fda advisory panel miltenyi biotec clinimacs ® cd34 reagent system september 23, 2011 with sincere...

FDA Advisory PanelMiltenyi Biotec

CliniMACS® CD34 Reagent SystemSeptember 23, 2011

With Sincere Thanks and Appreciation To:

2

The CliniMACS® CD34 Reagent System

FDA Advisory PanelSeptember 23, 2011

Nancy Johansen

Director, Regulatory Affairs

Miltenyi Biotec Incorporated

3

Company Overview, Product Introduction and Registration of the CliniMACS® CD34 Reagent System as a Humanitarian Use Device

Overview of the Clinical Indication and Unmet Medical Need and Summary of the BMT CTN 0303 Clinical Trial

Summary of the CliniMACS® CD34 Reagent System Performance

Summary of the BMT CTN 0303 versus BMT CTN 0101 Data Analysis Protocol Findings

Summary of Safety and Probable Benefit of the CliniMACS® CD34 Reagent System

Agenda and Presenters Nancy JohansenDirector, Regulatory Affairs Miltenyi Biotec Incorporated

Steven Devine, M.D.Ohio State UniversityArthur G. James Cancer Center

Carolyn Keever-Taylor, PhDMedical College of Wisconsin

Marcelo Pasquini, M.D., M.S.Center for International Blood and Marrow Transplant Research (CIBMTR)Medical College of Wisconsin

Kai Pinkernell, M.D.Head of Clinical DevelopmentMiltenyi Biotec GmbH

4

• Founded in 1989 in Bergisch Gladbach, Germany

• Roughly 1100 employees worldwide

• Subsidiaries in 10 countries; N.A. Headquarters in Auburn, CA

Miltenyi Biotec Corporate Overview

5

The overall function of the CliniMACS® CD34 Reagent System

is to select CD34+ cells from heterogeneous hematologic cell populations

CliniMACS® CD34 Reagent System

6

CliniMACS®plus Instrument

CliniMACS® CD34 Reagent

CliniMACS® PBS/EDTA Buffer

CliniMACS® Tubing Sets (Standard and Large Scale)

Standard: 0.6 x 109 CD34+ Cells

from 60 x 109 Cells

Large Scale: 0.6-1.2 x 109 CD34+ Cells from 60-120 x 109 Cells

CliniMACS® CD34 Reagent System

7

Magnetic labeling

Magnetic Separation (elution of the non-labeled

cell fraction)

Elution of the labeled cell

fraction

The Principle of the CliniMACS® CD34 Reagent System

8

Location of CliniMACS®plus

Instruments in the USA

162 instruments within 97 institutions in the U.S.

9

84 IDE protocols utilize the CliniMACS® CD34 Reagent System Strict distribution procedures are in place to

ensure that investigational products are provided only for FDA/IRB approved protocols

CliniMACS® CD34 Reagent System Protocols (as of July 2011)

10

CliniMACS® plus Instruments are installed by qualified Miltenyi personnel Installation and Operational Qualification (IQ/OQ) is

performed at time of installation All subsequent servicing and Preventative Maintenance are

performed by qualified Miltenyi personnel Customer Training

Performed by qualified Miltenyi personnel Training validated by written test

Emergency Hotline Support Monday through Friday (9 a.m. – 9 p.m. EST) If pre-arranged, outside of normal business hours

Installation, Training and Customer Support

11

1997 CE marked

1998 US MF Submitted

2004 Pre-IDE Meeting

2004-2008 BMT CTN

Study Conducted

2005-HUD Designation

2011 HDE Submitted

Dec 2009FDA pre-HDE meeting

2010 DAP Finalized

12

Humanitarian Use Device The device is designed to treat or diagnose a

disease or condition that affects fewer than 4,000 individuals per year in the U.S.

The device is not available otherwise, and there is no comparable device available to treat or diagnose the disease or condition; and

The device will not expose patients to unreasonable or significant risk, and the benefits to health from the use outweigh the risks

Clinical data must support “safety” and “probable benefit” argument

Exempt from “effectiveness requirement” consistent with the HDE requirements

13

Miltenyi supported a Phase II multi-center clinical trial sponsored by the BMT CTN (BB-IDE 11965) which enrolled 47 AML patients from October 2005-December 2008 Evaluated the use of the CliniMACS® CD34 Reagent

System for selecting CD34+ cells from HLA-matched related donors for allogeneic stem cell transplantation after myeloablative therapy in patients with Acute Myeloid Leukemia (AML) in 1st or 2nd CR, without additional GVHD prophylaxis

Clinical Trial Supporting the HUD Registration of the

CliniMACS® CD34 Reagent System*

* Miltenyi provided material goods only in the support of this study.

MBI has negotiated rights through the National Marrow Donor Program (NMDP) to cross reference the BMT CTN 0303 IDE submission for purposes of product registration

14

“Humanitarian Use Device: Authorized by U.S. Federal law for processing allogeneic HLA-matched hematopoietic progenitor cells-apheresis (HPC-A) from a related donor to obtain a CD34+ cell enriched population intended for hematopoietic reconstitution following a myeloablative preparative regimen without the need for additional graft-vs-host disease (GVHD) prophylaxis in patients with acute myeloid leukemia (AML) in first or second morphologic complete remission”

CliniMACS® CD34 Reagent SystemProposed Humanitarian Use Indication

15

Steven Devine, M.D.Professor of Internal Medicine

Director, Blood and Marrow Transplant ProgramThe Ohio State University

Arthur G. James Cancer Center

BMT CTN 0303

Co-Study Chair

16

1 http://www.Cancer.org; 8/26/102 Koreth, J et al. JAMA 2009

Acute Myeloid Leukemia (AML)

Most common leukemia diagnosis in adults1

U.S. incidence: ~ 12,330 new cases diagnosed annually Mortality is roughly 8,950 cases per year However, less than 2,500 patients progress to transplant

Allogeneic stem cell transplantation (SCT) is the single most effective therapy currently available for the prevention of relapse and shows significant survival benefit in AML patients with intermediate and poor risk cytogenetics in first complete remission (CR1)2

17

Reduced incidence of leukemic relapse and overall survival often not realized due to complications caused by GVHD

Acute GVHD (aGVHD) risk is 35-45%

33-81% of these patients will develop chronic GVHD (cGVHD), resulting in post-transplant morbidity, mortality and reduced quality of life

Immunosuppressive agents used to prevent and treat aGVHD do not affect incidence of cGVHD

Previous studies demonstrate that T cell depletion reduces the risk of severe acute and chronic GVHD

Graft Versus Host Disease (GVHD) Complicates Allogeneic

Transplantation From Matched Related Donors (MRD)1-6

1 Ferrara J, et al. Lancet 2009 2 Chao N, et al. NEJM 1993 3 Devine S, et al. J Lab Clin Med 20034 Clift R, et al. Blood 1991 5 Nash R, et al. Blood,2000 6 Ratanatharathorn V, et al. Blood 1998

18

Chronic GVHD of the Skin

Walker, I; 2011 BMT Tandem Meetings CBMTG Section; Clinical Trials Network Meeting. www.cbmt.org

19

Chronic GVHD of the Oral Mucosa

Walker, I; 2011 BMT Tandem Meetings CBMTG Section; Clinical Trials Network Meeting. www.cbmt.org

20

Chronic GVHD and Quality of Life

Quality of life (QoL) at 6 or 12 months is significantly worse in patients with acute or cGVHD after transplant1

QoL at 12 months improves unless cGVHD develops1

Significantly less patients return to work if they develop cGVHD after allogeneic transplantation2

Only 41% of patients with cGVHD return to work at 3 years, compared to 95% of patients without cGVHD2

1 Lee et al. BMT 2006; (38) 305-102 Wong et al. Blood. 2010; 115(12)2508-19

21

Chronic GVHD Treatment

The treatment of cGVHD with long-term corticosteroids increases the risk of cataract formation, avascular necrosis, and osteoporosis1

The 10-year survival is less than 5% for patients affected by severe cGVHD

There are no effective options for the prevention or treatment of chronic GVHD

1 Horowitz, ME., and Sullivan, KM. Blood Reviews (2006); 20: 15–27

22

The incidence and severity of GVHD are most effectively reduced by ex vivo T cell depletion (TCD) of the allograft

There is currently no approved method for ex vivo TCD for allogeneic SCT in the United States

If approved, the CliniMACS® CD34 Reagent System will be the only FDA approved method of CD34+ enrichment and passive TCD available

Unmet Medical Need Served by The CliniMACS® CD34 Reagent System

23

Use of ex vivo T cell depletion (TCD) has been limited by logistical difficulties and variability in TCD

methods lack of an FDA-approved method concerns regarding potential risk of graft

rejection and leukemic relapse

A multi-center trial of TCD in AML patients in complete remission (CR1/CR2) using standard eligibility criteria and a uniform method of TCD was warranted

Clinical Study Rationale

24

HLA-Identical Sibling-Matched, CD34+ Selected, T cell Depleted Peripheral Blood Stem Cells

Following Myeloablative Conditioning For First or Second Remission Acute Myeloid Leukemia

(AML): Results of Blood and Marrow Transplant Clinical Trials Network*

S Devine, S Carter, R Soiffer, M Pasquini, P Hari, A Stein, H Lazarus, C Linker, E Stadtmauer, E Alyea, C Keever-Taylor, and R O'Reilly

(BMT CTN) Protocol 0303

* Devine, S et al; BBMT, 2011

Blood and Marrow Transplant Clinical Trials Network (BMT CTN)

• Established: Sept. 2001; renewed July 2011• Funded by NHLBI/NCI• 20 Core Center cooperative agreements• 1 DCC cooperative agreement• >80 affiliate centers access trials through

DCC

• Goal of the Program:

• Provide the infrastructure needed to allow promising HCT therapies to be developed/ evaluated in high quality multicenter studies.

25

= PBMTC Centers= Affiliate Centers= Core Centers

Mmh06_16.ppt

BMT CTN Centers, 2011>100 centers have enrolled >3900

patients since 2003

26

Single center studies show reduced GVHD without increased relapse rates in AML patients receiving T cell depleted (TCD) allografts in CR1-3

One randomized, prospective, multi-center TCD trial showed no increase in relapse in AML patients receiving TCD allografts4

BMT CTN 0303 Historical References

1 Aversa et al. Blood Cells Mol and Disease 20082 Pappadopoulos et al, Blood, 19983 Soiffer et al; Blood 19974 Wagner, J. et al. Lancet 2005 27

28

Randomized, Prospective, Multi-center T Cell Depletion (TCD) Vs. Methotrexate and

Cyoclosporine (M/C) Trial

Wagner et al., Lancet 366:733, 2005

29

The sample size was 45 patients, wherein 47 patients were enrolled and 44 completed treatment

There were no blinding or randomization aspects to this trial

The median follow up of the patients was 34 months (Range: 11.5- 51.5 months)

BMT CTN 0303 Statistical Sampling and

Time Points

BMT CTN 0303 Study Eligibility

AML in CR1 or CR2 Age 18-65 HLA-identical sibling available No more than 2 induction cycles of chemotherapy

required to induce remission No more than six months from CR to transplant

(three months for CR2) Other standard organ function criteria No uncontrolled bacterial/fungal/viral infections Karnofsky performance status > 70%

30

31

Primary Endpoint: Disease-Free Survival (DFS) at 6 months >75%

Secondary Endpoints: Acute and chronic GVHD Overall Survival (OS) Disease-Free Survival at 2 years Transplant-Related Mortality (TRM) Relapse Engraftment/graft failure Infusional Toxicities Incidence of EBV reactivation and PTLD Proportion of grafts containing > 5 x 106 CD34+ cells/kg and < 1 x 105

CD3+ cells /kg

BMT CTN 0303 Study Endpoints

Site Patients Accrued

Dana Farber/Partners Cancer Center 18

Ohio State University 8

Memorial Sloan Kettering Cancer Center 7

Medical College of Wisconsin 7

City of Hope National Medical Center 3

University Hospitals of Cleveland 2

University of CA, San Francisco 1

University of Pennsylvania 1

TOTAL 47

Eight Centers Enrolled Patients onto BMT CTN 0303

44 patients were evaluable on study32

BMT CTN 0303Patient

CharacteristicsPatient Age Mean (range) 46.3 (21-59 )

Donor age Mean (range) 46.2 (16-63)

GenderMale 16 (36%)

Female 28 (64%)

Leukemia stageCR1 37 (84%)

CR2 7 (16%)

Cytogenetic Risk (CR1/CR2)

Favorable 0 / 2

Intermediate 25 / 3

Unfavorable 10 / 1

Unknown* 2 / 1

* Unknown cytogenetic risk due to lack of metaphase during testing33

34

BMT CTN 0303 Patient Conditioning Regimen

Day of Tx -9 -8 -7 -6 -5 -4 -3 -2 -1 0

TBI 1375 cGy*

11 total doses; administered on days -9 through -6

Thiotepa @ 5mg/kg

Thymoglobulin @ 2.5 mg/kg

Cyclophosphamide @ 60mg/kg

CliniMACS® CD34-enriched cells

35

BMT CTN 0303 Donor Mobilization &

Leukapheresis Received daily G-CSF for mobilization

following screening and enrollment

Leukapheresis performed according to institutional standards

Daily leukapheresis with subsequent CD34+ cell selection using the CliniMACS® CD34 Reagent System continued until a post-selection target dose of > 5.0 x 106 CD34+

cells/kg and < 1 x 105 CD3+ cells/kg was met

36

Carolyn Keever-Taylor, PhDProfessor of Medicine

Director BMT Laboratories Division of Hematology and Oncology

Medical College of Wisconsin

BMT CTN 0303

Steering Committee Laboratory Representative

37

The Manuscript Entitled:

“Characteristics of CliniMACS® System CD34-Enriched T Cell-Depleted Grafts in a Multi-Center Trial for Acute Myeloid Leukemia-Blood and Marrow

Transplant Clinical Trials Network (BMT CTN) Protocol 0303”

has been submitted and accepted for publication by the peer reviewed journal,

“Biology of Blood and Marrow Transplantation”

38

Leukapheresis collections from a Matched Related Donor were performed in order to obtain a minimum of ≥ 2.0 x 106 CD34+ cells/kg Target of > 5.0 x 106 CD34+ cells/kg and

< 1 x 105 CD3+ cells/kg

Up to three collections were allowed to achieve the minimum CD34+ cell dose

The CliniMACS® Tubing Sets (Standard or Large Scale) were used based on starting nucleated cell counts

Secondary Endpoint: CliniMACS® CD34 Reagent System

Performance

39

Cellular Testing Requirements

Cell Viability (7-AAD), TNC and CD34+ cell content At product receipt After platelet and antibody wash On CliniMACS® CD34-enriched fraction

CD3+ T cell content At product receipt On CliniMACS® CD34-enriched fraction

Other cellular testing on CliniMACS® CD34-enriched fraction only CD14+ monocytes CD19+ or CD20+ B cells CD56+ NK Cells

40

Donors and Products

47 patients enrolled, 44 proceeded to transplant

86 products collected Total lots (cells from one tubing set)

assessed=84– Collections pooled for 2 patients

4 sites processed from 9 to 34 lots

4 sites processed ≤ 4 lots

41

CliniMACS® CD34 Reagent System Post-Processing Performance

N = 84

% CD34+ Recovery

% CD34+ Purity Log10 TCD % Viability

Mean 66.06 93.0 4.78 96.57

SD±20.25 ±8.3 ±0.55 ±3.84

Min 29.9 61.5 3.2 74.0

Max 125.6 99.8 5.9 100.0

42

Center to CenterStatistical Analysis

Sites processing ≥ 9 lots compared individually (N=4)

Sites processing ≤ 4 lots pooled (N=4)

Multivariate analysis used a linear mixed effect model to account for repeated measures (≥ 2 lots for most patients)

Pairwise center comparisons were performed with Tukey-Kramer adjustment for multiple comparisons

43

Pre-Processing Cell Counts

44

Post Processing Outcomes

All centers were able to process grafts that met the study criteria

45

CD34+ Cells x 106/kg of Patient Weight Infused

CD34+ Target Dose

All patients received the minimum CD34+ dose (> 2.0x106 cells/kg)

84.1% of patients received > 5 x 106 CD34+ cells/kg

CD34+ Minimum

Dose

CD

34+

/kg

46

CD3+ Cells x 105/kg of Patient Weight Infused

Upper limit of CD3+

dose

No patients received more than 1.0x105 CD3+ cells/kg

CD

3+/k

g

47

All gram stains/14 day cultures were negative All endotoxin < 5.0 EU/kg No significant infusion related toxicities observed

Parameter Result

Median CD34+ dose 7.92 x 106/kg

Range 2.4 - 30.3 x 106/kg

Median CD3+ dose 0.7 x 104/kg

Range 0.1 – 8.3 x 104/kg

Median Log10 TCD 4.9 logs

Range 3.2 – 5.9 logs

Final Cellular Product Summary

48

All sites, and all products met and most exceeded study goals for: CD34+ cell infusion dose > 2 x 106/kg

– 84% met the goal of > 5 x 106/kg CD3+ cell infusion dose < 1 x 105/kg

The performance of the CliniMACS® CD34 Reagent System was stable and reproducible, resulting in a consistently high degree of CD34+ cell enrichment,

T cell depletion and sterility in a multi-center setting

Conclusions - Secondary EndpointCliniMACS® CD34 Reagent System

Performance

49

Steven Devine, M.D.Professor of Internal Medicine

Director, Blood and Marrow Transplant ProgramThe Ohio State University

Arthur G. James Cancer Center

BMT CTN 0303

Co-Study Chair

50

Primary Endpoint6 Month Disease-Free Survival of >75%

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0

Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24

Disease Free Survival for All Transplanted Patients

N=44

81.8% @ 6 months (95% CI 66.9-90.5)

Secondary EndpointsNeutrophil/Platelet Engraftment

Analysis NMedian Days

to EngraftmentDay 30

EstimateDay 100 Estimate

Platelet Engraftment

>20K/µL 44 16 days

93.2% (95% CI: 85.2-100)

97.7 %(95% CI: 92-100)

Cumulative Incidence of Neutrophil

Engraftment

>500/µL44 12 days

100%

(95% CI:

85.5-100)

• No primary graft failures • One secondary graft failure at Day +54 after initially engrafting on Day +12

51

52

Secondary Endpoint Cumulative Incidence of Transplant-Related

Mortality (1yr)

Stopping guideline of <30% TRM at 1 year was not exceeded

TRM at 2 years was 19.9% (95% CI: 7.1-32.7)

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0


Cumulative Incidence of TRM for All Transplanted Patients

N=44

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0


Cumulative Incidence of TRM by Remission Stage

First CR (N=37) Second CR (N=7)

All Patients By CR1/CR2

13.6% @ 1yr(95% CI: 3.4-23.8)

53

Secondary Endpoint Cumulative Incidence of EBV Reactivation


13.6% (95% CI: 3.4-23.8)

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0


Cumulative Incidence of EBV for All Transplanted Patients

N=44

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0


Cumulative Incidence of EBV by Remission Stage


18.2% @ 2 yrs 18.9% @ 2 yrs

14.3% @ 2 yrs

• 8 patients treated for EBV DNA levels >1000 copies/mL• One case of PTLD with subsequent death • EBV monitoring performed weekly

54

Secondary EndpointCumulative Rate of Relapse

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0


Cumulative Incidence of Relapse for All Transplanted Patients

N=44

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0


Cumulative Incidence of Relapse by Remission Stage


20.6% @ 1 yr

23.7% @ 2 yrs

57.1% @ 2 yrs

17.4%* @ 2 yrs


* N=7 patients treated in CR2; 4 patients relapsed (95% CI: 14.6-99.6%)

Secondary Endpoint - Cumulative Incidence ofAcute GVHD Grades II-IV

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0

Days Post Transplant

0 7 14 21 28 35 42 49 56 63 70 77 84 91 98

Cumulative Incidence of Acute GVHD Grades II-IV for All Transplanted Patients

N=44

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0


0 7 14 21 28 35 42 49 56 63 70 77 84 91 98

Cumulative Incidence of Acute GVHD Grades II-IV by Remission Stage


22.7% @ 100 days(95% CI: 10.2-35.2)

• No Grade IV acute GVHD observed• Published acute GVHD risk 35-45%


55

56

Secondary Endpoint - Cumulative Incidence of Acute GVHD Grades III-IV

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0


0 7 14 21 28 35 42 49 56 63 70 77 84 91 98

Cumulative Incidence of Acute GVHD Grades III-IV for All Transplanted Patients

N=44

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0


0 7 14 21 28 35 42 49 56 63 70 77 84 91 98

Cumulative Incidence of Acute GVHD Grades III-IV by Remission Stage


• No Grade IV acute GVHD observed

4.5% @ 100 days(95% CI: 0 – 10.8%)


57

Secondary Endpoint Cumulative Incidence of Chronic GVHD (2 yrs)

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0


Cumulative Incidence of Chronic GVHD for All Transplanted Patients

N=44

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0


Cumulative Incidence of Chronic GVHD by Remission Stage


19% @ 2 years (95% CI: 6.8-31.1)

Includes Limited and Extensive


• Published chronic GVHD risk 33-81%

Secondary Endpoint Cumulative Incidence of Extensive

Chronic GVHD (2 Years)

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0


Cumulative Incidence of Extensive Chronic GVHD for All Transplanted Patients

N=44

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0


Cumulative Incidence of Extensive Chronic GVHD by Remission Stage


6.8% @ 2 years

(95% CI: 0-14.4)


58

59

Secondary EndpointDisease-Free Survival at 2 Years


By Stage

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0


Disease Free Survival for All Transplanted Patients

N=44 P

roba

bilit

y0.0

0.2

0.4

0.6

0.8

1.0


Disease Free Survival for All Transplanted Patients by Remission Stage


65.7% @ 1 yr 56.4%

@ 2 yrs

61.9% @ 2 yrs

28.6% @ 2 yrs

• Historical data estimates 2 year DFS < 60% in CR11-3

• 2º endpoints were > 70% for CR1 and > 60% for CR21 Suciu Blood 2003 2 Brunet et al, Hematologica 2004 3 Cornelissen et al, Blood 2007

Secondary EndpointOverall Survival at 2 Years

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0


Overall Survival for All Transplanted Patients

N=44

77.3% @ 1 yr

59.4% @ 2 yrs

60

61

Adverse Events (AEs)

Toxicities were reported as AEs No Unexpected Grade 3-5 AEs were reported AEs were due to regimen related events and

toxicities common to allo HCT and could not be attributed to the CliniMACS® CD34 Reagent System

The most common toxicities within 1 year post-transplant: Regimen related Grade 3 or 4 GI toxicity (40.9%) Abnormal liver function (36.4%)

• Graded using the NCI’s CTCAE version 3.0

Causes of Death by2 Years Post-Transplant

Cause N

Recurrence 6

Infection 4

Idiopathic Pneumonia

Organ failure

Other*

2

2

1

PTLD 1

Total 16

* Possibly cardiac related 62

63

HCT following myeloablative preparative regimen for patients with AML in CR1 or CR2 can be performed in a multicenter setting using the CliniMACS® CD34 Reagent System without additional post-transplant pharmacologic GVHD prophylaxis

All 1º and most 2º endpoints were met, demonstrating: 81.8% Disease-Free Survival 6 months post TX No primary graft failure; consistent neutrophil and platelet

engraftment Acute GVHD grades II-III <23%. No Grade IV aGVHD Chronic GVHD at 2 years 19%; extensive 6.8% TRM <20% at 2 years Overall risk of relapse was low at 23.7% at 2 years

The CliniMACS® CD34 Reagent System consistently produced a graft with > 2 x 106 CD34+ cells/kg and < 1 x 105 CD3+ cells/kg with no reported device related toxicities

BMT CTN 0303 Conclusions

64

Marcelo Pasquini, M.D., M.S.

Assistant Professor of Medicine Medical College of Wisconsin

Assistant Scientific Director Center for International Blood and Marrow

Transplant Research (CIBMTR)

Principal InvestigatorBMT CTN 0101 versus BMT CTN 0303

Data Analysis Protocol

65

A Single Arm, Multi-center Phase II Trial of Transplants of HLA-Matched, CD34+ Enriched T cell Depleted Peripheral Blood Stem Cells Isolated by the CliniMACS® System in the Treatment of Patients

with AML in First or Second Morphologic Complete Remission (BMT CTN) Protocol 0303

A Randomized Double-blind Trial of Fluconazole versus Voriconazole for the Prevention of Invasive Fungal Infections in Allogeneic Blood

and Marrow Transplant Patients(BMT CTN) Protocol 0101

66

Performed according to FDA approved Data Analysis Protocol #1001-34 which was a prospective statistical comparison of retrospective data

This comparison of the 0101 and 0303 data has been submitted for publication. The manuscript is currently under review.

The Data Analysis Protocol (DAP)

67

Enrollment Period BMT CTN 0101 versus BMT CTN 0303

15 53

23% of 0101 47.5% of 0303

0101

0303

2003 2006

2005 2008

Enrolling Centers by Protocol, and Their Contribution to Each Study

68

Test the hypothesis that T cell depletion using the CliniMACS® CD34 Reagent System as the sole form of immune suppression (BMT CTN 0303) demonstrates a comparable safety profile as compared to conventional GVHD prophylaxis post-transplant (BMT CTN 0101) in AML patients in CR1/CR2 receiving a Peripheral Blood Stem Cell (PBSC) allograft from a matched related donor

Data Analysis Protocol (DAP) Objective

69

Disease-Free Survival (DFS) Overall Survival (OS) Engraftment Graft Failure Transplant-Related Mortality (TRM) Relapse Incidence and Severity of Acute GVHD (aGVHD) Incidence and Severity of Chronic GVHD (cGVHD)

The Following One Year* Endpoints Were Statistically Compared

* BMT CTN 0101 follow-up was limited to 1 year

70

Patient Age 18-65 Unmodified PBSC Allograft HLA identical sibling donor AML in CR1 or CR2 All cytogenetic risk patients included in

0101 Only CR2 patients in 0303 enrolled favorable

cytogenetic risk patients

Eligibility Criteria for 0303 was Matched in 0101 Patient Subsets

71

DAP Patient Selection

Patients Randomized

N=600

No TransplantN=1

Received Transplant

N=599

Patients meeting eligibility

N=84

Eligibility CriteriaAge 18-65

HLA Match-SiblingPBSC

AML in CR1 or CR2

Patients Enrolled

N=47

AML CR2N=19

AML CR1N=65

No TransplantN=3

Received Transplant

N=44

AML CR2N=7

AML CR1N=37

Patients meeting eligibility

N=44

BMT CTN 0101 BMT CTN 0303

72

Baseline Characteristics

Karnofsky Performance Status Similar in Both Protocols 100% 22 (26.2%) 17 (38.6%)

0.36> 90% 46 (54.8%) 17 (38.6%)

> 80% 13 (15.5%) 8 (18.2%)

> 70% 3 (3.6%) 2 (4.5%)

Median Age 45.1 48.5 0.14

% > 50 yrs of Age 32.1% 43.2% 0.22

Patient Ages Similar in Both Protocols

0101 (N=84) % of patients

0303 (N=44) % of patients p-Value

Significantly More Females in 0303Female 44% 63.6%

0.04Male 56% 36.4%

73

Cytogenetic Risk Profile By Protocol

Cytogenetic Risk Profile*

Control (0101) (N=84) N (%)

CD34+ Enriched (0303) (N=44) N (%)

p Value

Favorable9

(10.7%) 2 (4.5%)

0.34Intermediate 55 (65.5%)

28(63.6%)

Unfavorable 12 (14.3%)

11 (25.0%)

Unknown 8 (9.5%)

3 (6.8%)

Slightly more unfavorable cytogenetics in 0303 than in 0101;overall, statistically similar

* Slovak M et al. Blood 2001. SWOG/ECOG classification used for profile determination.

74

0101 (N=84)# (%)

0303(N=44) # (%)

Conditioning Regimen

TBI based 43 (51) 44 (100)

Busulfan based 41 (49) 0

ATG 7 (8) 44 (100)

GVHD Prophylaxis

T cell depletion 0 44 (100)

Tacrolimus based 48 (57) 0

Cyclosporine A based 37 (43) 0

Conditioning RegimenBMT CTN 0101 versus BMT CTN 0303

75

Day +30 Neutrophil Engraftment (> 500/µL)*

Prob

abilit

y

0.0

0.2

0.4

0.6

0.8

1.0

Days Post Transplant0 7 14 21 28 35 42

0101 (N=84)0303 (N=44)

96.4% in Control (0101)

100% in CD34+ (0303)

*Cumulative Incidence

3 primary graft failures in the Control (0101) 0 primary graft failures in the CD34+ Enriched (0303) 1 secondary graft failure in each trial

p=0.002

76

Day +100 Platelet Engraftment (≥ 20,000/µL)*

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0

Months Post-Transplant0 1 2 3 4 5 6

0101 (N=84)0303 (N=44)

88.1% in Control (0101)

97.7% in CD34+ (0303)

p=0.228


77

Transplant-Related Mortality*P

roba

bilit

y

0.0

0.2

0.4

0.6

0.8

1.0

Months Post-Transplant0 1 2 3 4 5 6 7 8 9 10 11 12

0101 (N=84)0303 (N=44)

Prob

abilit

y

0.0

0.2

0.4

0.6

0.8

1.0


0101 and CR1 (N=65)0101 and CR2 (N=19)0303 and CR1 (N=37)0303 and CR2 (N=7)

All Patients by Protocol CR1/CR2 and Protocol

16.7% in Control (0101)

13.6% in CD34+ (0303)

p=0.62


78

p=0.91

20.3% in Control (0101)

20.6% in CD34+ (0303)

Incidence of 12 Month Relapse*


79

12 Month Relapse* CR1/CR2 By Protocol

Prob

abilit

y

0.0

0.2

0.4

0.6

0.8

1.0



CR2p=N/A**

**Statistical calculations not performed due to low patient numbers 4/7 in 0303 and 6/19 in 0101 relapsed

CR1 p=0.57

57.1%

31.6%

17%

13.7%


p=

0.02

80

12 Month Disease-Free Survival

Pro

bability

0.0

0.2

0.4

0.6

0.8

1.0


Pro

babili

ty

0.0

0.2

0.4

0.6

0.8

1.0

Disease-Free SurvivalBy Protocol: CR1 and CR2

0101 (N=84)0303 (N=44)

I I III IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIIII

65.7% in CD34+ (0303)

63% in Control (0101)

p=0.59

81

12 Month DFS in CR1/CR2 By Protocol

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0


Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0

Disease-Free SurvivalBy Protocol and Remission Status: CR1 and CR2


IIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

I I IIIIIIII

I IIIIIIIIIIIIIIIIIIIIIIII

II

p=N/A*CR2

p=0.39CR1

72.8%

66.1%

52.6%

28.6%

p=0.7

* Statistical comparisons were not performed on CR2 patients due to low patient numbers

82

DFS Stratification by Age > 50CR1 and CR2

p=0.88

68.3% 0101 < 50

51.9% 0101 > 50

59.7% 0303 < 50

73.7% 0303 > 50

83

12 Month Overall SurvivalP

roba

bilit

y

0.0

0.2

0.4

0.6

0.8

1.0


Prob

abili

ty

0.0

0.2

0.4

0.6

0.8

1.0

Overall SurvivalBy Protocol: CR1 and CR2

0101 (N=84)0303 (N=44)

I I III IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0


Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0

Overall SurvivalBy Protocol and Remission Status: CR1 and CR2


I III IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

I I IIIIIIIII

I IIIIIIIIIIIIIIIIIIIIIIIIIII

IIII

p=0.87

All Patients by Protocol CR1/CR2 and Protocol

p=0.61

77.3% in CD34+ (0303)

73.8% in Control (0101)

84

Acute GVHD Grades II-IV*

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0

Days Post-Transplant0 7 14 21 28 35 42 49 56 63 70 77 84 91 98

0101 (N=84)0303 (N=44)

39.3% in Control (0101)

22.7% in CD34+ (0303)


p=0.068

85

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0


0101 and <=50 years (N=57)0101 and >50 years (N=27)0303 and <=50 years (N=25)0303 and >50 years (N=19)

Acute GVHD Grades II-IV in Patients < 50 Years of Age*

47.4% in Control < 50 (0101)

24% in CD34+ < 50 (0303)p=0.028


86

Acute GVHD Grades III-IV *

Pro

babili

ty

0.0

0.2

0.4

0.6

0.8

1.0


0101 (N=84)0303 (N=44)

p=0.31

9.5% in Control (0101)4.5% in CD34+ (0303)


87

Limited/Extensive Chronic GVHD*

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0


0101 (N=84)0303 (N=44)

p=0.000449.9% in Control (0101)

15.9% in CD34+ (0303)

1 year post-hoc power for the comparison between 0101 and 0303 was 98%


88

Infectious ComplicationsControl (0101)N=84

CD34+ Enriched (0303)N=44

# of Infectious Reports # of Patients

1-3 44 20

4-5 7 7

6-10 6 3

>10 0 2

Total # of Patients with Infections (% of Patients)

57

(67.9%)

32

(72.7%)

Patients with Infections

89

Control(0101)N=84

CD34+ Enriched (0303)N=44

# of Infections and (# of Patients)

Bacterial 103 (48) 62 (25)

Viral 46 (30) 41 (24)**

Fungal 9 (9)* 8 (5)

Protozoal 0 (0) 1 (1)

Other 4 (3) 0 (0)

Total Infection Events 162 112

Types of Infections Seen By Protocol

* Represents confirmed infections only; 10 possible and 3 presumptive infections not included

** 8 of 24 viral infections in CD34+ enriched cohort (0303) were due to EBV reactivation

90

Control (0101)N=84

CD34+ Enriched(0303)N=44

Maximum Severity by Patient# of Patients

(% of Patients)

None 28 (33.3%) 12 (27.3%)

Moderate 30 (35.7%) 15 (34.1%)

Severe 23 (27.4%) 13 (29.5%)

Life Threatening/Fatal 3 (3.6%) 4 (9.1%)

Infection Events

Percentage of all deaths due to infection were

18.2% in 0101 and 20% in 0303

91

Causes of Death atOne Year Post-Transplant

Control (0101)

N and % of Deaths

CD34+ Enriched (0303)

N and % of Deaths

Recurrence 9 (40.9%) 3 (30%)

Acute GVHD 1 (4.5%) 0

Chronic GVHD 1 (4.5%) 0

Infection 4 (18.2%) 2 (20%)

Interstitial Pneumonia 0 2 (20%)

Veno-occlusive Disease 1 (4.5%) 0

ARDS 1 (4.5%) 0

Organ Failure 5 (22.7%) 2 (20%)

PTLD 0 1 (10%)

Total 22 (23.1%) 10 (18.9%)

92

The incidence of chronic GVHD at one year post-transplant was significantly lower for recipients of CD34+ enriched allografts (p= 0.0004)

Between patients receiving CD34+ enriched versus unmanipulated grafts, there was no significant difference in: Platelet and Neutrophil Engraftment, Acute GVHD, DFS, OS,

TRM, and Relapse Low numbers of CR2 patients in both cohorts make statistical

comparisons of relapse inconclusive

DAP Statistical Comparison Summary

93

DAP Conclusion

The DAP results support a comparable safety profile for CD34+ enriched

transplants as compared to patients receiving unmanipulated grafts and conventional GVHD prophylaxis but

with a significant reduction in cGVHD

94

Kai Pinkernell, M.D.Head of Clinical Development

Miltenyi Biotec GmbH

Overall Conclusions of Safety and Probable Benefit of the CliniMACS® CD34 Reagent

System

95

The CliniMACS® CD34 Reagent System consistently produced a graft with > 2 x 106 CD34+ cells/kg and < 1 x 105 CD3+

cells/kg 84% of the grafts contained > 5 x 106 CD34+ cells/kg

There was no significant difference between CD34+ enriched and unmanipulated allografts for: Platelet and Neutrophil Engraftment, Acute GVHD, DFS, OS,

TRM, and Relapse

While 0303 patients experienced more infectious episodes/patient (112/44 patients in 0303 versus 162/84 patients in 0101), these did not translate to higher infectious death rates (18.2% of deaths in 0101 vs. 20% in 0303) Increased incidence of EBV reactivation reports most likely

due to stringent protocol specified monitoring of EBV in 0303

Performance and Safety ConclusionsCliniMACS® CD34 Reagent System

96

The CliniMACS® CD34 Reagent System was shown to consistently yield CD34+ enriched, T cell depleted, sterile cellular grafts in a multi-center setting

Low rates of both acute and chronic GVHD without the risks associated with traditional pharmacologic GVHD prophylaxis while maintaining consistent engraftment, excellent DFS and OS, low TRM, and a low incidence of relapse

Significantly reduced incidence of chronic GVHD without compromising survival

Probable Benefit Conclusions CliniMACS® CD34 Reagent System

97

Safety and Probable Benefit Objectives Met

The CliniMACS® CD34 Reagent System is safe, and has a probable benefit in

significantly reducing the incidence of chronic GVHD while eliminating the need for pharmacologic GVHD prophylaxis for

AML patients in complete remission, undergoing PBSC transplantation from a

matched related donor

98

Acknowledgements

BMT CTN NHLBI/NCI CIBMTR/EMMES/NMDP Investigators and Contributors

Steven Devine Marcelo Pasquini Carolyn Keever-Taylor Richard O’Reilly Robert Soiffer John Wingard Adam Mendizabal, EMMES Shelly Carter, EMMES Nancy DiFronzo, NHLBI Mary Horowitz, CIBMTR Nancy Poland, NMDP Many, Many others

The patients and their families who have made these trials possible

99

Thank You

fda advisory panel miltenyi biotec clinimacs ® cd34 reagent system september 23, 2011 with sincere...

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