Dasatinib pharmacokinetics and exposure-response (E-R): Relationship to safety and efficacy in patients (pts) with chronic myeloid leukemia (CML)

Wang, X.; Hochhaus, Andreas; Kantarjian, Hagop; Agrawal, Shruti; Roy, Amit; Pfister, Marc; Chen, T.; Bleickardt, Eric; Nicaise, Claude; Shah, Nirav

doi:10.1200/jco.2008.26.15_suppl.3590

Cited by 33 publications

(37 citation statements)

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“…The safety benefits of once-daily dasatinib treatment have been examined in a recent pharmacokinetic analysis in patients with CML-CP. 28 Dasatinib administered as 140 mg once daily or 70 mg twice daily resulted in similar plasma steady-state average concentrations, but the plasma steady-state trough concentration (C min ) was lower with 140 mg once daily. Importantly, C min levels correlated with dasatinib safety parameters.…”

Section: Discussionmentioning

confidence: 99%

Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up

Kantarjian

Cortes

Kim³

et al. 2009

Blood

151

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Dasatinib is the most potent BCR-ABL inhibitor, with 325-fold higher potency than imatinib against unmutated BCR-ABL in vitro. Studies have demonstrated the benefits of dasatinib 70 mg twice daily in patients with acceleratedphase chronic myeloid leukemia intolerant or resistant to imatinib. A phase 3 study compared the efficacy and safety of dasatinib 140 mg once daily with the current twice-daily regimen. Here, results from the subgroup with acceleratedphase chronic myeloid leukemia (n ‫؍‬ 317) with a median follow-up of 15 months (treatment duration, 0.03-31.15 months) are reported. Among patients randomized to once-daily (n ‫؍‬ 158) or twice-daily (n ‫؍‬ 159) treatment, rates of major hematologic and cytogenetic responses were comparable (major hematologic response, 66% vs 68%; major cytogenetic response, 39% vs 43%, respectively). Estimated progression-free survival rates at 24 months were 51% and 55%, whereas overall survival rates were 63% versus 72%. Once-daily treatment was associated with an improved safety profile. In particular, significantly fewer patients in the once-daily group experienced a pleural effusion (all grades, 20% vs 39% P < .001). These results demonstrate that dasatinib 140 mg once daily has similar efficacy to dasatinib 70 mg twice daily but with an improved safety profile. This trial is registered at www. IntroductionChronic myeloid leukemia (CML) is characterized by a triphasic natural course comprising a chronic phase (CP), typically followed by an accelerated phase (AP), and finally a blast phase (BP). 1,2 Approximately two-thirds of patients progress to BP via AP with a median survival for patients in AP of 1 to 2 years. 1,3 Although the mechanisms behind progression to advanced phase disease in CML have not been fully elucidated, several processes may play a role, including additional cytogenetic abnormalities (clonal evolution), genetic mutations and deletions, and up-regulation of specific genes. [3][4][5][6] Current first-line therapy for AP-CML is imatinib mesylate (Glivec [in the United States, Gleevec]; Novartis, Basel, Switzerland), an oral tyrosine kinase inhibitor of BCR-ABL. 7-9 Although imatinib induces notable hematologic and cytogenetic responses in patients with accelerated-phase chronic myeloid leukemia (CML-AP), these responses are frequently short-lived, with a median progression-free survival (PFS) of 8.8 months. 7 Development of resistance to imatinib represents an important clinical issue affecting approximately 50% of patients with CML-AP within 2 years of treatment. 10 Because progression on imatinib is associated with poor prognosis, 11 alternative treatment options are required.Dasatinib (SPRYCEL; Bristol-Myers Squibb, Stamford, CT) was the first agent approved to overcome the problems of imatinib therapy in patients with CML. Dasatinib is structurally unrelated to imatinib and is approximately 325-fold more potent than imatinib at inhibiting unmutated BCR-ABL in vitro. 12 Preclinical studies have also shown that dasatinib has potent activity against ot...

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Section: Discussionmentioning

confidence: 99%

Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up

Kantarjian

Cortes

Kim³

et al. 2009

Blood

151

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“…drug effect analysis was performed using four dasatinib-sensitive ovarian cancer cell lines to determine the nature of the interaction between dasatinib and carboplatin or paclitaxel (synergy, addition, or antagonism). The dasatinib concentrations used for these experiments ranged between 0.031 and 0.5 mmol l À1 for OVCAR5, 0.050 and 0.8 mmol l À1 for SKOV3 cells, 0.008 and 0.125 mmol l À1 for RMG1, and 0.016 and 0.250 mmol l À1 for CAOV3 cells and were below the reported peak plasma concentrations achievable in humans (Wang et al, 2008). The drug concentrations of carboplatin and paclitaxel used for these experiments were similarly below the reported peak plasma concentrations that have been previously published (Pegram et al, 2004).…”

Section: Combination Of Dasatinib and Chemotherapeutic Agentsmentioning

confidence: 99%

Activity of the multikinase inhibitor dasatinib against ovarian cancer cells

Glas

Dering

et al. 2009

Br J Cancer

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BACKGROUND: Here, we explore the therapeutic potential of dasatinib, a small-molecule inhibitor that targets multiple cytosolic and membrane-bound tyrosine kinases, including members of the Src kinase family, EphA2, and focal adhesion kinase for the treatment of ovarian cancer. METHODS: We examined the effects of dasatinib on proliferation, invasion, apoptosis, cell-cycle arrest, and kinase activity using a panel of 34 established human ovarian cancer cell lines. Molecular markers for response prediction were studied using gene expression profiling. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions with chemotherapeutic drugs. RESULTS: Concentration-dependent anti-proliferative effects of dasatinib were seen in all ovarian cancer cell lines tested, but varied significantly between individual cell lines with up to a 3 log-fold difference in the IC 50 values (IC 50 range: 0.001 -11.3 mmol l À1 ). Dasatinib significantly inhibited invasion, and induced cell apoptosis, but less cell-cycle arrest. At a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for dasatinib plus carboplatin (mean CI values, range: 0.73 -1.11) or paclitaxel (mean CI values, range: 0.76 -1.05). In this study, 24 out of 34 (71%) representative ovarian cancer cell lines were highly sensitive to dasatinib, compared with only 8 out of 39 (21%) representative breast cancer cell lines previously reported. Cell lines with high expression of Yes, Lyn, Eph2A, caveolin-1 and 2, moesin, annexin-1, and uPA were particularly sensitive to dasatinib. CONCLUSIONS: These data provide a clear biological rationale to test dasatinib as a single agent or in combination with chemotherapy in patients with ovarian cancer.

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“…A significant inhibition of resorption was observed at X1.25 nM dasatinib in huCD14 þ cultures (Po0.001; IC 50 ¼ 2.4 nM; Figures 1d and f), and at X2.5 nM dasatinib in mBM cultures (Po0.05; IC 50 ¼ 3.5 nM; Figures 1e and f), relative to vehicle controls. Thus, therapeutically relevant concentrations of dasatinib (C max ¼ 110.0 nM) 7 significantly reduced the formation and activity of osteoclasts from huCD14 þ and mBM at IC 50 concentrations of p10 nM dasatinib.…”

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confidence: 99%