Mills, Glenn

INTRODUCTION: Modeling supporting recommendations for colonoscopy and stool-based colorectal cancer (CRC) screening tests assumes 100% sequential participant adherence. The impact of observed adherence on the long-term effectiveness of screening is unknown. We evaluated the effectiveness of a program of screening colonoscopy every 10 years vs annual high-sensitivity guaiac-based fecal occult blood testing (HSgFOBT) using observed sequential adherence data. METHODS: The MIcrosimulation SCreening ANalysis (MISCAN) model used observed sequential screening adherence, HSgFOBT positivity, and diagnostic colonoscopy adherence in HSgFOBT-positive individuals from the National Colonoscopy Study (single-screening colonoscopy vs ≥4 HSgFOBT sequential rounds). We compared CRC incidence and mortality over 15 years with no screening or 10 yearly screening colonoscopy vs annual HSgFOBT with 100% and differential observed adherence from the trial. RESULTS: Without screening, simulated incidence and mortality over 15 years were 20.9 (95% probability interval 15.8–26.9) and 6.9 (5.0–9.2) per 1,000 participants, respectively. In the case of 100% adherence, only screening colonoscopy was predicted to result in lower incidence; however, both tests lowered simulated mortality to a similar level (2.1 [1.6–2.9] for screening colonoscopy and 2.5 [1.8–3.4] for HSgFOBT). Observed adherence for screening colonoscopy (83.6%) was higher than observed sequential HSgFOBT adherence (73.1% first round; 49.1% by round 4), resulting in lower simulated incidence and mortality for screening colonoscopy (14.4 [10.8–18.5] and 2.9 [2.1–3.9], respectively) than HSgFOBT (20.8 [15.8–28.1] and 3.9 [2.9–5.4], respectively), despite a 91% adherence to diagnostic colonoscopy with FOBT positivity. The relative risk of CRC mortality for screening colonoscopy vs HSgFOBT was 0.75 (95% probability interval 0.68–0.80). Findings were similar in sensitivity analyses with alternative assumptions for repeat colonoscopy, test performance, risk, age, and projection horizon. DISCUSSION: Where sequential adherence to stool-based screening is suboptimal and colonoscopy is accessible and acceptable—as observed in the National Colonoscopy Study—offering screening colonoscopy can increase screening effectiveness.

8592 Background: Accrual to NCI clinical trials(CT)is often slower than planned at times mandating premature closure resulting in loss of valuable resources and delay of scientific progress. Methods: The NCI-MYSC AWG identified 10 potential BtA. SWOG, ECOG and Alliance investigators were queried and agreed that these barriers impede accrual (results stratified for academic and community sites). The MYSC AWG developed in collaboration with NCI and FDA strategies to overcome these barriers. Results: Strategies listed for the 3 most often cited BtA: 1. Reimbursement for CT related expenses:increase awareness of improved reimbursement for phase II CT; tailor reimbursement according to CT complexity; request funds from industry and other sources ( http://biqsfp.cancer.gov ) for qualifying ancillary CT components. 2. Spectrum of available treatment options influences CT participation: educate patients and providers about the significance of a new CT using social media, presentations at national meetings and by adding educational material to CT protocol; encourage opinion leaders and advocacy groups not to promote a new therapy as “standard” in the absence of phase III data. 3. Requirement of CT specific therapy at NCI designated sites only: “MYSC AWG Drug Administration Table” describes NCI/FDA approved rules for CT specific drug administration; CT protocol will outline which standard treatment components of a CT can be administered at any site as long as protocol specific guidelines are followed and conduct is supervised by enrolling investigator. Examples of additional strategies to overcome identified BtA: determine feasibility, indication and insurance coverage of CT specific tests during protocol development; discourage narrow eligibility criteria; avoid competing CT; allow up to 1 cycle of commercially available therapy prior to enrollment; CIRB support for phase II CT. Conclusions: The MYSC Accrual Working Group developed in collaboration with NCI and FDA strategies to overcome barriers to myeloma clinical trial accrual. These strategies may be applicable to NCI-sponsored clinical trials evaluating interventions in other diseases.

Abstract Abstract 3165 Background: Accrual to large oncology group studies in the United States is often slower than planned, especially in less common malignancies such as Multiple Myeloma (MM). To improve the treatment of patients with MM, it is essential that we address the barriers to accrual (BtA) to national clinical trials. The NCI Myeloma Steering Committee (MYSC) formed the Accrual Working Group (AWG), charged to analyze this problem. Methods: The members of the MYSC have developed a list of 10 potential BtA to NCI MM-CT under the leadership of the AWG at meetings conducted in person and by monthly telephone conference. This list was distributed via Survey Monkey among investigators and research staff of the SWOG, ECOG/ACRIN and Alliance research bases for the purpose of ranking the perceived importance of the 10 selected BtA. Responses based on a 0–5 Likert Scale were analyzed as continuous and categorical. For the latter, responses were grouped: Impedes Accrual – No (0,1), Yes (2–5); Significantly Impedes Accrual – No (0–3), Yes (4,5). Results: 246 survey responses were received. 50 participants who indicated that they had never attempted to or actually never enrolled a patient into a MM-CT were excluded. Of 196 responders, 61% had enrolled at least 5 patients, 43% practiced in academic centers (A) and 57% in community centers (C). 26% identified themselves as research staff, 74% as primarily physician investigators including Principal Investigators (12%). 78% have current access to NCI MM-CT. 46% identified their research base affiliation with SWOG, 20% with ECOG/ACRIN, 17% with Alliance, 17% as CTSU, NRG and other. The majority of survey responders confirmed agreement in the perception that all 10 identified BtA impede accrual, ranging from 60–84% depending on the specific barrier identified, while significant impediment to accrual ascribed to these BtA ranged from 22–47%. The perceived barriers most often cited as impeding accrual were (1) spectrum of available treatment options, (2) level of reimbursement for clinical trial related expenses and (3) patient‘s need for prompt treatment intervention (84%, 80%, 76% respectively). The first two barriers along with the requirement that patients receive their treatment exclusively at the NCI designated treatment site were rated most often as significantly impeding accrual (37%, 47%, 34% respectively). The first two were also identified most often as perceived BtA independent of practice setting (A, C), type of research engagement (physician investigator, research staff) and level of experience with MM-CT. Interestingly, the perception that patients must receive their treatment at the NCI designated treatment site and competing industry sponsored clinical trials were substantially more often cited as impeding accrual in academic centers compared to community centers and by physician investigators compared to research staff. The complexity of required diagnostic work up and the complexity of the treatment protocol and follow up testing were substantially more often cited as BtA in the community setting and by research staff compared to their peers in the academic setting and by physician investigators. The NCI MYSC AWG has proposed specific solutions to potentially lower perceived BtA. These include guidelines to allow protocol specific administration of commercially available agents by the patient‘s local oncologist, a simplified diagnostic work up and treatment plan and eligibility inclusion of patients who have received up to one cycle of specified urgent therapy prior to enrollment in MM-CT. Conclusions: We have queried experienced clinical investigators and research staff on 10 potential MM-CT specific BtA and found substantial consensus among responding participants in this survey. There are apparent differences in perceived BtA between the respondents from academic and community centers as well as between research staff and physician investigators. These data suggest that a structured approach to identification of BtA to clinical trials is feasible and creates opportunities to overcome them. This may have application to clinical trials across other diseases and may also lead to improvements in accrual. Disclosures: Barlogie: Celgene, IMF, MMRF, Millennium, Genzyme: Consultancy; Celgene, IMF, Millennium: Honoraria; Celgene, Novartis, NCI, Millennium, Onyx, Icon: Research Funding; GEP: Patents & Royalties.

Abstract Background: We recently clarified the use of consolidative autologous stem cell transplantation (ASCT) as first remission consolidation therapy for high grade diffuse aggressive T and B non-Hodgkin's lymphoma (NHL)in patients with high-intermediate (HI) or High (H) age adjusted IPI disease (Stiff et al, NEJM 369:1681). After receiving CHOP or R-CHOP for 5 cycles responding patients were randomized to either 3 more induction cycles or 1 cycle followed by an ASCT using either a BCNU or TBI based preparative regimen. We found a PFS but not OS advantage for those randomized to transplant and no differential treatment effect for those with T-NHL patients as compared to B-NHL in the initial analysis of this study. In light of Phase II data suggesting a value of early ASCT for T-NHL, a lack of randomized ASCT trials for T-NHL and the inferior prognosis for T-NHL as compared to B cell disease, we further evaluated this sub group, since a post hoc analysis of the entire trial did find a survival advantage for those with H IPI disease. This then provided a unique opportunity to evaluate the role of ASCT consolidation for T-cell NHL in the setting of a prospective randomized trial. Method: Among the 370 eligible B-NHL and T-NHL patients with HI/H IPI disease treated on this trial, 40 had a T-NHL phenotype and were the subject of this analysis. Individual patient files were re-reviewed and those randomized after the first 5 cycles of CHOP were further analyzed for stage, IPI group, histology (centrally reviewed), and response to induction and consolidation and updated survival outcome. Results: Of the 40 T-NHL patients enrolled on study, 28 (70%) were randomized after induction therapy, a similar ratio to the entire trial (68%). Twelve were not randomized; 1 was ineligible for study, and of the eligible 11, 9 were HI IPI and 8 had peripheral T cell (PTCL-NOS). These 11 were not randomized due to patient choice in 2, and all of the remaining 9 pts progressed early: 2 after C1; 3 after C3, 1 after C4, and 3 after C5. For the 28 randomized, their median age was 50 and 19 were males. Of the group, 21/28 had B symptoms at diagnosis, 14 had stage IV disease, and 18 and 10 were in the HI and H IPI groups respectively. Histologies included 11 with PTCL-NOS, 7 angioimmunoblastic and 10 anaplastic large cell NHL. At randomization 13 were to continue CHOP and 15, ASCT. Of the 15 assigned to ASCT, 3 did not undergo transplant (2-refusals, 1- unable to mobilize); 7 received the BCNU-etoposide-cyclophosphamide and 5 the TBI-etoposide-cyclophosphamide preparative regimen. The 5 year estimates of PFS and OS for the randomized ASCT vs CHOP only groups (intent to treat) were 40% vs 38% (p=0.56) and 40% vs 45% (p=0.98) respectively. We found no difference in outcome based on IPI group, histology or stage of disease. Interestingly, only 1/7 patients who received BCV as the ASCT preparative regimen are long term survivors vs 4/5 receiving the TBI-based regimen. Conclusions: We did not observe a PFS/OS advantage for those with high-risk T-NHL in first remission randomized to ASCT following CHOP induction vs CHOP alone in this retrospective analysis. In addition, the 30% early drop out rate before randomization due primarily to early progression strongly suggests that more optimal induction regimens need to be developed for this disease. While the numbers are small the finding that TBI based preparative regimens might be associated with a higher PFS is of interest and deserves further study. Support: NIH/NCI grants CA180888 and CA180819; Bristol-Myers Squibb. Contributions of Dr. Raymond R Tubbs, deceased, are gratefully acknowledged. Figure 1 Figure 1. Disclosures Porcu: miRagen: Other: Investigator in a clinical trial; celgene: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial. Winter:Pharmacyclics: Research Funding; Medivation: Other: Provision of investigational agent for clinical trial; Seattle Genetics: Research Funding; GSK: Research Funding. Kahl:This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Smith:Juno: Consultancy; TGTX: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Genentech: Consultancy, Other: on a DSMB for two trials ; Gilead: Consultancy; Portola: Consultancy; Amgen: Other: Educational lecture to sales force; Pharmacyclics: Consultancy. Rimsza:NCI/NIH: Patents & Royalties: L.M. Rimsza is a co-inventor on a provisional patent, owned by the NCI of the NIH, using Nanostring technology for determining cell of origin in DLBCL.. Fisher:Gilead: Consultancy; Seattle Genetics: Consultancy; Johnson and Johnson: Consultancy. Friedberg:Bayer: Honoraria, Other: Data Safety Monitoring Board.