Upload
others
View
2
Download
0
Embed Size (px)
Citation preview
Mitchell E. Horwitz, MD
Duke University Medical Center
Duke Cancer Institute
NiCord Single Unit Expanded Umbilical
Cord Blood Transplantation: Results of
Phase I/II Trials
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 2010)
– Clinical outcomes comparable to HLA-matched unrelated donor transplantation (Brunstein et al Blood 2010)
• 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. 2012 Apr;40)
• 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
Cultured + NAM
Cultured
0
No
. of
CD
34
+ ce
lls
180
30
Non-cultured
90
60
120
150
Increased BM Homing Efficacy
*P < 0.001
*
Impact of Nicotinamide (NAM) on Ex Vivo Expanded CD34+ Cells; Pre-clinical Data
*P < 0.03
Increased Engraftment Efficacy(From limiting dilution experiments, number of cells infused; 6 x 103 )
Cultured + NAM
CulturedNon-cultured
Hu
man
cel
ls
engr
aftm
ent(
%)
0.50.5
24
7
NiCord® Dual Cord Pilot Trial Schema
Cultured 21±2d in cytokines + Nicotinamide
Transported Fresh to Site
Cultured fraction (CF)
Lymphocyte ContainingCryopreserved
Non-cultured fraction (NF)
+
CD 133+ Cell Selection NiCord Graft
Unmanipulated GraftUnit #1
Unit #2
-14 Day 0-7 +60
TBI 1350 cGy
Fludarabine +/-
Cyclosphosphamide
NiCord Graft
Unmanipulated Graft
+180
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 >500 (mean days): 25 11 • Platelets > 20K (mean days): 4131 • 3 year overall survival: 67%• 3 year progression-free survival: 67%
Horwitz et al. JCI 2014
• 12-65yrs old
• AML, ALL, MDS, CML, Lymphoma
• Myeloablative Conditioning regimen;
– Regimen A: TBI 1350cGy, Fludarabine and Cyclophosphamide/Thiotepa
– Regimen B: Thiotepa, Busulfan, Fludarabine
– Regimen C: Clofarabine, Fludarabine, Busulfan
• GvHD prophylaxis
– Mycophenolate mofetil, Tacrolimus or cyclosporine
Phase I/II Multicenter Study of NiCord® as a Stand-alone Graft
Objectives1. To assess the cumulative incidence neutrophil engraftment at 42
2. To assess incidence of secondary graft failure at 180 days
Design
NiCord® Phase II Multicenter Trial Schema
Cultured fraction (CF)
Cultured 21±2d in cytokines + Nicotinamide
Cryopreserved*
Lymphocyte Containing Fraction
Cryopreserved
Non-cultured fraction (NF)
+
CD 133+ Cell Selection NiCord Graft
Unit #1
-14 Day 0-7 +60
MyeloablativeConditioning
a. TBI based
b. Chemotherapy only
NiCord Graft
+180
MMF
Tacrolimus or Cyclosporine
Median 100 fold CD34+
cell Expansion
Consort Diagram
Follow-up Analysis
Allocation
Enrollment Assessed for eligibility (n=30)
Excluded (n=9)uScreen Failure
Allocated to intervention (n=21)uReceived allocated intervention*
(n=16)uDid not receive allocated intervention
(n=5)
Lost to follow-up (n=0)Withdrawal from study
(n=0)
Analyzed (n=16))u Excluded from analysis (n=5)
(did not receive allocated
intervention)
ReasonsfornotreceivingallocatedinterventionuFalse positive gram stain during production (n=3)
uNiCord production cancelled (n=1)u Inadequate cell dose in negative fraction (n=1)
*AllocatedIntervention- TransplantationofNiCordasastand-alonegraft
N %Number of evaluable patients 16 100Gender Male
Female88
5050
Age (years) 12-1718-3940 +
0412
02575
Weight (Kg) Median (range): 90.0kg (55.9-108.0)<6060-8080-100100-120
1573
6314419
HLA Match Score (Patient to NiCord®)
4/65/66/6
1042
622512
Regimen Regimen A (TBI, Fludarabine +/- Cy)TBI, FluTBI, Flu, CyRegimen B (Thiotepa, Busulfan, Fludarabine)
8358
50193150
Demographic and Baseline Characteristics
Primary Diagnosis
Acute Lymphoblastic LeukemiaHigh risk first complete morphologic remission (CR1)Second or Subsequent Remission
Acute Myelogenous LeukemiaFirst complete morphologic remission (CR1) that is NOT considered favorable riskSecond or Subsequent Remission
Myelodysplastic SyndromeLowINT-1INT-2High
Non-Hodgkin’s LymphomaHodgkin’s DiseaseChronic Myelogenous LeukemiaChronic phaseAccelerated phaseBlast Crisis with disease control
N =16
532
550
3021
0
12101
%
31
31
19
0612
Demographic and Other Baseline Characteristics
Neutrophil Engraftment
p<0.0001
Controls: similar patients that meet NiCord® study eligibility criteria (age, disease, conditioning, CBU dose), transplanted with unmanipulated cord blood during the years 2010-2013, CIBMTR data
*All patients
>95% donor
Platelet Engraftment
p=0.03
p=0.015
Controls: similar patients that meet NiCord® study eligibility criteria (age, disease, conditioning, CBU dose), transplanted with unmanipulated cord blood during the years 2010-2013, CIBMTR data
Non-relapse mortality vs. CIBMTR control
p=0.12
Immune Reconstitution: NiCord vs. Unmanipulated Dual Cord
*Barker et al: Results of a prospective multicenter; myeloablative adult double-unit
cord blood transplantation trial N=56 Brit J Haem 2015
NiCord
*Unmanipulated Dual Cord
Ce
lls/µ
l (m
ed
ian
)
Ce
lls/µ
l (m
ed
ian
)
Day 180
154
29
156
316
100
2715
207
0
50
100
150
200
250
300
350
CD4+ CD8+ B-cells NK-cells
Day 100
341
156
461 453
165
55
189
240
0
50
100
150
200
250
300
350
400
450
500
CD4+ CD8+ B cells NK cells
NiCord® Single CordPhase I/II Study Results Summary; n=16
Median follow-up of survivors: 365 days (334-829)
Endpoint
10 days (range 6-26) Time to neutrophil engraftment (median, n=16)
32 days (range 26-96)Time to platelet engraftment (median, n=13)
50% and 12.5%aGvHD grade II-IV and III-IV at 100 days
14% (all moderate)cGvHD Moderate-Severe at 1 year
19 daysPrimary hospitalization (median, n=16)
18.8%Transplant Related Mortality at 1 year
56%Disease-free Survival at 1yr
54%Overall survival at 1yr
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 2016)• Fewer days in hospital during first 100 days post transplantation (Anand
et al. EBMT 2016)Phase II extension study currently ongoing
• N=24 (all 24 patients are now >100 days post transplant)• CI engraftment=96%• Median time to neutrophil engraftment is 11 days• Transplant related mortality is 14.5%
Summary of NiCord® Clinical Studies to Date
• Randomized controlled study comparing transplantation of NiCord® to
unmanipulated cord blood
• 120 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
Phase III Registration Study to Begin in Summer 2016 in The U.S. and EU
Acknowledgments
Duke Adult BMT Program
Tony Peled
David Snyder
Einat Galamidi
Iddo Peled
Efrat Landau
Dorit Harati
Etty Friend
Manufacturing team
Nelson Chao
Gwynn Long
David Rizzieri
Cristina Gasparetto
Keith Sullivan
Richard Lopez
Staphanie Sarantopolous
Anthony Sung
Janet Adcock
Barbara Waters-Pick
Gamida Cell Ltd. Co-Investigators
G. Sanz (protocol Co-Chair)
P. Montesinosi- Valencia
D. Valcarcel- Barcelona
M. Jagasia- Nashville
D Cilloni- Turin
JJ Boelens, Utrecht