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Registration Studies. Registration studies – Phase III. Objectives To gain regulatory approval Robustness of trial and endpionts are paramount Design of trial can be discussed with regulatory agency To assess the efficacy of the drug compared to existing ‘gold standard’

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registration studies phase iii
Registration studies – Phase III

Objectives

  • To gain regulatory approval
  • Robustness of trial and endpionts are paramount
  • Design of trial can be discussed with regulatory agency
  • To assess the efficacy of the drug compared to existing ‘gold standard’
  • To assess the toxicity of the drug compared to existing ‘standard of care’
  • Collect QOL where appropriate
  • Collect relevant pharmaco-economic data
phase iii studies patient selection
Phase III Studies – Patient selection

Regulatory authorities wish the population to be as homogenous as possible .

Specific tumour type

    • Stage, grade, target expression, geographical location increasingly important
    • Biomarkers may be mandatory
  • Good performance status
  • Any exclusion criteria based on population and any toxicities seen in earlier studies
  • Informed consent
  • Ability to read and write - QOL
phase iii studies study design
Phase III Studies – Study Design
  • Consider choice of endpoints- PFS, OS (RECIST, BIR)
  • Consider duration of therapy
  • Consider design
    • Parallel
    • Factorial
    • Crossover
  • Consider mode of randomisation - reduces selection bias
    • Equal/unequal
    • Stratification
phase iii studies study design1
Phase III Studies – Study Design
  • Consider degree of blinding - reduces reporting bias
    • Open label studies are common
    • Single
    • Double
  • Sample size calculations
    • "Is my trial large enough to demonstrate a clinically significant difference between the groups if one is truly present?"
sample size calculation
Sample size calculation
  • In oncology studies, this calculation determines the number of events, not the number of patients, required
  • Depends on:
    • Natural intra-patient variability - less important in oncology
    • Minimum difference between groups considered important by investigator
    • Acceptable levels of α and β
  • Remember effect of interim analyses
endpoints
Overall Survival - time to death from any cause

Progression-free survival - time to first observation of disease progression

Time to treatment failure- time to first observation of disease progression, death or discontinuation

Duration of response – time to first observation of response to progression / death

Quality of Life- mainlyfor blinded studies.

Endpoints
quality of life
Quality of Life
  • 2 main instruments used
    • Functional Assessment of Cancer Therapy- General ( FACT-G)
    • European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire- C30 ( EORTC- C30)
  • Both modular set up with generic core questionnaires in combination with disease specific modules
  • Generic core includes:
    • Physical functioning and well-being, social functioning, social / family well-being etc
health outcomes
Health Outcomes
  • Instruments commonly used and accepted:
    • SF-36
    • Health utility Index
    • EQ-5D
  • Increasing importance due to reimbursement / cost containment
basis for nda approval
Basis for NDA Approval
  • Demonstration of efficacy with acceptable safety in adequate and well-controlled studies
  • Ability to generate product labeling that
    • Defines an appropriate patient population for treatment with the drug
    • Provides adequate information to enable safe and effective use of the drug
accelerated approval fast track priority review
Accelerated Approval, Fast Track, Priority Review
  • Accelerated Approval
    • serious or life-threatening disease
    • demonstrable benefit over available therapy.
    • use of surrogate markers
    • mandated phase IV trials
  • Fast Track
    • life-threatening disease
    • potential to address unmet medical need
  • Priority review
    • drug would be a significant improvement compared to available drugs
    • Review of filing in 6 months
challenges for oncology drug regulations
Challenges for Oncology Drug Regulations
  • New “targeted therapies”
    • Re-define definitions of diseases (based on mechanism of pathogenesis, genetics)
    • Greater efficacy in selected population may result in smaller patient populations
    • Novel surrogates to be validated
    • Dosing aimed at target rather than MTD
    • Dose studies, chronic administration
slide14

EGFR biomarkers were discovered late in the gefitinib development programme

ISEL, INTEREST: Unselected trials in pre-treated setting

ISEL

Gefitinib registration Japan

INTEREST

IPASS

2002

2005

2007

2009

EGFR protein expression

IPASS: Clinically selected trial in first line setting

EGFR gene copy number

EGFR mutations

the real challenge was to determine which tumours were really dependent on the egfr pathway

Gefitinib

Placebo

The real challenge was to determine which tumours were really dependent on the EGFR pathway

ISEL study: Median follow-up 7 months (range 3-15), 58% deaths

Median, months

1-year survival, %

Log-rank HR (95% CI), 0.89 (0.77, 1.02); p=0.087Cox analysis, p=0.030

Gefitinib

5.6

27

Placebo

5.1

21

Proportionsurviving

1.0

0.8

0.6

0.4

0.2

0.0

0

2

4

6

8

10

12

14

16

Time (months)

1692

1347

877

485

252

104

31

At risk

Thatcher et al 2005

slide16

The dangers of dilution……..

Probability of success in pivotal trial in the presence of a non-responsive subgroup

Assumes responders have 33% effect and non-responders 0% effect,

trial sized assuming all patients have a 33% effect

isel rigorously predefined subgroups showed a statistically significant increase in survival
ISEL: Rigorously predefined subgroups showed a statistically significant increase in survival

Never smoked (n=375)

Ever smoked (n=1317)

1.0

HR 0.67; 95% CI 0.49, 0.92; p=0.012

HR 0.92; 95% CI 0.79, 1.06; p=0.242

Gefitinib

0.8

Placebo

0.6

Proportion surviving

0.4

0.2

0.0

0

2

4

6

8

10

12

14

16

0

2

4

6

8

10

12

14

16

Asian origin (n=342)

Non-Asian origin (n=1350)

1.0

HR 0.66; 95% CI 0.48, 0.91; p=0.010

HR 0.92; 95% CI 0.80, 1.07; p=0.294

0.8

0.6

Proportion surviving

0.4

0.2

0.0

0

2

4

6

8

10

12

14

16

0

2

4

6

8

10

12

14

16

Time (months)

Cox regression analysis

Thatcher et al 2005

ipass phase iii study of gefitinib versus doublet chemotherapy in first line nsclc
IPASS: Phase III study of gefitinib versus doublet chemotherapy in first line NSCLC

Gefitinib250 mg/day

1:1 randomization

Carboplatin AUC 5 or 6 and Paclitaxel 200mg/m2 3 wkly

Endpoints

  • Patients
  • Adenocarcinoma histology
  • Never smokers or light ex-smokers*
  • PS 0-2
  • Provision of tumour sample for biomarker analysis strongly encouraged
  • Primary
  • Progression free survival (non-inferiority)
  • Secondary
  • Objective response rate
  • Quality of life
  • Disease related symptoms
  • Overall survival
  • Safety and tolerability
  • Exploratory
  • Biomarkers
    • EGFR mutation
    • EGFR gene copy number
    • EGFR protein expression
  • 1217 patients from East Asian countries

*Never smokers:<100 cigarettes in lifetime; light ex-smokers: stopped 15 years agoand smoked 10 pack yrs

Carboplatin/paclitaxel was offered to gefitinib patients upon progression

PS, performance status; EGFR, epidermal growth factor receptor

ipass superior pfs and orr with gefitinib vs doublet chemotherapy pfs effect not constant over time
IPASS: Superior PFS and ORR with gefitinib vs doublet chemotherapy; PFS effect not constant over time

Probabilityof PFS

Carboplatin /

paclitaxel

1.0

Gefitinib

N

Events

609

453 (74.4%)

608

497 (81.7%)

0.8

HR (95% CI) = 0.741 (0.651, 0.845) p<0.0001

0.6

5.874%48%7%

Median PFS (months)4 months progression-free6 months progression-free12 months progression-free

5.761%48%25%

0.4

Primary objective exceeded: Gefitinib demonstrated superiority relative to carboplatin / paclitaxel in terms of PFS

0.2

0.0

0

4

8

12

16

20

24

Months

At risk :

Gefitinib

609

363

76

24

5

0

212

Carboplatin / paclitaxel

608

412

118

22

3

1

0

Objective response rate 43% vs 32% p=0.0001

Primary Cox analysis and logistic regression with covariates; ITT population

HR <1 implies a lower risk of progression on gefitinib

ipass gefitinib has a more favourable tolerability profile than doublet chemotherapy
IPASS: Gefitinib has a more favourable tolerability profile than doublet chemotherapy

Most common AEs (10% on either treatment) with >3% difference between treatments

Gefitinib (N=607)

Carboplatin/paclitaxel (N=589)

#Absolute neutrophil count, white blood cell count, or haemoglobin worsened from baseline to CTC grade 3/4; gefitinib N=599, carboplatin / paclitaxel N=577 *Grouped term (sum of several preferred terms)

slide21
IPASS: EGFR mutation is a strong predictor for differential PFS benefit between gefitinib and doublet chemotherapy

Gefitinib EGFR M+ (n=132)Gefitinib EGFR M- (n=91)Carboplatin / paclitaxel EGFR M+ (n=129)

Carboplatin / paclitaxel EGFR M- (n=85)

Probabilityof PFS

1.0

EGFR M+HR=0.48, 95% CI 0.36, 0.64

p<0.0001

EGFR M-

HR=2.85, 95% CI 2.05, 3.98

p<0.0001

0.8

Treatment by subgroup interaction test, p<0.0001

0.6

0.4

0.2

0.0

0

4

8

12

16

20

24

Time from randomisation (months)

M+, mutation positive; M-, mutation negative

mutation status causes conformational change and increased activation
Mutation status causes conformational change and increased activation

WT EGFR

Mutant EGFR

Ligand

Extracellular domain

Trans-membrane domain

ATP

Tyrosine kinase domain

Tyrosine phosphorylation

Ras-Raf-MAPK

Proliferation

Pi3K-AKT

Survival

EGFR internalisation

Degradation/recycling

EGFR signals longer

at the cell membrane

slide23
IPASS: Superior quality of life and symptom improvement rates for gefitinib in EGFR mutation positive patients

p<0.0001

p=0.0003

p<0.0001

% patientswith sustained clinically relevant improvement

p-values from logistic regression with covariates. Post-hoc analysis, EFQ populationClinically relevant improvement pre-defined as 6-point improvement for FACT-L and TOI;2-point improvement for LCS, maintained for at least 21 days.

EFQ, evaluable for quality of life; FACT-L, Functional Assessment of Cancer Therapy-Lung; TOI, Trial Outcome Index; LCS, Lung Cancer Subscale

conclusions phase iii trial considerations
Conclusions – phase III trial considerations
  • Patient selection
    • Activity in specific subsets
  • Study design
    • Experimental (& control!) arm – dose, duration of treatment
    • Frequency of evaluations
  • Study endpoints
    • Survival vs PFS?
    • Use of biomarkers?
    • Qol
    • Health economics
  • Post phase III plans
    • Early access
    • Phase IIIb/IV
    • Investigator Initiated Studies
slide25

STAMPEDE: Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy

Sponsor number: MRC PR08ISRCTN number: ISRCTN78818544EUDRACT number: 2004-000193-31CTA number: 00316/0026/001-0001

Slide set (abridged)

design rationale
Design rationale

STAMPEDE is multi-arm, multi-stage trial

3 investigational drugs in original design

Intergroup randomised controlled trial

Using Multi-Arm Multi-Stage methodology

MAMS design

design rationale1
Design rationale

Many interesting agents

Different classes and modes of action

Many used in later stages of disease

Others new

No clear reason to choose a particular one

Many choices

Don’t want to choose arbitrarily

Want to assess all interesting agents

Quicker and efficient to use MAMS design

Start by test many agents

Focus to more active agents using LOB analyses

why multi arm multi stage trials
Why Multi-arm, Multi-stage trials?

Typical (academic) Phase III trial

Hundreds or thousands of patients

5 to 10 years from idea to result

Hundreds of research staff

Cost millions in development

Years of investment from the key players

High chance of finding new treatment is not superior

Whether to continue testing a new treatment?

mams vs traditional
MAMS vs traditional

T1

Traditional Approach

Multi-arm, Multi-stage

T2

Phase II

T3

C

T1

T2

T3

T4

T4

Phase II

C T1

Phase III

C T3

C T4

Phase III

trial design stages
Trial Design Stages

Stage Outcome Measures

Primary Secondary

(Pilot) (Safety) (Feasibility)

ActivityI-IIIFailure-free survival Overall survival

(phase II) Toxicity (safety)

Skeletal-related events

EfficacyIVOverall survival Failure-free survival

(phase III) Toxicity (safety)

Skeletal-related events

Quality of life

intermediate analysis potential outcomes
Intermediate Analysis – Potential Outcomes

Arms/Drugs might be dropped for Safety Reasons

All patients on that arm/drug stop treatment

Arms/Drugs might be dropped for lack of activity

Patients on that arm/drug could continue treatment depending on the results seen

TSC recommended that patients that were still being treated on celecoxib-containing arms stopped celecoxib. However, decision ultimately left to patient.

slide33
STAMPEDE DESIGN

Slide set (abridged)

stampede original design
STAMPEDE original design

Man with high-risk prostate cancer starting long-term hormone therapy

Trial IDs

MRC PR08

CRUK/06/019

ISRCTN78818544

NCT00268476

Slide set (abridged)

slide35
STAMPEDE: A FLEXIBLE TRIAL

Slide set (abridged)

flexibility
Flexibility
  • Adaptive trial design
  • Uses lack-of-benefit analyses to focus accrual away from insufficiently active arm
  • Require evidence of activity to continue accrual
  • Accrual to both celecoxib-containing arms was stopped on IDMC recommendation at 2nd intermediate analysis

Slide set (abridged)

flexibility1
Flexibility
  • Can include new research arms
  • Use same intermediate hurdles for new arms
  • Compare against common control arm
  • New arm added in Nov-2011
    • Abiraterone Acetate
  • Further new arm planned for 2012
    • Local radiotherapy for M1 patients

Slide set (abridged)

accrual

Past accrual

Possible future accrual

Accrual

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

  • Following slides show accrual activity over time

Follow-up

Slide set (abridged)

accrual1

Past accrual

Possible future accrual

Accrual

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

A

B

C

D

E

F

Follow-up

Slide set (abridged)

accrual initial plans

Past accrual

Possible future accrual

Accrual: initial plans

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

A

ADT-alone

B

ADT + zoledronic acid

C

ADT + docetaxel

D

ADT + celecoxib

E

ADT + zoledronic acid + docetaxel

F

ADT + zoledronic acid + celecoxib

Follow-up

Slide set (abridged)

accrual end of pilot phase

Past accrual

Possible future accrual

Accrual: end of Pilot Phase

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

A

ADT-alone

B

ADT + zoledronic acid

C

ADT + docetaxel

D

ADT + celecoxib

E

ADT + zoledronic acid + docetaxel

F

ADT + zoledronic acid + celecoxib

Follow-up

Slide set (abridged)

accrual end of activity stage i

Past accrual

Possible future accrual

Accrual: end of Activity Stage I

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

A

ADT-alone

B

ADT + zoledronic acid

C

ADT + docetaxel

D

ADT + celecoxib

E

ADT + zoledronic acid + docetaxel

F

ADT + zoledronic acid + celecoxib

Follow-up

Slide set (abridged)

accrual end of activity stage ii

Past accrual

Possible future accrual

Accrual: end of Activity Stage II

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

A

ADT-alone

B

ADT + zoledronic acid

C

ADT + docetaxel

D

ADT + celecoxib

E

ADT + zoledronic acid + docetaxel

F

ADT + zoledronic acid + celecoxib

Follow-up

Slide set (abridged)

accrual from nov 2011

Past accrual

Possible future accrual

Accrual: from Nov-2011

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

A

ADT-alone

B

ADT + zoledronic acid

C

ADT + docetaxel

D

ADT + celecoxib

E

ADT + zoledronic acid + docetaxel

F

ADT + zoledronic acid + celecoxib

G

ADT + abiraterone

Follow-up

Slide set (abridged)

accrual plans from late 2012

Past accrual

Possible future accrual

Accrual: plans from late 2012

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

A

ADT-alone

B

ADT + zoledronic acid

C

ADT + docetaxel

D

ADT + celecoxib

E

ADT + zoledronic acid + docetaxel

F

ADT + zoledronic acid + celecoxib

G

ADT + abiraterone

M1 only

H

ADT + RT

Follow-up

Slide set (abridged)

stampede s future
STAMPEDE’s future
  • Original research arms will stop accrual within 18m
    • Stop early at 3rd intermediate analysis for lack-of-benefit
    • Complete accrual to end of Efficacy Stage 4
  • Active, original research arms will present data in around 3 years
  • HT vs HT + abiraterone will recruit up to Nov-2014
  • HT vs HT + local RT will start in 2012
  • Further arms considered

Slide set (abridged)

further reading
Further Reading
  • Thatcher N et al, Gefitinib plus best supportive care in previously treated patients with refractory non-small-cell lung cancer: results from a randomisd, placebo controlled, multicentre study (Iressa Survival Evaluation in lung Cancer). Lancet 2005;366:1527-1537.
  • Chang A et al, Gefitinig (IRESSA) in patients of Asian origin with refractory advanced non-small cell lung cancer: subset analysis from the ISEL study. J ThoracOncol 2006;1:847-855.
  • Kelloff GJ et al, New science-based endpoints to accelerate oncology drug development. Eu J Can 2005;41:491-501
  • Booth CM et al, Reflections on Medical Oncology: 25 years of clinical trials – where have we come & where are we going. J ClinOncol 2008;26(1):6-8
  • Gutierrez ME et al, Next generation oncology drug development: opportunities & challenges. Nat Rev ClinOncol 2009;6:259-265
  • Nathan DG. The Cancer Treatment Revolution, Wiley & Sons, Inc., 2007
  • Mukherjee S. The emperor of all maladies. A biography of cancer. Fourth Estate, 2010
  • James ND et al, Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage randomised controlled trial. Lancet Oncol 2012;13(5):549-558
  • Sydes et al, Flexible trial design in practice – stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial. Trials 2012;13:168
clinical trial design
Clinical Trial Design
  • Stratification: Categorizing subjects into subgroups by specific characteristics
    • Enables researchers to look into separate subgroups to see whether differences exist
interim analyses
Interim analyses
  • 1 analysis p=0.05
  • 2 analyses p=0.083
  • 3 analyses p=0.107
  • 10 analyses p=0.193
  • Designs exist to reflect this - extreme p values used for initial analyses to avoid loss of power
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