2cmLVEF ≥ 50%

CTrastuzumabLapatinib

MIZ

ERY 51.3%

≥ 50%N=450

CTrastuzumabPaclitaxel

ZE

Y

+ 12 weeks6 weeks

Baselga J et al, SABCS 2010

CLINICAL ENDPOINTSCLINICAL ENDPOINTS

Clinical Endpoints Definition: Clinical Endpoints Definition: Colorectal CancerColorectal CancerColorectal CancerColorectal Cancer

Comparability between studies

D fi i i DFSPETACC‐31 MOSAIC2

Definition DFS Stage III CRC Irinotecan/ 5‐FU/FA vs 5‐FU/FA

Stage IIFOLOFOX vs 5‐FU/FA

Locoregional recurrence E E

Distant Metastases E E

Second primary, same cancer E E

d hSecond primary, other cancer E I

Death from same cancer E E

Death from other cancer E EDeath from other cancer E E

Non‐cancer related death E E

Treatment related death E E

Loss to follow up C C

Failed to meet primary endpoint

Met Primary endpointendpoint

DFS=Disease free survival; E=Event; I=Ignored; C=Censored

1.Van Cutsem E., Proc Am Soc Clin Oncol 2005;23:10902. Andre T, N Eng J Med 2004; 350:2343

Clinical Endpoints Definition: Clinical Endpoints Definition: BreastBreast CCancerancer

Definition of DFS1 BIG‐1982 MA‐173 ATAC4 IES5 ARNO6

Breast Breast CCancerancer

Local/Regional recurrence ✔ ✔ ✔ ✔ ✔

Distant Metastasis ✔ ✔ ✔ ✔ ✔Distant Metastasis ✔ ✔ ✔ ✔ ✔

Death from any cause ✔ ✔ ✔

Invasive contralateral breast cancer ✔ ✔ ✔ ✔ ✔

Second primary invasive cancer (non breast) ✔

Ipsilateral DCIS ✔ ✔

Contralateral DCIS ✔ ✔

Ipsilateral LCIS ✔

Contralateral LCIS ✔Contralateral LCIS ✔

DFS=Disease free survival

1.Hudis CA et al, J Clin Oncol, 2007; 25:2127-21321.Hudis CA et al, J Clin Oncol, 2007; 25:2127 21322.Thurliman B et al, N Eng J Med, 2005; 353:2747

3.Goss PE et al, N Eng J Med, 2003; 349:1793-18024. Baum M et al, Lancet, 2002; 359:2131-2139

5. Coombes RC et al, N Eng J Med, 2004; 350:1081-10926. Jakesz R et al, Lancet, 2005; 366:455-462

Problems with Clinical Problems with Clinical EEndpoint ndpoint DDefinitionsefinitions

No formal consensus of definitions

Not consistently

used

Formal definitions/expert

opinions exist only for a fewopinions exist only for a few

cancer sites

Clinical Endpoints in Phase III Trials: Clinical Endpoints in Phase III Trials: OverallOverall SSurvivalurvivalOverall Overall SSurvivalurvival

Confounder:Lines of Rx

Easy to measure& interpret Confounder:

Cause deathSimple to measure

Extended

Cause death

GOLD standard

Extended Follow‐up

Advantages Disadvantages

Alternatives to Conventional Alternatives to Conventional EEndpointsndpoints

SURROGATE END POINTMetastatic trials PFS instead of Overall survivalAdjuvant trials DFS instead of Overall survival

SURROGATE END POINTMetastatic trials PFS instead of Overall survivalAdjuvant trials DFS instead of Overall survival

h h d

ADVANTAGES OF SURROGATE END POINTSADVANTAGES OF SURROGATE END POINTS

l d l

DISADVANTAGES OF SURROGATE ENDPOINTSDISADVANTAGES OF SURROGATE ENDPOINTS

• Reach the surrogate endpoint more rapidly

Ad t f t ti l d d t

• Misleading results

• Advantage of potential reduced cost of trials

Validated Surrogate Validated Surrogate EEndpointsndpoints

• A validated surrogate endpoint: the surrogate must reliably predict the overall effect on the clinical outcomepredict the overall effect on the clinical outcome

Greatest potential for valid surrogate endpointGreatest potential for valid surrogate endpoint

Reliably predicts endpointDisease

Surrogate End Point True clinical End Point

• Surrogate‐endpoint validation requires a pooled or meta‐analysis of clinical trial dataanalysis of clinical trial data. – At least three trials with 500 patients each are preferable to one

– Reasonable heterogeneity in the trials is desirable, as it minimizes theReasonable heterogeneity in the trials is desirable, as it minimizes the impact of any one particular treatment or trial

Adapted from Fleming T.R. et al., Ann Intern 1996; 125(5):605

Reason for Failure of Surrogate Reason for Failure of Surrogate EEndpointsndpointsA Example CRC and CEA

? IMPACT on Clinically relevantClinically relevant

outcome Disease

B Example Intervention

False positiveDisease

B Example Intervention

False negative

C Example Cytostatic Agent Intervention

False negativeDisease

InterventionD Example RR &Toxicity OS

Miss effectDisease

InterventionD Example RR &Toxicity OS

Adapted from Fleming T.R. et al., Ann Intern 1996; 125(5):605

TimeTimeSurrogate End Point True clinical End Point

Validation Trial: Advanced Validation Trial: Advanced CColorectal olorectal CCancerancer

5 FU/LV

10 Historical Trials 3 Registration Trials

5‐FU/LVvs

5‐FU(1744 pts)

5‐FU/LV vs

Ralitrexed(1345 pts)

5‐FU/LVvs

FOLFOX or FOLFIRI

(1263 pts)(1263 pts)

FDA APPROVAL OF VALIDATED SURROGATE ENDPOINT PFS IN ADVANCED COLORECTAL TRIALS

Buyse M. et al.,J Clin Oncol 2007;25:5218

Other ExamplesOther Examplespp

TRIALS IN TUMOUR TYPE ENDPOINT VALIDATED VALIDATION FDA APPROVAL

Advanced colorectal cancer1 PFS for OS ✔ ✔

Adjuvant colorectal cancer2 3 year DFS for 5yr OS ✔ ✔

Advanced head and neck cancer3

PFS for OS ✔ ✗

Adjuvant lung cancer DFS for OS ✔ ✗

Metastatic breast cancer PFS for OS ✗ ✗

1.Buyse M. et al.,J Clin Oncol 2007;25:52182. Sargent D et al., J Clin Oncol 2005; 23:8664

3. Michiels S et al., Lancet Oncology 2009; 10:3414. Michiels S et al., ASCO 2011

Summary: Consideration when Designing Summary: Consideration when Designing Clinical Clinical TTrialsrials

• Properties of new therapy to be investigated

• Role of a biomarkers prior to designing the phase III

trial (this can be difficult)

• Novel trial design to test a hypothesis• Novel trial design to test a hypothesis

• Endpoint choice and use of surrogate endpoints –p g p

the need for standardisation!

AcknowledgementsAcknowledgementsgg

Lina Pugliano, MDResearch FellowResearch Fellow

Back upBack up

Clinical Trial Design for Biomarkers: Clinical Trial Design for Biomarkers: Randomise AllRandomise AllRandomise AllRandomise All

Randomise ALLRandomise ALL Targeted DesignTargeted Design Strategy DesignStrategy Design

POPULATION

g gg g

POPULATION

gy ggy g

POPULATIONPOPULATION

Assessment Marker (M)Assessment Marker (M)



M‐M‐ M+M+



Allocation/Randomisation


TREATMENT A TREATMENT B

EligibleEligible


MM

TREATMENT ATREATMENT A

MM Allocation/Randomisation

Tx NOT based on M

Tx based on M


M+M+ M‐M‐ M+M+M‐M‐

M+M+ M+M+TREATMENT BTREATMENT BTREATMENT ATREATMENT A

M+M+ M‐M‐ M+M+M‐M‐TxATxATx ATx A Tx BTx B

Data AnalysisData Analysis AssessmentAssessment





Clinical Trial Design for BiomarkersClinical Trial Design for BiomarkersTable 1: Randomised Phase III trials for Targeted Agents

Randomise All Targeted Design Strategy DesignRandomise All Targeted Design Strategy Design

Best Used • If treatment works for M-

as well as M+ patients

• When the treatment helps

only M+ patients

• Generally inferior to

other designs

• Large marker prevalence

• Cut points of M+ and M-

• Small marker prevalence

• Cut point of M+ and M+ is

not well established well established

Cautions • If the treatment is harmful

for M patients

• Small benefit of treatment

in M

• Does not compare

efficacy of 2 treatmentsfor M- patients in M-

• Cut point of M+ and M- not

well established

efficacy of 2 treatments

Disadvantages • Generally requires higher

sample size

• Requires highest number

of patients for screening

• Generally requires

higher sample size


Consensus Agreement: Adjuvant Consensus Agreement: Adjuvant CColorectal Trialsolorectal Trials

Definition DFS DFS RFS TTR TTF CSS OSDefinition DFS DFS RFS TTR TTF CSS OS

Locoregional recurrence E E E E I I

Distant Metastases E E E E I I

Second primary, same cancer E I I E I I

Second primary other cancer E I I E I ISecond primary, other cancer E I I E I I

Death from same cancer E E E E E E

Death from other cancer E E C E C E

Non‐cancer related death E E C C C E

Treatment related death E E C E C E

Loss to follow up C C C C C CDFS=Disease free survival; RFS:= Relapse free survival; TTR=Time to recurrence; TTF=Time to treatment failure; CSS=Cancer specific survival; OS=Overall Survival;E=Event; I=Ignored; C=CensoredE=Event; I=Ignored; C=Censored

Cornelis J.A. et al., JNCI 2007; 99(13):998

Proposed Standard Proposed Standard DDefinitions: Breast efinitions: Breast CCancerancer

Proposed Standard Definitions1 OSDFS‐DCIS

IDFS DDFS DRFS RFS RFI BCFI DRFI

Invasive ipsilateral breast tumour recurrence ✔ ✔ ✔ ✔ ✔✔ ✔ ✔ ✔ ✔

Local/Regional recurrence ✔ ✔ ✔ ✔ ✔

Distant recurrence ✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔

Death from breast cancer ✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔

Death from non breast cancer cause ✔ ✔ ✔ ✔ ✔ ✔

Death from unknown cause ✔ ✔ ✔ ✔ ✔ ✔Death from unknown cause ✔ ✔ ✔ ✔ ✔ ✔

Invasive contralateral breast cancer ✔ ✔ ✔

Ipsilateral DCIS ✔ ✔✔ ✔

Contralateral DCIS ✔ ✔

Second primary invasive cancer (non breast) ✔ ✔ ✔Notes: Lobular carcinoma in situ not included as an event in these definitions as it is not generally considered to be a direct precursor of breast cancer‘Contralateral invasive breast cancer’ is preferred to ‘second primary breast cancer’ as it is less ambiguousIpsilateral invasive breast cancer are presumed to be a recurrenceSecond non‐breast primary cancers should NOT include squamous or basal skin cancers or new in situ carcinomas of any site

OS O ll i l DFS DCIS Di f i l d t l i i it IDFS I i di f i l i i DDFS Di t t di fOS=Overall survival; DFS‐DCIS=Disease free survival –ductal carcinoma in situ; IDFS=Invasive disease free survival‐invasive; DDFS=Distant disease freesurvival; DRFS=Distant relapse free survival; RFS=Recurrence free survival; RFI=recurrence free interval; BCFI=Breast cancer free interval; DRFI=Distant recurrence free interval.

1.Hudis CA et al, J Clin Oncol, 2007; 25:2127-2132

clinical design phase iii€¦ · clinical endpoints in phase iii trials: overall survival...

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