NiCord Single Unit Expanded Umbilical Cord Blood ...2016/06/04  · NiCord® Umbilical Cord Blood...

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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

Transcript of NiCord Single Unit Expanded Umbilical Cord Blood ...2016/06/04  · NiCord® Umbilical Cord Blood...

Page 1: NiCord Single Unit Expanded Umbilical Cord Blood ...2016/06/04  · NiCord® Umbilical Cord Blood Expansion Technology • Developed in the laboratories of Gamida Cell Ltd. Jerusalem

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

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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

Page 3: NiCord Single Unit Expanded Umbilical Cord Blood ...2016/06/04  · NiCord® Umbilical Cord Blood Expansion Technology • Developed in the laboratories of Gamida Cell Ltd. Jerusalem

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

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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

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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

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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

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• 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

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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

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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

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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

Page 11: NiCord Single Unit Expanded Umbilical Cord Blood ...2016/06/04  · NiCord® Umbilical Cord Blood Expansion Technology • Developed in the laboratories of Gamida Cell Ltd. Jerusalem

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

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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

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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

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Non-relapse mortality vs. CIBMTR control

p=0.12

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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

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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

Page 17: NiCord Single Unit Expanded Umbilical Cord Blood ...2016/06/04  · NiCord® Umbilical Cord Blood Expansion Technology • Developed in the laboratories of Gamida Cell Ltd. Jerusalem

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

Page 18: NiCord Single Unit Expanded Umbilical Cord Blood ...2016/06/04  · NiCord® Umbilical Cord Blood Expansion Technology • Developed in the laboratories of Gamida Cell Ltd. Jerusalem

• 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

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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