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Blood and Marrow Transplant Clinical Trials Network (BMT CTN): Past, Present and Future

Blood and Marrow Transplant Clinical Trials Network (BMT CTN): Past, Present and Future. Hillard M. Lazarus, MD The George & Edith Richman Professor and Distinguished Scientist in Cancer Research Director of Novel Cell Therapy University Hospitals Case Medical Center

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Blood and Marrow Transplant Clinical Trials Network (BMT CTN): Past, Present and Future

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  1. Blood and Marrow Transplant Clinical Trials Network (BMT CTN): Past, Present and Future Hillard M. Lazarus, MD The George & Edith Richman Professor and Distinguished Scientist in Cancer Research Director of Novel Cell Therapy University Hospitals Case Medical Center Case Western Reserve University

  2. E Donnall Thomas, MD 1920-2012 Nobel Prize in Physiology or Medicine, 1990

  3. BONE MARROW TRANSPLANTATIONInitial Report: Mary Imogene Bassett Hospital ED Thomas, et al. N Engl J Med 257: 491-496, 1957 • N=6 pts: variety of diseases, malignant & non-malignant • differing marrow products infused • demonstrated safety (no marrow emboli) • demonstrated some donor engraftment F Appelbaum. N Engl J Med 357: 1472-1475, 2007

  4. Genesis

  5. I can’t cover everything

  6. BLOOD AND MARROW TRANSPLANT CLINICAL TRIALS NETWORK • Established November 2001 • Mission: Conduct scientifically meritorious multicenter trials in an efficient manner to improve transplant outcomes • Provide infrastructure to allow promising therapies to be developed/evaluated in high quality, multicenter studies that give definitive answers as rapidly as possible

  7. BMT CTN Organizational Structure NHLBI& NCI Data and Safety Monitoring Board Protocol Review Committee 20 Clinical Cores; High-performing Affiliate Centers NCI Coop Group Chairs (ex officio) STEERING COMMITTEE Protocol Teams Technical Committees Administrative Committees Affiliate Clinical Centers Data and Coordinating Center BMT03new_2.ppt

  8. Patient Advocacy NMDP Contracting BMT CTN Data and Coordinating Center Electronic Communications Statistical Design/Analysis Overall Coordination CIBMTR Data Management * EMMES Scientific Leadership Protocol Development/ Implementation Trial Oversight/Monitoring Lab/Repository Management Medical Monitoring * professional partner to clinicians, scientists, program leaders

  9. BLOOD & MARROW TRANSPLANTATION 1st State of Science Symposium: 4/01/2000 • Stem cell source & donor selection – Horowitz, Champlin, Anasetti, Hansen, Wagner, Confer • Regimen-related toxicity – Armitage, Blume, McDonald, Jones • Graft-versus-host disease – Blazar, Martin, Guinan, Parkman, Storb, Ferrara • Recurrence after autograft– Nadler, Vose, Press, Gribben, Antman

  10. BLOOD & MARROW TRANSPLANTATION 1st State of Science Symposium: 4/01/2000 • Recurrence after allograft – O’Reilly, Scheinberg, Barrett, Levitsky, Riddell • Infectious complications – Wingard, Forman, Zaia, Heslop • Late complications & immune recovery – Sullivan, Weinberg, Gress, Vogelsang

  11. BLOOD & MARROW TRANSPLANTATION 1st State of Science Symposium • Conclusions: • Necessity of multi-institutional studies • Studies can be adapted to multi-institutional setting • Studies could be completed in a responsible time

  12. BLOOD & MARROW TRANSPLANTATION 1st State of Science Symposium • Conclusions for studies needed: • Blood vsmarrow in matched sibling donors – (NA) • Blood vs marrow in matched unrelated donors – (0201) • Techniques to improve cord blood engraftment – (0501) • T-cell depletion studies – (0303) • Methods to improve autologous cell collection – (NA) • Comparisons of related and unrelated HCT vs • standard chemotherapy for high risk patients – (S1203)

  13. BMT CTN FOUNDATION Creation and Organization/Administration • RFA from NHLBI in 2001 • Competition for Data Coordinating Center (DCC) • Emmes Corp, NMDP and CIBMTR awarded • Competition for Centers • Established 16 Core Centers • Case Consortium original Core Center • ( Re-competition: expanded to 20 in July 2011 )

  14. BMT CTN Case Consortium (Original & Current) • Case Western Reserve University (CWRU); • Oregon Health Sciences University (OHSU); • University of Illinois Chicago • Transition to add Washington University (St. Louis) and Ohio State University (through 2011) • Present configuration • CWRU, OHSU • Cleveland Clinic, West Virginia University

  15. BMT CTN FOUNDATION Creation and Organization/Administration • Formation of committees and teams: • Manual of Policies/Procedures (MOP) • Disease-specific teams • Protocol-specific teams • Liaison relation with cooperative oncology groups • Electronic data capture system • Per patient reimbursement model • Websites for members & public • Metrics for center performance: “Report Card”

  16. Clinical Population Scientific Rationale Logistical/ budgetary Constraints Feasibility Issues • Protocol Development & Prioritization

  17. Collaboration with cooperative groups to avoid duplication No. pts440 1,058 1,615 2,133 2625 3048 4,200 5,200 C 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2001 2002 1101 Haplo vs. 2 UCB 0903 Allo Tx for HIV+ 0901 Full vs RIC - MDS/AML 0804 High Risk CLL 0902 Post Tx Stress Mgmt 0803 HIV+ Lymphoma 0702 PIII Myeloma Follow-on 0801 P II/III CGVHD Treatment 0802 PIII AGVHD Treatment 0701 PII NST for NHL 0604 PII DCB in Adult 0603 PII Haplo in Adult 0601 PII Sickle Cell NST 0703 PII HD 0403 PIII Etanercept for IPS(closed early) 0704 PIII MM maintenance = Enrollment complete = Enrollment on-going = Cumulative actual [projected] accrual = Coop group collaboration(see color key above) 0402 PIII GVHD prophylaxis 0501 III Single vs Double CBT 0502 PII NST for AML >60y 0301 PII Unrelated Tx for aplastic anemia 0401 PIII BEAM vs BEAM-Bexxar for Lymphoma 0302 PII AGVHD therapy 0303 PII T-depleted HCT for AML 0202 PIII follicular NHL (closed early) 0201 PIII Unrelated PBSC vs. Marrow 0101 PIII Vori vs. Fluconazole 0102 PIII Myeloma Tandem HCT

  18. BMT CTN Centers, 2013>115 centers enrolled >5000 ptssince 2003 = Core Centers = PBMTC Centers = Affiliate Centers Mmh11_9.ppt

  19. BMT CTN: Numbers of Protocols Opened 0702 0803 0801 0804* 0802 0805* 1102 1202 1203 1204 1205 0601 0603 0604 0703* 0403 0502* 0704* 0302 0303 0401 0301 0402 0501 0101 0102 0903 1101 0201 0202 0901 0902 0701

  20. BMT CTN Yearly & Cumulative Accrual All Protocols, 2004-2012

  21. BMT CTN TRIALS Protocol Categories

  22. BMT CTN Publications Summary • 2012: • 7 peer-reviewed papers (+1 in press) • 28 total: • 10 primary results papers: 0101, 0102, 0202, 0301, 0302, 0303, 0401, 0601, 0603/0604, 0704 (100104) • 8 other protocol-related papers • 3 methodology papers • 7 other Network publications

  23. BLOOD & MARROW TRANSPLANTATION 2nd State of Science Symposium • BMT CTN organized and led • June 7-8, 2007 @ Ann Arbor, MI • Goal: identify key transplant-related issues • Propose critical trials to address these issues • may be sequential phase II  III • may require cooperative oncology group or other participants • trials should be ready to start quickly

  24. BLOOD & MARROW TRANSPLANTATION 2nd State of Science Symposium • Optimal donor and graft source – C. Anasetti • Regimen-related toxicity – E. Stadtmauer • Graft-versus-host disease – J. Antin • Infection &immune reconstitution – J. Wingard • Late effects/quality of life – S. Lee • Pediatrics – K. Schultze, J. Levine

  25. BLOOD & MARROW TRANSPLANTATION 2nd State of Science Symposium (con’t) Leukemia– F. Appelbaum Lymphoma– R. Negrin Plasma cell myeloma – S. Giralt 10. Non-malignant disorders – C. Bredson 11. Gene and cell therapy – H. Heslop, D. Kohn 12. Cinicaltrial design – M. Horowitz

  26. BLOOD & MARROW TRANSPLANTATION Timeline: 2nd State of Science Symposium April 2006 Committees named and charged June-Dec 2006 Committee conference calls Dec 2006 Committee in-person mtgs @ ASH Feb 2007 Committee in-person mtg @ Tandem May 2007 Document due June 2007 SOSS JL Ferrara, BMT CTN. Biol Blood Marrow Transplant 13: 1268-1285, 2007

  27. BLOOD & MARROW TRANSPLANTATION 2nd State of Science Symposium: Conclusions • 1. GVHD: Phase II trial calcineurin-free regimen – 0402 • 2. QOL: Phase III study stress management – 0902 • 3. Myeloma: Phase III comparison tandem HCT vs. consolidation and maintenance – 0702 • 4. AML: Phase III chemotherapy vs. URD HCT – SWOG 1203 • 5. AML: Phase III full intensity vs. RIC HCT - 0901 • 6. Ph+ ALL: Phase III chemotherapy vs. Allo HCT – S0805

  28. BLOOD & MARROW TRANSPLANTATION 2nd State of Science Symposium: Conclusions 7. CLL: Phase II RIC Allo HCT for high risk CLL – 0804 8. Lymphoma: Phase II RIC Allo HCT in T cell lymphoma – NA 9. HLH: Phase II RIC for children with HLH – planning 10. Non-malignant: Phase II auto HCT in Crohndisease – NA 11. Cell Therapy: Phase II viral-specific CTL adenovirus - NA

  29. MAJOR SCIENTIFIC PUBLICATIONS Potentially Practice-Changing

  30. BMT CTNDonor Graft Source Questions Blood versus Marrow Extremely complex undertaking; Dual consent: donor and recipient

  31. BLOOD vs MARROW GRAFT SOURCE Matched Unrelated Donors (MUD): Engraftment C Anasetti, BMT CTN. N Engl J Med367: 1487-96, 2012.

  32. BLOOD vs MARROW GRAFT SOURCE Matched Unrelated Donors (MUD): GVHD C Anasetti, BMT CTN. N Engl J Med367: 1487-96, 2012.

  33. BLOOD vs MARROW GRAFT SOURCE Matched Unrelated Donors (MUD): Relapse & TRM C Anasetti, BMT CTN. N Engl J Med367: 1487-96, 2012.

  34. BLOOD vs MARROW GRAFT SOURCE Matched Unrelated Donors (MUD): Survival C Anasetti, BMT CTN. N Engl J Med367: 1487-96, 2012.

  35. BMT CTN 0401Reduce Relapse After Autograft: NHL DLBCL: BEXXAR-BEAM vs Rituximab-BEAM No differences in patient outcome except increased mucositis

  36. Randomized to Bexxar/BEAM or Rituxan/BEAM Within 3 mo of mobilization Day -19 Bexxar 5 mCi Rituxan 375 mg/m2 dosimetry Bexxar 75 cGy TBD Rituxan 375 mg/m2 Day -12 BCNU 300 mg/m2 Etoposide [VP-16] 100 mg/m2 BID (8 doses) Ara-C [Cytarabine] 100 mg/m2 BID (8 doses) Melphalan 140 mg/m2 Day -6 Days -5 to -2 Days -5 to -2 Day -1 Infusion of mobilized hematopoietic cells Day 0 Day +5 G-CSF 5 µg/kg daily until ANC >500/mm3 x 3 days

  37. BMT CTN 0401Autograft BEXXAR-BEAM vs Rituximab-BEAM 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Probability Progression-free survival (PFS) Rituxan/BEAM (N=113) Probability, % Bexxar/BEAM (N=111) Bexxar/BEAM @ 2 yr: 48.6% p=0.65 Rituxan/BEAM @ 2 yr: 49.0% 0 6 12 18 24 30 36 42 48 Months JM Vose, BMT CTN. J ClinOncol 31: 1662-1668, 2013.

  38. BMT CTN 0401Autograft BEXXAR-BEAM vs Rituximab-BEAM 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Probability Survival Rituxan/BEAM (N=113) Probability, % Bexxar/BEAM (N=111) Bexxar/BEAM @ 2 yrs: 60.1% p=0.29 Rituxan/BEAM @ 2 yrs: 66.3% 0 6 12 18 24 30 36 42 48 Months JM Vose, BMT CTN. J ClinOncol 31: 1662-1668, 2013.

  39. BMT CTNRelapse Prevention Questions: Myeloma Tandem AutograftvsAutograft-Allograft

  40. TRANSPLANTATION IN MYELOMA Tandem AutograftvsAutograft-RIC Allograft Autografts: Melphalan 200 mg/m2 Allograft: TBI 200 cGy A Krishnan, BMT CTN. Lancet Oncol12: 1195-203, 2011.

  41. TRANSPLANTATION IN MYELOMA Tandem AutograftvsAutograft-RIC Allograft Standard-risk A Krishnan, BMT CTN. Lancet Oncol12: 1195-203, 2011.

  42. TRANSPLANTATION IN MYELOMA Tandem AutograftvsAutograft-RIC Allograft High-risk A Krishnan, BMT CTN. Lancet Oncol12: 1195-203, 2011.

  43. BMT CTNRelapse Prevention Questions: Myeloma Post-Autograft Maintenance Therapy

  44. AUTOGRAFT IN MYELOMA Post-Transplant Lenalidomidevs Placebo Joint BMT CTN and CALGB study 88% @ 3 yr Median TTP 46 mo 80% @ 3 yr Median TTP 27 mo PL McCarthy, BMT CTN. N Engl J Med 366: 1770-81, 2012.

  45. AUTOGRAFT IN MYELOMA Post-Transplant Lenalidomidevs Placebo Risk 2ndmaligancy PL McCarthy, BMT CTN. N Engl J Med 366: 1770-81, 2012.

  46. BMT CTNNovel GVHD Prevention Strategies T Cell Depletion and Other Strategies

  47. HEMATOPOIETIC CELL TRANSPLANTAllograft & High-dose Rituximab in FCC NHL Survival Graft-vs-Host Disease IF Khouri, MD Anderson. Blood 111: 5530-5536, 2008

  48. BMT CTN 0701Allograft & High-dose Rituximab in FCC NHL • Rituximab 375 mg/m2 (day –13) • Rituximab1,000 mg/m2(day – 6) • Fludarabine+ Cyclophosphamide conditioning • Tacrolimus+ Methotrexate (GVHD prophylaxis) • Rituximab 1,000 mg/m2 day +1 and +8 • Blood allograft infusion (matched-related or MUD) • PK studies for rituximab blood concentration • Accrual completed: awaiting DSMB recommendations

  49. GRAFT-VS-HOST DISEASEProphylaxis: T Cell Depletion • Decades of failure • Engraftment failure • Prolonged immune incompetence • viral, opportunistic infections • High relapse rates VT Ho, RJ Soiffer. Blood 98: 3192-204, 2001.

  50. GRAFT-VS-HOST DISEASEProphylaxis: AML CR1 & T Cell Depletion • Multi-center BMT CTN trial: CD34 selection, Miltenyi device • Few AML CR2; early follow-up Grade 3-4 Acute GVHD Chronic GVHD S Devine, BMT CTN. Biol Blood Marrow Transplant 17: 1343-51, 2010

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