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Blood and Marrow Transplant Clinical Trials Network (BMT CTN): Past, Present and Future Hillard M. Lazarus, MD The George & Edith Richman Professor and.

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Presentation on theme: "Blood and Marrow Transplant Clinical Trials Network (BMT CTN): Past, Present and Future Hillard M. Lazarus, MD The George & Edith Richman Professor and."— Presentation transcript:

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 Nobel Prize in Physiology or Medicine, 1990

3 N=6 pts: variety of diseases, malignant & non-malignant differing marrow products infused demonstrated safety (no marrow emboli) demonstrated some donor engraftment ED Thomas, et al. N Engl J Med 257: , 1957 BONE MARROW TRANSPLANTATION Initial Report: Mary Imogene Bassett Hospital F Appelbaum. N Engl J Med 357: , 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 NHLBI & NCI STEERING COMMITTEE Administrative Committees Technical Committees Data and Coordinating Center BMT03new_2.p pt Protocol Teams Affiliate Clinical Centers 20 Clinical Cores; High-performing Affiliate Centers NCI Coop Group Chairs (ex officio ) Protocol Review Committee Data and Safety Monitoring Board BMT CTN Organizational Structure

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

9 BLOOD & MARROW TRANSPLANTATION 1 st 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 1 st 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 1 st State of Science Symposium Conclusions: 1.Necessity of multi-institutional studies 2.Studies can be adapted to multi-institutional setting 3.Studies could be completed in a responsible time

12 Conclusions for studies needed: 1. Blood vs marrow in matched sibling donors – (NA) 2. Blood vs marrow in matched unrelated donors – (0201) 3. Techniques to improve cord blood engraftment – (0501) 4. T-cell depletion studies – (0303) 5. Methods to improve autologous cell collection – (NA) 6. Comparisons of related and unrelated HCT vs standard chemotherapy for high risk patients – (S1203) BLOOD & MARROW TRANSPLANTATION 1 st State of Science Symposium

13  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 ) BMT CTN FOUNDATION Creation and Organization/Administration

14  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 BMT CTN Case Consortium (Original & Current)

15 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” BMT CTN FOUNDATION Creation and Organization/Administration

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

17 No. pts 440 1,058 1,615 2, ,200 5,200 Collaboration with cooperative groups to avoid duplication C =Enrollment complete =Enrollment on-going =Cumulative actual [projected] accrual =Coop group collaboration (see color key above) PIII Vori vs. Fluconazole 0201 PIII Unrelated PBSC vs. Marrow 0102 PIII Myeloma Tandem HCT 0202 PIII follicular NHL (closed early) 0301 PII Unrelated Tx for aplastic anemia 0302 PII AGVHD therapy 0303 PII T-depleted HCT for AML 0401 PIII BEAM vs BEAM-Bexxar for Lymphoma 0402 PIII GVHD prophylaxis 0403 PIII Etanercept for IPS (closed early) 0501 III Single vs Double CBT0502 PII NST for AML >60y 0601 PII Sickle Cell NST 0603 PII Haplo in Adult 0604 PII DCB in Adult 0701 PII NST for NHL 0702 PIII Myeloma Follow-on 0703 PII HD 0704 PIII MM maintenance 0801 P II/III CGVHD Treatment 0802 PIII AGVHD Treatment 0803 HIV+ Lymphoma 0804 High Risk CLL 0901 Full vs RIC - MDS/AML 0902 Post Tx Stress Mgmt 0903 Allo Tx for HIV Haplo vs. 2 UCB

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

19 BMT CTN: Numbers of Protocols Opened * 0704* * * *

20 BMT CTN Yearly & Cumulative Accrual All Protocols,

21 BMT CTN TRIALS Protocol Categories All TrialsPhase IIPhase III Donor/Graft Source1266 GVHD532 Infection321 Disease Control1266 Regimen Toxicity422 QOL725 TOTAL2814

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 2 nd State of Science Symposium -BMT CTN organized and led -June 7-8, 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 2 nd State of Science Symposium 1.Optimal donor and graft source – C. Anasetti 2.Regimen-related toxicity – E. Stadtmauer 3.Graft-versus-host disease – J. Antin 4.Infection & immune reconstitution – J. Wingard 5.Late effects/quality of life – S. Lee 6.Pediatrics – K. Schultze, J. Levine

25 BLOOD & MARROW TRANSPLANTATION 2 nd State of Science Symposium (con’t) 7. Leukemia – F. Appelbaum 8. Lymphoma – R. Negrin 9. Plasma cell myeloma – S. Giralt 10. Non-malignant disorders – C. Bredson 11. Gene and cell therapy – H. Heslop, D. Kohn 12. Cinical trial design – M. Horowitz

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

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

28 7. CLL: Phase II RIC Allo HCT for high risk CLL – 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 Crohn disease – NA 11. Cell Therapy: Phase II viral-specific CTL adenovirus - NA BLOOD & MARROW TRANSPLANTATION 2 nd State of Science Symposium: Conclusions

29 MAJOR SCIENTIFIC PUBLICATIONS Potentially Practice-Changing

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

31 C Anasetti, BMT CTN. N Engl J Med 367: , BLOOD vs MARROW GRAFT SOURCE Matched Unrelated Donors (MUD): Engraftment

32 C Anasetti, BMT CTN. N Engl J Med 367: , BLOOD vs MARROW GRAFT SOURCE Matched Unrelated Donors (MUD): GVHD

33 C Anasetti, BMT CTN. N Engl J Med 367: , BLOOD vs MARROW GRAFT SOURCE Matched Unrelated Donors (MUD): Relapse & TRM

34 C Anasetti, BMT CTN. N Engl J Med 367: , BLOOD vs MARROW GRAFT SOURCE Matched Unrelated Donors (MUD): Survival

35 BMT CTN 0401 Reduce 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 Day -19 Day -12 Day -6 Days -5 to -2 Day -1 Day 0 Bexxar 75 cGy TBD Bexxar 5 mCiRituxan 375 mg/m 2 Infusion of mobilized hematopoietic cells BCNU 300 mg/m 2 Etoposide [VP-16] 100 mg/m 2 BID (8 doses) Ara-C [Cytarabine] 100 mg/m 2 BID (8 doses) Melphalan 140 mg/m 2 Day +5 G-CSF 5 µg/kg daily until ANC >500/mm 3 x 3 days Within 3 mo of mobilization dosimetry

37 Probability, % Months Rituxan/BEAM (N=113) Bexxar/BEAM (N=111) 2 yr: 48.6% p= yr: 49.0% BMT CTN 0401 Autograft BEXXAR-BEAM vs Rituximab-BEAM Probability Progression-free survival (PFS) JM Vose, BMT CTN. J Clin Oncol 31: , 2013.

38 Probability, % Months Rituxan/BEAM (N=113 ) Bexxar/BEAM (N=111) 2 yrs: 60.1% p= yrs: 66.3% BMT CTN 0401 Autograft BEXXAR-BEAM vs Rituximab-BEAM Probability Survival JM Vose, BMT CTN. J Clin Oncol 31: , 2013.

39 BMT CTN Relapse Prevention Questions: Myeloma Tandem Autograft vs Autograft-Allograft

40 A Krishnan, BMT CTN. Lancet Oncol 12: , TRANSPLANTATION IN MYELOMA Tandem Autograft vs Autograft-RIC Allograft Autografts: Melphalan 200 mg/m 2 Allograft: TBI 200 cGy

41 A Krishnan, BMT CTN. Lancet Oncol 12: , TRANSPLANTATION IN MYELOMA Tandem Autograft vs Autograft-RIC Allograft Standard-risk

42 A Krishnan, BMT CTN. Lancet Oncol 12: , TRANSPLANTATION IN MYELOMA Tandem Autograft vs Autograft-RIC Allograft High-risk

43 BMT CTN Relapse Prevention Questions: Myeloma Post-Autograft Maintenance Therapy

44 AUTOGRAFT IN MYELOMA Post-Transplant Lenalidomide vs Placebo PL McCarthy, BMT CTN. N Engl J Med 366: , Joint BMT CTN and CALGB study Median TTP 46 mo Median TTP 27 mo 3 yr 3 yr

45 AUTOGRAFT IN MYELOMA Post-Transplant Lenalidomide vs Placebo PL McCarthy, BMT CTN. N Engl J Med 366: , Risk 2 nd maligancy

46 BMT CTN Novel GVHD Prevention Strategies T Cell Depletion and Other Strategies

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

48 BMT CTN 0701 Allograft & High-dose Rituximab in FCC NHL Rituximab 375 mg/m 2 (day –13) Rituximab 1,000 mg/m 2 (day – 6) Fludarabine + Cyclophosphamide conditioning Tacrolimus+ Methotrexate (GVHD prophylaxis) Rituximab 1,000 mg/m 2 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 DISEASE Prophylaxis: T Cell Depletion Decades of failure Engraftment failure Prolonged immune incompetence viral, opportunistic infections High relapse rates VT Ho, RJ Soiffer. Blood 98: , 2001.

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

51 GRAFT-VS-HOST DISEASE Prophylaxis: AML CR1 & T Cell Depletion S Devine, BMT CTN. Biol Blood Marrow Transplant 17: , 2010 Relapse No engraftment failures Survival

52 AML CR1 ALLOGRAFTS: BMT CTN T Cell Depletion vs Immune Suppression MC Pasquini, BMT CTN. J Clin Oncol 30: , 2012 GVHD-Free Survival Survival N=44 T Cell Depletion; N=88 Immune Suppression Relapse

53 GRAFT-VS-HOST DISEASE Prophylaxis: Combination C Cutler, BMT CTN. Blood 120: 2012 (abstract #739). Myeloablative conditioning: Cy or VP-16 plus TBI > 1200 cGy Mobilized blood graft Median (range) age 44 (13-59) yr

54 Sirolimus/tacrolimus: No advantage in 114-day acute GVHD-free survival 2 and 3 days faster neutrophil and platelet engraftment Reduction in acute GVHD  8% absolute  II-IV, p = 0.17  7% absolute  III-IV, p = 0.05 More chronic GVHD  9% absolute , p = 0.05 Less mucositis but more endothelial injury (all p  0.05) Acceptable alternative to tacrolimus/methotrexate BMT CTN GVHD PROPHYLAXIS Sirolimus/Tacrolimus vs Tacrolimus/Methotrexate

55 BMT CTN Regimen-Intensity Questions Acute Leukemia and MDS

56 ACUTE MYELOID LEUKEMIA CR1 Reduced-Intensity Conditioning in Elderly

57 CALGB & BMT CTN: 21 centers Median age 65 (60-74) yr N= 58 matched-related donor; N=65 MUD 82 intermediate cytogenetics; 25 adverse cytogenetics Fludarabine + busulfan ± ATG SM Devine, CALGB, BMT CTN. Blood 120: 2012 (abstract #230). 2 Yr Treatment-related mortality14% Acute GVHD gr 100 days Chronic GVHD26% Relapse47% Overall survival46%

58 ACUTE MYELOID LEUKEMIA CR1 Prospective Randomized: RIC vs Myeloablative M Bornhäuser, German AML. Lancet Oncol 13: , German AML Study Group: small series

59 ACUTE MYELOID LEUKEMIA & ALLOGRAFT Myeloablative vs Reduced-Intensity Conditioning BMT CTN 0901

60 BMT CTN Alternative Donor Graft Source Questions No Matched-Related or MUD Available

61 GRAFT-VS-HOST DISEASE Post-Transplant Cyclophosphamide L Luznik, Hopkins. Blood 115: , N=117; Bu/CY T-replete marrow CY 50 mg/kg/d T+3, T+4 Chronic GVHD Acute GVHD

62 BMT CTN Protocol 1101 Multi-center, Phase III, Randomized Trial of Reduced Intensity Conditioning and Transplantation Of Double Unrelated Umbilical Cord Blood versus HLA-Haploidentical Related Bone Marrow for Patients with Hematologic Malignancies Followup to 2 independent BMT CTN phase II studies BMT CTN 0603 and 0604

63 45% 31% 54% CG Brunstein, BMT CTN. Blood 118: , 2011

64 Patient ≥ 18 and ≤70 yr Acute leukemia or lymphoma Adequate organ function Performance score ≥70 No sibling or matched unrelated donor available, BUT: Double umbilical cord blood (UCB) graft Haploidentical related donor marrow (Haplo-BM) No donor specific anti-HLA-Ab Randomization Stratified by Transplant Center Double UCB Haplo-BM BMT CTN Study Design Protocol 1101

65 BMT CTN Protocol 1101 Minnesota Protocol (0604) Hopkins Protocol (0603) Eliminate alloreactive T cells Haploidentical

66 BMT CTN Manuscripts in Preparation  0402 – Sirolimus vs methotrexate (in combo with tacrolimus) to prevent acute GVHD : NO BENEFIT  0403 – Etanercept for Idiopathic Pneumonia Syndrome: NO BENEFIT  0501 – Single vs double UCB transplant in children: MORE GVHD with double; NO ADVANTAGE engraftment or survival  0502 – RIC HCT for older AML adults: GOOD RESULTS  0802 – MMF as initial therapy for AGVHD: NO BENEFIT

67 BMT CTN Future Continued accrual enhancement Continued publications in high-impact journals Repository trials: GVHD blood biomarkers

68 BMT CTN Protocol 1202 Prospective Multi-Center Cohort for the Evaluation of Biomarkers Predicting Risk of Complications and Mortality Following Allogeneic HCT 1,500 allogeneic patients over 4 yr: HCT US centers Samples collected for DNA, RNA, and proteins: R24 Building upon University of Michigan data and other sources Data collection for post-transplant complications

69 Biomarker Approach Sample No. Pts Pre- Conditioning Pre-HCT Day -1 or 0 Days post-HCT 7 ±2 14 ± 2 21 ± 2 28 ± 2 42 ± 3 56 ± 3 90 ±10 Genetic DNA 17mL blood 1500X Proteomic Serum (10 mL blood) 1500 XXXXXXXX Gene Expression PAXgene Lysates- (20 mL blood) 240 X X Recipient Samples BMT CTN Protocol 1202

70 BMT CTN Future (con’t) Partnering with other groups: IFM Canadians Germans Increased companion translational trials: obesity 3 rd State of the Science Symposium

71 IFM/DFCI 2009 Phase III: Untreated Myeloma Arm A  RVD Cycles 2-3  HD Cytoxan; collect cells  RVD Cycles 4-8  Maintenance lenalidomide (Melphalan + relapse) Arm B  RVD Cycles 2-3  HD Cytoxan; collect cells  HD Melphalan + HCT  RVD for 2 more cycles  Maintenance Lenalidomide RANDOMIZERANDOMIZE Symptomatic myeloma with measurable disease  <65 yrs and transplant-eligible; ECOG <2 (KPS ≥60% ) 1° Endpoint: PFS 2° Endpoints: relapse, TTP, survival, QOL, economics, genetic prognostic Initial Therapy RVD Cycle 1 RVD=lenalidomide; bortezomib; dexamethasone

72 BMT CTN Future (con’t) Partnering with other groups: IFM Canadians Germans Increased companion translational trials: obesity 3 rd State of the Science Symposium

73  Myeloma patients within 9 months of diagnosis  Single autograft +/- consolidation versus tandem autograft and maintenance  N=750 patients (250 each arm)  Uniformity of treatment:  Melphalan 200 mg/m 2 IV plus autograft  Accrual nearly reached COOPERATIVE ONCOLOGY GROUPS Obesity and Myeloma: BMT CTN 0702

74 Myeloma is an obesity-driven disease Critical questions -What is impact of obesity on treatment and disease? -If obesity has detrimental effects, what are the mechanisms & how can these be addressed & improved? -If obesity has beneficial effects, how can these be identified and used to enhance therapeutic outcomes? COOPERATIVE ONCOLOGY GROUPS Companion Investigation: Example

75 OBESITY AND MYELOMA  Limitations of BMI (body mass index)  Anthropomorphic measures of abdominal adiposity  correlate with cardiovascular and cancer mortality:  independent of BMI  Which anthropomorphic measurements are better?  Waist:Hip measure better indicator of visceral fat  better correlation with incidence colon & ovarian cancer C Zhang, et al. Circulation 117: , 2008 YC Wang, et al. Obesity 15: , 2007

76 OBESITY AND MYELOMA  Opportunity to study prospectively other biologic measurements  Identify mechanisms by which obesity impacts therapy  Identify mechanisms by which obesity affects disease progression  Identification of potential markers and mediators to impact disease progression

77 Companion translational obesity study to transplant trial Investigators: HM Lazarus E Campagnaro NA Berger Anthropomorphic measures at frequent intervals Analysis of prospectively collected/archived blood samples COOPERATIVE ONCOLOGY GROUPS Clinical Investigation: Example

78 Measure Hip & Waist Circumference

79 OBESITY AND TRANSPLANT Myeloma: BMT CTN 0702 Waist:Hip measurement Plasma biomarkers Adipokines/cytokines: adiponectin, leptin, IL-6, TNF-α Hormones: insulin, C-peptide, pancreatic peptide (PP), peptide YY (PYY) Growth factors: IGF-1, IGFBP-3

80 BMT CTN Future (con’t) 3 rd State of the Science Symposium February 24-25, Grapevine, TX

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