NiCord Single Unit Expanded Umbilical Cord Blood Transplantation: Results of Phase I/II Trials Mitchell E. Horwitz, MD Duke University Medical Center Duke Cancer Institute
Adult Umbilical Cord Blood Transplantation Advantages Readily available stem cells source HLA-matching not required Lower incidence of chronic GvHD (Eapen M et al Lancet 21) Clinical outcomes comparable to HLA-matched unrelated donor transplantation (Brunstein et al Blood 21) Disadvantages Low stem cell dose Delayed hematopoietic recovery Delayed immunologic recovery Increased resource utilization Potential Solution Ex-vivo Expansion of the UCB graft
NiCord Umbilical Cord Blood Expansion Technology Developed in the laboratories of Gamida Cell Ltd. Jerusalem Israel An ex vivo expanded cell product derived from a single umbilical cord blood unit Nicotinamide; active molecule in cell culture system Vitamin B3 derivative Precursor of NAD Potent inhibitor of enzymes that utilize NAD SIRT-1 (Peled et al. Exp Hematol. 212 Apr;4) Culture system includes TPO, IL-6, FLT-3 ligand and SCF Expansion utilizes an epigenetic approach to inhibit differentiation and to increase functionality of hematopoietic stem and progenitor cells
No. of CD34+ cells Human cells engraftment(%) Impact of Nicotinamide (NAM) on Ex Vivo Expanded CD34+ Cells; Pre-clinical Data Increased BM Homing Efficacy * 18 15 *P <.1 12 24 7 Increased Engraftment Efficacy (From limiting dilution experiments, number of cells infused; 6 x 1 3 ) *P <.3 9 6 3 Cultured Cultured + NAM.5 Noncultured Noncultured Cultured Cultured + NAM
NiCord Dual Cord Pilot Trial Schema + Unit #1 CD 133+ Cell Selection Non-cultured fraction (NF) Lymphocyte Containing Cryopreserved NiCord Graft Unmanipulated Graft Unit #2 Cultured fraction (CF) Cultured 21±2d in cytokines + Nicotinamide Transported Fresh to Site TBI 135 cgy Fludarabine +/- Cyclosphosphamide Unmanipulated Graft NiCord Graft -14-7 Day +6 +18 MMF Tacrolimus
Summary of Pilot Dual Cord NiCord Trial 11 patients received NiCord - containing dual UCB transplantation NiCord unit was dominant in 8 of 11 recipients NiCord engraftment is stable with robust hematopoiesis Median f/u 4yrs (range 3-5 years) NiCord engraftment shortens the time to hematopoietic recovery (compared to historical controls) Neutrophils >5 (mean days): 25 11 Platelets > 2K (mean days): 41 31 3 year overall survival: 67% 3 year progression-free survival: 67% Horwitz et al. JCI 214
Phase I/II Multicenter Study of NiCord as a Stand-alone Graft Objectives 1. To assess the cumulative incidence neutrophil engraftment at 42 2. To assess incidence of secondary graft failure at 18 days Design 12-65yrs old AML, ALL, MDS, CML, Lymphoma Myeloablative Conditioning regimen; Regimen A: TBI 135cGy, Fludarabine and Cyclophosphamide/Thiotepa Regimen B: Thiotepa, Busulfan, Fludarabine Regimen C: Clofarabine, Fludarabine, Busulfan GvHD prophylaxis Mycophenolate mofetil, Tacrolimus or cyclosporine
NiCord Phase II Multicenter Trial Schema + Unit #1 CD 133+ Cell Selection Non-cultured fraction (NF) Lymphocyte Containing Fraction Cryopreserved NiCord Graft Cultured fraction (CF) Cultured 21±2d in cytokines + Nicotinamide Cryopreserved* Median 1 fold CD34+ cell Expansion MyeloablativeConditioning a. TBI based b. Chemotherapy only NiCord Graft -14-7 Day +6 +18 MMF Tacrolimus or Cyclosporine
Consort Diagram Enrollment Assessed for eligibility (n=3) Excluded (n=9) u Screen Failure Allocation Allocated to intervention (n=21) u Received allocated intervention* (n=16) u Did not receive allocated intervention (n=5) Reasons for not receiving allocated intervention u False positive gram stain during production (n=3) u NiCord production cancelled (n=1) u Inadequate cell dose in negative fraction (n=1) Follow-up Lost to follow-up (n=) Withdrawal from study (n=) Analyzed (n=16)) u Excluded from analysis (n=5) (did not receive allocated intervention) Analysis *Allocated Intervention- Transplantation of NiCord as a stand-alone graft
Demographic and Baseline Characteristics N % Number of evaluable patients 16 1 Gender Male Female 8 8 5 5 Age (years) 12-17 18-39 4 + 4 12 25 75 Weight (Kg) Median (range): 9.kg (55.9-18.) <6 6-8 8-1 1-12 HLA Match Score (Patient to NiCord ) Regimen 4/6 5/6 6/6 Regimen A (TBI, Fludarabine +/- Cy) TBI, Flu TBI, Flu, Cy Regimen B (Thiotepa, Busulfan, Fludarabine) 1 5 7 3 1 4 2 8 3 5 8 6 31 44 19 62 25 12 5 19 31 5
Demographic and Other Baseline Characteristics Primary Diagnosis Acute Lymphoblastic Leukemia High risk first complete morphologic remission (CR1) Second or Subsequent Remission Acute Myelogenous Leukemia First complete morphologic remission (CR1) that is NOT considered favorable risk Second or Subsequent Remission Myelodysplastic Syndrome Low INT-1 INT-2 High Non-Hodgkin s Lymphoma Hodgkin s Disease Chronic Myelogenous Leukemia Chronic phase Accelerated phase Blast Crisis with disease control N =16 5 3 2 5 5 3 2 1 1 2 1 1 % 31 31 19 6 12
Neutrophil Engraftment *All patients >95% donor p<.1 Controls: similar patients that meet NiCord study eligibility criteria (age, disease, conditioning, CBU dose), transplanted with unmanipulated cord blood during the years 21-213, CIBMTR data
Platelet Engraftment p=.3 p=.15 Controls: similar patients that meet NiCord study eligibility criteria (age, disease, conditioning, CBU dose), transplanted with unmanipulated cord blood during the years 21-213, CIBMTR data
Non-relapse mortality vs. CIBMTR control p=.12
Cells/µl (median) Immune Reconstitution: NiCord vs. Unmanipulated Dual Cord Cells/µl (median) 35 3 25 2 15 1 5 154 NiCord *Unmanipulated Dual Cord 1 29 Day 1 27 156 15 316 27 CD4+ CD8+ B-cells NK-cells 5 45 4 35 3 25 2 15 1 5 341 165 156 55 Day 18 461 453 189 24 CD4+ CD8+ B cells NK cells *Barker et al: Results of a prospective multicenter; myeloablative adult double-unit cord blood transplantation trial N=56 Brit J Haem 215
NiCord Single CordPhase I/II Study Results Summary; n=16 Endpoint Time to neutrophil engraftment (median, n=16) Time to platelet engraftment (median, n=13) agvhd grade II-IV and III-IV at 1 days cgvhd Moderate-Severe at 1 year Primary hospitalization (median, n=16) Transplant Related Mortality at 1 year Disease-free Survival at 1yr Overall survival at 1yr 1 days (range 6-26) 32 days (range 26-96) 5% and 12.5% 14% (all moderate) 19 days 18.8% 56% 54% Median follow-up of survivors: 365 days (334-829)
Summary of NiCord Clinical Studies to Date Transplantation of NiCord resulted in: Significantly shorter time to engraftment of neutrophils and platelets Robust and durable engraftment Prompt immune reconstitution Compared to standard dual cord blood transplantation reduced risk of bacterial infections (Anand et al. EBMT 216) Fewer days in hospital during first 1 days post transplantation (Anand et al. EBMT 216) Phase II extension study currently ongoing N=24 (all 24 patients are now >1 days post transplant) CI engraftment=96% Median time to neutrophil engraftment is 11 days Transplant related mortality is 14.5%
Phase III Registration Study to Begin in Summer 216 in The U.S. and EU Randomized controlled study comparing transplantation of NiCord to unmanipulated cord blood 12 patients Projected accrual duration of 2 years with a 1 year of follow up Primary endpoint: time to neutrophil engraftment Secondary endpoints include additional parameters of clinical benefit
Acknowledgments Duke Adult BMT Program Gamida Cell Ltd. Co-Investigators Nelson Chao Gwynn Long David Rizzieri Cristina Gasparetto Keith Sullivan Richard Lopez Staphanie Sarantopolous Anthony Sung Janet Adcock Barbara Waters-Pick Tony Peled David Snyder Einat Galamidi Iddo Peled Efrat Landau Dorit Harati Etty Friend Manufacturing team G. Sanz (protocol Co-Chair) P. Montesinosi- Valencia D. Valcarcel- Barcelona M. Jagasia- Nashville D Cilloni- Turin JJ Boelens, Utrecht