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Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 25, No 18S (June 20 Supplement), 2007: 7004
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Abstract

, {( z# J. u: o8 a  J" D3 pDasatinib 50 mg or 70 mg BID compared to 100 mg or 140 mg QD in patients with CML in chronic phase (CP) who are resistant or intolerant to imatinib: One-year results of CA180034
9 F! X4 _0 L. w8 ~' I  A+ {N. P. Shah, D. W. Kim, H. M. Kantarjian, P. Rousselot, P. E. Dorlhiac-Llacer, J. H. Milone, E. Bleickardt, S. Francis and A. Hochhaus
UCSF School of Medicine, San Francisco, CA; St Mary's Hospital, Seoul, Democratic People's Republic of Korea; MD Anderson Cancer Center University of Texas, Houston, TX; Centre Hospitalier, Paris, France; Hospital das Clinicas, Sao Paulo, Brazil; Istituto de Trasplante de Médula Osea (ITMO), Buenos Aires, Argentina; Bristol-Myers Squibb, Wallingford, CT; Bristol-Myers Squibb, Braine-l’Alleud, Belgium; University Heidelberg, Mannheim, Germany

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- r* H, N2 Q" G  g" tBackground: Previous data with dasatinib (SPRYCEL®), a short-acting oral multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, have shown the safety and efficacy of the 70 mg BID dose in CP-CML patients. Surprisingly, phase-I data (NEJM 2006;354:2531) demonstrated complete hematologic (CHR) and major cytogenetic responses (MCyR) among CP-CML patients at total daily doses (TDD) of 100 mg and 140 mg in both the BID and QD schedule, despite the achievement of only transient inhibition of BCR-ABL by dasatinib when administered once daily. Methods: Patients with CP-CML resistant or intolerant to imatinib were randomized to one of 4 dasatinib arms: 1) 100 mg QD; 2) 50 mg BID; 3) 140 mg QD; 4) 70 mg BID. In this randomized, prospective, open-label trial, the primary objective compared the CyR rate among the BID and QD arms. Secondary objectives included comparison of the CyR rate between TTDs of 100 and 140 mg and the safety among the 4 arms. Results: 662 patients were randomized from July 2005 to March 2006 and received treatment. Response rates, with a median duration of treatment of 8 months, are shown below. Duration of CyR and progression-free survival were similar across all 4 arms. There was significantly less grade (Gr) 3–4 neutropenia (P=0.035), thrombocytopenia (P=0.001), anemia (P=0.032), and pleural effusions (P=0.028) in the 100-mg QD arm compared to the other 3 arms combined. No differences were seen across the 4 arms in the rates of other adverse events. There were fewer interruptions and reductions and the least number of patients discontinuing treatment for drug-related toxicity in the 100-mg QD arm. Conclusions: Dasatinib 100 mg QD offers the most favorable benefit-risk ratio in CP-CML. This trial provides the first evidence that intermittent kinase inhibition can achieve deep clinical remissions and is associated with an improved safety profile. One-year follow-up on all subjects, molecular response rates, and BCR-ABL mutation data will be presented.

New dosing schedules of dasatinib for CML and adverse event management
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Preclinical data have shown that the solubility of dasat-
* a; e+ G) T* @' C+ q& ~inib is pH-dependent, which suggests that concomitant
& K$ l2 v  G& _+ C1 z( dadministration of antacids could decrease the absorption
, H, j/ F  Z' [3 @$ O6 qof dasatinib. In a clinical study evaluating the pharmacok-
inetics of dasatinib, a 55% decrease in AUC was observed
when dasatinib was administered simultaneously with
antacids. However, no decrease in AUC was reported
* c7 J" m) P! a* b8 X7 H5 _' Z# vwhen antacids were administered 2 hours prior to dasat-
$ u: p3 U: E5 S! T( Ninib [39]; therefore, antacids should be taken at least 2
; \6 T- {. X# ~$ \hours before or after dasatinib administration. The use of
1 i5 M3 K+ G* L) b% [* U6 r& ]6 Xproton pump inhibitors and histamine-2 (H2) blockers
should be avoided, because such use is likely to decrease
the bioavailability of dasatinib for up to 10 hours. The use
of antacids in place of proton pump inhibitors or H2
  W- u  H5 r- ~# T. d5 K, Ublockers is recommended

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