INTRODUCTION TO I-SPY2. May 15, 2009 Jane Perlmutter I-SPY2 Advocate Lead

Transcription

1 INTRODUCTION TO I-SPY2 May 15, 2009 Jane Perlmutter I-SPY2 Advocate Lead

2 Topics Introduction: From I-SPY1 to I-SPY2 I-SPY2 Overall Design Characteristics I-SPY2 Details Agents Biomarkers Trial Sites Summary & Q & A 2

3 Neo-Adjuvant Treatment: Systemic Treatment Before Surgery Patient Perspective Allows more breast conservation Provides time for planning prior to surgery Identifies patients with high risk of recurrence and provides opportunity for additional treatments 3 Researcher Perspective Provides an opportunity to rapidly investigate the impact of new therapies Provides an opportunity to acquire high quality tissue for molecular analysis before, during and after treatment

4 Key Trial Characteristics Primary Goal I-SPY1 Identify the best MRI and molecular markers of early response to systemic treatment for breast cancer. I-SPY2 Rapidly identify promising new agents and the patients who are most likely to benefit from them. Sponsors CALGB, ACRIN, InterSPORE FNIH, Biomarker Consortium, ACRIN Trial Design Patient Population Primary Endpoint Start/End Date Neo-adjuvant, single-arm design (non-treatment trial) ~400 Stage III breast cancer patients 3-year disease free survival following surgery Randomized, adaptive, ne0-adjuvant design (Phase II treatment trial) ~ 800 breast cancer patients at high risk of recurrence Pathological complete response (pcr) at time of surgery Fall

5 I-SPY2 Innovation Unique partnerships involving all stakeholders Innovative process to assess new agents Innovative process to learn about biomarkers Infrastructure that can be leveraged in other trials Innovative engagement of advocates throughout I-SPY2 For more detail see DCLG Presentation at 5

6 Topics Introduction: From I-SPY1 to I-SPY2 I-SPY2 Overall Design Characteristics I-SPY2 Details Biomarkers Agents Trial Sites Summary & Q & A 6

7 Trial Design Working Group Scientific Chair Don Berry (MD Anderson) Advocates Laura Nikolaides Jane Perlmutter 7

8 PICO:Trial Design Components Design Component P atients I nvestigational Intervention C ontrol O utcome I-SPY-2 Breast Cancer patients at high risk of recurrence MammaPrint High (~30% chance of metastases within 10 years) Investigational agents that have adequate safety data when paired with a Taxane, Plus all control interventions Taxane (12 weekly cycles) with Herceptin if HER2+ Followed by Anthracycline (4 cycles) Followed by surgery (lumpectomy or mastectomy) Core biopsies (3) MRIs (4) Primary: pathological complete response (pcr) Secondary: DFS, MRIs, biomarkers 8

9 I-SPY2 Patient Schedule Screening Informed Consent Treatment Informed Consent Taxane +/ Investigational Agent +/-Herceptin based on HER2 status (12 weekly) AC (4 cycles) Eligible? Register & On Study Surgery Biopsy, Blood & MRI MRI MRI MRI Biopsy, MRI Blood Tissue 9

10 Design Goals Accurate Minimize errors Efficient Rapid, fewer patients, less costly Ethical Provide superior treatment for patients in trial Smart Continuing to learn during the trial Flexible Adapt as more is learned 10

11 Randomized, Adaptive Design: Why They re Good Patient Perspective Generally provides patients on trial with better treatment 80% of patients will receive an investigational agent Assigns agents to patients based on their individual biology Researcher Perspective Assesses new agents accurately Assesses as many agents as possible with the fewest number of patients and shortest amount of time 11

12 Randomized Adaptive Trial Designs: What they Are Monitor data as it is being collected Change design characteristics, based on the data that are accruing, but Must specify rules for change prior to starting the trial Randomize patients to different arms, but May change the proportion of patients assigned to different arms 12

13 Assignment to Treatment Based on Biomarkers Prevalence Hi-MP1 Hi-MP2 (from I- SPY1) HER2+ HR+ HR- HR+ HR- 16% 7% 4% 10% HER2-23% 6% 6% 28% HR+ = ER+ and/or PR+ HR- = ER- and PR- HI-MP = MammaPrint High divided equally into moderate High (1) and Highest Risk (2) 13

14 Probability of Achieving pcr in Control Group (from I-SPY 1) %pcr (from I- SPY1) HER2+ Hi-MP1 Hi-MP2 HR+ HR- HR+ HR- 47% 67% 35% 55% HER2-25% 43% 17% 32% HR+ = ER+ and/or PR+ HR- = ER- and PR- HI-MP = MammaPrint High 14

15 Topics Introduction: From I-SPY1 to I-SPY2 I-SPY2 Overall Design Characteristics I-SPY2 Details Agents Biomarkers Trial Sites Summary & Q & A 15

16 Agents Working Group Scientific Chair Doug Yee (U. of Minnesota) Advocates Susie Brain Sandra Finestone Nancy Lambert 16

17 Hallmarks of Cancer From D. Hanahan & R.Weingberg(2001) The Hallmarks of Cancer, Cell. Vol. 100, pp

18 Targeted Therapies Herceptin FasL TRAIL HER2 IGFR EGFR Tumor Cell Angiopoietin-1 VEGF Endothelial Cell TIE P PI3K PIP 2 PIP 3 PTEN Taxanes Cytoskeletal Damage Caspase-2 Activated AKT RAS/RAF Protein Damage DNA Damage HSP90 Nucleus AC Chemo tbid Bax Bcl-2 Bak mito Bcl-xL MDM2 p53 MEK MET DNA Repair Growth, Proliferation Cell Cycle Arrest Apoptosis 18 Survival, Metabolism Angiogenesis Invasion & Metastisis

19 Agent Selection 65 Pipeline Agents Identified 16 Agent Classes 8 Pathways Grouped Prioritized Selected Prioritize by pathways of interest Only include agents with adequate safety date Select best agent from among interested manufacturers One Agent per class ~10 Investigational Agents will be Tested in I-SPY2 19

20 Proposed New Agents Tier 1 being considered for Fall, 2009 IGFR inhibitors MTOR plus antiangiogenesis drugs HER2 target agents Death pathway agents (APO/TRAIL) cmet inhibitors Mulitkinases inhibitors Tier 2 being considered for later introduction PI2kinase inhibitors Hedgehog inhibitors Notch Inhibitors AKT inhibitors MEK combinations

21 Process: Adapting Agents Add New Agent Select Initial Investigational Agents Futility? No Yes Flunk-out Randomize Patients to Systemic Treatment Using Current Proportion* Superior to Standard? No Adequately Tested? Yes Yes Graduate Drop-out No Following Each Patient s Surgery Assess Outcomes Modify Randomization Assignment 21 ** Initial randomization proportion assigns equally to investigational and standard treatment

22 Investigational Agent Report Card Describes: How many patients who received the agent had a pcr, compared to patients who received the standard of care, broken down by biomarker profile The likelihood of a successful phase 3 trial with various subgroups of patients Provided to the manufacturer when their agent is graduated, flunked, or dropped Most information will also be available publically at the same time 22

23 Biomarkers Working Group Scientific Chair Laura Van t Veer (UCSF, Netherlands) Advocates Michelle Esser Cindy Geoghegan* Susan Samson 23

24 Biomarkers: Predictors of Beneficial Therapy THE HOPE: personalized medicine Based on biomarkers, only provide therapies to patients who will benefit from them THE REALITY: In breast cancer we have some good biomarkers (i.e., ER and HER2) We are still a long way from the hope We need more and better biomarkers 24

25 I-SPY2 Biomarkers Classifier biomarkers Validated biomarkers that will be used to assign agents to patients Qualifying biomarkers Show promise for predicting response to standard agents or novel therapies Performed under CLIA conditions I-SPY2 data may be used for FDA submissions Exploratory biomarkers Reflect next generation technology I-SPY2 data will provide evidence of their potential value 25

26 I-SPY2 Biomarkers Category Classifying Qualifying Exploratory Examples ER, PR, HER2 by IHC & FISH MammaPrint Panomic s assay RPMA pathway markers RCB DNA methylation Exon capture sequencing RPMA pathway discovery & profiling Copy number & NP chip Pharmacogenomics (germline SNP) mirna Panomics 2 nd generation Circulating tumor cells MRI SER segmentation 26

27 Process: Classifier Biomarker Selection Select Initial Classifier Biomarkers (ER, PR, HER2, MammaPrint) Stratify Patients to Treatments Based on Classifiers Continuously Model Outcomes by Biomarkers Superior Biomarkers? 27 Yes No Revise Classifier Biomarkers Maintain Classifier Biomarkers

28 Biomarkers: Early Endpoints THE HOPE: Early and/or surrogate endpoints will allow us to: Complete trials more rapidly Change treatments early to ensure patients only receive treatments that are helping them THE REALITY: In breast cancer, no surrogate endpoints have been approved by FDA, but pcr can be used in phase 2 neoadjuvant trials Trials like I-SPY2 may lead to approval of biomarkers as surrogate endpoints 28

29 Clinical Trial Operations Working Group Scientific Chair Angie DeMichelle (University of Pennsylvania) Advocates Barbara Beckwith Cindy Irwin Bev Parker* 29

30 Process: Site Selection Qualification Criteria Include: >20 patients expected per year Appropriate MRI equipment Enthusiastic, qualified investigators Select Potential Sites Distribute Site Qualification Questionnaire Qualified? Yes Engage & Train Investigators Submit Protocol to Local IRB Open Trial 30

31 I-SPY2 Likey Sites 1. U Ca San Francisco 2. Emory Winship 3. U. Kansas Medical Center 4. U Minnesota 5. Mayo 6. U Penn 7. MD Anderson 8. George Mason 31

32 Other Potential Sites 1. U Alabama at Birmingham 2. U of Colorado HSC 3. Georgetown 4. U Texas Southwest--Dallas 5. U of Washington 6. Oregon 7. Other 32

33 Topics Introduction: From I-SPY1 to I-SPY2 I-SPY2 Overall Design Characteristics I-SPY2 Details Biomarkers Agents Trial Sites Summary & Q & A 33

34 I-SPY2: A Paradigm Shift in Clinical Trials Adaptive trial design allows efficient learning by adding and dropping investigational agents over the course of the trial Assesses, tests and validates biomarkers to tailor therapy Collaborative, multi-disciplinary team approach (including advocates) Public-private funding partnership 34

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36 Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And molecular analysis I-SPY1 Site translation_research/ispy I-SPY2 Advocate Site ISPYHome.pdf 36