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CML- Imatinib Mesylate (Gleevec™)

CML- Imatinib Mesylate (Gleevec™). Philadelphia Chromosome Short chromosome 22 Bcr region of chromosome 22 with Abl proto-oncogene of chromosome 9. CML- Imatinib Mesylate (Gleevec™). Normal Abl gene product is a tightly regulated tyrosine kinase involved in cell division and apoptosis

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CML- Imatinib Mesylate (Gleevec™)

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  1. CML- Imatinib Mesylate (Gleevec™) Philadelphia Chromosome Short chromosome 22 Bcr region of chromosome 22 with Abl proto-oncogene of chromosome 9

  2. CML- Imatinib Mesylate (Gleevec™) Normal Abl gene product is a tightly regulated tyrosine kinase involved in cell division and apoptosis Bcr-Abl gene product is a constitutively active tyrosine kinase induces a CML-like illness in mice induces CML in man

  3. CML- Imatinib Mesylate (Gleevec™) Blocks proliferation and induces apoptosis of Bcr-Abl expressing cell lines and fresh leukemic cells.

  4. CML- Imatinib Mesylate (Gleevec™) Potent inhibitor of the receptor tyrosine kinases for PDGF, stem cell factor and c-Kit (CD 117) Active in c-kit expressing GIST

  5. CML- Imatinib Mesylate (Gleevec™) Toxicology 13-week dog 6-month rat 9-month monkey Toxicity: Hematopoietic, renal, hepatic, gastrointestinal, testis and ovary

  6. CML- Imatinib Mesylate (Gleevec™) Clinical Pharmacology Bioavailability 98% 95% protein bound CGP74588 is major active metabolite. Its plasma AUC is 16% of Imatinib AUC Metabolized by CYP3A4

  7. CML - Submitted Studies • Phase I • Phase II -Blast crisis (BC) CML -Accelerated Phase (AP) CML -Chronic phase (CP) CML - IFN Refractory, Resistant, Intolerant

  8. Study Patient Characteristics BC AP CP Characteristic N=260) N=235 N=532 Age Median 56 56 57 Sex - Male/Female % 52/48 50/50 58/42 Race - Caucasian % 85 89 87 PS - 0-1 % 58 77 91 Ph + & other % 64 54 16 Extramedullary disease 68 68 24 STI-571 - % 400mg/d 14 33 86

  9. BC CML - Definition • > 30% blasts in PB or BM or • Extramedullary involvement other than spleen or liver PB=peripheral blood; BM=bone marrow

  10. BC CML - Hematologic Remission Characteristic N=260 Hematologic Response 68 (26%) -Complete 11 (4%) -No evidence of leukemia 7 (3%) -Return to chronic phase 50 (19%) Time to HR- median (d) 29 (26-64) Censored for response duration 57 (84%)

  11. BC CML - Cytogenetic Remission Characteristicn=260 Major response 35 (13.5%) Complete 9 (3%) Confirmed 3 (1%)

  12. Accelerated phase (AP) definition • > 15% <30% blasts in PB or BM • > 30% blasts+promyelocytes in PB or BM but <30% blasts in PB or BM • > 20% basophils in PB • <100 x 109/L platelets at least one of the 4 criteria must be fulfilled

  13. AP CML - Hematologic Response Characteristic N=235 Hematologic Response 148 (63%)-Complete 60 (26%) -No evidence of leukemia 27 (11%) -Return to chronic phase 61 (26%) Time to HR- median (d) 29 (26-334) Censored for response duration 133 (90%)

  14. AP CML - Cytogenetic Response Characteristicn=235 Major response 50 (21%) Complete 17 (7%) Confirmed 10 (4%)

  15. Chronic Phase (CP) CML Definition • < 15% blasts in PB & BM • < 30% blasts+promyelocytes in PB & BM • < 20% basophils in PB • > 100 x 109/L platelets • No extramedullary involvement other than spleen or liver All 5 criteria must be fulfilled

  16. CP CML - Patient Characteristics Characteristic n=532 IFN Hematologic resistant/refractory 152 (29) IFN Cytogenetic resistant/refractory 186 (35) IFN intolerant 194 (36) Median Duration of prior IFN (mo) IFN hematologic failure 12.1 (1-83) IFN cytogenetic failure 22.0 (4-135) IFN intolerant 7.1 (3-15)

  17. CP CML - Cytogenetic Response Characteristicn=532 Major response 265 (49.8%) Complete 107 (20%) Confirmed 84 (16%) Time to MCyR (d) 91 (77-315)

  18. CP CML - Hematologic Remission Characteristic N=532 Complete Hematologic Response 468 (88%) Days to CHR- median (range) 22 (5-267) Censored for response duration 438 (93.6%)

  19. Common SAE’s BC CML AP CML CP CML n= 260 (%) n=235 (%) n=532 (%) All grades3/4All grades3/4All grades3/4 Nausea 68 3 68 5 55 2 Fluid retent 67 10 68 6 52 2 Vomiting 49 3 54 3 28 1 Muscle cramps 25 .4 34 .4 46 .9 Diarrhea 39 3 49 4 33 .9 Dermatitis 32 4 39 4 36 3 Hemorrhage 48 16 35 8 13 .4

  20. Grade 4 Hematology Abnormalities (%) BCAPCP Hgb 10 5 <1 WBC 46 34 8 ANC 61 34 8 Platelets 31 12 <1

  21. Grade 3/4 Biochemistry Abnormalities (%) BC AP CP Hepatic 1.9-3.5 1.3-3.0 0.4-1.7 Renal 1.2 1.3 0

  22. Imatinib mesylate-FDA Action 5/10/01 Accelerated Approval, Subpart H, CFR§314.510, for CML BC, AP, and CP after interferon- failure

  23. Phase IV Commitments Interval F/U of Phase II BC, AP, CP trials Interval F/U of Phase III CP trial Pediatric trials Hepatotoxic drug interaction study Concomitant medication-Gleevec interaction Pathogenesis and Rx of fluid retention

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