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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 106 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/ 109 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! 112 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 • • • • • • 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 29 115 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 116