I-SPY un nouveau paradigme dessais cliniques.pptx

I-SPY 2
Regulatory Workshop
March, 2nd to 3rd 2015
DADEZ Justine
DALLE Martin
GILLET Delphine
HOLOGNE Pauline
LEBAS Fanny
Contents
• Breast Cancer
• Clinical Trials in Oncology
• I-SPY 1
• I-SPY 2 – Adaptive Design
• Limit of I-SPY : NeoAltto/Altto
• I-SPY 3
• Patient first
2
Breast cancer
3
I. Epidemiology of Breast Cancer
 Research : Many patients followed for a long time to show a significant efficacy.
Source : http://seer.cancer.gov/statfacts/html/breast.html
4
II. Female breast anatomy
5
Source : http://www.cancer.gov/cancertopics/pdq
III. Stages
Carcinoma in situ
Invasive breast cancer
6
The 5-year survival rate for
cancer stages
7
Source : https://www.summahealth.org/GetScreened
8
•
National Cancer Institute: PDQ® Breast Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified
<02/15/2015>. Available at: http://cancer.gov/cancertopics/pdq/treatment/breast/Patient. Accessed <02/15/2015>
9
•
National Cancer Institute: PDQ® Breast Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified
<02/15/2015>. Available at: http://cancer.gov/cancertopics/pdq/treatment/breast/Patient. Accessed <02/15/2015>
10
•
National Cancer Institute: PDQ® Breast Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified
<02/15/2015>. Available at: http://cancer.gov/cancertopics/pdq/treatment/breast/Patient. Accessed <02/15/2015>
11
•
National Cancer Institute: PDQ® Breast Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified
<02/15/2015>. Available at: http://cancer.gov/cancertopics/pdq/treatment/breast/Patient. Accessed <02/15/2015>
12
•
National Cancer Institute: PDQ® Breast Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified
<02/15/2015>. Available at: http://cancer.gov/cancertopics/pdq/treatment/breast/Patient. Accessed <02/15/2015>
IV. Detection and diagnostic
• Physical exam and history
• Biopsy
• Mammogram
13
• Clinical Breast Exam (CBE)
• MRI
V. Tests on tumor cells
• Biopsy
• Diagnostic biopsy
• Biomarkers search
• Hormonal Status
• HER2 Status
• Important to choose the treatment
and know agressivity of tumor
14
Source : http://www.breastcancer.org/symptoms/diagnosis/hormone_status
V. Tests on tumor cells
• Estrogen and progesterone receptor test :
• Estrogen-receptor-positive or negative (ER+ or ER-)
• Progesterone-receptor-positive or negative (PR+ or
PR-)
 Hormone-receptor-negative or positive (HR+ or HR-)
15
Source : http://www.breastcancer.org/symptoms/diagnosis/hormone_status
V. Tests on tumor cells
• Human epidermal growth factor type 2 receptor
(HER2/neu) test :
• HER2 positive :
The cancer cells are overexpressing HER2.
• HER2 negative :
The cancer cells are not overexpressing HER2.
16
Source : http://www.cancer.ca/en/cancer-information/diagnosis-and-treatment/tests-and-procedures/her2-statustesting/?region=on#ixzz3QKDrJAiJ
Hormonal status
HER2 overexpression
Poor prognostic and
predictive factor
• PR+/ER+
• PR+/ER• PR-/ER+
HER2HR+
HER2+
HER2+
• PR-/ER-
HRHER2-  triple negative
17
 Different hormonal status/HER2 status = several appropriate treatment
VI. Treatments
Radiation therapy
Surgery
Chemotherapy
Hormonotherapy
Targeted therapy
18
VI. Treatments – Targeted therapy
Tyrosine kinase inhibitors
Monoclonal
antibodies
Signal
transduction
inhibitors
19
VI. Treatments –Targeted therapy
 Targeted Therapy - HER2+
• Trastuzumab (Herceptin)
• FDA approval in 1998
• Humanized monoclonal anti- body targeting HER2
• Increases survival in HER2 positive metastatic and early breast
cancer patients, especially when given in combination with
chemotherapy.
20
Source :Alexandra Canonici, Merel Gijsen, Maeve Mullooly, Neratinib overcomes
trastuzumab resistance in HER2 amplified breast cancer, Oncotarget. 2013 Oct
Mecanism of action of Herceptin
21
Treatments
Issue : Emergence of Trastuzumab resistance (60 to 70 % as
monotherapy and 30 % in combination with chemotherapy),
because other signaling pathways are involved.
That’s why, it lead to the development of new targeted
therapy targeting or not HER2
- New monoclonal antibodies
- New tyrosine kinase inhibitors
- PARP inhibitors
Many clinical trials are underway to test these drugs like
I- SPY.
22
Clinical trial in Oncology
23
I. Old Concept vs New Concept
One Drug
Complex
Mechanism
One
Disease
≠ Stages
One
Population
≠ Subgroups
SCREENING
Targeted
Therapy
≠ Types
(Biomarkers…)
≠ Responses
to Treatment
++
Clinical Trials
Failed
24
I. Old Concept vs New Concept
Drug A
Drug C
Drug B
Drug D Drug E
Pool of Patients
Biomarker A
Couples Biomarker / Drug
SCREENINGBiomarker E
Biomarker C
Biomarker B
Biomarker D
25
II. Endpoints in Oncology
• Overall Survival (OS)
• The preferred endpoint of Phase III clinical trials by FDA
= the time from randomization or initiation of treatment to
patient death, irrespective of cause
• Limits ?
• Time
•
•
•
•
Increase of effective treatments available
Breast cancer, « relative high » expectation of life
much longer follow-up (the number of deaths requires)
Take many time to approve drug
• Public Health
• unmet need for patients  Loss of opportunity
•
Cost
•
increase the cost of clinical trials
Source : Endpoints in cancer clinical trials, F. Fiteni, V. Westeel, Journal of Visceral Surgery (2014) 151, 17—2, Elsevier Masson
26
II. Endpoints in Oncology
Time
EFS
DFS/RFS
Middle term Prediction
PREDICTION WITH
SURROGATE ENDPOINTS
OS
Long term Prediction
27
II. Endpoints in Oncology
• SURROGATE ENDPOINTS :
• Could be assessed earlier
• EFS = Event Free Survival
In cancer, the length of time after primary treatment for a cancer ends that the patient remains
free of certain complications or events that
the treatment was
intended to prevent or delay. These
Tumor-centered
Endpoints
events may include the return of the cancer or the onset of certain symptoms, such as bone pain from
cancer that has spread to the bone.  To see how well new treatment works
• DFS = Disease Free Survival
In cancer, the length of time after primary treatment for a cancer ends that the patient survives
without any signs or symptoms of that cancer.
Can we find earlier endpoints ?
• RFS = Relapse-free Survival
In cancer, the length of time after primary treatment for a cancer ends that the patients remains
free of any event, irrespective of cause. Recurrence of or death from the same cancer and all
YES
treatment-related deaths or deaths from
other causes are events. Second primary same cancers
and other primary cancers are ignored, and loss to follow-up is censored.
Source : National cancer institute
28
II. Endpoints in Oncology
Time
pCR
Short term Prediction
EFS
Middle term Prediction
DFS/RFS
OS
Long term Prediction
29
PREDICTION WITH
SURROGATE ENDPOINTS
II. Endpoints in Oncology
• pCR : Pathologic Complete Response
• Absence of invasive tumor in both breast and axillary
lymph nodes after neoadjuvant therapy (NAC)
NeoAdjuvant
Adjuvant
Surgery
Adjuvant
Drugs given to reduce the risk of breast cancer recurrence after
defenitive breast surgery
• Limit of pCR: Biopsies needed !
Neoadjuvant
Source : Journal
of clinical oncology
Reserved
for patients with locally advanced breast cancer in
Source : Oncology Letters , Analysis of complete response by MRI following neoadjuvant chemotherapy predicts
the goal
wasfortomolecular
rendersubtypes
largeofbreast
cancers
operable
pathological whom
tumor responses
differently
breast cancer;Yuji
Hayashi,
Hiroyuki Takei; Satoshi Nozu
30
III. Accelerated Approval
Goal : to market highly effective drugs sooner
Target patients at high risk for recurrence and death
Surrogate Endpoint : pCR
NOW : Scientific reasons to consider neoadjuvant treatment for early stage
breast cancer And could avoid mastectomy
31
III. Accelerated Approval
• For each Type of Treatments … Differents Endpoints
NeoAdjuvant
pCR
EFS
Adjuvant
Surgery
DFS
OS
32
Accelerated Approval
Process
33
•
Source : FDA,Considerations for Neoadjuvant Breast Cancer Trials to Support Accelerated Approval. Tatiana M.
Prowell, M.D.
Adjuvant vs Neoadjuvant
Source : FDA, Pathologic Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast
Cancer: Use of an Endpoint to Support Accelerated Approval , Tatiana Prowell, MD
•
,
34
I SPY
Breast Cancer
(High Risk )
New
Treatment
Find
Couple
Biomarker(s)/Drug
Adaptive Trial
+
Accelerated approval
Neoadjuvant
&
Adjuvant
35
Concept of I SPY
Biomarkers Phase
• Find biomarkers
• Validation
correlation
pCR/RFS
Screening Phase
Confirmatory Phase
I-SPY 2
• Neoadjuvant
• pCR to predict
EFS
• Neoadjuvant +
Adjuvant
• DFS to predict
OS
I-SPY 1
I-SPY 3
Accelerated
approval
Full
approval
37
I-SPY 1
38
Not to evaluate drugs !
- Study differents biomarkers profiles
- Correlate pCR and RFS
- pCR is depending on biomarkers
 To prepare I-SPY 2
39
I-SPY 1 TRIAL
Investigation of Serial Studies to Predict Your Therapeutic
Response with Imaging and molecular Analysis
40
I-SPY 1
• Collecting molecular and imaging data
• 2 protocols
• Aim 1: identify indicators of response to neoadjuvant
chemotherapy
• Response to therapy predict RFS ?
• Develop a resource of clinical, molecular, genetic, imaging
biomarker data
• Aim 2 : Define relationship between biomarkers and RFS
41
Source : http://www.ispy2trial.org/about/background-i-spy-1-trial
Journal of clinical oncology
I-SPY 1 - Sum up
I-Spy 1
Aim 1 :
Aim 2 :
Indicators of
response
Relationship
Biomarkers – RFS ?
pCR/imaging data
predict RFS ?
Develop Data
42
I-SPY 1 - Design
Accrued
(N = 237)
Exclusion various reasons
(N = 16 )
Available for analysis
(N = 221)
No surgery
(N = 6 )
With pathology
assessment after
neoadjuvant
chemotherapy
(N = 215)
No HR/HER2 status
(N = 6 )
With HR/HER2 status
(N = 210)
43
I-SPY 1 - Design
221
patients
Surgery
Biopsy => biomarkers
Magnetic resonance images : MR
Anthracycline based chemotherapy
44
I-SPY 1
• Samples tested (biopsies) :
• ER (Estrogen receptor) status
• PR (Progesteron receptor) status
• HER2 status overexpression
= HR status
• 3 subtypes :
• HR +/HER2 –
• HR -/HER2 – (triple negative)
• HER2 + ( HR-/ HER2+ and HR+ /HER2+)
• pCR assessed
45
Source : Journal of clinical oncology
Non Significatif
Source : Journal of clinical oncology
46
I-SPY 1 – Results
• Patients with high risk invasive breast cancer :
• 3 years RFS
• Least sensitive : HR+/HER2-
• Higher rate of pCR : HR-/HER2+ (45%)
• Lower rate of pCR : HR+/HER2- (9%)
pCR predict favorable RFS
• Hazard ratio for RFS :
•
•
•
•
pCR vs no pCR = 0,29
HR+/HER2- : 0,00 NS
HR-/HER2- : 0,25
HER2+ : 0,14
Source : Journal of clinical oncology
47
I-SPY 1 – Conclusion
48
I-SPY 2 – Adaptive Design
49
I-SPY2
Investigation of Serial Studies to PredictYour Therapeutic
Response With Imaging And moLecularAnalysis 2
• Find biomarkers
• Validation
correlation
pCR/RFS
I-SPY 1
Biomarkers Phase
To predict a probability
of success in phase III
I-SPY 2
• Neoadjuvant
• pCR to predict
EFS
Screening Phase
50
I-SPY2
Investigation of Serial Studies to PredictYour Therapeutic
Response With Imaging And moLecularAnalysis 2
 Sponsor : QuantumLeap Healthcare Collaborative
 Launched in March 2010
 Estimated Study Completion Date : Novembre 2015
 Estimated Enrollment : 800 patients
 Primary outcome measures:
 Probability of pathologic complete response (pCR)
 Secondary outcome measures :
 Three and five years Relapse-Free-Survival (RFS) and Overall Survival (OS)
 Incidence of (serious) adverse events
51
https://clinicaltrials.gov/ct2/show/NCT01042379
I-SPY 2 - Eligibility
 High probability of recurrence (classifying, exploratory
biomarkers…
 Stage II - III
 No prior cytotoxic regimens
 ≥ 2.5cm invasive tumor
 One of three criteria :
High risk score on MammaPrint test
Low-risk score on MammaPrint test BUT Estrogen
Receptor (ER) negative tumor
Low-risk score on MammaPrint test BUT ER
positive AND HER2 positive tumor.
(IHC, FISH and TargetPrint)
Genetic signatures’ identification (10 identified)
https://clinicaltrials.gov/ct2/show/NCT01042379
52
I-SPY 2 - MammaPrint®
53
http://middleeasthospital.com/?page_id=964
I-SPY 2 - Design
High Risk
HR+
Her2+
U.High
Risk
High Risk
HR-
U.High
Risk
High Risk
Her2-
HR-
U.High
Risk
54
I-SPY 2 - Design
56
I-SPY 2 - Design
Clinicaltrial.gov
57
Berry, D. A. Nat. Rev. Clin. Oncol. 9, 199-207 (2012); published online 8 November 2011;
I-SPY 2 - Design
58
I-SPY 2 - Design
59
I-SPY 2 - Design
 « Classifying » biomarkers:
FDA-approved biomarkers for breast cancer : HR, Her2
status
 « Qualifying » biomarkers:
Not FDA-approved
BUT useful for supporting utility
 « Exploratory » biomarkers :
Not FDA-approved
Predictive or prognostic values
 10 possible genetic signatures (pre-identified):
Correlation between pCR and EACH possible genetic
signature.
60
I-SPY 2 - Bayesian model
 How experiment may change our opinion on an outcome?
 a priori opinion : distribution of possible values for an outcome (pCR)
Combined with…
 Evidence from data during the clinical trial (distribution of measured values)
To obtain…
 a posteriori opinion : distribution of combined values for an outcome (pCR)
61
Dr. Marie-Cécile Le Deley – Essais cliniques dans les pathologies rares : quoi de neuf docteur? – Université Paris-Sud 11 – 26/05/2010
I-SPY 2 - Bayesian model
Quantity of informations
62
Dr. Marie-Cécile Le Deley – Essais cliniques dans les pathologies rares : quoi de neuf docteur? – Université Paris-Sud 11 – 26/05/2010
I-SPY 2 - Bayesian model
 For each compound : probability of success in a Phase III trial for each
genetic signature
 If a compound achieves an 85% probability of success (statistically
superior to SOC) : qualified for a phase III trial (Neoadjuvant / Adjuvant) for
a well defined population (specific genetic signature).
 300 patients required
 After only 20 patients in a given subgroup : futility analysis
No-go decision
Futility analysis
(compound
dropped)
(given subgroup)
Patients added
63
I-SPY 2 - Bayesian model : adaptive
randomization
64
http://www.thecco.net/article/view/4210/5898
I-SPY 2 - Bayesian model : adaptive
randomization
65
Sources : http://www.onclive.com/publications/Oncology-live/2014/March-2014/I-SPY-2-Designer-Describes-Programs-ManyInnovations
ADAPTIVE RANDOMIZATION
I-SPY 2 - Adaptive Design
66
I-SPY 2 - Adaptive Design – Regulatory
aspects
Prospective
modifications
Treated arm
added / dropped
Statistical
aspects (study
power, futility
analysis…)
Adaptation of
patient
population
Risk of bias
Adaptive
randomization
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM201790.pdf
67
I-SPY 2 - Results
 At least 60 patients before a determination of a probability of success in a phase
III trial.
 Neratinib (Puma Biotechnology) : Addition of Neratinib has 94,7% probability
of success (p-value : 0,053) in a phase III trial (neoadjuvant / adjuvant) in HER2+ /
HR-, statistically superior to SOC.
 SOC : (paclitaxel + trastuzumab) / (doxorubicin + cyclophosphamide)
 Probability based on 115 patients : qualified for I-SPY3
 Veliparib (AbbVie) : 92% de probability of success in a phase III trial (neoadjuvant
/ adjuvant) in HER2- / HR – (triple-negative breast cancer), statiscally superior to
SOC.
 Probability based on 71 patients : qualified for a phase III trial managed by
AbbVie.
 Elements of comparison:
 « 60 - 70 % of phase III cancer trials fail » (Investigator)
http://www.pumabiotechnology.com/pr20131204.html
68
I-SPY 2 - Several benefits
 Reduce the number of patients
 Reduce loss of opportunity
 Improve innovation
 Improve success rate
 Improve efficiency
 Reduce time
70
 Reduce costs
« Quizz Break » session
Which endpoint is the gold standard in Oncology ?
A. pCR : Pathologic Complete Response
B. EFS : Event Free Survival
C. DFS : Disease Free Survival
D. OS : Overall Survival
After which treatment pCR is measured ?
A. Neoadjuvant
B. Adjuvant
Which method is essential to determine the grade of pCR?
A. Clinical Symptoms
B. MRI
C. Biopsy
71
« Quizz Break » session
What are the objectives of I SPY 1 ?
A. To test new drugs
B. Select biomarkers
C. Correlate pCR and EFS
72
« Quizz Break » session
I-SPY 2 is a pivotal clinical trial to obtain an Marketing
Authorization.
A. Right
B. Wrong
For each treated arm corresponds a placebo arm.
A. Right
B. Wrong
Futility analysis after futility analysis, new patients included have a
greater probability to receive an efficacy treatment corresponding
to their genetic signatures.
A. Right
B. Wrong
73
« Quizz Break » session
Only drugs described in the initial clinical trial request for
authorization are allowed to be evaluated in I-SPY 2.
A : Right
B : Wrong
74
But… A current controversy :
Altto/NeoAltto
75
Limit of I-SPY ? NeoAltto/Altto
Clinical Trial : In women with HER2+ breast cancer
Investigational compound = Lapatinib
• Neoadjuvant
• pCR
NeoAltto
Altto
• Neoadjuvant
+ Adjuvant
• DFS
• Overall
Survival
Results
76
Limit of I-SPY ? NeoAltto/Altto
 1st STEP
Lapatinib adding to standard Traztuzumab in
neoadjuvant phase give a higher pCR rates than the
standard treatment alone.
 Prediction of an improved survival (better OS) ?
Good results of pCR
77
Limit of I-SPY ? NeoAltto/Altto
 2st STEP
In adjuvant phase, there is no statistically significant
difference in DFS between Lapatinib adding to standard
treatment and standard treatment alone.
 Results of higher pCR doesn’t lead to improvement of
DFS
FAILED
Source : ALTTO Fallout Focuses Debate on the Meaning of pCR. Medscape. Jul 29, 2014.
78
Limit of I-SPY ? NeoAltto/Altto
OS is not improve with the addition of
Lapatinib
• These results question the prognosis
value of pCR .
• In fact, in this case the pCR was not a
good criteria to predict survival.
• But to have a drug approval, OS
represents the only criteria
recognize by the FDA.
79
Source : ALTTO Fallout Focuses Debate on the Meaning of pCR. Medscape. Jul 29, 2014.
Limits of I-SPY ? NeoAltto/Altto
 Nevertheless :
This case cannot be applied generally. In fact, many reasons can
explain that Altto failed :
- It can be due to the molecule (Lapatinib)
- The marker could mutate
- They are inconsistencies in the 2 trial populations, so it’s difficult
to extrapolate the findings of one trial to the other :
- differences in estrogen receptor status,
- node status,
- duration and sequence of therapy.
80
Source : ALTTO Fallout Focuses Debate on the Meaning of pCR. Medscape. Jul 29, 2014.
Explanations of Failure with
Adjuvant ?
81
Source FDA
Limit of I-SPY ? NeoAltto/Altto
Conclusion :
- We cannot conclude that pCR is not a surrogate endpoint
- 1 clinical trial is not sufficient to stop this type of design
I-SPY 3 will start
82
I-SPY 3
83
Screening Phase
Confirmatory Phase
Biomarkers Phase
• Find biomarkers
• Validation
correlation
pCR/RFS
I-SPY 1
I-SPY 2
• Neoadjuvant
• pCR to predict
EFS
• Neoadjuvant +
Adjuvant
• DFS to predict
OS
I-SPY 3
Confirm results of I-SPY 2
Obtain FDA approval
84
I-SPY 3
 I-SPY 3 will be open to graduates of I-SPY 2 and other Phase IIIready candidates
 Master protocol has been discussed with FDA
 Difference with I-SPY 2 : study will be run not by academics, but by
a newly launched for-profit company that will specialize in adaptive
Phase III studies
 I-SPY 3 will be powered to measure :
- pCR as a co-primary surrogate endpoint and
- disease-free survival (DFS) as the co-primary confirmatory
endpoint.
 According to FDA’s 2014 guidance, accelerated approval could be
granted based on pCR and full approval could be based on the later
read out of DFS from a single trial.
85
I-SPY 3
Launch in 2014
Reminder : Investigational drugs progress to phase III if they
have a higher estimated pCR rate than the control group and
meet the Bayesian predictive probability treshold for success
in a 300 patient phase III trial in a least one of 10 pre-defined
biomarker signatures.
 Compared to a conventional trial fewer patients needed
Goal of the study : Obtain FDA approval for these
treatments in the 2 indications  neoadjuvant and
adjuvant
86
I-SPY 3 – Design
Initial
Biopsie
Neoadjuvant
On Study
Surgery
Randomisation
Adjuvant
1 biomarker profile
 1 drug *
FULL
APPROVAL
DFS (+ OS)
pCR (+ EFS)
ACCELERATE
APPROVAL
87
*10 pre-defined
biomarker signatures
Accelerated Approval Process
In DFS or OS
88
I-SPY 3
After 300 patients included in neoadjuvant phase :
If good pCR rates  Accelerated approval is possible
(time saving)
Allows to treat other patients earlier
without their inclusion in a clinical trial
And after 3 years if DFS confirm pCR results  Full
approval
“ For confirmatory trials conducted in the adjuvant setting, in which
patients are presumed to be free of disease at the time of
randomization, the long-term clinical benefit endpoints for regular
approval should be termed DFS or OS.”
Source : Guidance for Industry, Pathological Complete Response in Neoadjuvant Treatment of HighRisk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval
89
I SPY 3
For the moment :
2 Small molecules but only one include in I-SPY 3 trials :
• Neratinib : Puma Biotechnology
• Veliparib : Abbvie conducts is own phase 3
90
I-SPY 3 - Neratinib
• Small molecule tyrosine kinase inhibitor
 irreversible pan-HER inhibitor (HER1, HER2 and HER4) with
potential antineoplastic activity
• Highly effective agent in the HER2+ subset, especially
HER2+/HR- tumors
6,7-disubstituted-4-anilinoquinoline-3carbonitrile
91
I-SPY 3 -Veliparib
• A poly(ADP-ribose) polymerase (PARP) -1 and -2 inhibitor
with chemosensitizing and antitumor activities.
• Highly effective in triple negative breast cancer
2-((R)-2-Methylpyrrolidin-2-yl)-1Hbenzimidazole-4-carboxamide
94
I-SPY 3 -Veliparib
What are PARPs (poly (adenosine diphosphate [ADP])-ribose)
polymerases) ?
95
Source : Tinoco G, Warsch S, Glück S, Avancha K, Montero AJ. Treating Breast Cancer in the 21st Century: Emerging Biological
Therapies. J Cancer 2013; 4(2):117-132. doi:10.7150/jca.4925
I SPY 3 -Veliparib
Mechanism of action
PARP inhibitor
96
Source : Kapila Ratnam and Jennifer A. Low , Current Development of Clinical Inhibitors of Poly(ADP-Ribose) Polymerase in Oncology
Clin Cancer Res March 1, 2007
• Find biomarkers
• Validation
correlation
pCR/RFS
I-SPY 1
I-SPY 2
• Neoadjuvant
• pCR to predict
EFS
• Neoadjuvant +
Adjuvant
• DFS to predict
OS
I-SPY 3
OS is now determined…
But the only endpoint ?
97
Patient First
98
Other Endpoints ? Other Outcomes?
• In contrary to pCR, EFS, DFS : Tumor-centered
Endpoints (Biopsies)
Health-related Quality of life (QoL)
• Levels of physical, mental, social, and patient
satisfaction with treatment as well as treatment
outcome
99
How’s this ?
• QoL questionnaires for cancer patients are
available: (e.g)
• the European Organization for Research and
Treatment of Cancer QoL Questionnaire (EORTC
QLQ-C30),
• the Functional Assessment of Cancer Therapy
(FACT),
• the Rotterdam Symptom Checklist (RSCL)
• the Functional Living Index- Cancer (FLIC).
100
What else ?
• In addition to this questionnaires
• FDA develop a program called :
 Patient focused drug development
101
Patient focused drug
development
102
http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm347317.htm
103
Patient focused drug
development
• Development of PFDD for lung cancer
• Meeting : June 28, 2013
104
http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM379698.pdf
PFDD - Lung cancer
• Opportunity for FDA to hear directly from patients
• 2 key topics :
• Disease symptoms and daily impacts that matter most to
patients
• Patient perspective on treatment of this condition
105
http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM379698.pdf
PFDD – Results
• Difficult to distinguish between symptoms of disease and side
effects of cancer treatments
• Fatigue, breathing difficulties, chronic pain
• Effects of treatment can continue long after the treatment has
stopped
• Impact lung cancer has on patients’ lives varies widely
• Normal life vs debilitating
• Different cases :
• Higher priority : prolonging life
• Higher priority : better quality of life
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http://www.fda.gov
PFDD – Conclusion
• In conclusion :
• Experience is individual
• Depending on :
•
•
•
•
The patient’s disease manifestation
The treatment options available
Their experiences with treatment
Their personal circumstances
107
http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM379698.pdf
What about EMA ?
108
•
•
•
•
The same definition as FDA for pCR
pCR predict EFS (middle term) and OS (long term)
pCR rates differs according to molecular subtypes
Stronger association between pCR and EFS in patient with agressive
tumour subtypes compared to patients with less agressive tumours
Source : http://www.ema.europa.eu/ema/
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Activities where patients and
consumers are involved
EMA
• Scientific Advice Working Party : SAWP
• Orphan medicines : since 2005
• Medicines for non-rare indications : January 2013
• Share their « real-life » perspective and experience with SAWP
and pharmaceutical companies
• Patients at CHMP : Committee for Medicinal Products for
Human Use
• Beginning in September 2014
• Patients are directly include in the benefit-risk evaluation of
medicines with CHMP
Source : http://www.ema.europa.eu/ema/
110
Conclusion
111
Take Home message
• Adaptive design :
•
•
•
•
Several drugs can be tested in the same time
Identification of biomarkers/drugs couples
Adaptive Randomization (Bayesian model)
Probability of success in Phase III trial
• Surrogate endpoints allow accelerated approval
• New way of thinking for other diseases!
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I-SPY 1
GLOBAL PROCESS
OF I-SPY TRIAL
I-SPY 2
I-SPY 3
113
Thank you for your attention!
114
References
https://clinicaltrials.gov/ct2/show/NCT01042379
http://www.thecco.net/article/view/4210/5898
Tatiana M. Prowell - Considerations for Neoadjuvant Breast Cancer Trials to Support Accelerated Approval – FDADr. Marie-Cécile Le Deley – Essais cliniques dans les pathologies rares : quoi de neuf docteur? – Université Paris-Sud 11 – 26/05/2010
http://middleeasthospital.com/?page_id=964
National Cancer Institute: PDQ® Breast Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last
modified <02/15/2015>. Available at: http://cancer.gov/cancertopics/pdq/treatment/breast/Patient. Accessed
<02/15/2015>
Source : http://www.breastcancer.org/symptoms/diagnosis/hormone_status
Source : http://www.cancer.ca/en/cancer-information/diagnosis-and-treatment/tests-and-procedures/her2-statustesting/?region=on#ixzz3QKDrJAiJ
•
•
•
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• Endpoints in cancer clinical trials, F. Fiteni, V. Westeel, Journal of Visceral Surgery (2014) 151, 17—2, Elsevier Masson
• National cancer institute
Journal of clinical oncology
Oncology Letters , Analysis of complete response by MRI following neoadjuvant chemotherapy predicts pathological
tumor responses differently for molecular subtypes of breast cancer;Yuji Hayashi, Hiroyuki Takei; Satoshi Nozu
http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM379698.pdf
Source : http://www.ema.europa.eu/ema/
Pathologic complete response predicts recurrence-free survival more effectively by cancer subset, Esserman LJ, J Clin
Oncol. 2012 Sep 10;30(26):3242-9. doi: 10.1200/JCO.2011.39.2779. Epub 2012 May 29
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References
•
•
•
•
•
•
•
Source : V. Diéras, Nouvelles thérapeutiques ciblant le récepteur HER2-New anti-HER2 therapeutic strategies, La
Lettre du Cancérologue • Vol. XIX - n° 9 - novembre 2010
Source :Alexandra Canonici, Merel Gijsen, Maeve Mullooly, Neratinib overcomes trastuzumab resistance in HER2
amplified breast cancer, Oncotarget. 2013 Oct
Source : ALTTO Fallout Focuses Debate on the Meaning of pCR. Medscape. Jul 29, 2014
Source : http://www.ema.europa.eu/ema
Source : Tinoco G, Warsch S, Glück S, Avancha K, Montero AJ. Treating Breast Cancer in the 21st Century:
Emerging Biological Therapies. J Cancer 2013; 4(2):117-132. doi:10.7150/jca.4925
Source : Kapila Ratnam and Jennifer A. Low , Current Development of Clinical Inhibitors of Poly(ADP-Ribose)
Polymerase in Oncology
Clin Cancer Res March 1, 2007
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