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NDA 21-877

Nelarabine

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Proposed Indication

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

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Submitted Phase 2 Studies

Study Total Pts

Pts receiving

proposed dose

COG 149 70

CALGB 39 39

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Nelarabine Dose and Schedule

Pediatric:Nelarabine 650 mg/m2/day administered intravenously over 1 hour daily for 5 consecutive days repeated every 21 days.

Adult:Nelarabine 1,500 mg/m2 administered intravenously over 2 hours on days 1, 3 and 5 repeated every 21 days.

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Response Definitions

• CR: - no circulating blasts or extramedullary disease; - an M1 bone marrow (< 5% blasts); and ANC >1.5 × 103/mcL - platelets >100 × 103/mcL and Hgb >10 or 11 g/dL.

• CR*: - Patients who have met all criteria for CR except for recovery of peripheral blood counts or marrow cellularity .

Independent review of marrow aspirates and/or biopsies for responders whose slides were available

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Study Objectives

• Primary Objective

- CR plus CR* rate

• Secondary Objectives

- Remission duration

- Overall survival ( OS)

- Safety

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Pediatric Study

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Inclusion criteria

• Age < 21• Refractory or recurrent T-ALL or T-LBL• First or subsequent relapse • Performance status >50• Adequate organ status• Patients with >grade 2 neurotoxicity were

excluded.

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Study participants

78 Sites: United States and Canada

109 Investigators

Independent pathology review

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COG Study Groups

Group Description N

2 T-ALL or T-LBL in second or later relapse (>25% marrow blasts, with or without concomitant extramedullary relapse – other than CNS)

39

1 T-ALL or T-LBL in first relapse (>25% marrow blasts, with or without concomitant extramedullary relapse – other than CNS)

31

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AML - Demographics and KPSVariable Group 2 Group 1

Age [mean (range)] 11.52 mo-21 yrs

11.62-21 yrs

Sex F/M 36%/64% 13%/87%

Ethnicity White Black Hispanic Other

64% 8% 18% 10%

61%19%16% 3%

KPS 100 90-80 70-60 50-40

21%39%21%13%

29%58%6%6%

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COG - Disease Characteristics

Variable Group 2 Group 1Diagnosis ALL LBL

79%21%

90%10%

Disease Sites Marrow CNS Extramedullary

92%3%

44%

100%3%

32%

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Group 2 Prior Therapies

Prior inductions

2

3

4

5

Unknown

N=39

69%

18%

5%

5%

3%

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COG Best Response

Response Group 2

N=39

Group 1

N=31

CR 5 (13%) 13 (42%)

CR+CR* 9 (23%) 15 (48%)

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Response by Disease Type

Group 2 Group 1

ALL

N=31

LBL

N=8

ALL

N=28

LBL

N=3

CR (%) 3 (10) 2 (25) 13 (46) 0

CR+CR*

(%)

7 (23) 2 (25) 15 (54) 0

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T-ALL/LBL - Patients Transplanted

Group No. of patients

%

2 4 of 9 44

1 10 of 15 67

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Non-Transplant

Remission duration (weeks)

Group 2 Group 1

42.1 (IT+Sys @ week 14)

9.3

6.1

3.6

3.3

33.1 (Sys @ week 8)

9.1 (IT)

6.3

2.3

1.4+

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Adult Study

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CALGB - Demographics and KPSVariable Group 2

N=28

Group 1

N=11Age [median (range)]

31.516-65 yrs

30.023-66 yrs

Sex F/M 18%/82% 18%/82%Ethnicity White Black Hispanic Other

61% 32% 4% 3%

91% 0% 0% 9%

PS 0-1 2 3

72%14%14%

72%19% 9%

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CALGB - Disease Characteristics

Variable group 2

N=28

group 1

N=11Diagnosis ALL LBL

61%39%

82%18%

Extramedullary Disease

71% 55%

Prior Transplant 14% 9%

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CALGB Best Response

Response Group 2

N=28

Group 1

N=11

CR 5 (18%) 2 (18%)

CR+CR* 6 (21%) 3 (27%)

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Response by Disease Type

Group 2 Group 1

ALL

N=17

LBL

N=11

ALL

N=9

LBL

N=2

CR (%) 3 (18) 2 (22) 1 (11) 1 (50)

CR+CR* 4 (24) 2 (22) 2 (22) 1 (50)

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CALGB - Patients Transplanted

Group No. of patients

%

2 1 of 6 17

1 1 of 3 33

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CALGB Non-Transplant

Remission duration (weeks)

Group 2 Group 1

195+

30

19

15

4

217

5

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Supportive Phase 1 Trials

Group No. of Studies

No. of Patients

CR

Pediatric 3 25 36%

Adult 3 25 16%

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Grade 3/4 Non-Neurologic AE’s; Pediatric N=84

• Hematologic (~90%)• Infections (3%)• Increased Transaminases (4%)• Increased Bilirubin (9%)• Decreased Albumin (6%)• Decreased Potassium (6%)• Asthenia (1%)

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Pediatric Neurologic AE’s N=84 (%)

Term Grade 3/4 All Grades

Headache 6 17

Somnolence 2 7

Hypoesthesia 4 6

Neuropathy 7 12

Seizures 6 6

Paresthesias 1 4

Tremor 0 4

Ataxia 1 2

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Grade 3/4 Non-Neurologic AE’s; Adult N=103

• Hematologic (~70%)• Infections (9%)• Gastrointestinal (3%)• Fatigue (12%)• Asthenia (1%)• Respiratory Disorders (10%)• Transaminase increase (2%)

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Adult Neurologic AE’s N=103 (%)

Term Grade 3/4 All Grades

Headache 1 15

Somnolence 0 23

Hypoesthesia 2 17

Neuropathy 2 18

Dizziness 0 21

Paresthesias 0 15

Tremor 0 5

Ataxia 2 9

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Efficacy Conclusions>2 Prior Induction Regimens

Response Pediatric

N=39

Adult

N=28

CR (%) 5 (13) 5 (18)

CR+CR* 9 (23) 6 (21)

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Efficacy Conclusions1 Prior Induction Regimen

Response Pediatric

N=31

Adult

N=11

CR (%) 13 (42) 2 (18)

CR+CR* 15 (48) 3 (27)

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Efficacy Conclusions>2 Prior Induction Regimens

Response ALL

N=52

LBL

N=24

CR (%) 7 (13) 5 (21)

CR+CR* 12 (23) 6 (25)

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Safety Conclusions

• Principal toxicities in pediatric patients were laboratory abnormalities

• Principal toxicities in adult patients were hematologic, gastrointestinal, fever, fatigue and respiratory.

• Neurologic toxicity was dose limiting. Most neurologic toxicity resolved over time.

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Nelarabine Efficacy Considerations

• Traditional endpoints: - CR rate and duration, OS• Study confounding factor: - Transplantation