Progress Report. April 2015 March

Transcription

1 Progress Report April 2015 March

2 Center for International Blood and Marrow Transplant Research 9200 W. Wisconsin Avenue, Suite C5500, Milwaukee, WI USA Phone: (414) Fax: (414) The Emmes Corporation 401 N. Washington Street, Suite 700, Rockville, MD USA Phone: (301) Fax: (301) National Marrow Donor Program/Be The Match 500 N. 5 th Street, Minneapolis, MN USA Phone: (763) Fax: (763) This is a publication of the Blood and Marrow Transplant Clinical Trials Network Data and Coordinating Center 2016 All Rights Reserved

3 Table of Contents Table of Contents 1.0 Value the BMT CTN Brings to the HCT Community Areas of Study Accrual Success Dissemination of Results Publications Presentations Significant Findings and Impact Biorepository and Clinical Trial Data Resources Network Efficiency Funding Leverage Key Collaborations Organizational Overview Data and Coordinating Center Clinical Centers Core Centers Affiliate Centers Committee Structure Steering Committee Protocol Teams Technical Committees Administrative Committees Ad Hoc Committees Review Committees Administrative Functions of the DCC DCC Partner Organizations Policies and Procedures Administrative Support Fiscal Planning and Contracting Support Cost-Saving Mechanisms Communication Maintaining BMT CTN Websites Developing Patient Support and Marketing Materials Communicating Trial Results Social Media Engagement Training Transplant Center Monitoring Specimen Repository Support Specimen Collection i

4 Table of Contents Research Sample Repository and Central Processing Lab Maximizing Sample Collection, Quality, and Availability Concept to Publication: The Protocol Process Concept Evaluation and Approval DCC Review Executive Committee Review Steering Committee Review Protocol Development Establishment of a Protocol Team Statistical Design Accrual Planning Budget Preparation Federal Regulations Final Draft Protocol Protocol Approval Steering Committee Review Protocol Review Committee Data and Safety Monitoring Board Review Final Review Prior to Release to Centers Protocol Pre-Activation Designing Case Report Forms Educational Materials and Other Study Documents Release to Center IRBs Site Initiation Training Medical Monitor Assignment Protocol Activation Protocol Maintenance Accrual Monitoring and Intervention High-Quality Clinical and Laboratory Data Collection Data Audits Amendments Study Completion Notice to Cease Enrollment Follow-up Data Collection after Closure Data Review and Analysis Dissemination of Results Authorship Ancillary and Correlative Studies Collaborations with other NIH-funded Research Networks ii

5 Table of Contents 6.0 Future Directions Continued Planning for the Current Grant Cycle State of the Science Symposia State of the Science Symposium State of the Science Symposium Projected Study Activities during the Next Reporting Period Anticipated Results Studies Nearing Completion of Accrual Studies Activated Studies to be Activated Future Study Concepts Conclusions Protocol Descriptions Protocols Open to Accrual BMT CTN 07LT BMT CTN BMT CTN BMT CTN BMT CTN BMT CTN BMT CTN BMT CTN BMT CTN 1304 / DFCI / IFM/DFCI 2009 (The DETERMINATION Study) BMT CTN Protocols that Completed Accrual during this Reporting Period BMT CTN BMT CTN Protocols that Completed Accrual during a Previous Reporting Period BMT CTN BMT CTN BMT CTN BMT CTN BMT CTN BMT CTN BMT CTN BMT CTN BMT CTN BMT CTN BMT CTN BMT CTN 0502 / CALGB iii

6 Table of Contents BMT CTN BMT CTN 0603 / BMT CTN BMT CTN BMT CTN 0703 / SWOG BMT CTN 0704 / CALGB / ECOG BMT CTN BMT CTN BMT CTN BMT CTN 0804 / CALGB BMT CTN 0805 / SWOG BMT CTN BMT CTN Protocols Released to Centers BMT CTN Attachment A: Committee Rosters Attachment A1: Steering Committee Roster Attachment A2: Biomarkers Committee Roster Attachment A3: Clinical Research Associates Committee Roster Attachment A4: Pharmacy Committee Roster Attachment A5: Special Populations (Pediatrics / Human Subjects) Committee Roster Attachment A6: Toxicity and Supportive Care Committee Roster Attachment A7: Publications, Abstracts, and Presentations Committee Roster Attachment B: Publications, Abstracts, and Presentations Attachment B1: Publications by Year Attachment B2: Presentations by Year Attachment C: Center Performance Report Attachment C1: Center Performance Report Template Attachment C2: Center Performance Report Rating Metric Attachment D: Terms and Abbreviations iv

7 1.0 Value the BMT CTN Brings to the HCT Community 1.0 Value the BMT CTN Brings to the HCT Community The Blood and Marrow Transplant Clinical Trials Network (BMT CTN or the Network ) was established in October 2001 to conduct large, multi-institutional clinical trials to improve the outcomes of hematopoietic cell transplantation (HCT) for patients facing life-threatening disorders. The BMT CTN allows the HCT community to conduct prospective, collaborative, clinical research within an infrastructure expressly designed to: Facilitate effective communication and cooperation among transplant centers and collaborators at the National Institutes of Health (NIH), particularly the National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute (NCI); Implement and complete well-designed, multicenter trials of high scientific merit; Offer participation in HCT clinical trials to patients in all regions of the United States (US). About 21,000 HCTs are performed in the US annually, and the number increases by approximately 2% per year. This increase reflects the utility of HCT in treating both malignant and non-malignant diseases, higher donor availability, and treatment advances that allow HCT to be performed in older and sicker patients. While HCT is a rapidly evolving field, HCT clinical trials face unique challenges, including the relatively small number of transplantations performed at any single center, the diverse indications for HCT, the complexities of the procedure, and multiple competing risks in the post-transplant period. The BMT CTN was established to address these challenges and execute multicenter HCT trials with broad national participation. The Network: Effectively fosters development of innovative and important concepts into well-designed trials that answer questions in the most efficient manner; Supports timely implementation and completion of those trials; Ensures protection of subjects (both donors and recipients); Provides high-quality data and adherence to regulatory requirements in an increasingly complex environment; Promotes timely publication of study results, which advances the field of HCT and impacts patient care. The BMT CTN and its network of Core and Affiliate Centers (Section 2.2) play a critical role in improving patient outcomes and advancing the science of HCT. The BMT CTN s many scientific achievements include: Launching 39 trials, including one this reporting period; Completing accrual to 28 trials, including 2 this reporting period; Accruing almost 8,900 patients to its trials from more than 100 centers, including almost 1,000 patients this reporting period; Achieving an overall accrual rate that is 129% of projections among trials that are currently open for enrollment; Establishing a Research Sample Repository that currently includes more than 366,475 biospecimens; Engaging in 38 ancillary and correlative studies; 25 of these studies used cryopreserved biospecimens from the BMT CTN Research Sample Repository or samples shipped directly to a project laboratory, and 4 were completed and published this reporting period; Publishing 58 manuscripts, including 8 this reporting period; Presenting 65 abstracts, including 15 this reporting period. 1

8 1.0 Value the BMT CTN Brings to the HCT Community This Progress Report highlights the following: 1. Accomplishments of the BMT CTN, including a detailed report of the Network s progress for the period of April 1, 2015, through March 31, 2016, (highlights bolded throughout the report) as well as plans for the upcoming year; 2. Organizational structure of the Network; 3. Structure, responsibilities, and focus of the Network s Data and Coordinating Center (DCC); 4. Network collaborations; 5. Protocol selection, development, and management processes; 6. Past, current, and future protocol status updates. 1.1 Areas of Study The BMT CTN studies diverse transplant and cellular therapy treatment options, including both allogeneic and autologous transplantation, with a focus on more complex allografting issues. During this reporting period, 100% of the transplants performed on BMT CTN studies were allogeneic. Comparatively, 54% of the US transplants reported to the CIBMTR (Center for International Blood and Marrow Transplant Research ) were allogeneic transplants. The BMT CTN has answered relevant research questions in both common and rare diseases. Its research portfolio includes studies in leukemia, myelodysplasia, lymphoma, and multiple myeloma as well as rare transplant indications, such as aplastic anemia, sickle cell disease, human immunodeficiency virus (HIV)- associated cancers, and hemophagocytic syndromes / primary immune deficiencies. Issues addressed and being addressed include: Comparison of HCT to non-transplant standard therapies for myelodysplastic syndromes (MDS) and sickle cell disease; Optimal timing of HCT; Pre-transplant conditioning regimens; Graft source [autologous, human leukocyte antigen (HLA)-identical and haploidentical related donors, unrelated donors, and umbilical cord blood]; Anticancer vaccine therapy; Acute and chronic graft-versus-host disease (GVHD); Graft manipulation to decrease GVHD; Maintenance therapy; Post-transplant infection; Post-transplant organ toxicity; Disease control; Biomarkers for transplant complications; Outcomes of transplant in patient populations of all ages, including children and older adults; Quality of life; Better ways of obtaining consent. 1.2 Accrual Success During this reporting period, BMT CTN trials accrued more than 1,000 patients, bringing the Network total to almost 8,900. Among the eight Network-led protocols currently open, the overall accrual rate is at 129% of target projections. Figure 1.1 displays a graph of BMT CTN total annual accrual by progress report time frame (April 1 March 31). 2

9 1.0 Value the BMT CTN Brings to the HCT Community Figure 1.1. BMT CTN annual and cumulative accrual Annual Accrual Cumulative Accrual Actual Accrual Cumulative Accrual Reporting Period ending March 31 3

10 1.0 Value the BMT CTN Brings to the HCT Community To fully leverage accrual efforts, several BMT CTN studies are designed for co-enrollment, including studies on quality of life (0902), consent form evaluation (1205), and a biomarker repository protocol (1202). Approximately 400 patients co-enrolled on more than one Network study. The BMT CTN also leverages the outcomes registry of the CIBMTR, which is funded by the NHLBI, NCI, National Institute of Allergy and Infectious Diseases (NIAID), and Health Services and Research Administration. This registry captures data on almost all transplants performed in the US, and the Network utilizes it to design studies to maximize accrual, recruit centers likely to accrue to specific protocols, and monitor accrual so that issues can be addressed early in the course of protocols. Accrual to BMT CTN studies closely mirrors the CIBMTR database in gender and racial composition. Males are over-represented because several of the common indications for transplantation (e.g. multiple myeloma, acute lymphoblastic leukemia, etc.) are either more common in males or have a worse prognosis with standard chemotherapy in males, leading to increased use of transplantation. During the current reporting period, the BMT CTN continued several initiatives to increase participation of underrepresented populations in BMT CTN trials (Section ). Eleven centers in the Network are participating in the RECRUIT trial, a national study exploring the effectiveness of novel recruitment approaches to increase minority participation on clinical trials. Also, to increase the number of research specimens from both children and minorities, the biomarkers repository protocol, 1202, was kept open to pediatric and minority enrollment after rapidly meeting its original overall accrual goal. The aim was to accrue specimens from at least 200 African American and 200 pediatric patients. The pediatric cohort accrual target was met, and accrual was closed; the African American target is anticipated to be met in April Dissemination of Results Publications BMT CTN investigators have published 58 manuscripts, including 16 primary study results papers, from 20 trials and the DCC / Network in the peer-reviewed journals listed below. Eight manuscripts were published during this reporting period in the journals listed in bold below. Two of these manuscripts were primary results papers. An additional six manuscripts were submitted for publication, including two primary results manuscripts. American Journal of Health-System Pharmacy; Biology of Blood and Marrow Transplantation; Blood; Cancer; Clinical Infectious Diseases; Clinical Trials; Current Malignancy Hematology Reports; Journal of Antimicrobial Chemotherapy; Journal of Clinical Oncology; Journal of Comparative Effectiveness Research; Journal of Immunology; Journal of the National Cancer Institute; Journal of the Society for Clinical Trials; Lancet Haematology; Lancet Oncology; Molecular Therapy; New England Journal of Medicine; 4

11 1.0 Value the BMT CTN Brings to the HCT Community Statistics in Medicine. All trials with primary results available for publication were published or submitted with the exception of 0601, 0801, and 0901, for which data only became available during the current reporting period. Manuscripts for all three studies are drafted and will be submitted early in the next reporting period. A full list of the Network s publications is provided in Appendix B Presentations BMT CTN investigators have presented 65 abstracts from 25 trials and the DCC / Network at the national and international meetings listed below. Fifteen abstracts were presented during this reporting period at the meetings listed in bold below. A full list of the Network s presentations is provided in Appendix B2. American Society of Clinical Oncology (ASCO); American Society of Hematology (ASH), including the 2011 Plenary Session; BMT Tandem Meetings; European Group for Blood and Marrow Transplantation (EBMT); European Hematology Association; International Myeloma Workshop; International Society for Cellular Therapy; Interscience Conference on Antimicrobial Agents and Chemotherapy; Institute for Healthcare Advancement s Annual Health Literacy Conference; IPOS/APOS World Congress on Psycho-Oncology; NCI-ASCO Cancer Trial Accrual Symposium; Public Responsibility in Medicine and Research; Society for Clinical Trials. 1.4 Significant Findings and Impact The research findings of the BMT CTN provide information with effects on clinical practice. To date, BMT CTN trials have provided important insights into several areas of HCT (Table 1.1). Full citations for the publications listed in the table, as well as all others from the BMT CTN, are provided in Appendix B1. 5

12 1.0 Value the BMT CTN Brings to the HCT Community Table 1.1. Significant findings and impact of BMT CTN studies Significant Findings and Impact of BMT CTN Studies BMT CTN Study Results Relevant Publications Impact / Future Outlook CONDITIONING REGIMENS / INTENSITY 0401: Phase III Rituxan / BEAM versus Bexxar / BEAM with autologous hematopoietic stem cell transplantation for persistent or relapsed chemotherapy sensitive diffuse large B cell non- Hodgkin s lymphoma (DLBCL) Determined the addition of radioimmunotherapy to the standard conditioning regimen of BEAM provides no clinical benefit for patients undergoing autologous HCT for DLBCL Phase III randomized study of rituximab/carmustine, etoposide, cytarabine, and melphalan (BEAM) compared with Iodine-131 tositumomab / BEAM with autologous hematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: results from the BMT CTN 0401 Trial. Journal of Clinical Oncology May 1; 31(13): Epub 2013 Mar 11. Although several small Phase II studies suggested that doseintensification might decrease relapse, the primary cause of treatment failure after autologous HCT for DLBCL, this study failed to show an impact on relapse but did show increased toxicity. Future trials will focus on maintenance strategies and/or immune therapies after HCT to improve disease control, marking a significant change in direction for the field. BMT CTN collaborated with Alliance to design a randomized double blind Phase III study of ibrutinib during and following autologous HCT vs. placebo in patients with relapsed or refractory DLBCL (Alliance A / BMT CTN 1201). This protocol will be released during the next reporting period. 0502: A Phase II study of allogeneic transplant for older patients with acute myeloid leukemia (AML) in first morphologic complete remission using a nonmyeloablative preparative regimen Demonstrated the feasibility and effectiveness of allogeneic transplant using reducedintensity conditioning in this first prospective US cooperative group trial conducted in a homogeneously treated group of older AML patients in first remission Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: Results from Cancer and Leukemia Group B (Alliance for Clinical Trials in Oncology) / Blood and Marrow Transplant Clinical Trial Network Journal of Clinical Oncology Dec 10; 33(35): Epub 2015 Nov 2. This protocol was a collaborative effort between the BMT CTN and Cancer and Leukemia Group B (CALGB). CALGB accrual began in 2006, but enrollment was low; BMT CTN activated the study, and the trial rapidly met its original accrual goal. The study demonstrates that, with reduced-intensity conditioning, patients older than 60 can benefit from the graft-versus-leukemia effects of allogeneic HCT with outcomes similar to younger patients. These data should increase the use of HCT in older AML patients. 6

13 1.0 Value the BMT CTN Brings to the HCT Community Significant Findings and Impact of BMT CTN Studies BMT CTN Study Results Relevant Publications Impact / Future Outlook CONDITIONING REGIMENS / INTENSITY (continued) 0701: Phase II trial of nonmyeloablative allogeneic hematopoietic cell transplantation for patients with relapsed follicular non-hodgkin s lymphoma beyond first complete response Determined that a rituximab-containing reduced intensity conditioning regimen is safe and efficacious for patients with relapsed follicular non- Hodgkin lymphoma Primary results presented at 2014 ASH Annual Meeting; the manuscript was submitted and is being revised per reviewer request to include an additional analysis. This study demonstrated that allogeneic HCT using a rituximabcontaining reduced intensity conditioning regimen confers high complete response rates, a low incidence of relapse / progression, and prolonged survival with acceptable toxicity in heavily pretreated follicular lymphoma patients. This study provides justification for future trials comparing nontransplant with transplant salvage strategies in this disease. 0901: A randomized, multicenter Phase III study of allogeneic stem cell transplantation comparing regimen intensity in patients with myelodysplastic syndrome or acute myeloid leukemia Found that reducedintensity conditioning results in higher relapse rates and lower treatmentrelated mortality compared to myeloablative conditioning Primary results presented at 2015 ASH Annual Meeting; manuscript is drafted and will be submitted in May The data from this trial support myeloablative conditioning as the standard of care for patients who are able to receive it. For patients who are not candidates for myeloablative conditioning, novel regimens, which incorporate enhanced anti-leukemia activity without increasing toxicity, are needed. One such regimen of maintenance therapy post-hct for FLT3-positive acute myeloid leukemia (AML) patients will be evaluated in an upcoming study (BMT CTN 1506). 7

14 1.0 Value the BMT CTN Brings to the HCT Community Significant Findings and Impact of BMT CTN Studies BMT CTN Study Results Relevant Publications Impact / Future Outlook GRAFT SOURCES 0201: A Phase III randomized, multicenter trial comparing G-CSF mobilized peripheral blood stem cell with marrow transplantation from HLA compatible unrelated donors Found no difference in survival for recipients of unrelated donor peripheral blood versus bone marrow grafts, but an increased risk of chronic GVHD requiring prolonged immune suppression with peripheral blood grafts Five year quality of life follow-up results showed that recipients of bone marrow grafts have better psychological wellbeing and less burdensome chronic GVHD symptoms than recipients of peripheral blood grafts Peripheral-blood stem cells versus bone marrow from unrelated donors. New England Journal of Medicine Oct 18; 367(16): Comparison of characteristics and outcomes of trial participants and nonparticipants: Example of Blood and Marrow Transplant Clinical Trials Network 0201 Trial. Biology of Blood and Marrow Transplantation Oct 1; 21(10): Epub 2015 Jun 11. Infections after transplantation of bone marrow or peripheral blood stem cells from unrelated donors. Biology of Blood and Marrow Transplantation Feb 1; 22(2): Epub 2015 Sep 25. Recovery of unrelated donors of peripheral blood stem cells versus bone marrow: A prespecified analysis from the Phase III BMT CTN Protocol Biology of Blood and Marrow Transplantation Mar 21. [Epub ahead of print]. Peripheral blood has largely replaced bone marrow as a graft source for unrelated donor transplantation. This study suggests this may not be appropriate in the myeloablative conditioning setting since it offers no survival advantage but produces higher rates of chronic GVHD requiring prolonged immune suppression. Five year results of patient-reported outcomes showed a quality of life advantage for recipients of bone marrow grafts although the impact on unrelated donor requests is yet to be determined. These results were presented, and the manuscript was submitted for publication. Ancillary studies of immune reconstitution, infection, and donor clinical outcomes and quality of life were published. An analysis performed in collaboration with the CIBMTR demonstrated that the patients and outcomes in this study were representative of the larger BMT population was also published. This is the largest study of unrelated donor transplantation ever performed and would not have been possible without the infrastructure provided by the BMT CTN. 8

15 1.0 Value the BMT CTN Brings to the HCT Community Significant Findings and Impact of BMT CTN Studies BMT CTN Study Results Relevant Publications Impact / Future Outlook GRAFT SOURCES (continued) 0501: Multi-center, open label, randomized trial comparing single versus double umbilical cord blood transplantation in pediatric patients with leukemia and myelodysplasia Demonstrated no survival benefit and more acute GVHD for children receiving infusion of two umbilical cord blood units versus one umbilical cord blood unit after transplantation for hematologic malignancies One- versus two-unit cord blood transplant for leukemia. New England Journal of Medicine Oct 30; 371(18): This study indicates, unexpectedly, that increasing cell dose beyond the accepted minimum by adding another cord blood unit does not improve survival after cord blood transplantation in children and increases the risk of acute GVHD. This has important implications for future strategies to improve hematopoietic recovery and decrease transplantrelated mortality after cord blood HCT / 0604: Multicenter, Phase II trials of nonmyeloablative conditioning and transplantation of partially HLAmismatched bone marrow / umbilical cord blood from unrelated donors in patients with hematologic malignancies Confirmed singlecenter results in a multicenter setting using reducedintensity conditioning and haploidentical bone marrow transplantation or double cord blood transplantation in adults with hematologic malignancies, with data supporting a subsequent Phase III trial Alternative donor transplantation: results of parallel Phase II trials using HLAmismatched related bone marrow or unrelated umbilical cord blood grafts. Blood Jul 14; 118(2): Epub 2011 Apr 28. Mismatched related and unrelated donors for allogeneic hematopoietic cell transplantation for adults with hematologic malignancies. Biology of Blood and Marrow Transplantation Oct 1; 20(10): Epub 2014 May 23. Acceptable outcomes of double cord and haploidentical bone marrow transplantation suggest that many more adults should be offered HCT, even when an HLA-matched adult donor is not available. Publication of these studies led to substantial increase in use of haploidentical donors for transplantation in the US. These approaches are now being compared in a randomized Phase III trial (BMT CTN 1101). A subsequent three year follow-up analysis was conducted and showed continued evidence of equipoise between HLA haploidentical related donor and double umbilical cord blood transplantation. 9

16 1.0 Value the BMT CTN Brings to the HCT Community Significant Findings and Impact of BMT CTN Studies BMT CTN Study Results Relevant Publications Impact / Future Outlook GVHD PREVENTION AND TREATMENT 0302: Initial systemic treatment of acute GVHD: a Phase II randomized trial evaluating etanercept, mycophenolate mofetil, denileukin diftitox (Ontak), and pentostatin in combination with corticosteroids Identified MMF plus corticosteroids as the most promising regimen to compare against corticosteroids alone in a Phase III trial Determined that GVHD biomarker panels can be used for early identification of patients at high or low risk for treatment non-responsiveness or death and that biomarker panels may provide opportunities for early intervention and improved survival following HCT Etanercept, mycophenolate, denileukin or pentostatin plus corticosteroids for acute graftversus-host disease, a randomized Phase II trial from the BMT CTN. Blood Jul 1; 114(3): Epub 2009 May 14. Graft-versus-host disease treatment: predictors of survival. Biology of Blood and Marrow Transplantation Dec; 16(12): Epub 2010 Jun 10. Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a BMT CTN study. Blood Apr 19; 119(16): Epub 2012 Mar 1. The results from the 0302 study were used to create and conduct BMT CTN 0802, a Phase III randomized study of MMF / corticosteroids vs. corticosteroids alone. The wider use of biomarkers to identify patients at high risk of GVHD will allow us to tailor our therapies to better control this complication in these patients and to reduce toxicity in patients who are unlikely to benefit from intensive immune suppression. The BMT CTN is now incorporating biomarker-defined risk stratification into the design of GVHD treatment trials, currently with the BMT CTN 1501 protocol (treatment of low risk GVHD as identified by biomarkers), which will be released during the next reporting period. A prognostic score for acute graft-versus-host disease based on biomarkers: A multicentre study. Lancet Haematology.2015 Jan 1; 2(1): Epub 2014 Dec 22. A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplantrelated mortality. Biology of Blood and Marrow Transplantation Apr 1; 21(4): Epub 2015 Jan 10. Additional secondary analyses published in previous reporting periods are listed in the BMT CTN 0302 Protocol Table in Section

17 1.0 Value the BMT CTN Brings to the HCT Community Significant Findings and Impact of BMT CTN Studies BMT CTN Study Results Relevant Publications Impact / Future Outlook GVHD PREVENTION AND TREATMENT (continued) 0303: A single-arm, multicenter Phase II trial of transplants of HLA-matched, CD34+ enriched, T cell depleted peripheral blood stem cells isolated by the CliniMACS system in the treatment of patients with AML in first or second morphologic complete remission Confirmed in a multicenter setting the feasibility and consistency of T cell depletion by CD34 selection, with results in AML that warranted consideration of a Phase III trial versus non-t cell depleted transplantation Low risk of chronic graft-versushost disease and relapse associated with T cell depleted peripheral blood stem cell transplantation for acute myeloid leukemia in first remission: results of the Blood and Marrow Transplant Clinical Trials Network Protocol Biology of Blood and Marrow Transplantation Sep; 17(9): Epub 2011 Feb 12. Characteristics of CliniMACS( ) System CD34-enriched T celldepleted grafts in a multicenter trial for acute myeloid leukemia- Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol Biology of Blood and Marrow Transplantation May; 18(5): Epub 2011 Aug 26. These data were used by the US Food and Drug Administration (FDA) in its determination to approve a CD34 selection column for clinical use in the US. A comparative analysis of outcomes for patients enrolled on this study and patients enrolled on another BMT CTN study who received T-replete grafts was also undertaken. The results suggested that T cell depletion via CD34 selection may lower long term morbidity as a result of less chronic GVHD. A Phase III three arm trial comparing outcomes of CD34-selected transplants using this approach vs. another calcineurin inhibitor-free strategy (post-transplant cyclophosphamide) vs. standard calcineurin-inhibitor based GVHD prophylaxis (tacrolimus / methotrexate) was activated during this reporting period (BMT CTN 1301). Comparative outcomes of donor graft CD34+ selection and immune suppressive therapy as graft-vs-host disease prophylaxis for patients with acute myeloid leukemia in complete remission undergoing HLA-matched sibling allogeneic hematopoietic cell transplantation. Journal of Clinical Oncology Sep 10; 30(26): Epub 2012 Aug 6. 11

18 1.0 Value the BMT CTN Brings to the HCT Community Significant Findings and Impact of BMT CTN Studies BMT CTN Study Results Relevant Publications Impact / Future Outlook GVHD PREVENTION AND TREATMENT (continued) 0402: A Phase III randomized, multicenter trial comparing sirolimus / tacrolimus with tacrolimus / methotrexate as GVHD prophylaxis after HLA-matched, related peripheral blood stem cell transplantation Identified a high risk of toxicity when sirolimus is substituted for standard methotrexate for GVHD prophylaxis when the conditioning regimen includes busulfan and no advantage in acute GVHD-free survival Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation. Blood Dec 1; 112(12) Epub 2008 Sep 5. Tacrolimus / sirolimus versus tacrolimus / methotrexate as GVHD prophylaxis after matched, related donor allogeneic hematopoietic cell transplantation. Blood Aug 21; 124(8): Epub 2014 Jun 30. Although the study showed a modest improvement in grade III-IV acute GVHD, the findings do not support substituting sirolimus for methotrexate since it may increase toxicity in patients who receive busulfan for conditioning, it was associated with higher risks of chronic GVHD, and it did not improve survival. Novel approaches to preventing GVHD are needed and are being explored in the soon to be completed BMT CTN 1203 PROGRESS I study and the recently opened BMT CTN 1301 PROGRESS II study. 0802: A multicenter, randomized, double blind, Phase III trial evaluating corticosteroids with mycophenolate mofetil (MMF) versus corticosteroids with placebo as initial systemic treatment of acute GVHD Found no GVHD-free survival benefit with the addition of MMF See page 10 for 0302 / 0802 ancillary study results Phase III clinical trial steroids / mycophenolate mofetil vs steroids / placebo as therapy for acute graft-versus-host disease: BMT CTN Blood Nov 20; 124(22): Epub 2014 Aug 26. Although the 0802 results were discouraging, the BMT CTN has used these studies to focus on a newer therapeutic agent, sirolimus, in the upcoming BMT CTN 1501 study using a biomarker risk stratification developed in BMT CTN 0302 and The Network s ability to conduct GVHD studies in timely manner allows for definitive Phase III results to be quickly disseminated and promising agents to be efficiently tested in new studies. 12

19 1.0 Value the BMT CTN Brings to the HCT Community Significant Findings and Impact of BMT CTN Studies BMT CTN Study Results Relevant Publications Impact / Future Outlook MULTIPLE MYELOMA TREATMENT 0102: A trial of tandem autologous stem cell transplants with or without postsecond autologous transplant maintenance therapy versus single autologous stem cell transplant followed by matched sibling nonmyeloablative allogeneic stem cell transplant for patients with multiple myeloma Determined, in the second largest study of HCT for multiple myeloma ever conducted (superseded only by BMT CTN 0702), that tandem autologous HCT and autologous HCT followed by allogeneic HCT offer similar progressionfree survival rates in patients with standard risk disease Autologous haemopoietic stemcell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a Phase 3 biological assignment trial. Lancet Oncology Dec 1; 12(13): Epub 2011 Sep 29. This study highlights the need to reduce transplant-related toxicity in the allogeneic HCT setting to allow the graft-versus-tumor effect of allografts to translate into survival benefits. It also indicated that the graft-versustumor effect in standard risk myeloma may not be as important as previously thought. The use of tandem autologous-allogeneic HCTs has decreased substantially over the past few years, in part, because of the data from this trial. Evaluation of the high-risk cohort informed the Network's next allogeneic transplant trial in this disease (BMT CTN 1302), which was recently activated. 0704: A Phase III, randomized, double-blind study of maintenance therapy with CC-5013 or placebo following autologous stem cell transplantation for multiple myeloma Determined lenalidomide maintenance therapy dramatically improves progression-free survival and overall survival after autologous HCT for multiple myeloma Phase III study of lenalidomide versus placebo after HCT for multiple myeloma. New England Journal of Medicine May 10; 366(19): Anatomy of a successful practicechanging study: A Blood and Marrow Transplant Clinical Trials Network-National Cancer Institute Cooperative Group Collaboration. Biology of Blood and Marrow Transplantation Jun 1; 19(6): Epub 2013 Mar 29. The data have led to a major change in clinical practice, with most myeloma patients now receiving lenalidomide maintenance after transplantation. The BMT CTN was an important contributor to this study, which was led by CALGB, and used its Network and the CIBMTR Research Database to devise an accrual plan that allowed the trial to successfully meet its enrollment target after initial accrual difficulties. Details of this collaboration were published in a commentary article. Its success provides a paradigm for ensuring timely accrual to future national BMT studies. 13

20 1.0 Value the BMT CTN Brings to the HCT Community Significant Findings and Impact of BMT CTN Studies BMT CTN Study Results Relevant Publications Impact / Future Outlook QUALITY OF LIFE 0902: A Phase III randomized, multicenter trial testing whether exercise or stress management improves functional status and symptoms of autologous and allogeneic recipients Demonstrated no improvement in physical or mental quality of life with exercise training, stress management training, or combined stress management and exercise training compared to usual care Exercise and stress management training prior to hematopoietic cell transplantation: Blood and Marrow Transplant Clinical Trial Network (BMT CTN) Biology of Blood and Marrow Transplantation Oct 1; 20(10): Epub 2014 Jun 6. Patient-reported physical functioning predicts the success of hematopoietic cell transplantation (BMT CTN 0902). Cancer Jan 1; 122(1): Epub 2015 Oct 6. This trial tested modest, easily applied interventions in the early transplant period. While lack of an effect was disappointing, the trial enrolled more than 700 patients in 19 months, demonstrating that the BMT CTN has an effective infrastructure to conduct studies addressing quality of life issues. An ancillary analysis was published during this reporting period showing that a patient-reported outcome (pre-hct Medical Outcomes Study Short Form-36 Health Survey physical component summary scale) independently predicted overall mortality in allogeneic HCT recipients, adding to the prognostic information of currently used performance and comorbidity scores. This easily applied measure could aid in patient selection and counseling. Additional ancillary studies are in progress. 14

21 1.0 Value the BMT CTN Brings to the HCT Community Significant Findings and Impact of BMT CTN Studies BMT CTN Study Results Relevant Publications Impact / Future Outlook RARE DISEASES 0301: Fludarabinebased conditioning for allogeneic marrow transplantation from HLAcompatible unrelated donors in severe aplastic anemia Identified the optimal dose of cyclophosphamide for unrelated donor HCT in severe aplastic anemia is less than 150 mg/kg Fludarabine-based conditioning for marrow transplantation from unrelated donors in severe aplastic anemia: early results of a cyclophosphamide dose deescalation study show lifethreatening adverse events at predefined cyclophosphamide dose levels. Biology of Blood and Marrow Transplantation July 1; 18(7): Epub 2012 Apr 30. Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: A Phase 1-2 dose de-escalation study. Lancet Haematology Sept 1; 2(9): Epub 2015 Sep 8. Optimizing transplantation regimens for rare diseases is difficult and requires a multicenter effort. This study determined that fludarabine is not sufficiently immune suppressive to replace cyclophosphamide in conditioning regimens for unrelated donor transplantation for aplastic anemia. Additionally, it found excess toxicity with a commonly used dose of cyclophosphamide when combined with fludarabine. This unexpected finding is anticipated to change practice in many centers. A follow-up study for aplastic anemia patients is in development (BMT CTN 1502) using the optimal cyclophosphamide dose found in this study. Additionally, the upcoming study will incorporate cord blood and haploidentical donors to reach patients who are not able to find an unrelated donor. 15

22 1.0 Value the BMT CTN Brings to the HCT Community Significant Findings and Impact of BMT CTN Studies BMT CTN Study Results Relevant Publications Impact / Future Outlook RARE DISEASES (continued) 0601: Unrelated donor reduced intensity bone marrow transplant for children with severe sickle cell disease Determined that a reduced-intensity conditioning regimen of alemtuzumab, fludarabine, and melphalan, followed by bone marrow HCT resulted in low rates of regimen-related organ toxicity and a one year event-free survival of 76% but unacceptably high rates of GVHD Initially found that this regimen, although effective for engraftment of bone marrow, was associated with unacceptably high levels of graft failure after cord blood transplantation; this led to the closure of the cord blood cohort Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one cohort from the Phase II study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Biology of Blood and Marrow Transplantation Aug 1; 18(8): Epub 2012 Feb 16. Primary results presented at 2015 ASH Annual Meeting; manuscript is drafted and will be submitted in Spring This finding confirmed that using a reduced-intensity regimen followed by bone marrow HCT results in acceptable rates of engraftment and survival but high risks of chronic GVHD, underscoring the need for future trials on effective GVHD prophylaxis. Additionally, early on in the study, there was a disappointing finding that using cord blood as a stem cell source resulted in unacceptably high levels of graft failure, which indicates the need for novel transplant strategies for the large number of sickle cell disease patients who cannot find an HLAmatched adult donor. Two additional BMT CTN sickle cell transplant trials are currently in development. One compares HLA-matched bone marrow HCT to standard of care (BMT CTN 1503), and the other uses haploidentical donors (BMT CTN 1507). 0803: High dose chemotherapy with autologous stem cell rescue for aggressive B cell lymphoma and Hodgkin lymphoma in HIV-infected patients Determined that patients with HIVassociated lymphoma may successfully undergo autologous transplant with favorable outcomes Primary results presented at 2014 ASH Annual Meeting; manuscript was submitted for publication. The BMT CTN conducted this study in collaboration with the AIDS Malignancy Consortium in an effort to assess whether autologous HCT is a viable therapeutic option for a patient population frequently excluded from HCT clinical trials. Based on the study findings, autologous transplant should be considered the standard of care for patients with relapsed / refractory HIV-associated lymphoma who meet standard eligibility criteria. The BMT CTN and AIDS Malignancy Consortium are also evaluating the use of allogeneic HCT for HIV-infected patients with hematological cancers and MDS in the newly completed BMT CTN 0903 trial. 16

23 1.0 Value the BMT CTN Brings to the HCT Community Significant Findings and Impact of BMT CTN Studies BMT CTN Study Results Relevant Publications Impact / Future Outlook SUPPORTIVE CARE 0101: A randomized double-blind trial of fluconazole versus voriconazole for the prevention of invasive fungal infections in allogeneic blood and marrow transplant recipients Demonstrated that fluconazole, a lowcost antifungal agent, generally has similar efficacy as and is generally more costeffective than the newer and more expensive drug, voriconazole, in preventing serious fungal infections in the first six months after HCT but that voriconazole may be cost-effective for those undergoing an allogeneic HCT for AML Randomized double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood Dec 9; 116(24): Epub 2010 Sep 8. Cost-effectiveness analysis of voriconazole compared with fluconazole for prevention of invasive fungal infection in patients receiving allogeneic hematopoietic cell transplants. American Journal of Health- System Pharmacy Sept 1; 70(17): This study of a Phase III comparison of fluconazole and voriconazole indicates that newer is not always better and that, for most patients, standard fluconazole is effective fungal prophylaxis. However, an ancillary study suggested there is a subset of patients for whom primary antifungal prophylaxis with voriconazole may be cost-effective, allowing more informed treatment planning by transplant centers. 0403: A Phase III, randomized doubleblind, placebo controlled trial of soluble tumor necrosis factor receptor: Enbrel (etanercept) for the treatment of acute non-infectious pulmonary dysfunction (idiopathic pneumonia syndrome) following allogeneic stem cell transplantation Showed no increase in response with the addition of etanercept to corticosteroids in the treatment of idiopathic pneumonia syndrome; however, the reduced sample size (34 instead of 120 patients) precluded a definitive conclusion A randomized double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor: Enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome following allogeneic stem cell transplantation: Blood and Marrow Transplant Clinical Trials Network protocol. Biology of Blood and Marrow Transplantation Jun 1; 20(6): Epub 2014 Mar 7. This study failed to show an advantage for etanercept and also highlighted the decreasing incidence of idiopathic pneumonia syndrome in an era of reduced conditioning regimen intensity and better diagnostic tests for infectious pathogens. 17

24 1.0 Value the BMT CTN Brings to the HCT Community 1.5 Biorepository and Clinical Trial Data Resources The Network s Research Sample Repository is a valuable resource. To date, protocols have yielded a biological research sample collection of more than 366,470 stored specimens provided by more than 5,680 subjects. An inventory of BMT CTN research samples collections is available on the Network s public website as a resource for investigators planning correlative and ancillary studies. This website section summarizes the planned sample collection schedules and sample processing, and it lists biological samples available for all BMT CTN studies by time point and sample type. Clinical trial outcome data associated with completed trials represent another resource for investigators who want to examine research objectives other than those addressed in the original trials. During this reporting period, new sections were added to the Network s public website to provide investigators with general patient and clinical characteristics summaries and case report forms for completed trials to assist in the development of secondary data analyses. Analyses and published results using data derived from the analysis of biorepository samples and associated trial outcome data are listed, along with other ancillary studies, in Tables 4.2a and 4.2b. 1.6 Network Efficiency Over the past several years, initiatives were undertaken to improve Network efficiency. These included creating an Activation Task Force to evaluate performance and make recommendations to improve processes, reevaluating the protocol development process, and implementing a shorter study development timeline. New practices were implemented because of these initiatives. During this reporting period, the DCC evaluated time point data to assess Network performance as part of its continuous process improvement process. Figure 1.2. Increasing efficiency by decreasing timeframes: BMT CTN median milestone timeframes in previous vs. current grant cycles Protocol Team Formation to Study Activation PRC Submission to PRC Approval PRC Approval to DSMB Submission PRC Submission to DSMB Approval DSMB Approval to Protocol Release to Centers Protocol Release to Centers to Study Activation Protocol Team Formation to PRC Submission Evaluable Data to Manuscript Submission Months Acronyms: PRC = Protocol Review Committee, DSMB = Data and Safety Monitoring Board 18

25 1.0 Value the BMT CTN Brings to the HCT Community Data in Figure 1.2 represent the median Network milestone times for BMT CTN-led studies. Two comparative timeframes are shown: (previous BMT CTN grant cycles) and (current BMT CTN grant cycle). The data show a decrease in times for every category except one Data and Safety Monitoring Board approval to protocol release, with an increase from 1.5 to 3.6 months due to 4 studies that were not released until more than 7 months after approval because of difficulty in contracting with the companies providing drug and support, additional FDA-mandated training requirements for vaccine manufacture, and/or a protocol amendment prior to release. Notably, the median timeframe during this current grant cycle from protocol team formation to protocol activation decreased from 23.0 months to 18.6 months, a decrease of 4.4 months. The DCC also reviewed center performance data for the current and previous grant cycles and found there has been continued improvement in overall assessment scores over the course of eight years. In 2015, the most successful year yet, no centers received a Needs Improvement score (Section 3.7). The DCC also evaluates publication timelines. The time from evaluable data to manuscript submission decreased significantly from 12.6 to 8.7 months from the previous to current grant cycle. Of note, of the 20 BMT CTN-led studies that have reached primary endpoint, only three are not submitted or published, and data only became available for these studies during the current reporting period. Manuscripts for all three studies are drafted and will be submitted early in the next reporting period. While the improvements in milestone times and center performance data are impressive, the DCC continues efforts to improve upon them further. Two initiatives undertaken during this reporting period include hosting one day in-person protocol development meetings for the 1501 and 1507 protocols to shorten protocol development timeline and using an Institutional Review Board (IRB) of Record for the 1501 and 1503 studies to shorten protocol release to activation timeframe. It is too early to evaluate the impact, if any, of these initiatives. 1.7 Funding Leverage BMT CTN leadership understands that optimizing external funding is critical at any time but particularly in the current economic environment. The Network works hard to leverage NIH support with public-private partnerships that provide both direct and in-kind contributions. The DCC develops relationships and contracts with pharmaceutical companies and laboratory vendors for additional budgetary support and for drugs used in studies, always with proper attention paid to avoid potential conflicts of interest. This year, the following supplemental support activities took place: BMT CTN 1302: Multicenter Phase II, placebo controlled trial of maintenance ixazomib after allogeneic hematopoietic stem cell transplantation for high risk multiple myeloma. o An agreement was fully executed with Millennium Pharmaceuticals, Inc. to provide funding in the amount of $1.15 million as well as in kind contributions of ixazomib, bortezomib, and placebo. o Millennium Pharmaceuticals, Inc. agreed to provide additional funding in the amount of $290,000 for minimal residual disease (MRD) testing. The revised funded amount will total $1.44 million. BMT CTN 1401: Phase II multicenter trial of single autologous hematopoietic cell transplant followed by lenalidomide maintenance for multiple myeloma with or without vaccination with dendritic cell / myeloma fusions. o An agreement was fully executed with Celgene Corporation to provide $5.1 million as well as in kind contributions of lenalidomide. BMT CTN 1506: A multi-center, randomized, double-blind, placebo-controlled Phase III trial of the FLT3 inhibitor gilteritinib administered as maintenance therapy following allogeneic transplant for patients 19

26 1.0 Value the BMT CTN Brings to the HCT Community with FLT3/ITD AML. o Negotiations are in process with Astellas Pharma Global Development, Inc. to fully fund 1506, including providing gilteritinib and placebo. All non-government third party contributions are made through an NHLBI-approved Memoranda of Agreement. The total of all non-bmt CTN core funding additions has increased the effective investment from NIH by an estimated $376 million. The BMT CTN DCC also encourages investigators to apply for supplemental funding to support ancillary or correlative studies. During this reporting period, investigators were awarded the following grants: STRIDE: Unrelated donor transplantation for adults with sickle cell disease study (R01; $6.98 million) BMT CTN 1101 Ancillary cost-effectiveness analysis (R01; $1.72 million) 1.8 Key Collaborations As highlighted throughout this report, the BMT CTN fosters successful collaborations with other NIH Institutes, Networks / Consortia, and organizations: AIDS Malignancy Consortium; The Alliance for Clinical Trials in Oncology (formerly CALGB); Canadian Blood and Marrow Transplant Group; Centers for Disease Control and Prevention Office of Minority Health & Health Disparities; Children s Oncology Group (COG); Dana-Farber Cancer Institute (DFCI) / Intergroupe Francophone du Myelome (IFM); Deutsche Knochenmarkspenderdatei (DKMS) German Bone Marrow Donor Center; Eastern Cooperative Oncology Group (ECOG) American College of Radiology Imaging Network (ACRIN) Cancer Research Group; National Institute on Minority Health and Health Disparities; NCI National Clinical Trials Network; NCI-sponsored Cancer Trials Support Unit; NIAID; Office of Rare Diseases Research Pediatric Blood and Marrow Transplant Consortium (PBMTC); Sickle Cell Disease Clinical Research Network; SWOG. 20

27 2.0 Organizational Overview 2.0 Organizational Overview The BMT CTN is comprised of a network of organizations that work together to achieve common goals. It includes the following elements, each of which is described in this section: Data and Coordinating Center; Twenty Core Centers / Consortia; Affiliate Centers; Steering Committee; Protocol Teams; Technical Committees; Administrative Committees; Ad Hoc Committees; Review Committees. 2.1 Data and Coordinating Center The DCC is managed by three organizations with extensive HCT research expertise: the CIBMTR, the National Marrow Donor Program (NMDP)/Be The Match, and The Emmes Corporation (a contract research organization). Together they are responsible for maintaining continuity of operations and effective communications, data management, and statistical support for the Network. Figure 2.1 illustrates the DCC s relationship to the organization as a whole, which is explained more fully in Section 3. Figure 2.1. BMT CTN organizational structure Protocol Review Committee NHLBI & NCI Data and Safety Monitoring Board 20 Core Clinical Centers / Consortia BMT CTN Steering Committee Executive Committee Protocol Teams Administrative Committees Technical Committees Scientific Advisory Committees DCC Affiliate Clinical Centers 21

28 2.0 Organizational Overview 2.2 Clinical Centers Core Centers The BMT CTN has 20 Core Clinical Centers (Table 2.1), some of which are consortia of two or more centers. Each Core Center holds a cooperative agreement with the NHLBI to participate in the BMT CTN. These centers were chosen by virtue of the scientific merit of their grant applications to the NIH as well as evidence of their ability to collaborate in carrying out the Network mission of developing and completing high-quality trials as efficiently as possible. Table 2.1. Core Centers and Principal Investigators BMT CTN Core Centers and Principal Investigators Center Baylor College of Medicine / Methodist Hospital (Consortium) 1. Baylor College of Medicine / Methodist Hospital 2. Children s National Medical Center Case Western Reserve University Ireland Cancer Center (Consortium) 1. Case Medical Center 2. Oregon Health Sciences (Adults) 3. Cleveland Clinic 4. West Virginia University City of Hope National Medical Center Dana Farber / Partners in Cancer Care (Consortium) 1. Brigham & Women s Hospital 2. Massachusetts General Hospital 3. Boston Children s Hospital Duke University Medical Center Fred Hutchinson Cancer Research Center Principal Investigator 1. Helen Heslop, MD, DSc (Hon) 2. Catherine Bollard, MBChB, MD 1. Hillard Lazarus, MD 2. Richard Maziarz, MD 3. Ronald Sobecks, MD 4. Michael Craig, MD Ryo Nakamura, MD Joseph Antin, MD Joanne Kurtzberg, MD Frederick Appelbaum, MD H. Lee Moffitt Cancer Center Claudio Anasetti, MD Johns Hopkins University Oncology Center Memorial Sloan-Kettering Cancer Center Northside Hospital Atlanta Ohio State University Comprehensive Cancer Center (Consortium) 1. Ohio State University 2. Roswell Park Cancer Institute 3. University of North Carolina 4. University of California-San Francisco 5. Virginia Commonwealth University PBMTC (Pediatric Blood & Marrow Transplant Consortium) 47 pediatric centers in the US and Canada (see Table 2.2) Richard Jones, MD Sergio Giralt, MD Asad Bashey, MD, PhD 1. Steven Devine, MD 2. Philip McCarthy, MD Theresa Hahn, PhD 3. Thomas Shea, MD 4. Lloyd Damon, MD 5. John McCarty, MD Michael Pulsipher, MD 22

29 2.0 Organizational Overview BMT CTN Core Centers and Principal Investigators Stanford Hospital and Clinics Center University of Florida College of Medicine (Consortium) 1. University of Florida 2. Emory University University of Michigan Medical Center Consortium 1. University of Michigan 2. Mayo Clinic 3. Mount Sinai Hospital 4. Vanderbilt University University of Minnesota University of Nebraska Medical Center (Consortium) 1. University of Nebraska 2. University of Kansas University of Pennsylvania Hospital University of Texas MD Anderson Cancer Center Washington University Principal Investigator Robert Lowsky, MD 1. John Wingard, MD 2. Edmund Waller, MD, PhD 1. Gregory Yanik, MD, MS 2. William Hogan, MBBCh Mark Litzow, MD 3. John Levine, MD 4. Madan Jagasia, MBBS, MS Daniel Weisdorf, MD 1. Julie Vose, MD, MBA 2. Joseph McGuirk, DO Edward Stadtmauer, MD Amin Alousi, MD Peter Westervelt, MD, PhD Table 2.2. PBMTC Centers that have participated in BMT CTN studies PBMTC Centers that have Participated in BMT CTN Studies Center All Children's Hospital Ann and Robert H. Lurie Children's Hospital of Chicago British Columbia Children s Hospital Cardinal Glennon Children's Medical Center Saint Louis University CancerCare Manitoba Carolinas Medical Center / Levine Children's Hospital Children's Healthcare of Atlanta Children s Hospital at Oakland Children's Hospital Los Angeles Children's Hospital of Denver Children's Hospital of New Orleans Children's Hospital of Philadelphia Children's Medical Center of Dallas Children's Mercy Hospital and Clinics Location St Petersburg, FL Chicago, IL Vancouver, Canada St. Louis, MO Winnipeg, Canada Charlotte, NC Atlanta, GA Oakland, CA Los Angeles, CA Denver, CO New Orleans, LA Philadelphia, PA Dallas, TX Kansas City, MO 23

30 2.0 Organizational Overview PBMTC Centers that have Participated in BMT CTN Studies Center Children's National Medical Center Cincinnati Children's Hospital Medical Center Columbia University Medical Center Cook Children's Medical Center Hackensack University Medical Center Hopital Sainte-Justine Karmanos Cancer Institute / Children s Hospital of Michigan Mattel Children s Hospital at UCLA Medical University of South Carolina McGill University Midwest Children's Cancer Center Nationwide Children's Hospital Nemours / Alfred I. DuPont Hospital for Children Nemours Children s Clinic New York Medical College Oregon Health and Science University Penn State College of Medicine Phoenix Children's Hospital Primary Children's Medical Center Riley Hospital for Children-Indiana University Texas Transplant Institute The Steven and Alexandra Cohen Children's Hospital of New York University of California Los Angeles University of California San Francisco School of Medicine University of Alabama at Birmingham University of Iowa Hospital and Clinics University of Louisville / Kosair Children's Hospital University of Miami Miller School of Medicine Sylvester Cancer Center University of Mississippi Medical Center University of Rochester Medical Center University of Texas Southwestern Medical Center Vanderbilt University Washington University / St. Louis Children s Hospital Location Washington, DC Cincinnati, OH New York, NY Fort Worth, TX Hackensack, NJ Montreal, Canada Detroit, MI Los Angeles, CA Charleston, SC Montreal, Canada Milwaukee, WI Columbus, OH Wilmington, DE Jacksonville, FL Valhalla, NY Portland, OR Hershey, PA Phoenix, AZ Salt Lake City, UT Indianapolis, IN San Antonio, TX New Hyde Park, NY Los Angeles, CA San Francisco, CA Birmingham, AL Iowa City, IA Louisville, KY Miami, FL Jackson, MS Rochester, NY Dallas, TX Nashville, TN St. Louis, MO 24

31 2.0 Organizational Overview Affiliate Centers The BMT CTN has almost 70 Affiliate Centers (Table 2.3) that accrue patients to Network trials. About 17% of the BMT CTN s overall accrual comes from Affiliate Centers; for this reporting period, the figure is 12%. However, excluding BMT CTN 1202, which is a large, fast accruing biospecimen study that was only opened to a select few Affiliate Centers, the figure is 21%. Accrual from Affiliate Centers decreased throughout the years as more Affiliate Centers have become Core Centers, either individually or as part of a Consortium. In 2001, 20 non- PBMTC centers were Core Centers or part of Core Consortia; as of March 31, 2016, there are 35. The Network encourages and facilitates broad participation of the HCT community through its Affiliate Center system. Affiliate Centers participate in one or more BMT CTN trials through individual contracts with the DCC. Applications for participation in Network trials are available online at bmtctn.net. Table 2.3. Affiliate Centers BMT CTN Affiliate Centers Center Advocate Lutheran General Hospital Arizona Cancer Center / University of Arizona Aurora St. Luke s Medical Center Avera Hematology & Transplant Center Banner Research Institute Baylor University Medical Center Beth Israel Deaconess Medical Center British Columbia Children's Hospital Cancer Centers of the Carolinas Cancer Institute of New Jersey / Robert Wood Johnson University Christiana Care Health System Colorado Blood Cancer Institute DeKalb Medical Center Florida Hospital Cancer Institute Fox Chase - Temple University BMT Program Georgia Health Sciences University Hackensack University Medical Center Henry Ford Health System Indiana BMT Clinics Indiana University Medical Center / Riley Hospital Intermountain BMT Program Jewish Hospital BMT Program Kansas City Cancer Centers Kapi'olani Medical Center for Women and Children University of Karmanos Cancer Institute Location Park Ridge, IL Tucson, AZ Milwaukee, WI Sioux Falls, SD Phoenix, AZ Dallas, TX Boston, MA Vancouver, Canada Greenville, SC New Brunswick, NJ Newark, DE Denver, CO Decatur, GA Orlando, FL Philadelphia, PA Augusta, GA Hackensack, NJ Detroit, MI Beech Grove, IN Indianapolis, IN Salt Lake City, UT Cincinnati, OH Kansas City, MO Honolulu, HI Detroit, MI 25

32 2.0 Organizational Overview BMT CTN Affiliate Centers Center Louisiana State University Health Sciences Center Loyola University Medical Center Mayo Clinic Arizona Mayo Clinic Florida Medical College of Wisconsin Medical University of South Carolina Montefiore Medical Center Nashville VA Medical Center Healthcare National Cancer Institute - NIH North Shore University Hospital Northwestern University Penn State College of Medicine - The Milton S. Hershey Medical Center Providence Portland Medical Center Roger Williams Medical Center Rush University Medical Center Sarah Cannon BMT Program Spectrum Health St. Louis University St. Lukes Mountain States Tumor Institute Stony Brook University Medical Center SUNY Upstate Medical University Texas Transplant Institute Thompson Cancer Survival Center Tufts Medical Center University of Alabama at Birmingham University of California Davis Medical Center University of California Los Angeles University of California San Diego Medical Center University of Chicago University of Illinois University of Iowa Hospitals and Clinics University of Kentucky University of Maryland Medical Systems - Greenebaum Cancer Center University of Massachusetts / Memorial Medical Center Location Baton Rouge, LA Maywood, IL Phoenix, AZ Jacksonville, FL Milwaukee, WI Charleston, SC Bronx, NY Nashville, TN Bethesda, MD Manhasset, NY Chicago, IL Hershey, PA Portland, OR Providence, RI Chicago, IL Nashville, TN Grand Rapids, MI St. Louis, MO Boise, ID Stony Brook, NY Syracuse, NY San Antonio, TX Knoxville, TN Boston, MA Birmingham, AL Sacramento, CA Los Angeles, CA La Jolla, CA Chicago, IL Chicago, IL Iowa City, IA Lexington, KY Baltimore, MD Worcester, MA 26

33 2.0 Organizational Overview BMT CTN Affiliate Centers Center University of Miami University of Mississippi Medical Center University of Oklahoma Medical Center University of Pittsburgh Cancer Institute University of Rochester Medical Center (Adults and Pediatric) University of Texas Southwestern Medical Center University of Virginia University of Wisconsin Hospital & Clinics Utah BMT / University of Utah Medical School Vanderbilt University Medical Center Wake Forest University Health Sciences Weill Cornell Medical College / New York Presbyterian Hospital Western Pennsylvania Cancer Institute Wichita Community Clinical Oncology Program Yale University School of Medicine / Yale-New Haven Hospital Location Miami, FL Jackson, MI Oklahoma City, OK Pittsburgh, PA Rochester, NY Dallas, TX Charlottesville, VA Madison, WI Salt Lake City, UT Nashville, TN Winston-Salem, NC New York, NY Pittsburgh, PA Wichita, KS New Haven, CT 2.3 Committee Structure The BMT CTN committee structure ensures the Network works toward common goals. Each committee is described in this section Steering Committee The Steering Committee consists of the Principal Investigator of each Core Center or Consortium, the DCC Principal Investigator and Co-Principal Investigators, the NHLBI Project Officer, the NCI Project Officer, a representative of each of the NCI-funded Cancer Cooperative Groups, and representatives of Affiliate Centers that meet standards for exemplary accrual and participation in BMT CTN trials. Other members of the DCC, Core Centers, and NIH regularly participate in Steering Committee meetings. The Steering Committee roster is listed in Attachment A1. The Steering Committee sets the scientific agenda and oversees the selection, design, execution, and analysis of all BMT CTN studies. The Committee ensures the most relevant studies are chosen, they are appropriately designed and executed, and data analyses are properly conducted. Additionally, the Steering Committee works in collaboration with the DCC to ensure participating transplant centers adhere to BMT CTN policies and procedures. The Committee also resolves any operational issues raised by investigators, Clinical Research Associates, laboratory and repository staff, DCC members, or others. The Steering Committee selects a Committee Chair who first serves a two-year term as Vice Chair, then a one year term as Chair Elect, followed by a two-year term as Chair, and finally a one-year term as Immediate Past Chair. Steven Devine, MD, Ohio State University Medical Center, began a two-year term as Chair on January 1, Richard Jones, Johns Hopkins University, is the Vice Chair, and Frederick Appelbaum, MD, Fred Hutchinson Cancer Research Center, is the Immediate Past Chair. 27

34 2.0 Organizational Overview Protocol Teams Each Protocol Team consists of one to four Chairs; at least three co-investigators from Core and Affiliate Centers; an NHLBI and/or NCI representative; an NHLBI Statistician; and a DCC Protocol Officer, Coordinator, Statistician, and Contracts Representative. A Protocol Team is formed when a proposal is accepted by the Network. This team develops the study concept into a working study design and provides scientific oversight for the trial throughout its life cycle. The Protocol Team also: Reviews applications for participation from Affiliate Centers; Develops patient and physician educational materials; Monitors accrual and compliance with protocol requirements; Prepares amendments as necessary; Reviews endpoint data for accuracy and consistency; Analyzes and interprets study data; Prepares manuscripts Technical Committees Standing and ad hoc Technical Committees generally consist of a maximum of nine members who are not associated with the DCC or NIH. Each Technical committee is also assigned one or more NHLBI and NCI representatives and one or more DCC staff members. These committees conduct specified functions of Network activity, advise the Steering Committee on certain Network policies and procedures, and provide technical expertise to protocol design. All standing Technical Committees must review each protocol before they are distributed to centers for implementation. Most Technical Committee meetings are conducted by conference call. During this reporting period, the Technical Committees reviewed five new protocols (1501, 1502, 1503, 1506, and 1507). Committee members are appointed by the Executive Committee to three-year terms. Nominations are open to participating Core and Affiliate centers. A Nominating Committee reviews the nominations and proposes a slate of candidates. These candidates are approved by the Executive and Steering Committees Biomarkers Committee The Biomarkers Committee, which is made up of Core and Affiliate Center transplant physicians, was formed to: Inform the Network s scientific agenda with a focus on questions involving analysis of biologic specimens for genomic and proteomic markers; Review new and existing studies for opportunities to collect blood and tissue samples for analysis of potential prognostic markers; Advise the Network protocol teams in their review of ancillary study proposals that request the use of BMT CTN research samples. The current Biomarkers Committee roster is listed in Attachment A2. During this reporting period, the Biomarkers Committee participated in the review of a new protocol (BMT CTN 1506), focusing on the associated correlative study concepts and proposed biospecimen collection schedules written into the protocol. Recommendations and comments regarding the potential impact of the proposed study concepts and the use of calendar-driven research biospecimen collections were submitted to the protocol teams for consideration as they made final decisions regarding study approvals. The proposed research sample collection strategy, correlative study objectives, and clinical outcome data collection incorporated into the BMT CTN 1506 study was reviewed by the committee, and guidance was provided to the protocol team for consideration as they finalized the study and obtained necessary NHLBI approvals. 28

35 2.0 Organizational Overview During this reporting period, the BMT CTN Executive Committee, together with the 1202 Protocol Team and 1202 End Point Review Committee members, developed procedures associated with: The management of the 1202 biospecimen/clinical data collection; Submission of ancillary laboratory study proposals; The adjudication and final approval of meritorious studies. The Biomarkers Committee will play a lead role in the review, prioritization, and approval of ancillary studies submitted to the BMT CTN. Final review of proposals, together with Biomarkers Committee comments and recommendations, will be conducted by the BMT CTN Executive Committee Clinical Research Associates Committee The Clinical Research Associate Committee consists of Clinical Research Associates and Data Managers from Core and Affiliate Centers. This committee: Reviews each BMT CTN protocol before it is distributed to centers, focusing on reviewing and resolving logistical issues (e.g., shipping and receipt of specimens or drugs); Assists in developing and reviewing Case Report Forms; Reviews educational materials for use at participating clinical centers; Provides input for the BMT CTN Coordinators meeting held during the BMT Tandem Meetings. In addition to reviewing three new protocols this reporting period, the Clinical Research Associate Committee reviewed Case Report Forms for five protocols (07LT, 1301, 1302, 1401, and 1501). The Committee also provided feedback regarding the workflow for the collection of the blood sample for biomarker analysis as well as the communication of results to treating physicians for BMT CTN The current Clinical Research Associates Committee roster is listed in Attachment A Pharmacy Committee The Pharmacy Committee consists of pharmacists from Core and Affiliate Centers. It reviews BMT CTN protocols for appropriate use and administration of pharmaceuticals. It also advises Protocol Teams about possible pharmacokinetic or other ancillary studies. The current Pharmacy Committee roster is listed in Attachment A4. During this reporting period, the Pharmacy Committee continued to participate in the BMT CTN Chemotherapy Dosing Task Force that was formed last year. The Task Force, which includes Pharmacy Committee members and select Steering Committee members, was charged by the Steering Committee with reviewing the American Society for Blood and Marrow Transplantation (ASBMT) position statement on conditioning chemotherapy dose adjustment in obese patients (published January 2014) and provide recommendations for BMT CTN protocols. The Task Force presented their recommendations to the Steering Committee in September 2015, and the Steering Committee approved the recommendations with a few minor stipulations. The final recommendations were approved by the Executive Committee in December The recommendations included chemotherapy dosing adjustments in obese patients with template dose adjustment language for upcoming BMT CTN protocols, including recommendations on dosing adjustments for renal and hepatic insufficiency. The Task Force recommendations also included proposals for four amended / future research studies: Add a question that addresses obesity to a planned ancillary study (STaMINA myeloma study), which will use BMT CTN 0702 hip to waist ratio data (pre and post HCT) and conduct cytokine analyses using 0702 samples; Add an obesity analysis to a planned toxicity analysis of 2,000 BMT CTN patients; 29

36 2.0 Organizational Overview Conduct a new retrospective analysis of CIBMTR data regarding the effect of BEAM dose adjustments on the outcomes of patients with lymphoma (approved at the 2016 BMT Tandem Meetings by the Regimen Related Toxicity Working Committee); Consider a retrospective study of cyclophosphamide dosing in obese patients (applied for R01 funding in February 2016). Work on all of these projects will commence during the next reporting period. Additionally, the Task Force drafted a position manuscript and will submit for publication this year Special Populations Committee The Special Populations Committee consists of pediatric and adult transplant physicians from Core and Affiliate Centers as well as an ethicist. It ensures that children, women, and minority study participants are considered for inclusion in all appropriate investigational protocols developed by the Network. It also ensures that, for studies involving pediatric participants, appropriate modifications are addressed in informed consent, patient care, and monitoring documents. The current Special Populations Committee roster is listed in Attachment A5. Evaluation of HCT in the pediatric population presents some unique challenges. The Network is committed to developing strategies to address these challenges and increase the participation of children in HCT clinical trials. Sixteen Network trials have enrolled or are enrolling children (BMT CTN 0101, 0201, 0301, 0302, 0402, 0501, 0601, 0603, 0604, 0801, 0802, 0803, 0903, 1202, 1204, and 1301); three of them focused specifically on pediatric issues (BMT CTN 0501, 0601, and 1204). Four upcoming protocols also include children / adolescents (1501, 1502, 1503, and 1507), including one study for aplastic anemia patients and two others for patients with sickle cell disease. The proportion of BMT CTN trial participants under age 16 is only slightly lower than the overall proportion in the US transplant population. Since many US pediatric HCT recipients also have access to HCT trials through the COG, Network leadership feels these enrollment figures are appropriate. Last year, the Steering Committee charged the Special Populations Committee with a special project to evaluate the current special population participation on BMT CTN trials, identify underserved populations, and provide recommendations to increase special population participation. The Committee conducted their evaluation and presented recommendations to the Steering Committee in June The recommendations included: Develop a training module for centers regarding the accurate capture of race and ethnicity data; Offer double BMT CTN accrual credit for enrollment of underserved minorities, when feasible; Offer more pediatric trials, and lower the age requirement of adult trials to 15 to include adolescent and young adult populations; Remind Special Populations Committee members of their charge to carefully review eligibility criteria of new protocols to ensure the studies are inclusive of pediatric and other special population patients. The DCC is working with the Committee to implement the prioritized recommendations Toxicity and Supportive Care Committee The Toxicity and Supportive Care Committee consists of Core and Affiliate Center transplant physicians. This committee: Works with the DCC to define methods for evaluating adverse events and toxicities after transplantation; Reviews the evaluation and monitoring requirements for toxicities on BMT CTN protocols; Designs and approves forms and procedures for collecting toxicity data, including standards for expedited reporting of certain adverse events. The current Toxicity and Supportive Care Committee roster is listed in Attachment A6. 30

37 2.0 Organizational Overview Administrative Committees Executive Committee The Executive Committee consists of the Steering Committee Chair, Chair-Elect or Immediate Past Chair, Vice Chair, NHLBI and NCI Project Officers, and DCC Principal Investigator and Co-Principal Investigators. The Executive Committee is a subcommittee of the Steering Committee and works in collaboration with the DCC. Executive Committee members are indicated by an asterisk (*) in Attachment A1. The Executive Committee ensures participating transplant centers adhere to BMT CTN policies and procedures, and it works together with the Steering Committee to resolve operational issues raised by investigators, Clinical Research Associates, laboratory and repository staff, members of the DCC, and others. It appoints Technical and Administrative Committee members. The Executive Committee also: Addresses policy making issues; Reviews contractual arrangements and financial matters affecting the Network as a whole; Makes recommendations to the Steering Committee; Reviews and approves Transplant Center Performance Reports, audits, and corrective action plans; Provides initial review of research proposals submitted to the BMT CTN for new trials and ancillary studies; Assists in developing Steering Committee meeting agendas Publications, Abstracts, and Presentations Committee The Publications, Abstracts, and Presentations Committee consists of Core and Affiliate Center transplant physicians. This committee develops publication and presentation policies. It also reviews publications and presentations to ensure confidentiality of study participants and proprietary information as well as to ensure appropriate acknowledgements of contributions, sponsorship, and authorship. During this reporting period, the Committee reviewed 9 abstracts and 14 manuscripts. Publications Committee members are appointed by the Executive using the same nomination process as described above. The current Publications, Abstracts, and Presentations Committee roster is listed in Attachment A Ad Hoc Committees Additional administrative and technical committees are convened as needed. For example, a Nominating Committee is formed to propose candidates for open committee positions. Scientific Advisory Committees. As a result of the Network s 2007 State of the Science Symposium (Section 6.2.1), 12 Scientific Advisory Committees were formed to address specific areas pertinent to HCT trials. After the conclusion of the State of the Science Symposium, these Scientific Advisory Committees continued to operate and meet on an ad hoc basis to review and prioritize the Network s scientific agenda. In the summer of 2011, the committees reviewed and summarized protocol concepts submitted by Core Center applicants for discussion at the July Steering Committee Meeting, the first meeting with new Core Center representatives. The Committees were redesigned and reconvened to plan for the 2014 State of the Science Symposium (Section 6.2.2). GVHD Committee. During this reporting period, the GVHD Committee continued to work with BMT CTN investigators to evaluate and propose new GVHD study concepts. In particular the Committee assessed potential follow-on studies to BMT CTN 1203, which is slated to complete accrual in April, almost a year ahead of projections. Three acute GVHD study proposals were presented to the Steering Committee in February, and the Steering Committee approved further development of the concepts as well as exploration into external funding options. The Committee will continue their efforts this year 31

38 2.0 Organizational Overview and will report back to the Steering Committee when concepts are refined and funding secured. Returning Genetics Results Task Force. Also during this reporting period, a task force comprised of Network physicians and DCC staff was assembled to review and evaluate issues related to genetic testing and return of incidental findings to patients enrolled in BMT CTN protocols. The Returning Genetics Results Task Force evaluated current informed consent language regarding banked samples and potential future research using these samples for genetic tests. The Task Force also reviewed current recommendations from the NHLBI working group, actionable findings generated from genetic tests, and options for study participants in receiving these results. After this careful review, the Task Force determined that additional work was needed to draft language to be included in consent forms, review incidental genetic findings, confirm their validity, and outline a course of action and provide guidance for physicians in returning genetic results to subjects (patients and donors) involved in BMT CTN studies. The Task Force presented these recommendations to the Steering Committee in February The Steering Committee asked the Task Force to formally document these recommendations and work with the BMT CTN Biomarkers Committee (Section ) to draft necessary language and standard operating procedures Review Committees Three independent Review Committees provide additional oversight for BMT CTN trials: Protocol Review Committee. The Protocol Review Committee is appointed by the NHLBI and consists of a Chairperson and Members whose experience reflect areas of expertise necessary to evaluate the scientific merit and design of BMT CTN protocols. Consultants may be added on an ad hoc basis if needed. The Protocol Chair (or designee), Protocol Officer, Statistician, and senior members of the DCC represent the Protocol Team at Protocol Review Committee meetings. Data and Safety Monitoring Boards. The two Data and Safety Monitoring Boards are independent boards appointed by the NHLBI and/or NCI. Each is composed of a Chair and Members with expertise in biostatistics, clinical trials, bioethics, and the specific research area(s) of the Network studies. Consultants may be added on an ad hoc basis if needed. Each Board handles about half of the Network portfolio of trials. 32

39 3.0 Administrative Functions of the DCC 3.0 Administrative Functions of the DCC The DCC is a collaborative partnership of three organizations with extensive experience in multicenter, HCTrelated clinical research. The DCC is led by Mary Horowitz, MD, MS (CIBMTR); Adam Mendizabal, PhD (The Emmes Corporation); and Dennis Confer, MD (NMDP/Be The Match). The DCC supports and manages the efficient development, implementation, and completion of high-quality Phase II and III clinical trials for the Network, including: Evaluating and prioritizing study concepts; Developing protocols with appropriate statistical designs; Activating studies and developing plans to accrue patients in a timely manner; Monitoring for safety, regulatory, and protocol compliance as well as data accuracy; Collecting complete clinical and laboratory data; Analyzing and sharing research results. The DCC also coordinates and supports overall BMT CTN activities to enhance Network effectiveness, including: Maintaining the Administrative and Technical Manuals of Procedures; Facilitating communication and maintaining public and private websites; Maintaining a state-of-the-art research database; Maintaining systems for acquisition and storage of biologic specimens; Facilitating study completion, and publishing results in a timely manner ; Managing contractual arrangements and fiscal activities; Monitoring and improving overall center performance; Supporting all Network committees and activities with meeting planning and other logistical support; Collaborating with government organizations to avoid competing studies and foster intra-group participation. 3.1 DCC Partner Organizations The DCC consists of three partners: CIBMTR (Milwaukee, Wisconsin, and Minneapolis, Minnesota) is a research organization formed in 2004 from the affiliation of the International Bone Marrow Transplant Registry at the Medical College of Wisconsin (MCW) and the Research Department of NMDP/Be The Match. The CIBMTR has a proven history of clinical research and publication in both HCT and statistical methodology. It has fostered effective collaborations with a large network of transplant centers. It also maintains an extensive observational research database of virtually all allogeneic transplantations and most autologous transplantations performed in the US. The Emmes Corporation (Rockville, Maryland) is a contract research organization established in 1978 that has managed more than 1,000 Phase I-IV trials and registries in 60 countries on 6 continents. Emmes provides experience in planning, implementing, and managing multicenter clinical trials in a variety of areas, including HCT, statistical design and analysis, clinical trial design and management, complex data collection system design and implementation, site monitoring, and regulatory support. NMDP/Be The Match (Minneapolis, Minnesota) was established in It is the world leader in HCT donor registry and graft procurement management, and it operates the world s largest HCT-related Research Sample Repository. NMDP/Be The Match has a large network of donor, collection and transplant centers as well as cord blood banks; a skilled Contracts and Procurement Department that manages contracts with 178 US and international transplant centers and maintains contractual 33

40 3.0 Administrative Functions of the DCC relationships with specimen repositories and contract laboratories; an experienced Patient and Health Professional Services department that provides educational and counseling services to patients in need of a transplant; and a Case Management department that facilitates most of the unrelated donor transplantations performed in the US. Figure 3.1 illustrates the relationship among DCC organizations and its distribution of responsibilities, and Table 3.1 describes the specific responsibilities of each DCC member. Figure 3.2 displays the organizational structure of the DCC. Figure 3.1. DCC organization 34

41 3.0 Administrative Functions of the DCC Table 3.1. Responsibilities of DCC members DCC Member Responsibilities Administrative Functions CIBMTR NMDP/Be The Match Emmes Provide overall scientific /administrative leadership Lead Support Support Develop Manuals of Procedures / Standard Operating Procedures Support Support Lead Facilitate meeting logistics a Support Lead Support Coordinate meeting materials b Support Support Lead Manage electronic communications (general and study-specific) Support Support Lead Maintain roster of participants Support Support Lead Prepare budget and track financials Support Lead Support Trials Development & Management Develop / review concepts Lead Support Support Develop protocols Shared Shared Shared Protocol Team Serve as Protocol Officer Shared Shared Serve as Protocol Statistician Shared Shared Serve as Patient Services Representative Lead Serve as Protocol Coordinator Lead Manage Protocol Document Support Support Lead Provide Protocol Review Committee support c Shared Shared Shared Protocol Implementation Identify centers Lead Support Support Certify centers d Support Support Lead Contract with centers Support Lead Support Identify laboratories / repositories Support Lead Support Contract with laboratories Support Lead Support Maintain roster of study participants Support Lead Manage data management system e Support Support Lead Develop Case Report Forms Support Support Lead Coordinate laboratory & repository functions Support Lead Support Ensure quality of therapeutic & diagnostic modalities Support Support Lead 35

42 3.0 Administrative Functions of the DCC DCC Member Responsibilities Manage site activation process, including monitoring regulatory compliance CIBMTR NMDP/Be The Match Emmes Lead Train site personnel Support Support Lead Develop patient materials Support Lead Support Monitor Adverse Events Support Support Lead Develop and implement accrual plan Shared Shared Shared Provide Data and Safety Monitoring Board support Support Support Lead Review performance of centers Shared Shared Shared Monitor accrual Shared Support Shared Monitor data accuracy and conduct data review sessions Support Lead Prepare reports / manuscripts Shared Shared Shared Coordinate dissemination of results Shared Shared Shared Develop Statistical Methodology Shared Shared a Schedule site location, travel arrangements, conference calling, travel reimbursements b Develop agendas, supporting materials, reports, and minutes c Support Steering and Protocol Review Committees during review process d Certify ability of centers to execute special requirements of protocol e Including systems for registration, Web-based data entry, database design, study archive backup, contingency plans 36

43 3.0 Administrative Functions of the DCC Figure 3.2. DCC organizational structure as of March 31, 2016 The Emmes Corporation Adam Mendizabal, PhD DCC Co-Principal Investigator CIBMTR Milwaukee Mary Horowitz, MD, MS ^ DCC Principal Investigator NMDP / CIBMTR Minneapolis Dennis Confer, MD ^ DCC Co-Principal Investigator Iris Gersten, MS Project Director Beth Blackwell, ScD Denise King, MS Peter Dawson, PhD Project Director Jill El-Khorazaty, MS Georgia Koliou, MS Mat Makowski, PhD Veronica Garcia Cindy Wu, MS Kate Ketkaew ~ Maggie Wu, MS ~ Mary Magliocco Jessica Zhu, MS Iris Yu Statisticians Clinical Systems Analysts Brianne Allison ~ Jennifer Romeril, RN ~ Kate Bickett Audra Thompson, RN Achintya Jaitly Lauren Zahra Cathryn Mudrick, MPH Safety Monitors ~ Courtney Nelson Brady Nesbitt ~ Ellen Parker, MBA Kelly O Brien, PhD Jensen Podbielski Theresa Pritchard, MS Thomas Tamura Alyssa Ramirez Admin Coordinators Laura Rawls Whitney Sheffer ~ Samantha Wilkins, MA Gillian Armstrong, PhD Alan Heather Wittsack Ramnath Regulatory Protocol Coordinators Alex Borbely ~ Cynthia Couture, RN Sue Isman Protocol Monitor Brianna Johnson ~ Kristin Knust, MS Michelle LaMotteo Roe Wright Bill Karabelas Data Managers Programmer / Analysts Jeanette Carreras, MPH Raphael Fraser, PhD Brent Logan, PhD Waleska Perez, MPH Biostatisticians Kavita Bhavsar BMT CTN Data Coordinator Tucker Graczkowski Programmer Analyst Mita Desai Data Entry Coordinator ^ Anita D Souza, MD ^ * Mary Eapen, MD ^ Mehdi Hamadani, MD ^ * Marcelo Pasquini, MD ^ * Wael Saber, MD * Liza Thiel, MD * Weiyun Ai, PhD, MD * Christopher Bredeson, MD * Steven Deeks, MD * Dianna Howard, MD * Tammy Kindwall-Keller, MD * Gabrielle Meyers, MD ^ * Willis Navarro, MD * Eneida Nemecek, MD ^ * Marcie Riches, MD * Bipin Savani, MD * Shannon Smiley, MD * Angie Smith, MD * Trisha Wong, MD, MS Patricia Steinert, PhD Administrator Cristina Gonzalez Grants Financial Manager Jessica Gillis-Smith, MPH Publishing Coordinator Kim Jackson Administrative Asst Mary Frey Director, Contracts & Procurement Nancy Poland, MA Sr Mgr, Contracts & Procurement Pam Budnick Renee Carby, MS Kiila Lee Contract Representatives Susan Lahti Sr Paralegal Rebecca Drexler Senior Manager, Prospective Research Jana Dworski Project Coordinator Amy Foley, MA BMT CTN Project Manager NMDP/Be The Match Support Services Gina Graves Director, Finance and Controller Kevin Weber Sr Accountant, Contracts & Awards Jenna Dahlberg Supervisor, Contract & Award Accounting Peggy Schmidt Cost Accountant, Gov t Accounting Stephen Spellman, MBS Director, Immunobiology & Observational Research Alan Howard, PhD Principal Immunobiology Research Scientist Stephanie Waldvogel Immunobiology Research Scientist Ashley Spahn Immunobiology Research Scientist Elizabeth Murphy, EdD, RN VP, Patient Services Ellen Denzen, MS Sr Manager, Health Services Research Heather Moore, MPH, CHES Program Specialist Lensa Idossa Program Analyst KEY Emmes Corporation, Rockville, MD ^ Protocol Officer CIBMTR, Milwaukee, WI * Medical Monitor NMDP/CIBMTR, Minneapolis, MN ~ Group Manager Various Locations 37

44 3.0 Administrative Functions of the DCC 3.2 Policies and Procedures The BMT CTN has two Manuals of Procedures: Administrative and Technical. The Administrative Manual includes policies and procedures related to: Participation in Network protocols, including detailed steps for proposing, drafting, and executing studies; Roles and duties of Core and Affiliate Centers and Network committees; Roles of the CIBMTR, NMDP/Be The Match, and Emmes within the DCC; Transplant center site monitoring; Adverse event reporting; Human subject protection and regulatory procedures; Publications, abstracts, and presentations; Ancillary and secondary analysis studies. The Technical Manual of Procedures is a composite of policies and procedures pertinent to practice guidelines and laboratory evaluations unique to HCT. The Technical Manual includes detailed policies and procedures regarding: Acute and chronic GVHD; Characterization and processing for hematopoietic cellular products; Diagnosing and grading infectious diseases; Technical Committees policies. An updated version of the Administrative Manual of Procedures was released in August The Technical Manual will be updated during the next reporting period. These manuals and other procedural documents are available on the BMT CTN public website (bmtctn.net) and a password-protected, secure website for Network members (bmtctnsp.net). 3.3 Administrative Support The DCC coordinates and schedules meetings and conference calls for the Steering, Executive, Scientific Advisory, Administrative, and Technical Committees as well as for Protocol Teams. From April 1, 2015, through March 31, 2016, the DCC managed 436 conference calls. DCC representatives attend and participate in all Network meetings, providing logistical support to ensure the meetings are conducted efficiently and effectively. Two or more DCC staff members participate on all Technical Committee and Protocol Team calls, preparing and circulating agendas and minutes for these committees. The DCC also maintains version control of protocols during development and after their approval, including all amendments. 3.4 Fiscal Planning and Contracting Support NMDP/Be The Match manages fiscal planning and contract support for the BMT CTN. Personnel from the NMDP/Be The Match Contracts and Procurement Department participate in DCC conference calls, protocol development calls, Executive and Steering Committee calls, and in-person Steering Committee meetings. NMDP/Be The Match develops and executes Requests for Proposals, service agreements, and agreements for laboratory and pharmacy services to support specific protocols. Throughout the history of the BMT CTN, and in collaboration with both NHLBI and NCI, NMDP/Be The Match has negotiated a number of Memoranda of Agreement to sponsor contributions that offset the cost of individual protocols or provide pharmaceutical products. NMDP/Be The Match has also executed agreements with each of the NCI Cooperative Groups, fostering collaboration with groups outside the Network. On an ongoing basis, the NMDP/Be The Match Contracts and Procurement Department: 38

45 3.0 Administrative Functions of the DCC Executes Master Agreements and corresponding Clinical Study Protocol Riders for each protocol, facilitating participation of Affiliate and Core Centers in BMT CTN protocols; Coordinates and manages the protocol budget development process, including reimbursements for protocol-specific patient costs; generates financial reports on protocol spending; and provides forecasts of future spending based on observed patterns, when requested; Assists the protocol teams in selecting the best-performing Affiliate Centers by developing performance snapshots for each Affiliate Center applying to participate on a study. The snapshot shows the amount of time it takes a center to sign each rider as well as the average number of months for all BMT CTN riders; the amount of time it takes from approval to activation and the average for all BMT CTN studies; enrollment history on BMT CTN studies; and other relevant facts Cost-Saving Mechanisms The DCC carefully manages the resources of the Network. It established a uniform budgeting model to project trial costs accurately and uses a competitive bid process to procure laboratory, pharmacy, and other services, ensuring that NIH funds are used wisely. To minimize delays associated with contracting with private companies, the DCC established a policy of face-to-face meetings with potential contributors early in the protocol development process. These meetings familiarize potential contributors with the Network, its membership, and its research activities, and they allow the DCC to identify specific corporate contract liaisons. Additionally, the Steering Committee encourages Protocol Teams to consider cost-saving mechanisms such as: Restricting study requirements, such as research repository samples, to those that are essential to answering the primary and secondary questions; Limiting the number of secondary questions to the most scientifically important; Reducing the length of follow-up periods and using the established CIBMTR Research Database for long term follow-up of enrolled patients beyond the primary endpoint. 3.5 Communication Managing the large Network and its protocol activity requires excellent communication. Information must flow among DCC members, Network committees, transplant centers, laboratory and repository facilities, the medical community, and the lay public. Weekly teleconferences for leadership and DCC members and monthly teleconferences for the Executive Committee are conducted. Steering Committee meetings are scheduled either in-person or by teleconference each month. Additional communication efforts are described in this section Maintaining BMT CTN Websites The DCC maintains a public website (bmtctn.net) and a secure, password-protected website (bmtctnsp.net). The Network s public website features: A BMT CTN organizational overview and contact information; The current BMT CTN Progress Report; The current State of the Science Symposium Report; Current versions of open protocols; Educational materials for all open protocols; Applications to participate in BMT CTN protocols as an Affiliate Center; Administrative and Technical Manuals of Operations; A list of BMT CTN publications; A summary of the BMT CTN s research sample collection listing biological samples available for all studies, by time point and sample type, and two summary tables: GVHD treatment trial samples and 39

46 3.0 Administrative Functions of the DCC allogeneic transplant trial samples; Links to related DCC and government partner websites; A password-protected page for BMT CTN Principal Investigators and Coordinators that includes links to: o Data reports on site activation, accrual by site, projected accrual, demographics, missing forms summary, lab compliance (overall), monthly accrual by center, and data quality by center; o Private BMT CTN, AdvantageEDC data collection, and GlobalTrace specimen tracking websites; o AdvantageEDC and GlobalTrace training modules. The Network s secure, password-protected website uses Microsoft SharePoint Server software to allow Network participants to share confidential information. It features: Meeting materials, including agendas, minutes, and conference call materials; Protocol Team materials, including the current version of protocols in development; Rosters of personnel at participating centers; Rosters for the Steering, Administrative, and Technical Committees as well as Protocol Teams; Study accrual reports; Monthly recruitment reports. The DCC uses a separate password-protected area of the secure site to post Data and Safety Monitoring Board meeting materials, share confidential information, and distribute monthly safety monitoring reports. All necessary meeting materials are posted two weeks before scheduled meetings. Adverse events reports and stopping guideline (safety) tables and graphs are posted monthly. Data and Safety Monitoring Board members can access the accrual, monthly recruitment, data quality, and site activation status reports, which are updated nightly or monthly depending on the report. The CIBMTR s public website (cibmtr.org) has a page dedicated to the Network, including an overview of its functions, a list of all BMT CTN protocols, and a link to the BMT CTN public website. Additionally, the CIBMTR displays information about the Network and its protocols at national and international meetings. NMDP/Be The Match s public website (bethematch.org) also has a page dedicated to the BMT CTN, including an overview of the Network and links to the BMT CTN and government partner websites Developing Patient Support and Marketing Materials NMDP/Be The Match s Patient and Health Professional Services Department assists the Network in developing patient-friendly study materials. This department managed an extensive project to reformat the Network s patient consent and assent forms for easier readability and comprehension. This resulted in a 2011 manuscript that summarized recommendations of the review team for the development and formatting of accessible consent forms for multicenter clinical trials (Denzen et al., Biology of Blood and Marrow Transplantation, full citation listed in Appendix B1.) The intent of these recommendations is to guide the informed consent form writing process, simplify local IRB review of consent forms, enhance patient comprehension, and improve patient satisfaction. The recommendations are being tested in a randomized study of the updated consent versus the standard format in the Easy-to-Read Informed Consent study (BMT CTN 1205). Several members of the original Patient and Health Professional Services team who revised the consent form format are on the BMT CTN 1205 protocol team. The Patient and Health Professional Services Department and NMDP/Be The Match Marketing and Communications Department also support communications for accrual enhancement, help develop patient education materials, and assist in the design of Network publicity materials, such as protocol flyers and posters used for national meetings and ed accrual updates. 40

47 3.0 Administrative Functions of the DCC Communicating Trial Results Communicating trial results rapidly and accurately is a fundamental activity of the DCC. Efficient and accurate data collection, processing, and analysis each stage of which is supported by the DCC ensures the integrity of Network trials and provides the foundation for publication and dissemination of study results. For all BMT CTN primary results publications since inception, the median number of days from the DCC statistician s dissemination of the final analysis report to manuscript submission is 232 days. The median number of days from submission to publication is 134 days. The DCC helps Protocol Teams disseminate study results and publish as quickly as possible, assisting investigators in developing study slide sets and poster presentations for national and international meetings. The DCC also provides administrative support to the Publications Committee in its oversight of the publication process and assures proper acknowledgement of trial contributors. DCC staff members coordinate, compile, and distribute the annual BMT CTN Progress Report to the research community and the public to provide them with updated information on protocol activity, including published findings. These reports are available in print and digital format, and they are posted on the Network s public website ( Progress%20Reports.html) Social Media Engagement During the previous reporting period, the Steering Committee approved the Social Media Task Force s recommendations to target communications to healthcare providers via social media. The targeted audience includes those at BMT CTN Core, Consortia, and Affiliate Centers: physicians, physician assistants, nurse practitioners, pharmacists, nurses, study coordinators, data managers, statisticians, and laboratory and regulatory staff; NHLBI and NCI Project Officers; referring physicians and research staff outside the Network; related organizations (e.g. ASBMT, NMDP/Be The Match, ASH, American Association of Blood Banks); and medical students. The primary goals of the BMT CTN s adoption of social media forums are: Visibility of the Network increasing awareness of the BMT CTN, participating centers, and Network clinical trial portfolio and publications; Inclusiveness communicating with individuals at BMT CTN centers who are not included on BMT CTN distribution lists and do not attend meetings (e.g. junior investigators) as well as reaching referring hematology / oncology and community physicians; Collaboration engaging new, and therefore a wider variety of, voices within and outside the Network; Education sharing BMT CTN resources as well as linked content from other affiliated groups (e.g. ASBMT, NMDP/Be The Match, NIH). Based on the Task Force s background research, including interviews with other similar organizations and cooperative groups, it was determined the optimal platforms to reach the targeted audiences were Twitter and Facebook. After Steering Committee approval in June 2014, the DCC formed an internal Social Media Team to develop the Network s social media policy, develop content, and launch the accounts. The Network s Twitter (@BMTCTN) (Figure 3.3) and Facebook (facebook.com/bmtctn) (Figure 3.4) accounts were launched in October As of March 31, 2016, the BMT CTN has 607 Twitter followers and 142 Facebook likes, which is an increase of 332 and 30, respectively. The greatest activity continues to be during the annual ASH and BMT Tandem Meetings. A number of new Twitter followers and Facebook likes were gained during these meetings, and it proved to be an effective way of promoting BMT CTN activities and presentations during the meetings. 41

48 3.0 Administrative Functions of the DCC Figure 3.3. Screen shot of BMT CTN Twitter account Figure 3.4. Screen shot of BMT CTN Facebook account The DCC Social Media Team continues to meet weekly to develop content. During this reporting period, the team created a monthly dashboard, capturing key metrics to evaluate the Network s overall social media performance and, in particular, which content is most successful in reaching the target audience. In evaluating the annual metrics this year, the team discovered that the Twitter metrics were being met consistently while the Facebook metrics lagged. The DCC Social Media Team developed a comprehensive survey to assess usage by other similar organizations (e.g. NCI cooperative groups, other research networks). The survey will be sent this spring and will evaluate which accounts these groups are using, their activity level, the successfulness and usefulness of their accounts, the benefits and disadvantages of each, the amount of time spent on social media efforts, and their target metrics. Based on the survey results and re-evaluation of the metrics, the DCC Social Media Team will make recommendations to the DCC leadership regarding future strategies for the accounts. 42