NDA 21-877
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Transcript of NDA 21-877
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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