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Nelarabine 506U78 Compound 506 GW506U78 Nelarabine Arranon

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Presentation on theme: "Nelarabine 506U78 Compound 506 GW506U78 Nelarabine Arranon"— Presentation transcript:

1 Nelarabine 506U78 Compound 506 GW506U78 Nelarabine Arranon
GW506/BioCryst.ppt 5/1/2019 Nelarabine 506U78 Compound 506 GW506U78 Nelarabine Arranon Lambe, Cancer Res. 1995

2 SELECTIVE CYTOTOXICITY OF ara-G
GW506/BioCryst.ppt 5/1/2019 SELECTIVE CYTOTOXICITY OF ara-G T-Cell Specificity Cell Lines Leukemia Cells Associated with ara-GTP

3 CLINICAL DEVELOPMENT OF ara-G
GW506/BioCryst.ppt 5/1/2019 CLINICAL DEVELOPMENT OF ara-G Problems Low solubility Difficulty in synthesis Solution Synthesis of prodrug Nelarabine

4 Nelarabine to ara-G Nelarabine ara-G Ado Deaminase GW506/BioCryst.ppt
5/1/2019 Nelarabine to ara-G Ado Deaminase Nelarabine ara-G

5 Phase I Study with Nelarabine
GW506/BioCryst.ppt 5/1/2019 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 GW506/BioCryst.ppt 5/1/2019 Phase I Trial of Nelarabine –Pediatric and Adult with Hematologic Malignancies Total Patients: Age (<21 yrs:>21 yrs) 34 : 59 Male : Female 66 :27 Prior Rx: median (Range) 3 (1-11) Prior Transplant: Auto Allo Prior Vincristine Prior high dose ara-C Prior Intrathecal Rx

7 Phase I Trial of Nelarabine Response
GW506/BioCryst.ppt 5/1/2019 Phase I Trial of Nelarabine Response Pts. %CR %OR T-ALL/LBL Pediatric Adult T-CLL/PLL Other T-Cell Pre B/B-ALL B-NHL Other * 8 *CML BC (T-Cell)

8 Phase I Trial of Nelarabine Neurotoxicity
GW506/BioCryst.ppt 5/1/2019 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
GW506/BioCryst.ppt 5/1/2019 Site MDACC Phase I Study with Nelarabine 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)
GW506/BioCryst.ppt 5/1/2019 Response to Nelarabine in adults in Phase I Study (MDACC) Diagnosis Dose Pts. CR PR Fail T ALL/LBL T CLL/PLL Other * -- --  -- -- * B CLL CML-BC(T) Gandhi JCO 16,3605, 1998

11 Plasma Pharmacology Nelarabine and ara-G
GW506/BioCryst.ppt 5/1/2019 Plasma Pharmacology Nelarabine and ara-G

12 Nelarabine Converts to ara-G During Therapy
GW506/BioCryst.ppt 5/1/2019 Nelarabine Converts to ara-G During Therapy Ara-G Nelarabine Kisor, JCO 2000

13 Cellular Pharmacology ara-G triphosphate
GW506/BioCryst.ppt 5/1/2019 Cellular Pharmacology ara-G triphosphate

14 Metabolism of Nelarabine
GW506/BioCryst.ppt 5/1/2019 Metabolism of Nelarabine ara-GTP ara-GDP DNA dGTP ara-GMP dGuo Kinase dCyd Kinase ara-G Nelarabine Ado deaminase

15 PEAK CELLULAR ara-GTP DURING THERAPY
GW506/BioCryst.ppt 5/1/2019 PEAK CELLULAR ara-GTP DURING THERAPY

16 Relationship between Peak ara-GTP and Clinical Response to Nelarabine
GW506/BioCryst.ppt 5/1/2019 Relationship between Peak ara-GTP and Clinical Response to Nelarabine   - T-ALL  B-CLL  Non-T Gandhi, JCO

17 Summary of Clinical Trial
GW506/BioCryst.ppt 5/1/2019 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 for Mature Lymphoid Leukemia
GW506/BioCryst.ppt 5/1/2019 Regimen Used in Nelarabine for Mature Lymphoid Leukemia Dose Days Patients Nelarabine mg/Kg/day Nelarabine G/m2 1,3,5 22 Nelarabine G/m2 1,3,5 9 Fludarabine 30 mg/m ,5

19 Nelarabine in Mature Lymphoid Leukemia Characteristics
GW506/BioCryst.ppt 5/1/2019 Nelarabine in Mature Lymphoid Leukemia Characteristics Total Patients 37 Male/Female / 12 Age: Median (range) 64 (27 – 83) Prior Rx: Median (range) 2 (0 – 7) Hgb <11 G% (68%) Platelets <100x103/ 25 (68%)

20 Nelarabine in Mature Lymphoid Leukemia Diagnosis
GW506/BioCryst.ppt 5/1/2019 Nelarabine in Mature Lymphoid Leukemia Diagnosis Diagnosis Patients CR% OR% CLL CLL Accel/B-PLL Hairy Cell Variant T-CLL/PLL LGL

21 CELLULAR PHARMACOKINETICS OF ara-GTP &
GW506/BioCryst.ppt 5/1/2019 CELLULAR PHARMACOKINETICS OF ara-GTP & F-ara-ATP Fludarabine + Nelarabine Therapy

22 Response to Fludarabine and Nelarabine Combination (MDACC)
GW506/BioCryst.ppt 5/1/2019 Response to Fludarabine and Nelarabine Combination (MDACC) Diagnosis Pts. CR (%) PR (%) B-CLL (50) T-CLL PLL 3 1 (33) 1 (33) T-ALL (50) -- MF/CML-BC

23 Clinical Responses and Cellular ara-GTP
GW506/BioCryst.ppt 5/1/2019 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 = ara-GTP, mM number

24 Cellular ara-GTP versus Diagnosis
GW506/BioCryst.ppt 5/1/2019 Cellular ara-GTP versus Diagnosis Indolent Leukemias

25 CELLULAR PHARMACOKINETICS & PHARMACODYNAMICS
GW506/BioCryst.ppt 5/1/2019 CELLULAR PHARMACOKINETICS & PHARMACODYNAMICS Indolent Leukemias

26 GW506/BioCryst.ppt 5/1/2019 Phase II Study of Nelarabine in Refractory Hematologic Malignancies (Age <21yrs) Schedule: 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)
GW506/BioCryst.ppt 5/1/2019 Response of Pediatric T-Cell ALL in Nelarabine by Dose (ITT) Dose Diagnosis Salvage mg/m2/1-5 Pts. CR% OR% T-ALL T-ALL > T-ALL All (CNS-BM) T-LBL All tt

28 Neurological Toxicity by Dose in Pediatric T-ALL/LBL
GW506/BioCryst.ppt 5/1/2019 Neurological Toxicity by Dose in Pediatric T-ALL/LBL Dose Patients Grade %CNS %Periph > > > > }17 }50 }28 }19 }40 }28

29 Nelarabine in T-ALL, T-LBL –Adult (CALGB-SWOG)
GW506/BioCryst.ppt 5/1/2019 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)
GW506/BioCryst.ppt 5/1/2019 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 (%) (24) Median CR Duration: / 8 Months

31 Conclusions regarding Nelarabine
GW506/BioCryst.ppt 5/1/2019 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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