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National Cancer Institute U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Reorganization of NCI’s Clinical Trials: Cancer Research in the Community Setting North Carolina Oncology Society August 23, 2014 Worta McCaskill-Stevens, M.D., M.S. Chief, Community Oncology and Prevention Trials Research Group Division of Cancer Prevention In Collaboration with the Division of Cancer Treatment and Diagnosis and the NCI Center to Reduce Cancer Health Disparities Today’s Discussion • NCI National Clinical Trials Network (NCTN) • History of NCI’s Cancer Research Programs in Community Settings – NCI Community Oncology Research Program (NCORP) 2 NCI launched the Clinical Trials Cooperative Group Program in the late 1950’s Recent NCTN Milestones June 2005 The NCI Clinical Trials Working Group (CTWG) releases “Restructuring the National Cancer Clinical Trials Enterprise.” The consensus report recommends that NCI design a restructured national clinical trials system that is more efficient, better coordinated, and founded on the best science. 2006 NCI asks the Institute of Medicine (IOM) to conduct a consensus study to lend an outside perspective on NCI's ongoing efforts to improve the clinical trials system. June 2007 The NCI Translational Research Working Group (TRWG) releases “Transforming Translation—Harnessing Discovery for Patient and Public Benefit.” The report includes recommendations on improving the translation of research results into clinical practice. March 2010 The NCI Clinical Trials and Translational Research Advisory Committee’s Operational Efficiency Working Group (OEWG) releases “Compressing the Timeline for Cancer Clinical Trial Activation.” The report recommends accelerated timelines for activating and completing NCI Cooperative Group trials and steps to achieve the improvements. April 2010 Based on a request from NCI leadership, the IOM releases “A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program.” The report includes recommendations for improving the quality of NCI’s Clinical Trials Cooperative Group Program. Recent NCORP Milestones November 2010 NCI leaders present an initial plan for transforming the Clinical Trials Cooperative Group Program to the Cooperative Group Chairs. June 2011 The Cancer and Leukemia Group B, the American College of Surgeons Oncology Group, and the North Central Cancer Treatment Group form the Alliance September 2011 The American College of Radiology Imaging Network and the Eastern Cooperative Oncology Group form the ECOG-ACRIN Cancer Research Group. 2011 The National Surgical Adjuvant Breast and Bowel Project, Radiation Therapy Oncology Group, and Gynecologic Oncology Group (GOG) form NRG Oncology. November 2011 The NCI Board of Scientific Advisors approves NCI’s plan to transform the Clinical Trials Cooperative Group Program and a new Request for Application (RFA) for an integrated National Clinical Trials Network (NCTN). The plan includes a consolidated organizational structure with funding for one pediatric group and up to four adult groups. March 2014 NCI launches the National Clinical Trials Network (NCTN): Notice of Awards is sent to 5 U. S. Operations and Statistical Centers, 30 Lead Academic Participating Sites, 7 Integrated Translational Science Awards, 1 Imaging and Radiation Oncology Core Group, and 1 Canadian Collaborating Clinical Trials Network Cooperative Group Treatment Trials Accrual By Trial Phase FY2007 to FY2013 Phase 1 Phase 2 Phase 3 Other/Pilot Phase 1 Phase 2 Phase 3 Other/ Pilot 2007 341 3,947 19,843 488 24,619 2008 276 3,298 21,807 301 25,682 2009 488 2,933 25,370 430 29,221 2010 602 3,548 18,890 406 23,446 2011 544 4,547 14,516 168 19,775 2012 744 16,493 88 21,164 2013 201 3,839 3,571 17,709 329 21,810 Total 3,196 2% 25,683 15% 134,628 81% 2,210 1% 165,717 100% FY Total Cooperative Groups: Structure of Clinical Trials Program Prior to NCTN • 10 decentralized US groups • Operational redundancies identified in IOM Report RTOG ACOSOG ECOG • Less efficient SWOG CALGB NCCTG ECOG NCI & Cancer Trials Support Unit COG Other Centers, CCOPs/MB-CCOPs, & Canadian Collaborating Group LEGEND: Operations Statistics & Data Management NSABP ACRIN GOG Tumor Banks Disease Committees Member Sites NCTN Structure • 5 US groups (4 adult & 1 pediatric) and 1 Canadian group • More centralized functions for operational efficiencies • Will optimize use of scientific innovations • LAPS provide leadership in development and conduct of clinical trials in association with the adult clinical trial groups Canadian Network Group Alliance SWOG CCOP/ NCORP Site Participation NRG NCTN Centralized Functions LEGEND: Centralized Functions: • Centralized Institutional Review Board • Cancer Trials Support Unit • Radiotherapy/Imaging Cores • Common Data Management System Central Hosting 30 Lead Academic Participating Sites (LAPS) Operations COG (pediatric) ECOGACRIN Statistics & Data Management Tumor Banks Member Sites NCI-Developing a National Strategy for Precision Medicine • Advance molecular profiling from research use to the clinic • Select patients based on molecular alterations –Develop portfolio of trials across spectrum from early stage to advanced disease –Screen for molecular features that may predict response to a drug with a given mechanism of action –Analyze tumor specimens at relapse to define mechanisms of resistance –Develop public database that links clinical outcomes with molecular tumor characteristics Historical Timeline for Cancer Clinical Research 1978: Cooperative Group Outreach Program (CGOP) 1982: Community Hospital Oncology Program (CHOP) 1983: Community Oncology Research Program (CCOP) 1987: CCOP RFA includes cancer control & prevention 1990: Minority-Based CCOP (MB-CCOP) NCI Community Clinical Oncology Program Network Accrual 2000 – 2012 Minority accrual: MB-CCOPs: 63% CCOPs: 10% Total accrual 161,000 (40% to NCTN treatment) Participants (in thousands) 9 8 7 6 5 4 3 2 1 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012* Treatment Prevention & Control *9 month annualized data “Researchers have discovered that a drug used to prevent baldness can prevent prostate cancer. The only problem is that there is a side effect. It causes a hairy prostate. Imagine the discussion between a man and his wife.” Achievements • Breast Cancer Prevention - Breast Cancer Prevention Trials (tamoxifen) BCPT - Study of Tamoxifen and Raloxifene (STAR) • Serum and lymphocytes for 90% of 33,000 women; tumor blocks for the majority of cancers, atypical hyperplasia, and lobular carcinoma in-situ • Prostate Cancer Prevention - Prostate Cancer Prevention Trial (finasteride) PCPT - Selenium and Vitamin E Cancer Prevention Trial (SELECT) • Annual serum on 18,000 men for biomarker validation, nutrition and adherence data, and DNA from prostate cancer patients with age and race matched controls • Large portfolio of symptom management and toxicity mitigation studies Symptoms Under Study in Trials Since 1995 Symptom Number of Studies Anorexia & Weight Loss 15 Pain 14 Quality of Life 14 Fatigue 13 Hot Flashes Non-estrogenic Interventions Nausea & Vomiting MASCC Guidelines 12 11 Cognitive Function 11 Mucositis 9 Neuropathy 9 Osteoporosis 8 Diarrhea 7 Smoking Cessation 6 Infection 5 Skin Toxicities 4 Hand & Foot Syndrome 2 Others (e.g., Ascites, Depression, HRT, Sexual Functioning, Stress & Distress, osteonecrosis of jaw etc…) 35 Community Clinical Oncology Program Network: Achievements Chemotherapy Induced Peripheral Neuropathy • CALGB 170601: A phase III double blind trial of duloxetine to treat painful chemotherapy-induced peripheral neuropathy (CIPN). - Enrolled 231 patients who had completed therapy and rated their pain as > 4 (0-10 scale) for 3 months or more. • 59% of patients who were treated with duloxetine reported a decrease in pain compared with 38% of patients treated with placebo Radiation Induced Cognitive Dysfunction • RTOG: Randomized, Phase III, Double-Blind, Placebo-Controlled Trial of Memantine for Prevention of Cognitive Dysfunction in Patients Receiving Whole-Brain Radiotherapy. - Primary endpoint: memory decline at 24 weeks - Sample size 442 patients (80% power to detect an alpha of 0.025) • Memantine was associated with longer time to cognitive decline, in the reduction of recognition memory, executive function. and processing speed in pts receiving WBRT. Historical Timeline 2007: NCI Community Cancer Centers Program Cancer Care Continuum NCORP Vision: Preserve & Enhance Cancer Research in the Community • Build upon clinical trial success of the Community Clinical Oncology Program (CCOP) and Minority-Based CCOP (MB-CCOP) network – Development and conduct of cancer prevention and control trials – Accrual to National Clinical Trials Network (NCTN) treatment and imaging trials – Enrollment of minorities into clinical trials • Expand to include cancer care delivery research (CCDR) • Enhance focus on disparities questions in clinical trials and CCDR studies OVERARCHING GOAL Bring state-of-the art cancer prevention, control, treatment, and imaging trials, as well as CCDR and disparities studies, to 18 individuals in their own communities Why Support Cancer Research in the Community Setting? • Majority of cancer care is provided in the community • Access to larger, more diverse patient populations • Access to “real world” healthcare delivery settings • Tests feasibility of implementing new interventions and processes • Accelerates the uptake of new interventions and processes into routine practice • Enhances potential that outcomes will be broadly applicable in practice Future Research Agenda for Cancer Prevention and Control Trials • Mechanisms of cancer-related symptoms • Biomarkers of risk for treatment-related toxicities • Molecularly targeted agents • Post-treatment surveillance • Management of precancerous lesions • Enhance accrual of racial/ethnic and other under-represented populations • Over-diagnosis and under-diagnosis The Progression of Tumor Growth Size Size at which cancer causes death Size at which cancer causes symptoms Fast Slow This is over-Dx. Very Slow Non-progressive Abnormal cell Time From G. Welch and W. Black, JNCI 2010 Death from other causes NCORP’s Research Areas CCDR is an area of research expansion Why Support Cancer Care Delivery Research in the Community Setting? • Precision medicine increasingly complicates care • Rapidly changing health care system • • • • Affordable Care Act Accountable care organizations Merging of practices Diverse, often fragmented provision of care • Urgent need for evidence about how these changes influence: – Patient outcomes – Disparities in care Dynamic healthcare environment demands a better understanding of routine oncology care delivery 24 Local/State/National Policy Health Care Delivery System Provider Individual • PROMIS/PROCTCAE • MEPS: Improving cancer cost estimation • SEER POC/QOC Health Care Delivery Efforts Across Levels NCORP Cancer Care Delivery Potential Research Agenda • Observational studies - Patterns of care or service utilization data - Alternate organizational structures (e.g., integrated healthcare systems versus free-standing hospitals) - Alternate models for implementing multidisciplinary care planning (e.g. tumor boards versus multi-disciplinary clinics) • Interventional studies - Implementation of new technologies (e.g., decision-making tools) - Incorporation of patient reported information into clinical decision-making - Implementation of new supportive/palliative care models - Introduction of patient navigators targeted at an underserved population Why Focus on Cancer Disparities Research in NCORP? • Persistent disparities – Cancer incidence, mortality, and quality of life – Access to and quality of care • Increase in the number of underserved/underrepresented populations • Determinants of disparities (social factors, health care systems, co-morbidities) disproportionately affect outcomes for underserved populations • Challenging to fully and equitably implement new technologies and targeted therapies for the underserved Need for further research to reduce disparities and improve outcomes for underserved populations across the continuum of care 27 Synergy of Clinical Trials, Care Delivery, and Disparities Research - Cardiotoxicity • Acute and long-term cardiovascular adverse effects from therapy • Prospective studies - Cardiac biomarker study to predict anthracycline cardiac toxicities (BNP, troponin, ECHO, exam) - MD Anderson Research Base - ACE versus blocker/placebo study to prevent trastuzumab LV dysfunction/CHF – Sun Coast Research Base • Epidemiological studies - Population-based, retrospective cohort study of risk of CHF from anthracycline and trastuzumab NCORP Cardiotoxicity Research Future Directions • Clinical trials investigating mechanisms, pathways, genomic and other biomarkers, imaging/diagnostic tools • Longitudinal cohort studies of patients in routine care • Cancer disparities studies to assess differential adverse effects in populations with a higher inherent risk of cardiovascular disease NCORP Milestones April 2012 NCI Division of Cancer Prevention begins the planning of a single community-based research program – NCI Community Oncology Research Program (NCORP). May 2013 NCI Scientific Leadership Leaders approve the NCORP. June 2013 NCI’s Board of Scientific Advisors approves the NCORP concept November 2013 The NCORP Funding Opportunity Announcement released with a due date of January 8, 2014. April- May 2014 Peer Reviews of NCORP Applications August 1, 2014 NCI launches the NCI Community Oncology Research Program NCORP Structure • 34 Community Sites - Accrue participants to NCORP clinical trials and CCDR; NCTN treatment and imaging trials and quality of life studies • 12 Minority/Underserved Community Sites - Accrue participants to NCORP clinical trials and CCDR; NCTN treatment and imaging trials and quality of life studies - Have a patient population comprising at least 30% racial/ethnic minorities or rural residents NCORP Structure • 7 Research Bases - Serve as NCORP research hubs - Design and conduct multi-center cancer prevention, control and screening/posttreatment surveillance clinical trials and Cancer Care Delivery Research (CCDR) studies NCORP Organizational Structure Funding Principles for NCORP Research Bases • Annual infrastructure funding • Study specific support – – – – Protocol development Statistics and data management Trial monitoring and auditing Specimen collection and banking • Per case payments to non-NCORP sites for cancer prevention and control accrual • 5-Year Infrastructure development with shift toward study specific concepts for CCDR Funding Principles for NCORP Community Sites & Minority/Underserved • Fixed baseline funding per award – Establish and maintain a clinical trials infrastructure • Standardized per case funding based on the trailing three-year average annual accrual • High accruing sites (≥200 accruals/year) receive increased per case funding • CCDR –Standard vs. enhanced/experienced capacity Annual Funding Request NCI Community Oncology Research Program (NCORP) NCORP Component No. of Sites Clinical Trials $ Millions No. of Sites CCDR Funding $Millions Total Annual Funding NCORP Sites 40 $35.4 40 $5.4 $40.8 NCORP-M/U Sites: Subtotal 14 $7.3 14 $2.0 $9.3 SUBTOTAL: 54 $42.7 54 $7.4 $50.1 NCORP Research Bases 7 $38.3 7 $4.6 $42.9 $12.0 $93.0* Total RFA Funding $81.0 The 5-Year Total Grant Funding Request for NCORP for FY 2014 to FY 2018 is $465 Million. Clinical Trial Funding: NCORP and NCORP-M/U Sites - $280,000 Infrastructure funding + $2,500/accrual for sites with < 200 accruals annually or + $4,000/accrual for sites with >200 accruals annually. CCDR Funding for NCORP & NCORP M/U Sites: Standard funding at $100K per award and enhanced funding at $300K per award on average. Clinical Trial Challenges in Community Practices • Diverse Organizations • Infrastructure Support • Clinical Trial Culture • Patients Characteristics • Healthcare Environment • Workforce Culture Changes for Clinical Trials Cancer Prevention Symptom Management Genomics-driven Cancer Medicine Meharry MB-CCOP - Nashville Gen. Hosp. Relationship of NCTN and NCORP NCTN Focus: • Late-Phase Treatment Trials • Primary Advanced Imaging Trials NCTN NCORP Focus: • Cancer Prevention and Control Trials • Cancer Care Delivery • Comparative Effectiveness Research Site Participation in Treatment and Primary Advanced Imaging Clinical Trials NCORP NCTN/NCORP CENTRALIZED FUNCTIONS LungMAP: Ph II/III: 2nd Line Sq Cell Lung ALCHEMIST: Ph III: Adjuvant non-sq NSCLC Basket (ful) Protocol NCI MATCH: Ph II: Solid + Lymphoma S1400 Master Protocol Unique PrivatePublic Partnerships with the NCTN Alliance SWOG S1400 Master Protocol NCI-C ECOGAcrin NRG Significantly mutated genes in lung SQCC The Cancer Genome Atlas (TCGA: Nature 489:519; 2012) 178 lung SQCC provided landscape of genomic and epigenomic alterations with a potential therapeutic target, offering new avenues of investigation for the treatment of SQCC Metastatic Squamous NSCLC: Design Parameters Principle Eligibility Requirements: • • • • • Pathologically confirmed squamous Incurable IIIB or IV Failed at least one front-line chemotherapy Measurable Disease PS ≤ 2 Statistical Design: • Accrual rate: 500-1000 patients per year • Rolling phase II design Lung-MAP: Round One FMI NGS/MET IHC Non-match (Anti-PD-L1) PI3K PIK3CA mut 1 Arm2 Medi4736 2 Docetaxel FGFR FGFR ampl, mut, fusion HGF c-Met Expr 1:1 1:1 1:1 1:1 1:1 Arm1 CDK4/6 CCND1, CCND2, CCND3, cdk4 ampl Arm1 1 Arm2 GDC-0032 2 Docetaxel Arm1 1 Arm2 Palbociclib 2 Docetaxel Arm1 1 Arm2 AZD4547 2 Docetaxel Arm1 1 Arm2 Rilotumumab + erlotinib 2 Erlotinib Patient-level Schema Assign Sub-study by marker Patient Registration Consent Investigational Therapy Randomization NGS/IHC Tumor Submission (w/in 24 hrs) Central genomic screening Foundation Medicine: NGS test platform Clarient: .c-MET IHC Standard of Care Therapy NCORP: A Community-Based Research Organization - Potential Gains • Represents the “real world” of oncology practices • Responsive to extensive stakeholder input • Community Sites & Research Bases reevaluated their needs to support the scientific agenda of NCORP (e.g. recruitment and resource alignments) • Capacity to sustain or improve clinical trials accrual to all components of NCTN • Broader base of individuals at risk of cancer • Opportunity to evaluate the influence of the current health care system on the successful conduct and implementation of precision cancer therapy In Conclusion… “The vintage of history is forever repeating” – Faust • Community practices have played a critical role in identifying research questions, advocating for and implementing clinical advances from clinical trials, but not without challenges. • Community research stakeholders will need to, again, rigorously evaluate the organizations, patient characteristics/demographics, the health care environment, and resources needed to support a new generation of clinical trials. Additional Resources for NCORP NCORP Web Site http://ncorp.cancer.gov NCI Division of Cancer Prevention http://prevention.cancer.gov/NCORP NIH Grants and Funding http://grants.nih.gov/grants/