Incidence of Hypophosphatemia Phos (Low) Number of Subjects (%) Total N = 511 Grade 0 277 (55) Grade 1 36 (7) Grade 2 100 (20) Grade 3 80 (16) Grade 4.

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Presentation transcript:

Incidence of Hypophosphatemia Phos (Low) Number of Subjects (%) Total N = 511 Grade (55) Grade 1 36 (7) Grade (20) Grade 3 80 (16) Grade 4 7 (1) 15a - 70

Patients with GI Bleeds and Proton Pump Inhibitors (PPI) – NDA SU u All GI bleeds79 u PPI at anytime on-study62(78%) u PPI at baseline16(20%) –Relevant medical history4(5%) 12c - 6

Dasatinib Exposure: Dose Proportionality Dasatinib Exposure vs Dose with B7D Regimen u Study 002 – MAD study; 84 subjects with CML u At dose levels of 50–120 mg BID, the exposure increase was slightly more than dose proportional at steady state Regimen AUC (0-12h) (ng·h/mL) Goemetric Mean (CV%) Dose Ratio AUC Ratio 50 mg BID 83 (32) mg BID 155 (54) mg BID 255 (58) mg BID 301 (66)

Major Cytogenetic Responses in Imatinib-resistant Patients in Phase I Schedule No. of Responders Total Daily Dose <100 mg 100 mg 140 mg BID (n = 15) 113 QD (n = 17) 142 Chronic Phase CML – Study

Mechanism of Action of Pleural Effusion u Likely related to the inhibition of PDGF-β u PDGF-β regulates interstitial fluid homeostasis in mouse model (Heuschel et al, PNAS 1999) u Fluid retention described with other drugs known to inhibit PDGF-β –e.g. Imatinib, CDP860 (humanized antibody) 13c - 2

Pretreatment Characteristics n (%) of Patients Dasatinib N = 101 Imatinib N = 49 Median Duration of CML (months) 6452 Prior Imatinib Dose = 600 mg/day Dose = 600 mg/day 62 (61) 34 (69) Duration >3 years Duration >3 years 45 (45) 15 (31) Major Cytogenetic Response Major Cytogenetic Response 28 (28) 14 (29) Prior Interferon 74 (73) 33 (67) BCR-ABL mutations 42 (42) 10 (20) Study

Patient Disposition n (%) of Patients Dasatinib N = 101 Imatinib N = 49 Discontinuation 15 (15) 37 (76) Reason for discontinuation Progression / No response Progression / No response 8 (8) 27 (55) Intolerance Intolerance 7 (7) 9 (18) Non-compliance Non-compliance0 1 (2) Study

Efficacy n (%) of Patients Dasatinib N = 101 Imatinib N = 49 At 3 months Major Cytogenetic Response Major Cytogenetic Response 35 (35) 14 (29) Complete Cytogenetic Response Complete Cytogenetic Response 21 (21) 4 (8) At any time prior to cross over Complete Hematologic Response Complete Hematologic Response 93 (92) 40 (82) Major Cytogenetic Response Major Cytogenetic Response 42 (42) 16 (33) Complete Cytogenetic Response Complete Cytogenetic Response 27 (27) 6 (12) Study

Major Cytogenetic Response at 3 Months Percent Responders N = Study

Time to Treatment Failure Study 017 DasatinibImatinibN10149 Number Failed 1537 Median3.5 95% CI Months Dasatinib Imatinib Censored

Non-Hematological Adverse Events Dasatinib N = 101 Imatinib N = 49 Fluid retention 25 (25) 21 (43) Superficial edema Superficial edema 13 (13) 20 (41) Pleural effusion Pleural effusion 11 (11) 0 Diarrhea 26 (26) 14 (29) Headache 25 (25) 4 (8) GI hemorrhage 2 (2) 0 Fatigue 28 (28) 10 (20) Rash 16 (16) 8 (16) Other 6 (6) 2 (4) Study

Myelosuppression Dasatinib N = 101 Imatinib N = 49 WBC <2.0 x10 9 /L 18 (18) 9 (18) ANC <1.0 x10 9 /L 58 (58) 19 (38) Platelets <50 x10 9 /L 54 (54) 7 (14) Hemoglobin <8 g/dL 9 (9) 4 (8) Platelets transfusion 13 (13) 0 Red cell transfusion 17 (17) 6 (12) Study