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Blood and Marrow Transplant Clinical Trials Network (BMT CTN):

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Presentation on theme: "Blood and Marrow Transplant Clinical Trials Network (BMT CTN):"— 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 BONE MARROW TRANSPLANTATION Initial Report: Mary Imogene Bassett Hospital
ED Thomas, et al. N Engl J Med 257: , 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: , 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 Protocol Review Committee Data and Safety Monitoring Board 20 Clinical Cores; High-performing Affiliate Centers NCI Coop Group Chairs (ex officio) STEERING COMMITTEE Administrative Committees Technical Committees Protocol Teams Affiliate Clinical Centers Data and Coordinating Center BMT03new_2.ppt

8 BMT CTN Data and Coordinating Center CIBMTR * EMMES NMDP
Electronic Communications Overall Coordination Statistical Design/ Analysis CIBMTR Data Management * EMMES Scientific Leadership NMDP Patient Advocacy Contracting 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 vs marrow 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 Creation and Organization/Administration
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 Case Consortium (Original & Current)
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 Creation and Organization/Administration
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 Protocol Development & Prioritization
Feasibility Issues Scientific Rationale Logistical/ budgetary Constraints Clinical Population

17 Collaboration with cooperative groups to avoid duplication
No. pts ,058 1,615 2, , ,200 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 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 0502 PII NST for AML >60y = 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 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 pts since 2003
= Core Centers = PBMTC Centers = Affiliate Centers Mmh11_9.ppt

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

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

21 BMT CTN TRIALS Protocol Categories
All Trials Phase II Phase III Donor/Graft Source 12 6 GVHD 5 3 2 Infection 1 Disease Control Regimen Toxicity 4 QOL 7 TOTAL 28 14

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, 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. Cinical trial design – M. Horowitz

26 BLOOD & MARROW TRANSPLANTATION
Timeline: 2nd State of Science Symposium April Committees named and charged June-Dec Committee conference calls Dec Committee in-person ASH Feb Committee in-person Tandem May Document due June SOSS JL Ferrara, BMT CTN. Biol Blood Marrow Transplant 13: , 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 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 Crohn disease – NA 11. Cell Therapy: Phase II viral-specific CTL adenovirus - NA

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 30

31 BLOOD vs MARROW GRAFT SOURCE
Matched Unrelated Donors (MUD): Engraftment C Anasetti, BMT CTN. N Engl J Med 367: , 2012.

32 BLOOD vs MARROW GRAFT SOURCE Matched Unrelated Donors (MUD): GVHD
C Anasetti, BMT CTN. N Engl J Med 367: , 2012.

33 BLOOD vs MARROW GRAFT SOURCE
Matched Unrelated Donors (MUD): Relapse & TRM C Anasetti, BMT CTN. N Engl J Med 367: , 2012.

34 BLOOD vs MARROW GRAFT SOURCE Matched Unrelated Donors (MUD): Survival
C Anasetti, BMT CTN. N Engl J Med 367: , 2012.

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

36 Randomized to Bexxar/BEAM or Rituxan/BEAM
Within 3 mo of mobilization Day -19 Bexxar 5 mCi Rituxan 375 mg/m2 dosimetry Day -12 Bexxar 75 cGy TBD Rituxan 375 mg/m2 Day -6 Days -5 to -2 Day -1 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 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 0401 Autograft BEXXAR-BEAM vs Rituximab-BEAM
Probability Progression-free survival (PFS) 100 20 40 60 80 90 10 30 50 70 100 20 40 60 80 90 10 30 50 70 Rituxan/BEAM (N=113) Probability, % Bexxar/BEAM (N=111) 2 yr: 48.6% p=0.65 2 yr: 49.0% 6 12 18 24 30 36 42 48 Months JM Vose, BMT CTN. J Clin Oncol 31: , 2013.

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

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

40 TRANSPLANTATION IN MYELOMA Tandem Autograft vs Autograft-RIC Allograft
Autografts: Melphalan 200 mg/m2 Allograft: TBI 200 cGy A Krishnan, BMT CTN. Lancet Oncol 12: , 2011.

41 TRANSPLANTATION IN MYELOMA Tandem Autograft vs Autograft-RIC Allograft
Standard-risk A Krishnan, BMT CTN. Lancet Oncol 12: , 2011.

42 TRANSPLANTATION IN MYELOMA Tandem Autograft vs Autograft-RIC Allograft
High-risk A Krishnan, BMT CTN. Lancet Oncol 12: , 2011.

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

44 Post-Transplant Lenalidomide vs Placebo
AUTOGRAFT IN MYELOMA Post-Transplant Lenalidomide vs Placebo Joint BMT CTN and CALGB study 3 yr Median TTP 46 mo 3 yr Median TTP 27 mo PL McCarthy, BMT CTN. N Engl J Med 366: , 2012.

45 Post-Transplant Lenalidomide vs Placebo
AUTOGRAFT IN MYELOMA Post-Transplant Lenalidomide vs Placebo Risk 2nd maligancy PL McCarthy, BMT CTN. N Engl J Med 366: , 2012.

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

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

48 BMT CTN 0701 Allograft & High-dose Rituximab in FCC NHL
Rituximab mg/m (day –13) Rituximab 1,000 mg/m (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 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. 49

50 GRAFT-VS-HOST DISEASE Prophylaxis: 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: , 2010 50

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

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

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

54 BMT CTN GVHD PROPHYLAXIS Sirolimus/Tacrolimus vs Tacrolimus/Methotrexate
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

55 BMT CTN Regimen-Intensity Questions
Acute Leukemia and MDS 55

56 ACUTE MYELOID LEUKEMIA CR1 Reduced-Intensity Conditioning in Elderly

57 ACUTE MYELOID LEUKEMIA CR1 Reduced-Intensity Conditioning in Elderly
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 Event 2 Yr Treatment-related mortality 14% Acute GVHD gr 3-4 100 days Chronic GVHD 26% Relapse 47% Overall survival 46% SM Devine, CALGB, BMT CTN. Blood 120: 2012 (abstract #230).

58 ACUTE MYELOID LEUKEMIA CR1 Prospective Randomized: RIC vs Myeloablative
German AML Study Group: small series M Bornhäuser, German AML. Lancet Oncol 13: , 2012.

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

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

61 GRAFT-VS-HOST DISEASE Post-Transplant Cyclophosphamide
Acute GVHD Chronic GVHD N=117; Bu/CY T-replete marrow CY 50 mg/kg/d T+3, T+4 L Luznik, Hopkins. Blood 115: , 2010. 61

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 CG Brunstein, BMT CTN. Blood 118:282-288, 2011
45% 31% 54% CG Brunstein, BMT CTN. Blood 118: , 2011

64 BMT CTN Study Design Protocol 1101 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

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

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

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

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

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

73 COOPERATIVE ONCOLOGY GROUPS Obesity and Myeloma: BMT CTN 0702
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/m2 IV plus autograft Accrual nearly reached

74 COOPERATIVE ONCOLOGY GROUPS Companion Investigation: Example
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?

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 COOPERATIVE ONCOLOGY GROUPS Clinical Investigation: Example
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

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) 3rd State of the Science Symposium
February 24-25, Grapevine, TX

81


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