I-SPY essais cliniques.pptx

Sophie Skorupka, Stéphanie Crosetto, Hasnein Cheikh,
Juliette Desbonnet
AREIPS 2016-2017
Breast
Cancer
Key numbers
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Cancer Incidence
France, 2014
USA, 2014
3
Key numbers
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
120
100
80
60
40
20
0
1980 1985 1990 1995 2000 2005 2010
France
USA
http://globocan.iarc.fr/old/FactSheets/cancers/breast-new.asp
Limits of I-SPY
Evolution of mortality
Age-standardised rate per 100 000
Age-standardised rate per 100 000
Evolution of incidence
I-SPY 3
25
20
15
10
5
0
1975 1980 1985 1990 1995 2000 2005 2010
France
USA
4
Breast anatomy
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
5
Staging of breast cancer
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Disposition Titre et contenu avec
graphique
6
Staging of breast cancer
Breast Cancer
I-SPY 1
I-SPY 2
No tumor and cancer
has spread to the
lymph nodes
Accelerated Approval
I-SPY 3
Limits of I-SPY
Tumor 2 – 5 cm and
cancer has spread to
the lymph nodes
Tumor > 5 cm and
Tumor less than
2 cm et contenu avec
Disposition
Titre
cancer has not spread
and cancer has spread
to the lymph nodes
to the lymph nodes
graphique
Tumor 2 – 5 cm and
cancer has not spread
to the lymph nodes
7
Staging of breast cancer
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
•
Tumor is less than 2 cm and cancer
has spread to 4-9 lymph nodes
•
Tumor larger than 5 cm and cancer
clusters found in the lymph nodes
Limits of I-SPY
Disposition Titre et contenu avec
• Tumor larger than 5 cm and cancer
graphique
has spread to lymph nodes near the
breastbone or underarm
8
Staging of breast cancer
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Metastasis are found in the body
9
Different prognosis :
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
5-year survival rate
99
93
Survival Rate
72
22
0-I
II
III
IV
Breast Cancer Stages
https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-survival-rates.html
10
Breast Cancer Status
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
HER2
Receptor
HR: Hormone
Receptor
HER2 protein receptor:
Help control how a healthy
breast cell grows, divides
and repairs itself
Breast cell have receptor for
mormones
ER+: estrogen receptor +
EP+: progesteron receptor +
25% breast cancer are
HER2 +: tend to grow
faster and are more likely
to spread and come back
2/3 of breast cancer are
HR+
Treatment available
specifically for HER2 +:
Trastuzumab, T-DM1,
Pertuzumab, Lapatinib
Treatment for HR+:
SERMs, Aromatase
inhibitors, ERDs, LHRHs
Limits of I-SPY
11
Diagnosis
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Breast exam
Mammogram
Ultrasound
MRI
Biopsy
12
Breast Cancer Treatment
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
Targeted therapy
Hormonal therapy
Chemotherapy
I-SPY 3
Limits of I-SPY
Trastuzumab
Lapatinib
Anti-oestrogen
Anti-aromatase
Doxorubicin
Paclitaxel
Cyclophosphamid
Radiations
Surgery
13
Neoadjuvant or Adjuvant?
Breast Cancer
Breast Cancer
I-SPY 1
I-SPY 2
Neoadjuvant therapy
Accelerated Approval
Surgery
• Smaller sample
size
• Primary endpoint :
pCR (assessed
months)
• Short drug
exposure
• Needs prior safety
information
I-SPY 3
Limits of I-SPY
Adjuvant therapy
• Bigger sample size
• Primary endpoint :
DFS, OS (assessed
years)
• Best setting to
assess long-term
outcome (DFS, OS)
• Better safety
assessment
14
FDA :Guidance for Industry : Pathological Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval
Breast Cancer Clinical Trials
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
More than 2000 clinical trials
on-going all over the world
15
Issues in Oncology Clinical Trials
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Phase III trials increase in size, duration and expense
High failure rate (34% Phase II  Phase III)
 Adaptive Clinical Trials
Often result in very small improvements in outcome
Repeated analysis and fixed sample-size inflate probability of type I or type II error
16
Adaptive Clinical Trials
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
FDA : “An ADAPTIVE DESIGN CLINICAL STUDY is defined as a study that includes a prospectively planned
opportunity for modification of one or more specified aspects of the study design and hypotheses based on
analysis of data (usually interim data) from subjects in the study”
• Adaptive randomisation design
• Adaptive treatment-switching
design
• Sample size re-estimation
design
• Hypothesis-adaptive design
• Drop-the-loser design
• Adaptive seamless phase II/III
• Adaptive dose-finding design
• Multi-adpative design
17
Traditional Trial vs Adaptive Trial
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Traditional Phase II and III Studies
Group A
Group B
Data analysis
Planning phase III
Group B
Group C
Phase II results available
Placebo Group
Placebo Group
End of Phase III
Adaptive design – combined Phase II/III
Group A
Drop Group A
Group B
Group C
Drop C
Placebo Group
Interim
Analysis I
Interim
Analysis II
End of Phase III
18
Traditional Trial vs Adaptive Trial
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Group A
Group B
Data analysis
Planning phase III
Group B
Group C
Phase II results available
Placebo Group
Placebo Group
End of Phase III
Adaptive design – combined Phase II/III
Group A
Drop Group A
Group B
Group C
Drop C
Placebo Group
Interim
Analysis I
Interim
Analysis II
End of Phase III
19
Adaptive randomisation
Breast Cancer
Triple negative
I-SPY 1
I-SPY 2
Drug A
Accelerated Approval
Drug B
I-SPY 3
Limits of I-SPY
Control
HER2+ / HRHER2+ / HR+
Drop B
20
Concept of I SPY
Breast Cancer
I-SPY 1
Biomarkers Phase
• Find biomarkers
• Validation
correlation
pCR/RFS
I-SPY 1
I-SPY 2
Accelerated Approval
Screening Phase
I-SPY 2
• Neoadjuvant
• pCR to predict
EFS
I-SPY 3
Limits of I-SPY
Confirmatory Phase
• Neoadjuvant +
Adjuvant
• DFS to predict
OS
I-SPY 3
Accelerated
approval
Full
approval
21
I-SPY 1
Investigation of Serial Studies to Predict Your
Therapeutic Response with Imaging and molecular
Analysis
I-SPY 1: Objectives
I-SPY 1
Breast Cancer
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
 I-SPY 1:
multicenter neoadjuvant breast cancer study designed to establish
standards for collecting molecular and imaging data over the course of
care
 Objectives:
 Evaluate
whether response to therapy – as MRI or pCR – would predict recurrence-free
survival (RFS)
 Defining the relationship of biomarkers to RFS
Pathologic Complete Response (pCR) is defined as the absence of invasive cancer in breast and nodes
23
Pathologic Complete Response Predicts Recurrence-Free Survival More Effectively by Cancer Subset: Results From the I-SPY 1 TRIAL—CALGB 150007/150012, ACRIN 6657, Journal of Clinical Oncology
FDA Guidance: pCR
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated
I-SPY Approval
3
Accelerated
I-SPY Approval
3
Limits
Conclusion
of I-SPY
24
Biomarkers
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Hormone Receptor (HR)
Estrogen
receptor
MammaPrint
Progesterone
receptor
HER2
Biomarkers will be used to determine patient eligibility and randomization for the trial
25
Breast Cancer Status
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
HER2
Receptor
HR: Hormone
Receptor
MP:
MammaPrint
HER2 protein receptor:
Help control how a healthy
breast cell grows, divides
and repairs it self
Breast cell have receptor for
mormones
ER+: estrogen receptor +
EP+: progesteron receptor +
25% breast cancer are
HER2 +: tend to grow
faster and are more likely
to spread and come back
70 genes signatures which
can accurately select early
stage breast cancer
patients who are highly
likely to develop distant
metastasis
2/3 of breast cancer are
HR+
Treatment available
specifically for HER2 +:
Trastuzumab, T-DM1,
Pertuzumab, Lapatinib
Treatment for HR+:
SERMs, Aromatase
inhibitors, ERDs, LHRHs
Limits of I-SPY
Used to make treatment
decisions based on the
recurrence risk of earlystage
26
MammaPrint
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Only 14 signatures used
for I-SPY
27
http://www.agendia.com/healthcare-professionals/breast-cancer/mammaprint/
Study treatment and procedures
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
28
Pathologic Complete Response Predicts Recurrence-Free Survival More Effectively by Cancer Subset: Results From the I-SPY 1 TRIAL—CALGB 150007/150012, ACRIN 6657, Journal of Clinical
I-SPY 1 : Results
Breast Cancer
I-SPY 1
Hazard ratio for RFS of pCR vs no pCR
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
HR+ / HER2statistically insignificant result
30
I-SPY 1 : Results
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Hazard ratio for RFS of pCR vs no pCR
31
I-SPY 1 : Results
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Hazard ratio for RFS of pCR vs no pCR
32
I-SPY 1
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
Results from I-SPY 1
Tumor subsets defined
Subset HR+ / HER2- won’t be studied
pCR will be used as an early indicator of RFS
• Find biomarkers
• Validation
correlation
pCR/RFS
I-SPY 3
Limits of I-SPY
I-SPY 2
• Neoadjuvant
• pCR to predict
EFS
I-SPY 1
pCR will be primary endpoint in I-SPY2
33
I-SPY 2
Investigation of Serial Studies to Predict Your
Therapeutic Response with Imaging and molecular
Analysis
I-SPY 2 : a three tier model
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
35
Esserman L J. et al 2012 A model for accelerating identification and regulatory approval of effective investigational agents.
I SPY 2 participating organisations
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
I-SPY 2
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Phase II, multicenter, adaptively randomized trial, open label
Objectives:
 Match experimental regimens with responding cancer subtypes
 Rapidly identify which disease subtypes/signatures are sufficiently responsive to
treatment with a given regimen to enable a small, focused and sucessful phase III
trial
37
Inclusion and Exclusion criterias
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Inclusion criterias
 Women 18 years old
 Clinical stage II or III disease and had not received
surgical or systemic therapy for this cancer
 Diameter of tumor had to be at least 2,5 cm
(clinical assessment) and 2 cm (imaging)
 Eastern Cooperative Oncology Group performance
status score 0 or 1 (asymptomatic or mild
symptomatic)
 Able to undergo MRI and biopsies
Exclusion criterias
o HR + status and low risk
according to the 70-gene
assay
38
Biomarker signatures
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Focus on biomarker signatures = combination of subtypes
39
Berry, D. A. Nat. Rev. Clin. Oncol. 9, 199–207 (2012); published online 8 November 2011
Bayesian Method
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
 Pre-specified
thresholds of efficacy was defined as Bayesian predictive probability of
success of 85% or more in a simulated phase 3 trials of neoadjuvant therapy in 300
patients who had undergone randomization in a ratio 1:1
 Futility
was defined as Bayesian predictive probability of success in a phase 3 trial less
than 10% for all 10 biomarker signatures
40
Adaptive randomization
Breast Cancer
Triple negative
I-SPY 1
I-SPY 2
Drug A
Accelerated Approval
Drug B
I-SPY 3
Limits of I-SPY
Control
HER2+ / HRHER2+ / HR+
Drop B
41
Clinical Trial Design
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Randomization updated regarding new data = Adaptive Randomization
42
N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750
Clinical Trial Design
Breast Cancer
I-SPY 2
I-SPY 1
Accelerated Approval
I-SPY 3
Limits of I-SPY
Novel drugs in combination with standard chemotherapy VS standard therapy alone
ADAPT for new patients
Randomize
HER2
+
Paclitaxel 80 mg + trastuzumab ± new drug (12
weekly cycles)
Doxorubicin 60 mg +
cyclophosphamide
600 mg (4 cycles)
Surgery
Paclitaxel 80 mg ± new drug (12 weekly cycles)
Doxorubicin 60 mg +
cyclophosphamide
600 mg (4 cycles)
Surgery
On
study
HER2
Biopsy
blood
MRI
MRI
MRI
MRI
Tissue
Primary end point = pCR at time of surgery (5 months after initiation of chemotherapy)
43
Neratinib
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval

Tyrosine kinase inhibitor (HER2): HER2+ breast cancer

Oral route
I-SPY 3
Limits of I-SPY
Neratinib:
240 mg per day for the first 12
weeks
44
Trial Design
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
45
N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750
Randomization
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Neratinib + paclitaxel group n = 115
Paclitaxel ± trastuzumab group n = 78
46
N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750
Biomarker signatures
Breast Cancer
I-SPY 1
I-SPY 2
Signatures
Accelerated Approval
I-SPY 3
Limits of I-SPY
HR, HER2, MP
HER2+
+++
++-
-++
-+-
MP+
+++
+-+
-++
--+
HR-, HER2+
-++
-+-
HR+, HER2+
+++
++-
Only 2 subtypes excluded:
• HR+ HER2- MP• HR- HER2- MP47
Adverse Events and Toxic Effects
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
More Anemia and
gastrointestinal event
More early discontinuation for
toxic effects
48
Results
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
49
N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750
HER2+, HR- results
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Predictive probability of success in phase 3 trial = 79%
• Neoadjuvant +
Adjuvant
• DFS to predict
OS
I-SPY 3
50
N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750
Veliparib
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3

Poly (ADP-ribose) polymerase (PARP) inhibitor (PARP-1 and 2), BRCA1/2 Mutation

Association with Carboplatin
Limits of I-SPY
Veliparib:
50 mg oral routes 2/day for 12 weeks
Carboplatin:
6 mg·hr per liter on weeks 1, 4, 7, and 10
51
N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750
Trial Design
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
52
N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750
Randomization
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Veliparib + Carboplatin group n = 72
Paclitaxel + trastuzumab group n = 18
Paclitaxel group n = 44
53
N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750
Biomarker signatures
Breast Cancer
I-SPY 2
I-SPY 1
Signatures
Accelerated Approval
I-SPY 3
Limits of I-SPY
HR, HER2, MP
HER2-
+-+
+--
HR+, HER2-
+-+
+--
Triple
negative
---
--+
---
Only HER2+ excluded (for toxicity)
54
N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750
Adverse Events and Toxic Effects
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
More hematologic events
More early discontinuation
for toxic effects
55
N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750
Results
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
56
N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750
Triple negative results
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Predictive probability of success in phase 3 trial = 88%
• Neoadjuvant +
Adjuvant
• DFS to predict
OS
I-SPY 3
57
N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750
I-SPY 2
Breast Cancer
I-SPY 2
I-SPY 1
PLX3397
Accelerated Approval
T-DM1 +
Pertuzumab
I-SPY 3
Limits of I-SPY
Talazoparib +
Irinotecan
Pertuzumab +
Trastuzumab
Ganetespib
Breast Cancer
Neratinib
Veliparib
AMG 386 +/Trastuzumab
MK-2206 +/Trastuzumab
Patritumab +/Trastuzumab
AMG 479
Pembrolizumab
58
https://clinicaltrials.gov/ct2/show/record/NCT02032277
I-SPY 2
Breast Cancer
I-SPY 2
I-SPY 1
PLX3397
Accelerated Approval
T-DM1 +
Pertuzumab
I-SPY 3
Limits of I-SPY
Talazoparib +
Irinotecan
Pertuzumab +
Trastuzumab
Ganetespib
Breast Cancer
Neratinib
Veliparib
AMG 386 +/Trastuzumab
MK-2206 +/Trastuzumab
Patritumab +/Trastuzumab
AMG 479
Pembrolizumab
59
https://clinicaltrials.gov/ct2/show/record/NCT02032277
Accelerated
Approval
Pathway for accelerated approval
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
61
JAMA, December 21, 2011—Vol 306, No. 23
Pathway for accelerated approval
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
62
JAMA, December 21, 2011—Vol 306, No. 23
Pathway for accelerated approval
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
63
JAMA, December 21, 2011—Vol 306, No. 23
Pathway for accelerated approval
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
For products appearing to provide a benefit for:
• serious or life-threatening illnesses
• lacking satisfactory treatments
• subject to the requirement to verify benefit
Surrogate endpoint that is reasonably likely to predict clinical benefit : pCR
≈ EMA’s Conditional approval
64
Pathway for accelerated approval
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
number of indications granted accelerated approval
20
18
16
14
12
10
8
6
4
2
0
65
https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm
Pathway for accelerated approval
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Single large phase 3 trial
Biomarker proposed/phase1
complete
Biomarker
identified
3 years
Full drug approval
With companion diagnostic
Phase 2 screening trial
Accelerated drug approval
Biomarker approval
Investigational
agent
Small confirmatory trial
66
Esserman L J. et al 2012 A model for accelerating identification and regulatory approval of effective investigational agents.
Pathway for accelerated approval
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
FDA may withdraw approval
• If studies have not been conducted
• If studies fail to show an increase of survival
10% failed to confirm a benefit or failed to complete confirmatory trial accrual
67
I-SPY 3
Investigation of Serial Studies to Predict Your
Therapeutic Response with Imaging and molecular
Analysis
I-SPY 3
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
The I-SPY 3 TRIAL is an international confirmatory trial of successful agents who have
graduated from the I-SPY 2 TRIAL
 I-SPY 3 is designed to confirm the efficacy of new treatments
 Goal is to accelerate the phase III testing of agents
 Utilizes parallel approval pathways for FDA and EMA
69
Veliparib : Brightness Study
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
A Study Evaluating Safety and Efficacy of the Addition of Veliparib Plus Carboplatin Versus the
Addition of Carboplatin to Standard Neoadjuvant Chemotherapy Versus Standard Neoadjuvant
Chemotherapy in Subjects With Early Stage Triple Negative Breast Cancer
Phase III trial with 3 arms
Neoadjuvant therapy
Study conducted by
AbbVie
70
https://clinicaltrials.gov/ct2/show/record/NCT02032277
Veliparib: Brightness Study
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
* AC : doxorubicin/cyclophosphamide
Triple negative Breast Cancer
Arm A: Active Comparator
Arm B: Placebo Comparator
Arm C: Placebo Comparator
Veliparib
+ Carboplatin
+ Paclitaxel
Placebo
+ Carboplatin
+ Paclitaxel
Placebo
+ Placebo
+ Paclitaxel

followed by AC

followed by AC

followed by AC
71
https://clinicaltrials.gov/ct2/show/record/NCT02032277
Veliparib : Brightness Study
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Primary endpoint
• Pathological Complete Response (pCR) of breast and axillary tumor
Secondary endpoints
• Event-free Survival (EFS)
• Overall Survival (OS)
Final data collection date for primary outcome measure : March 2016
Estimated study Completion date : December 2026
72
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Neratinib : Phase III
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Based on I-SPY 2 results and other clinical data, Phase 3 testing of neoadjuvant neratinib is
moving forward in the successor I-SPY 3 program, aimed at generating accelerated approval
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Neratinib : Phase III future design
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
* AC : doxorubicin/cyclophosphamide
HER2 + Breast Cancer
Arm A
Arm B
Arm C
Neratinib
+ Pertuzumab
+ Trastuzumab
+ Paclitaxel
Placebo
+ Pertuzumab
+ Trastuzumab
+ Paclitaxel
Neratinib
+ Placebo
+ Trastuzumab
+ Paclitaxel

followed by AC

followed by AC

followed by AC
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I-SPY 3
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
Reduce Phase III duration
Reduce population
Reduce cost
Accelerated Approval – Early access to the market
Can adaptive trial become the new oncology trial gold standard ?
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I-SPY Limits
NeoALTTO Trial
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
HER2 + Breast Cancer
Lapatinib alone
Lapatinib plus trastuzumab
Trastuzumab alone
NeoALTTO’s aim : Showing that dual inhibition of HER2 might be a valid approach to treatment of
HER2+ breast cancer in the NEOADJUVANT SETTING
 Prediction
by pCR of an improved survival
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Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial ; www.thelancet.com Vol379 February18, 2012
NeoALTTO Trial
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
The combination of lapatinib
and trastuzumab resulted in
a significantly higher pCR
rate than did trastuzumab or
lapatinib alone for both HR+
and HR– tumours
ALTTO Trial
(adjuvant therapy)
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Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial ; www.thelancet.com Vol379 February18, 2012
ALTTO Trial
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
HER2 + Breast Cancer
Trastuzumab then Lapatinib
Lapatinib plus trastuzumab
Trastuzumab alone
Primary endpoint : Disease-free survival (DFS)
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Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting
ALTTO Trial
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY

Nonsignificant
reduction in DFS in
HER2-positive tumors
ALTTO Trial FAILED
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Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting
ALTTO Trial Failed
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
ALTTO Phase III trial FAILED to show improvement of DFS
 Results of higher pCR don’t lead to improvement of DFS
Can we start I-SPY 3 ?
Is pCR such a good surrogate marker ?
How can we explain those results ?
81
ALTTO Trial Failed
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Limits of I-SPY
ALTTO Phase III trial FAILED to show improvement of DFS
 Results of higher pCR don’t lead to improvement of DFS
Low events
2 Different studies
Different population
-
-
Different chemotherapy order
NeoALTTO 4years DFS =
75% VS 87%
More HR+ status in ALTTO
= less sensibility to antiHER2+ treatment
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Clin Cancer Res; 21(13); 2911–5. !2015 AACR
Adaptive trials still
the future of
clinical trials in
oncology?
Probability of Success: Traditional Trials
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Conclusion
2006 - 2015
Clinical Development Success Rates 2006-2015
84
I-SPY 2
Breast Cancer
I-SPY 1
I-SPY 2
PLX3397
Accelerated Approval
T-DM1 +
Pertuzumab
I-SPY 3
Talazoparib +
Irinotecan
Ganetespib
50% graduated from I-SPY 2
Breast Cancer
Neratinib
Conclusion
Pertuzumab +
Trastuzumab
Veliparib
AMG 386 +/Trastuzumab
MK-2206 +/Trastuzumab
Patritumab +/Trastuzumab
AMG 479
Pembrolizumab
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Towards other indications
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Conclusion
BATTLE Trial
Biomarker-integrated approaches of targeted
therapy for lung cancer elimination


Randomisation based on 4 biomarkers
Endpoint: eight-week progression-free survival
86
Conclusion
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Conclusion
Benefits
Disadvantages
87
Conclusion
Breast Cancer
I-SPY 1
I-SPY 2
Accelerated Approval
I-SPY 3
Conclusion
Benefits
 Great efficiencies in terms of
resources
Disadvantages
• Logistics more complicated (not
standard for CRO)
• Communication and tranparency
between stakeholders
• Enforce rigorous design
(population, compliance with FDA
pCR guidance +++)
Early access
 Accelerated approval
 Faster clinical development
 Assessment of a lot of
investigational drugs and
combinations in the same time
 Increase chances for patients
 Flexibility of phase III
 Increase probability of success
phase II to phase III
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Thank you for your
attention