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Nelarabine

Nelarabine. 506U78 Compound 506 GW506U78 Nelarabine Arranon. Lambe, Cancer Res. 1995. SELECTIVE CYTOTOXICITY OF ara-G. T-Cell Specificity Cell Lines Leukemia Cells Associated with ara-GTP. CLINICAL DEVELOPMENT OF ara-G. Problems Low solubility Difficulty in synthesis.

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Nelarabine

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  1. Nelarabine 506U78 Compound 506 GW506U78 Nelarabine Arranon Lambe, Cancer Res. 1995

  2. SELECTIVE CYTOTOXICITY OF ara-G T-Cell Specificity Cell Lines Leukemia Cells Associated with ara-GTP

  3. CLINICAL DEVELOPMENT OF ara-G Problems Low solubility Difficulty in synthesis Solution Synthesis of prodrug Nelarabine

  4. Nelarabine to ara-G Ado Deaminase Nelarabine ara-G

  5. Phase I Study with Nelarabine Dose 5, 10, 20, 40, 60, and 75 mg/kg over 1 hr Frequency Daily x 5 (repeat every 28 days) MTD 30 mg/kg (adult), 40 mg/kg (Ped.) 1.2 g/m2 DLT Neurotoxicity Kurtzberg, JCO 2005

  6. Phase I Trial of Nelarabine –Pediatric and Adult with Hematologic Malignancies Total Patients: 93 Age (<21 yrs:>21 yrs) 34 : 59 Male : Female 66 :27 Prior Rx: median (Range) 3 (1-11) Prior Transplant: Auto 15 Allo 11 Prior Vincristine 78 Prior high dose ara-C 11 Prior Intrathecal Rx 45

  7. Phase I Trial of Nelarabine Response Pts. %CR %OR T-ALL/LBL Pediatric 26 27 42 Adult 13 15 77 T-CLL/PLL 7 0 29 Other T-Cell 15 0 13 Pre B/B-ALL 10 0 10 B-NHL 6 0 16 Other 12 8* 8 *CML BC (T-Cell)

  8. Phase I Trial of Nelarabine Neurotoxicity Neurotoxicity: Overall 50% <21 yrs; 85% >21yrs Somnolence 3-8 days, reversible, >21 yrs. Neuropathy Severe in 11%, resolution slow or not Hematologic Grade I-II neutropenia, thrombocytopenia in 50-70%. No grade III-IV except BM involvement

  9. Phase I Study with Nelarabine Site MDACC Dose 20, 40, and 60 mg/kg over 1 hr per d x 5 Patients n = 27 (2 = ped.) Diagnoses Hematologic malignancies Gandhi, JCO 1998; Gandhi, JCO 2001

  10. Response to Nelarabine in adults in Phase I Study (MDACC) Diagnosis Dose Pts. CR PR Fail T ALL/LBL 20-30 2 -- 2 -- 40 6 2 2 2 60 2 2 -- -- T CLL/PLL 20-30 1 -- -- -- 40 2 -- -- -- Other 20-30 5 1* -- -- 40 5 1 -- -- 60 3 -- -- -- * B CLLCML-BC(T) Gandhi JCO 16,3605, 1998

  11. Plasma Pharmacology Nelarabine and ara-G

  12. Nelarabine Converts to ara-G During Therapy Ara-G Nelarabine Kisor, JCO 2000

  13. Cellular Pharmacology ara-G triphosphate

  14. ara-GTP DNA dGTP ara-GDP ara-GMP ara-G Nelarabine Ado deaminase Metabolism of Nelarabine dGuo Kinase dCyd Kinase

  15. PEAK CELLULAR ara-GTP DURING THERAPY

  16. Relationship between Peak ara-GTP and Clinical Response to Nelarabine  - T-ALL  - B-CLL - Non-T Gandhi, JCO

  17. Summary of Clinical Trial • Nelarabine an effective prodrug • ara-G readily phosphorylated • Prolonged retention of triphosphate • Cellular pharmacokinetics predict clinical response • Active in T-ALL

  18. Regimen Used in Nelarabine forMature Lymphoid Leukemia Dose Days Patients Nelarabine 20-60 mg/Kg/day 1-5 6 Nelarabine 1.5-2.9 G/m2 1,3,5 22 Nelarabine + 1.2 G/m2 1,3,5 9 Fludarabine 30 mg/m2 3,5

  19. Nelarabine in Mature Lymphoid LeukemiaCharacteristics Total Patients 37 Male/Female 25 / 12 Age: Median (range) 64 (27 – 83) Prior Rx: Median (range) 2 (0 – 7) Hgb <11 G% 25 (68%) Platelets <100x103/ 25 (68%)

  20. Nelarabine in Mature Lymphoid LeukemiaDiagnosis Diagnosis Patients CR% OR% CLL 9 44 55 CLL Accel/B-PLL 15 0 0 Hairy Cell Variant 1 0 0 T-CLL/PLL 11 18 27 LGL 1 0 0

  21. CELLULAR PHARMACOKINETICS OF ara-GTP & F-ara-ATP Fludarabine + Nelarabine Therapy

  22. Response to Fludarabine and Nelarabine Combination (MDACC) Diagnosis Pts. CR (%) PR (%) B-CLL 6 -- 3 (50) T-CLL PLL 3 1 (33) 1 (33) T-ALL 2 1 (50) -- MF/CML-BC 2 0 0

  23. Clinical Responses and Cellular ara-GTP Diagnosis  CLL  CLL-A  PLL Schedules d x 5 d 1, 3, 5 d 1, 3, 5 + F P = 0.0003 ara-GTP, mM 440 50 number 10 15

  24. Cellular ara-GTP versus Diagnosis Indolent Leukemias

  25. CELLULAR PHARMACOKINETICS & PHARMACODYNAMICS Indolent Leukemias

  26. Phase II Study of Nelarabine in Refractory Hematologic Malignancies (Age <21yrs) Schedule: 1200 mg/m2/day Day 1-5 Reduced to 900 mg/m2/day then to 650 mg/m2/day For CNS or extramedullary relapse 400 mg/m2/day Berg et al, JCO 23; 3376; 2005

  27. Response of Pediatric T-Cell ALL in Nelarabine by Dose (ITT) Dose Diagnosis Salvage mg/m2/1-5 Pts. CR% OR% T-ALL 1 900 6 33 33 650 34 47 53 T-ALL 2 >900 10 30 30 650 36 19 22 T-ALL All 900 2 -- -- (CNS-BM) 650 6 17 17 400 24 21 29 T-LBL All 650 8 13 38 400 27 -- 11 tt

  28. Neurological Toxicity by Dose in PediatricT-ALL/LBL Dose Patients Grade %CNS %Periph >900 18 >3 33 11 1-2 17 6 650 83 >3 5 7 1-2 23 12 400 50 >3 22 12 1-2 18 16 }17 }50 }28 }19 }40 }28

  29. Nelarabine in T-ALL, T-LBL –Adult(CALGB-SWOG) Total patients 40 T-ALL 22 T-LBL 18 Age (range) 16 – 66 Male/Female 33 / 7 All refractory / Relapses Dose 1.56/m/day Day 1, 3, 5

  30. Response to Nelarabine in T-ALL, T-LBL (CALGB-SWOG) Total patients 40 Evaluable 38 T-ALL CR / Total (%) 6 / 21 (24) T-LBL CR / Total (%) 4 17 (24) Median CR Duration: 9 / 8 Months

  31. Conclusions regarding Nelarabine • Active in and approved for T-Cell ALL/LBL • Active in T-Cell CLL/PLL • Active in B-CLL-indolent • Response related to intracellular ara-GTP level • Dose limited by neurotoxicity • Minimal hematologic toxicity • Optimal dose/schedule still to be explored as single agent/combination

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