arranon ® (nelarabine) injection nda 21-877 presentation to oncologic drugs advisory committee...

ARRANON® (nelarabine) InjectionNDA 21-877

Presentation to Oncologic Drugs

Advisory Committee September 14, 2005

2

ARRANON®

Presentation OverviewIntroduction Peter Ho, M.D., Ph.D.

VP, Discovery Medicine Oncology, GSK

Disease Overview Stephen Sallan, M.D.Professor of Pediatrics, HarvardChief of Staff, Dana-Farber

Efficacy Summary Richard Larson, M.D.Professor of Medicine, Univ. of ChicagoChair, Leukemia Committee, CALGB

Safety Summary Mark Russo, M.D., Ph.D.Group Director, Clinical Oncology, GSK

Role in Treatment William Carroll, M.D.Director, Pediatric Oncology, NYUChair, ALL Committee, COG

Conclusion Peter Ho, M.D., Ph.D.

3

ARRANON®

Additional Participants

Susan Blaney, M.D. Texas Children’s Cancer Center

Dan DeAngelo, M.D., Ph.D. Dana-Farber Cancer Institute

Joanne Kurtzberg, M.D. Duke University

Varsha Gandhi, Ph.D. M.D. Anderson Cancer Center

Arthur Forman, M.D. M.D. Anderson Cancer Center

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ARRANON®

Additional GSK Participants

Christopher Abissi

Ohad Amit

Andrew Beelen

Janet Begun

Michelle Casey

Ellen Cutler

Roxanne Jewell

Nelson Johnson

Tom Lampkin

Paolo Paoletti

Maria Richie

Debasish Roychowdhury

Robert Watson

5

ARRANON®

Proposed Indication

ARRANON® (nelarabine) Injection is indicated for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens

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ARRANON®

ARRANON® (nelarabine) Purine nucleoside phosphorylase (PNP) deficiency

– T-cell lymphopenia– Abnormal guanine nucleoside metabolism

Ara-G mimics PNP deficiency state– T-cells targeted for selective destruction

ARRANON is a soluble pro-drug of Ara-G First clinical trial in 1993 NCI collaborative development

– CALGB & COG pivotal studies– Cooperative group data for submission

7

ARRANON®

ARRANON® (nelarabine) ARRANON demonstrates

– Pharmacological selectivity for T-cells– Clinical efficacy

in children and adults in relapsed and refractory disease

– Well characterized safety profile – Favorable benefit-risk profile in heavily

pre-treated patients

Meets a significant unmet medical need

No proven effective alternative therapy available for T-ALL and T-LBL

8

ARRANON®

Disease Overview

Stephen Sallan, M.D.Professor of Pediatrics, Harvard

Chief of Staff, Dana-Farber

9

ARRANON®

Overview of Patients with T-ALL / T-LBL

Rare diseases (N~1600/yr)

T-cell ALL & LBL differ only by % lymphoblasts in bone marrow

Most in older children & young adults

Much biology age-independent

- e.g., Notch 1 mutations in ~ 50%

- e.g., Gene expression signatures

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ARRANON®

Current Treatment

Multi-agent chemotherapy at time of diagnosis and at 1st relapse

Treatment with curative intent– At diagnosis – chemotherapy– 1st relapse – chemotherapy to induce a 2nd

complete remission; then curative stem cell transplant

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ARRANON®

Pediatric Patients with ALL at Diagnosisby Immunophenotype

T-cell B-cell P-value

Induction Failure 12% 2% <0.0001

Induction Death 3.2% 0.7% 0.02

Leukemia Relapse 11% 18% 0.06

Goldberg et al. JCO. 2003.

Figure 1 T-ALL n=125 B-ALL n=1130

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ARRANON®

Patients with T-ALL / T-LBL at 1st Relapse

~500 patients per year

Treatment is with curative intent: multi-agent chemotherapy followed by a SCT

Outcome for T-cell ALL patients transplanted in 2nd remission is approximately 40% at two years for children and adults.

Treatment related mortality can be 5-10%.

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ARRANON®

Outcome After Second Relapse (Patients with T-ALL, N=13)

Sather, et al. COG (unpublished)

0 13 26 39 52 65 78 91 104 117 130 143

Tim e (W eeks)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

port

ion

Aliv

e

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ARRANON®

Current Drugs in Multi-Agent Regimens

VincristinePrednisoneDexamethasoneAsparaginaseDaunorubicinDoxorubicin

6-MP6-TGMethotrexateCyclophosphamideEtoposideCytarabine

New drugs are needed for patients with relapsed and refractory disease.

15

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Efficacy Overview

Richard Larson, M.D.Professor of Medicine, Univ. of Chicago

Chair, Leukemia Committee, CALGB

16

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Pivotal Studies

Adult: CALGB19801– A Phase II Study of Nelarabine (506U78) in

Subjects with Refractory or Relapsed T-Lineage Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL)

DeAngelo et al. Blood. 2002; 100(11):198a (Abstract 743).

Pediatric: COG P9673– A Phase II Study of 506U78 in Patients with

Refractory T-Cell MalignanciesBerg et al. JCO. 2005; 23(15):3376-82.

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Efficacy Endpoint Definitions

Parameter CR CR* Bone marrow - Blasts <5% <5% Hemogram - Blasts 0% 0% - Platelets >100,000 - Neutrophils >1500 Physical - Liver NED NED - Spleen NED NED - Other NED NED Extramedullary NED NED NED = no evidence of disease.

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ARRANON®

Rationale for CR* Endpoint

Similar to CRi and CRp for patients with AML

Heavily pretreated patients – may never have full hematologic recovery– benefit from the absence of disease

Retreatment & Stem Cell Transplant– may occur prior to full hematologic recovery

CR* was agreed with FDA June 1997

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ARRANON®

Patients with T-ALL/T-LBL

Prior Therapy – One prior induction/regimen

Primary refractory disease Relapsed disease

– Two or more prior inductions/regimens Refractory disease Relapsed disease

Refractory – Primary refractory disease– Less than CR following most recent induction attempt

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Adult: CALGB 19801 Open-label, multicenter Phase II study

Median age: 34 years (range: 16-66 years)

Refractory or relapsed T-ALL or T-LBL

Dose*: 1500 mg/m2 days 1, 3, 5, every 21 days

Two cycles for induction plus two for consolidation

39 patients treated:– 11 patients with 1 prior multi-agent induction/regimen – 28 patients with ≥ 2 prior multi-agent inductions/regimens

Enrolled over 37 months

* Recommended Dose

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Adult: CALGB 19801 Response Rate & Duration≥ 2 Prior Inductions (N=28)

Response CR CR plus CR*

Response Rate 18% 21%

Median Duration of Response (weeks)

29 24

Duration of Response (weeks)

15 to 195+ 4 to 195+

CR = complete response with full hematologic recoveryCR* = complete response without full hematologic recovery CR plus CR* = total of patients achieving best response in either category

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Adult: CALGB 19801 CR+CR* Rates

Brackets represent 95% confidence intervals for (CR+CR*)

Res

pons

e R

ate

(%)

0

10

20

30

40

50

60

70

N=28

>=2 P rior Inductions

21%

18%

CR* CR

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Res

pons

e R

ate

(%)

0

10

20

30

40

50

60

70

N =28 N=17

>=2 Prior Inductions

Refractory (>=2 Prior)

21% 24%

18% 18%

CR* CR

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Res

pons

e R

ate

(%)

0

10

20

30

40

50

60

70

1 Prior Induction

N=11N =28 N=17

>=2 Prior Inductions

Refractory (>=2 Prior)

21%

18%

24%27%

18% 18%

CR* CR

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ARRANON®

Adult: CALGB 19801 Duration of Best Response (≥2 prior multi-agent inductions)

+ Response on-going at last evaluation

0 20 40 60 80 100 120 140 160 180 200 220

Tim e from Start of Best Response (W eeks)

76143 (C R*)

83908 (C R)

77798 (C R)

82137 (C R)

79729 (C R)

78326 (C R) +

+

Refrac to ry D isease Re lapse D isease Time o f Transplant

Median 24 weeksMin-Max (4-195+)

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ARRANON®

Adult: CALGB 19801 Duration of Best Response (1 prior multi-agent induction)

0 20 40 60 80 100 120 140 160 180 200 220

Tim e from Start of Best Response (W eeks)

84144 (C R*)

82761 (C R)

77661 (C R)

Re lapse D isease Time o f Transplant

Median 51 weeksMin-Max (5 to 212)

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Adult: CALGB 19801 Overall Survival(≥ 2 Prior Multi-Agent Inductions)

+ Alive at last contact

0 26 52 78 104 130 156 182 208 234

Tim e Since Treatm ent Start (weeks)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

port

ion

Aliv

e

Median Surv iv al: 21 W eeks 95% CI: (10 , 36 )

One Year Surv iv al: 29%95% CI: (12% , 45% )

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Adult: CALGB 19801 Overall Survival

0 26 52 78 104 130 156 182 208 234


0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

port

ion

Aliv

e

1 Prior Induction(N= 11) > /= 2 Prior Inductions (N= 28)


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Pediatric: COG P9673 Open-label, multicenter Phase II study Refractory or relapsed T-ALL or T-NHL Dose*: 650 mg/m2 days 1-5, every 21 days Median: 11 years (range 3-20 years) 151 patients treated across 4 strata

– At the recommended dose 31 patients with 1 prior multi-agent induction 39 patients with ≥2 prior multi-agent inductions

Enrolled over 61 months

* Recommended Dose

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Pediatric: COG P9673 Response Rate & Duration≥ 2 Prior Inductions (N=39)

Response CR CR plus CR*

Response Rate 13% 23%

Median Duration of Response (weeks)

9 9

Duration of Response (weeks)

5 to 36 3 to 42

CR = complete response with full hematologic recoveryCR* = complete response without full hematologic recovery CR plus CR* = total of patients achieving best response in either category

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Pediatric: COG P9673 CR+CR* Rates


Resp

onse

Rat

e (%

)

0

10

20

30

40

50

60

70

80

90

N=39

>= 2 Prior Inductions

23%

13%

CR* CR

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Resp

onse

Rat

e (%

)

0

10

20

30

40

50

60

70

80

90

N=39 N=22


Re fractory (>= 2 Prior)

23%27%

13%18%

CR* CR

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Resp

onse

Rat

e (%

)

0

10

20

30

40

50

60

70

80

90

1 PriorInduction

N=31N=39 N=22 N=9


Re fractory (>= 2 Prior)

Re fractory(1 Prior)

23%

42% 44%

27%

48%56%

13%18%

CR* CR

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ARRANON®

Pediatric: COG P9673 Duration of Best Response (≥2 prior multi-agent inductions)

0 5 10 15 20 25 30 35 40 45

Tim e from Start of Best Response (weeks)

1068 (C R*)

1109 (C R*)

1081 (C R)

1036 (C R)

1093 (C R)

1132 (C R)

1039 (C R)

1131 (C R*)

1062 (C R*)

Re frac to ry D isease Re lapse D isease Time o f Transplant

Median 9 weeksMin-Max (3 to 42 )

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ARRANON®

Pediatric: COG P9673 Duration of Best Response (1 prior multi-agent induction)

+ Response on-going at last evaluation

0 20 40 60 80 100 120 140 160 180 200 220 240 260

Tim e from Start of Best Response (weeks)

1069 (C R)

1124 (C R)

1024 (C R)

1123 (C R)

1047 (C R)

1065 (C R)

1040 (C R*)

1140 (C R)

1133 (C R)

1078 (C R)

1074 (C R*)

1076 (C R)

1049 (C R)

1034 (C R)

1042 (C R)

++

+

+

+

+

+

Refrac to ry D isease Re lapse D isease Time o f Transplant

Median 234 weeksMin-Max (1 to 260)

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ARRANON®

Pediatric: COG P9673 Overall Survival(≥ 2 prior multi-agent inductions)


0 26 52 78 104 130 156 182 208 234 260 286


0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

port

ion

Aliv

e

Median Surv iv al: 13 W eeks :95% CI: (9 , 17 )

One Year Surv iv al: 14%95% CI: (3% , 26% )

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ARRANON®

Pediatric: COG P9673 Overall Survival

0 26 52 78 104 130 156 182 208 234 260 286


0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

port

ion

Aliv

e

1 Prio r Induc tion (N=31) >= 2 P rio r Induc tions (N=39)


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ARRANON®

Response Rate – Supportive Trials of Patients with Relapsed/Refractory T-ALL/T-LBL

Age Group Study N CR%

Adult TRC 9701Special Exceptions (Univ Frankfurt)

2416

13%56%

Adult PGAA1001PGAA1002PGAA1003

1438

29%00

Pediatric PGAA1001PGAA1002PGAA1003

1852

33%40%50%

Total 90

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ARRANON®

AdultCALGB 19801a

PediatricCOG

P9673a

Subjects with available data

n=6 n=21

Neutrophils (≥500/µL x3 days)

3 (50%) 20 (95%)

a Based on retrospective data collection. Data not available on all subjects.

Neutrophil Recovery Following Allogeneic Transplant

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ARRANON®

AdultCALGB 19801a

PediatricCOG

P9673a

Univ of Frankfurtb

Subjects with available data

n=6 n=21 n=18

Neutrophils (≥500/µL x3 days)

3 (50%) 20 (95%) 17 (94%)

b Report provided by Investigator. Patients enrolled in Special Exceptions Program.

a Based on retrospective data collection. Data not available on all subjects.

Neutrophil Recovery Following Allogeneic Transplant

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ARRANON®

Efficacy Summary≥ 2 Prior Multi-Agent Inductions

AdultCALGB 19801

Pediatric COG P9673

CR plus CR* 21% 23%

Duration of CR plus CR* 4 to 195+ weeks 3 to 42 weeks

Median Overall Survival 21 weeks 13 weeks

1-year Survival 29% 14%

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ARRANON®

Efficacy Conclusions

Clinically meaningful benefit as shown by: Induction of complete remission

Consistent rates of remission – Adult and pediatric patients– Patients with relapsed and refractory disease– Across Phase I and II studies

Duration of response

Documented successful transplantation

One year survival

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ARRANON®

Safety

Mark Russo, M.D., Ph.D.Group Director, Clinical Oncology, GSK

44

ARRANON®

Safety Overview

Safety populations

Phase I experience

Hematologic adverse events

Non-hematologic adverse events

Neurologic adverse events

Mortality due to adverse events

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ARRANON®

Safety Populations

980 patients have received ARRANON

Full safety database - 459 patients

Adult dose of 1500 mg/m2 on days 1,3,5– 36 CALGB19801 + 67 PGAA2003– 103 patients

Pediatric dose of 650 mg/m2 daily times 5– 84 patients COG P9673

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ARRANON®

Phase I Experience

181 patients (141 Adult, 40 Pediatric)

Dose Range: 104 mg/m2 – 2900 mg/m2

Schedules tested: Daily X 5; Daily X 3; Days 1, 3, 5

Neurotoxicity was dose-limiting

Adult Phase II Day 1, 3, 5 – 2200 mg/m2 decreased to 1500 mg/m2

Pediatric Phase II Daily X 5 – 1200 mg/m2 decreased to 650 mg/m2

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ARRANON®

Grade 4 Hematologic Adverse Events Regardless of Relationship

AdultN=103

PediatricN=84

Neutropenia 49% 62%

Anemia 14% 10%

Thrombocytopenia 22% 32%

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ARRANON®

Adult: Grade 3/4 Non-Hematologic Adverse Events (N=103)

Includes all grade 3/4 events occurring in at least 3 subjects

0% 10% 20% 30% 40% 50%

Incide nce Rate

Dys pne a

Effus ionPle ural

Hypoxia

Pain

Pyre xia

Pne um onia

In fe ction

De hydration

We ak ne s sM us cular

Ne utrope niaFe br ile

Fatigue

Related E vents Regardless of Relat ions hip

49

ARRANON®

Pediatric: Grade 3/4 Non-Hematologic Adverse Events (N=84)

Includes all grade 3/4 events occurring in at least 3 subjects

0% 10% 20% 30% 40% 50%

Incidence Rate

He a da che

Hypoa e sthe sia

Convulsion

Infe ction

Se psisBa cte ria l

Hypoglyce m ia

Incre a se dTra nsa m ina se s

Hypoka lem ia

Hypoa lbum ine m ia

Ne uropa thyPe riphe ra l Se nsory

Hype rbilirubine m ia

Re la ted E vents Regard less of Re la tionship

50

ARRANON®

Adult: Drug-related NeurologicAdverse Events (N=103)

Includes all grade 3/4 neurologic events

0% 10% 20% 30% 40% 50%

Incidence Rate

Consciousne ssLoss of

Le ukoe nce pha lopa thy

Ha e m orrha geIntra cra nia l

He m ipa re sis

Convulsion

Com a

Ha e m orrha geCe re bra l

Consciousne ssDe pre sse d

Ne uropa thyPe riphe ra l

Ata x ia

Hypoa e sthe sia

Grade 3/4 E vents A ll Grades

51

ARRANON®

Adult: Neurologic Adverse Events Regardless of Relationship (N=103)


0% 10% 20% 30% 40% 50%

Incidence Rate

Ence pha lopa thyMe ta bolic

Consciousne ssLoss of

Le ukoe nce pha lopa thyHa e m orrha ge

Intra cra nia lHe m ipa re sis

Convulsion

Com aHa e m orrha ge

Ce re bra lApha sia

Ne uropa thyPe riphe ra l

Consciousne ssDe pre sse d

Ne uropa thyPe riphe ra l Motor

Ata x ia

He a da che

Hypoa e sthe sia

Grade 3 /4 E vents A ll Grades

52

ARRANON®

Pediatric: Drug-related Neurologic Adverse Events (N=84)


0% 10% 20% 30% 40% 50%

Incidence Rate

EpilepticusStatus

Ataxia

Convuls ion

DysfunctionMotor

Paraesthes ia

NeuropathyPeripheral Motor

Headache

Som nolence

NeuropathyPeripheral

Hypoaesthesia

NeuropathyPeripheral Sensory


53

ARRANON®

Pediatric: Neurologic Adverse Events Regardless of Relationship (N=84)


0% 10% 20% 30% 40% 50%

Incidence Rate

Paralys is6th Nerve

EpilepticusStatus

Paralys is3rd Nerve

Hypertonia

ConvulsionGrand Mal

Ataxia

NeuropathyPeriphera l Motor

Paraesthesia

DysfunctionMotor

Convulsion

NeuropathyPeripheral Sensory

NeuropathyPeripheral

Hypoaesthesia

Som nolence

Headache


54

ARRANON®

Incidence of Neurologic Adverse Events Regardless of Relationship

Grade 3 Grade 4

Adults (N=103) 10% 3%

Pediatric (N=84) 11% 8%

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ARRANON®

Resolution of Neurologic Adverse Events Regardless of Relationship

Resolved Unresolved* UnknownAdults (1500 mg/m2)

217 events47% 24% 28%

Pediatrics (650 mg/m2)

80 events63% 18% 20%

*includes 2 patients with fatal neurologic events (1 Adult, 1 Pediatric)

56

ARRANON®

Clinical Presentation of Neurologic Adverse Events (1)Somnolence Onset often on day of administration

Drowsiness, increased sleep

Usually reversible, within days

Not clinically significant

57

ARRANON®

Clinical Presentation of Neurologic Adverse Events (2)Peripheral Neuropathies Onset generally after administration Mostly sensory

– Numbness/dysesthesia of lower extremities Similar to that seen with vincristine and taxanes Occasionally motor Resolution may take several months Severe ascending polyneuropathy seen in 14 of 980

patients (1.5%)

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ARRANON®

Nine in 187 patients (5%)– Six in adults, N=103– Three in pediatrics, N=84

Two (1%) attributed to ARRANON– Coma– Status epilepticus

Mortality Due to Adverse Eventsat Proposed Doses

59

ARRANON®

Safety Conclusions

Hematologic events were most common, and manageable

Neurologic events were frequent in this population– Most were grade 1 or 2– 13% G3/G4 for adults– 19% G3/G4 for pediatrics

1% of patients had fatal related adverse events

Recommended doses have acceptable risk for this patient population

60

ARRANON®

Role of ARRANON in TreatmentWilliam L. Carroll, M.D.

Director, Pediatric Oncology, NYUChair, ALL Committee,

Children’s Oncology Group

61

ARRANON®

Evaluation of New Agents for T-ALL/T-LBL

Treatment Setting - Relapsed/Refractory Disease Heavily pretreated patients Historically treatment is usually individualized based on

response to prior therapy Stem cell transplantation is often the intention of treatment,

chemotherapy used to induce remission

Rationale - Clinical Trials Evaluate ability to induce complete remission in heavily

pretreated patients Randomized studies not possible in relapsed or refractory

setting Integrate most promising compounds that provide clinical

benefit into front-line therapy

62

ARRANON®

ARRANON Provides clinical benefit in patients with:

– Two or more prior inductions Notable CR rates, especially for the treatment setting

– One prior induction Single agent activity at least equal to that provided by

aggressive multi-agent regimens

Safety profile in patients with: – Relapsed or refractory disease

Acceptable adverse event profile – Newly diagnosed disease

Proven ability to combine with multi-agent therapy AALL00P2 (new diagnosis higher risk T ALL)

Patients with Relapsed or Refractory T-ALL/T-LBL

63

ARRANON®

Phase III Randomized Trial – COG AALL0434 Randomized, multi-center, cooperative group trial (COG)

N=640 patients with T-ALL, aged 1-30 years

Study design– Modified BFM regimen (based on legacy CCG-1961C

and identical to current AALL0232 study for higher risk B precursor ALL)

– Randomized to (high and intermediate risk patients): with or without ARRANON high dose MTX vs escalating IV MTX (aka Capezzi MTX)

Primary endpoint: EFS at 4 years

Safety Phase: first 20 consecutive high risk patients

Efficacy phase: interim analyses at 20%, 40%, 60%, 80%, and 100% of the expected total # events

64

ARRANON®

AALL0434 Efficacy Phase High and Intermediate Risk Patients

V

P

L

D

Backbone Regimen: BFM (CCG 1961C)

Induction Consolid. Interim Delayed Maintenance Main. Intens.

ARRANON

Without ARRANON

CMTX

HDMTX

CMTX

HDMTX

A A A A A

A A A A A

A

A

65

ARRANON®

Phase III Randomized Trial – AALL0434

ARRANON administration – 650 mg/m2 for five consecutive days – Consolidation, delayed intensification and

maintenance

Assessment of:– Event free survival – Minimal residual disease post consolidation

66

ARRANON®

ARRANON – Role in Treatment

ARRANON provides – clinical benefit, and – acceptable risk to benefit profile

ARRANON is an effective treatment for patients with relapsed or refractory T-ALL/T-LBL

67

ARRANON®

Conclusions

Peter Ho, M.D., Ph.D.VP, Discovery Medicine Oncology, GSK

68

ARRANON®

Conclusions

T-ALL/T-LBL ≥ 2nd relapse or refractory disease– Poor prognosis and no standard of care

ARRANON: Acceptable safety profile– Expected & manageable non-neurological

(incl. hematologic) adverse events for indicated population

– Neurological adverse events Low grade events are common Grade 3 / 4 events are less common, but require

prescriber attention

69

ARRANON®

ARRANON: Clinically meaningful benefit as single agent in T-cell ALL/LBL– Consistent demonstration of CR

Second and third line patients Refractory patients Children and adults

– CR durable and allowed time for transplantation– Demonstrable survival at one year

Overall favorable benefit - risk profile for the proposed population of relapsed or refractory patients

Conclusions

Additional Slides Presented

E-71

ARRANON®Response Duration – Confounding Factors (Patients achieving CR or CR*)Pt ID Duration (wks)* Event Transplant Systemic Rx1131 9 Transplant Y -

79729 6 Transplant Y -




78326 195+ Censored N N

82137 30 Relapse N Y

77798 19 Relapse N N

83908 15 Relapse Y -

1093 12 Relapse N Y

1062 10 Toxicity N Y

1036 6 Relapse N Y

76143 4 Relapse N Y

1109 3 Relapse N Y

1068 3 Infectious Death

N N

* From initial response (≥ mCR) to transplant, systemic Rx, or relapse

Duration ≥ 8 Weeks

Duration < 8 Weeks

Transplanted in Remission

S-72

ARRANON®Nervous System Serious Adverse Eventspre and post January 1, 1999

P ivotals + G S K IND s tudies A ll P at ients Treated with A rranon

0

5

10

15

20

25

30

35

40P

erce

nt w

ith N

euro

logi

c E

vent

E nro lled P rior to January 1 , 1999 E nrolled A fter January 1 , 1999

(N= 459)

n= 691

n= 275

n= 239

n= 220

(N= 966)

T-73

ARRANON®

Transplantation by Response

Transplantation post nelarabine CR or CR* < CR*

Adult: CALGB 19801

≥ 2 prior therapies

1 prior therapy

2/6

2/3

2/221

1/8

Pediatric: COG P9673

≥ 2 prior therapies

1 prior therapy

4/9

12/15

4/302

5/163

1. Includes one mCR 2. Includes one mCR and one mPR3. Includes one mPR

T-74

ARRANON®

Adult: CALG19801 Survival (CR+CR* Subjects, ≥2 prior multi-agent inductions)

+ Indicates alive at last evaluation

0 20 40 60 80 100 120 140 160 180 200 220

Tim e Since Treatm ent Start (W eeks)

76143 (C R*)

83908 (C R)

77798 (C R)

82137 (C R)

79729 (C R)

78326 (C R) +

+

Re frac tory D isease Re lapse D isease Time o f Transplant

T-75

ARRANON®

Pediatric: COG P9673 Survival (CR+CR* Subjects, ≥ 2 prior multi-agent inductions)

+ Indicates alive at last evaluation

0 10 20 30 40 50 60


1068 (C R*)

1109 (C R*)

1081 (C R)

1036 (C R)

1093 (C R)

1132 (C R)

1039 (C R)

1131 (C R*)

1062 (C R*)

Re frac to ry D isease Re lapse D isease Time to Transplant

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+

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arranon ® (nelarabine) injection nda 21-877 presentation to oncologic drugs advisory committee...

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