1. Working Group 3: Clinical Trials
NSAYAO Scientific Update and Workshop
Bethesda, MD
September 16-17, 2013

2. Working Group 3: Clinical Trials
Name
Discipline
Affiliation
Key Experience
David Freyer (Chair)
Pediatric Oncology
Children’s Hospital Los Angeles , USC
Chair, COG AYAO Discipline Committee
Charles Blanke (Co-Chair)
Medical Oncology
Oregon Health & Sciences University
Group Chair, SWOG
Rashmi Chugh
University of Michigan
Sarcoma, SARC
Steve Friedman
Informatics/Data Mgt
CTEP/NCI
NCI Data Analyses
Sally Hunsberger
Biostatistics
NCI
Danny Indelicato
Radiation Oncology
University of Florida
RTOG, LiveStrong and Critical Mass Alliances
Wolf Lindwasser
Brain and Solid Tumor Steering Committees
CTEP Study Review and Prioritization
Michael Link
Stanford University
ASCO Chair, sarcoma
Ann O’Mara
Oncology Nursing, Palliative Care
DCP/NCI
Cancer Control, CCOP
Nita Seibel
NCI AYAO Committee
Wendy Stock
University of Chicago
Chair, C10403
Eric Tai
Pediatrics, Preventive Medicine
CDC
AYA Access to Clinical Trials Initiative

3. WG3: Primary Question
“Since enrollment was recognized as a factor in the lack of progress in AYA Oncology, what has been the clinical trial activity and what are the outstanding obstacles?”

4. Change in SEER 5-Year Survival from 1985-1992
vs. Accrual Proportion on National Treatment Trials, 0% 5%
10%
15%
20%
25%
Accrual Proportion
Accrual Proportion (log)
r = 0.93, p = 0.006
-1% 0% 1% 2% 3% 4%
10%
50%
Ave. Annual % Change
4.0%
3.2%
2.4%
Ave. Annual % Change
1.6%
An even stronger correlation (p = .006) exists between the average annual % change (AAPC) in survival duration, in this case 5-years (green bars), and treatment trial accrual (blue bars). This chart shows the relative lack of progress in 5-year survival from 1985, the midpoint in the SEER program, to 1993, the latest year of SEER data evaluable for 5- year survival. In comparison to the first half of the SEER program, year-olds have even lagged further behind during the second half of the SEER program.
Thus far, to our knowledge, no other factor considered to help explain the lack of progress in AYAs with cancer has been shown to have this degree of correlation. Whereas this does not prove causality, it does propose the strongest explanation for the outcome deficit considered to date.
.8% 0%
0-14
15-19
20-24
25-29
30-34
35-39
Age (Years)
Slide courtesy of Archie Bleyer, MD

5. Adolescent-Young Adult Gap in Cancer Clinical Trials
Sites of Care for
Adolescents and Young Adults with Cancer
Not at NCI-Sponsored Cooperative Group Institution
At Cooperative Group Institution; not on Cooperative Group Trial
On Cooperative Group Trial
The
Adolescent-Young Adult Gap
in Cancer Clinical Trials
Number of Patients
with
Cancer
in the US
92%
40%
79%
60%
21%
33%
29%
11%
60%
50% 6%
10% 2%
0-4
5-9
10-14
15-19
20-30
Age (Years)
Bleyer et al, J Adolesc Health 1997; Albritton, Bleyer Eur J Cancer 2003

6. The Other Side of the Coin: Adult Protocols for “Adult Cancers”
Older adolescents with certain “adult-type” cancers may have better outcomes when treated by medical oncologists
Bleyer A, Pediatr Blood Cancer 2010; 54:238-41

7. WG3: Approach-1 Five Working Group conference calls Many emails
Search strategy
Largely database- rather than literature-driven
Criteria
AYA = years old
Eligibility criteria inclusive of any AYA age segment
Focus on NCI-funded clinical trials and mechanisms
Limited to North American experience

8. WG3: Approach-2 Trends in Clinical Trial Enrollment
Seibel, Freyer, Friedman, Hunsberger, Lindwasser, Link
Existing Mechanisms to Improve Accrual
O’Mara, Freyer, Seibel
Inter-Group Clinical Trials and Initiatives to Improve Accrual
Indelicato, Chugh, Stock
Clinical Trials Accrual: Barriers and Solutions
Chugh, Blanke, Tai
Recommendations
Blanke and All

9. RFA-CA
SWOG
COG

10. AYAO Participation on NCI Clinical Trials
Objectives:
To compare the number of newly diagnosed AYAO patients enrolled on cooperative groups trials with the population based incidence of the same types of cancer
To compare the relative accrual from academic and community-based sites on these same trials

11. Methods
Identified studies in the NCI portfolio that met the following criteria:
Newly diagnosed patients between the ages of 15 to 39 years of age
Open to enrollment during
Following disease types
Number of AYA patients /total participants for disease; Compared to SEER 17 incidence

12. Clinical Trials Enrollment Project
Shanda Finnegan
Steve Friedman
Sally Hunsberger
Denise Lewis
Wolf Lindwasser
Ann O’Mara Troy Budd Pamela Maxwell

13. Clinical Trials Outcomes
Accrual of AYAs to NCI Cancer Trials (out of total accruals, all ages)
Highest enrollment for: Hodgkin , Bone , Cervix , AML , ALL
Highest enrollment for: Hodgkin , Bone (47%), Cervix, AML , ALL
Removed accrual percentages- not sure of source for this;
COG and SWOG to work with CCOPs to stimulate interest in enrolling AYA patients on protocols.

14. EXISTING MECHANISMS TO IMPROVE ACCRUAL
Ann O’Mara, PhD, RN
September 16, 2013

15. CTSU Background and Objectives
Established 1999
Primary Focus:
Provide Centralized Operational Support Activities for NCI Cooperative Group Program
Provide a wide choice of clinical trial options to the largest possible number of investigators
Involve a larger number of treating institutions in the clinical trials process
Increase enrollment to cancer clinical trials

16. CTSU Scope Most Phase III treatment trials Selected Phase II trials
Selected Division of Cancer Prevention Cancer Control and Prevention Trials
Adolescent/Young Adult (AYA) Trial collaborations with COG & Adult Groups
AEWS 1031 Ewings Sarcoma trial
Studies under development
Newly diagnosed non-rhabdomyosarcoma (w/RTOG)
Desmoid (w/Alliance)

17. Community Clinical Oncology Program CCOP
What is a CCOP?
A Group of Community Hospitals and Physicians
Funded by a Peer Reviewed Cooperative Agreement
To Participate In NCI-approved Cancer Prevention, Control, and Treatment Clinical Trials

18. CCOP Organizational Relationships
Research Bases
(Groups/Centers)
Develop Protocols
Data Management and Analysis
Quality Assurance
CCOPs & [MB-CCOPs]
Accrual to Protocols
Data Management
Quality Control
Members and Affiliates
Accrual to Prevention and Control Protocols

19. (47)
(16)
(395)
2013

20. Intergroup Collaborations and Initiatives to Improve Accrual
Wendy Stock, MD
Rashmi Chugh, MD
Danny Indelicato, MD

21. Intergroup Collaboration
Intergroup collaboration will be emphasized as the NCTN evolves
Rationale:
Avoid redundant study objectives
Harmonize study objectives
Minimize redundant costs
For AYA-based research, this provides a valuable opportunity to address one aspect of the clinical trial “gap”
Clinical trial participation among oncology patients is valuable, yet accrual of patients age to clinical trials is poor
Reasons are multifactorial, but two barriers may be national availability and local access

22. Intergroup Collaboration
Example: ALL
C-10403: First US intergroup trial for AYA patients
New diagnosis, untreated, B and T-ALL
Ages 16-39
Completed accrual in September 2012 – 318 patients enrolled; initial EFS results very promising but longer f/u needed (median survival not reached)
Good accrual by all three US cooperative groups
Challenges:
Major challenge: initiation of trial!
From time of initial discussions, more than 5 years before final trial design and protocol written with approval of CTEP and all cooperative groups

23. C-10403 Challenges/ Insights
Initial steep learning curve for treating teams
Assessment and management of specific toxicities
Hepatic toxicities during induction, high rates of grades 3-4 hypersensitivity, prolonged myelosuppression
Unique compliance, medication cost coverage, and psycho social issues in AYA population – highlighted by patient surveys
Tremendous benefit to monthly (initially every two weeks!) phone calls available to all investigators
Calls have continued through summer of 2013
Accrual halted early on for change in protocol due to reports of toxicity from 0232
Switch dex to prednisone
Resulted in slowing of accrual in first year of trial and some loss of momentum
Widespread efforts to publicize trial with highlights/posters at cooperative group meetings, webinars, fliers, support in advertising trial by SigmaTau facilitated awareness
During course of trial, enrollment increased from 3-5 patients per month to a steady rate of 7-9 patients in last 18 months of accrual

24. C-10403 Initial Attempt: A Success!
Use of pediatric regimen feasible in the AYA population
Early EFS analysis suggests tremendous improvement in outcomes (68% 2 year EFS) but longer f/u required
Toxicities not very different than matched population in AALL0232 (to be presented at ASH 2013)
Enthusiasm, comfort level, commitment grew with time
Fascinating insights emerging into differences in disease biology
Slower initial response with more MRD after induction
High rates of activated kinase signature
Provides impetus and direction for the successor study

25. Intergroup Collaboration
Example: Ewing Sarcoma
COG AEWS0031 ( )
Randomized controlled trial of interval-compressed chemotherapy
Eligibility: any patient ≤50 years old with non-metastatic Ewing sarcoma
Womer et al, JCO, 2012
Only 12% were ≥18 years old
Limits investigators ability to ascertain the cause(s)
AEWS1031/RTOG1172 opened 2010
First COG trial endorsed by RTOG
First COG trial open through CTSU
Currently, 21% of patients are ≥18 years old

26. Intergroup Collaboration
Example: Soft Tissue Sarcoma
COG ARST0332 ( )
Risk-based treatment protocol for soft tissue sarcoma (STS)
Eligibility: any patient ≤30 years old with non-metastatic STS
When closed, only 15% of patients years old
RTOG0630 ( )
Image guided radiation for STS
Eligibility: any patient >18 years old with non-metastatic STS
When closed only 6% of patients were years old
Less than 100 patients age with STS were enrolled in national cooperative group studies over the past 5 years…
… And those that did were split between 2 very different studies

27. Intergroup Collaboration
Example: Soft Tissue Sarcoma
ARST1321-RTOG1313 Pazopanib Neoadjuvant Trial In Non- Rhabdomyosarcoma Soft Tissue Sarcomas (PAZNTIS): A Phase II/III Randomized Trial of Preoperative Chemoradiation or Preoperative Radiation Plus or Minus Pazopanib
Hypotheses:
1. The addition of a multitargeted receptor tyrosine kinase inhibitor, pazopanib, to preoperative radiation is feasible and will improve pathologic response in adult and pediatric patients with newly diagnosed intermediate and high risk NRSTS
2. If sufficient pathologic necrosis is demonstrated, pazopanib will improve event-free survival
PALETTE results (Lancet 2012)
3-fold increase in PFS vs placebo
Study will be offered through CTSU and any age STS patient will be eligible
Intended to accelerate and unify therapeutic research into this rare family of AYA tumors
Compliments efforts by Sarcoma Alliance for Research through Collaboration (SARC)

28. Clinical Trials Enrollment: Barriers and Potential Solutions
Next Steps in Adolescent and Young Adult Oncology
Working Group 3
Clinical Trials Enrollment: Barriers and Potential Solutions
Charles Blanke
Rashmi Chugh
Eric Tai

29. Barriers: Location of Treatment Pediatric vs. Adult Hospitals
More likely to enroll in studies at pediatric hospitals
Pediatric hospitals more likely to have clinical trials available for typical AYA cancers
Medical oncologists may not be aware of trials available at their counterpart pediatric hospitals
Hospital age limits may hinder enrollment
Reimbursement/clinical trial credit for providers enrolling on counterpart studies

30. Barriers: Location of Treatment Academic vs. Community Hospitals
Older teens/younger adults more often treated in community
More convenient for most during time of life full of critical daily life obligations
Medical oncologists in community not be aware of trials available
May be reluctant to refer to not complicate life of pt
Academic oncologists may not look beyond own institution for rare cancers

31. Barriers: Regulatory Separate IRBs at pediatric and adult institutions
More difficult to participate in cross-age studies
Central IRBs
Still under-utilized but improving

32. Barriers: Logistics Limited trials available
$$$
Included diseases too rare
Patients with psychosocial barriers
Poor consent readability
Low health literacy
Financial limitations

33. Barriers: AYAs AYA Decision-making to participate in trial
Primary Factors affecting decision-making:
?Direct treatment benefit
Perceived harm due to mistrust of researchers
Logistics
Barakat et al, 2013

34. Barriers: AYAs AYA Decision-making to participate in trial
Ayas with cancer declining participation
18% -Thought it would not help
36% -Had too much else to think about
45% -Added too much time
18% -Added too much discomfort
0% - too risky
Read et al, 2010

35. Learning from our Northern Neighbors The Canadian Experience
Similar obstacles:
Lack of centralized IRB
Lack of knowledge within local IRBs
Difficult requirements for CTAs
Resource limitations
Plans to establish AYA Committee within NCIC-CTG

36. Potential Solutions Increased recognition of “AYAs” as specific entity
Patients unaware of this identifier, resources
Increase trial availability, funding, access
Utilize social media to disperse information
Facebook
Mobile phone-based interventions
Virtual support group
AYA specific clinics/interest groups/meetings

37. Potential Solutions
Mandated use of Central IRB by participating institutions
Increase cross-age enrollment

38. Working Group 3 (Clinical Trials) Recommendations
NSAYAO Workshop
September 16-17, 2013
Charles D. Blanke, MD, FACP, FASCO
Chair, SWOG
Professor, Department of Medicine/Knight Cancer Institute, OHSU
Co-Chair, NSAYAO WG3

39. Improve Utilization, Data Collection, and Reporting
Develop national mechanisms to capture # AYA pts with cancer
Require NCI-funded organizations to report # AYA pts with cancer and capture reasons for non-participation in trials
Develop mechanisms to capture AYA activity arising on pharma-sponsored oncology studies
Develop disease-targeted efforts to increase accrual onto cooperative group studies
1-link to databases reporting clinical trials enrollment; expand extent of age-related information captured by cancer.gov
2-includes cancer centers, LAPS, NCORP sites
4-trials for cervical cancer and GOG

40. Optimize Existing Mechanisms to Enhance Accrual
Expand CTSU use through operationalizing the NCTN
Encourage NCORP members to increase accrual
Increase awareness of trials
Resource community outreach
Provide institutional incentives

41. Expand Intergroup Research
Strengthen collaboration of COG with adult Groups
Modify COG and adult Group trial age eligibility
Co-develop intergroup studies of common AYA cancers
Consider developing an AYA “Super-Committee”
Ensure AYA experts attend adult and pediatric disease-focused Clinical Trials Planning Meetings
4-to coordinate AYA-focused efforts, including both concept development and review

42. Lower Barriers to Trials Participation
Increase use of Central IRB
Increase awareness among pts and allied health care professionals
Have AYA presentations at national nursing, primary care mtgs
Effectively utilize social media
Decrease barriers in gettings pts to Specialty Centers
Identify/develop transportation options for isolated patients
But, have AYA Centers help develop local delivery of sophisticated care and administration of trials
2-of both disparities and opportunities

43. OPEN DISCUSSION