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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/