Working Group 3: Clinical Trials

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

2. Working Group 3: Clinical Trials

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. 4% 3% r = 0.93, p = 0.006 25% 2% Ave. Annual % Change 20% 1% Accrual Proportion 0% 15% -1% 1% 10% 50% 10% Accrual Proportion (log) 5% 0% Change in SEER 5-Year Survival from 1985-1992 vs. Accrual Proportion on National Treatment Trials, 1990-98 4.0% 3.2% 2.4% Ave. Annual % Change 1.6% .8% 0% 0-14 15-19 20-24 25-29 30-34 35-39 Age (Years) Slide courtesy of Archie Bleyer, MD

5. 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 92% Number of Patients with Cancer in the US 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 = 15-39 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-12-010 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 2000-2010 • Following disease types Number of AYA patients /total participants for disease; Compared to SEER 17 incidence

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

13. Clinical Trials Outcomes Accrual of AYAs to NCI Cancer Trials (out of total accruals, all ages) 2000-2005 • Highest enrollment for: Hodgkin , Bone , Cervix , AML , ALL 2006-2010 • Highest enrollment for: Hodgkin , Bone (47%), Cervix, AML , ALL

14. EXISTING MECHANISMS TO IMPROVE ACCRUAL Ann O’Mara, PhD, RN September 16, 2013 omaraa@mail.nih.gov

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 ProgramCCOP 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

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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 15-39 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 (2001-2005) • Randomized controlled trial of interval-compressed chemotherapy • Eligibility: any patient ≤50 years old with non-metastatic Ewing sarcoma • 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 Womer et al, JCO, 2012

26. COG ARST0332 (2007-2012) 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 18-30 years old RTOG0630 (2007-2012) Image guided radiation for STS Eligibility: any patient >18 years old with non-metastatic STS When closed only 6% of patients were 18-30 years old Less than 100 patients age 18-30 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 Intergroup Collaboration Example: Soft Tissue Sarcoma

27. ARST1321-RTOG1313 PazopanibNeoadjuvant Trial In Non-Rhabdomyosarcoma Soft Tissue Sarcomas (PAZNTIS): A Phase II/III Randomized Trial of Preoperative Chemoradiation or Preoperative Radiation Plus or Minus Pazopanib Intergroup Collaboration Example: Soft Tissue Sarcoma • 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 3-fold increase in PFS vs placebo PALETTE results (Lancet 2012) • 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. 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 TreatmentPediatric 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 TreatmentAcademic 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: AYAsAYA 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 NeighborsThe 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

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

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

43. OPEN DISCUSSION