Phase 1 pharmacokinetic and drug‐interaction study of dasatinib in patients with advanced solid tumors

Abstract

BACKGROUND:The recently developed the Src and Abelson (Abl) kinase inhibitor dasatinib has antitumor effects in epithelial and mesenchymal tumors. Preclinical data have indicated that dasatinib is metabolized primarily through cytochrome P450 3A4 (CYP3A4) and may cause QT prolongation. In light of its improved tolerability, the authors were interested in the safety of a once-daily dasatinib regimen. METHODS: The authors conducted a phase 1 trial of dasatinib in 29 patients with advanced solid tumors. Segment 1 of the trial was short term and sequential and was designed to determine whether the coadministration of the potent CYP3A4 inhibitor ketoconazole had an effect on the pharmacokinetics of dasatinib. Segment 2 was designed to evaluate the safety of dasatinib as dosing was increased. QT intervals were monitored closely in both segments. Efficacy was assessed in Segment 2 using both positron emission tomography and computed tomography. RESULTS: Hematologic toxicities were markedly less than those observed in patients with leukemia, whereas nonhematologic toxicities were similar. The authors determined that the maximum recommended dose was 180 mg once daily based on the incidence of pleural effusion. Coadministration of ketoconazole led to a marked increase in dasatinib exposure, which was correlated with an increase in corrected QT (QTc) values of approximately 6 msec. No adverse cardiac events were observed. CONCLUSIONS: The dose-limiting toxic effect for dasatinib was pleural effusion. The pharmacokinetic and cardiac studies indicated that coadministration of dasatinib with potent CYP3A4 inhibitors or agents that prolong the QTc interval should be avoided if possible. Close monitoring for toxicity and dose reduction should be considered if the coadministration of such agents cannot be avoided. Cancer 2010;116:1582-91.

Phase I Study of Bosutinib, a Src/Abl Tyrosine Kinase Inhibitor, Administered to Patients with Advanced Solid Tumors

“…The thiazolecarboxamide Src inhibitor dasatinib (Src IC 50 ¼ 0.5 nmol/L; ref. 23) had an RP2D of 180 mg/day with pleural effusion as the DLT (24). Pleural effusion, fatigue, and vomiting were the most common drug-related adverse events.…”

Phase II Trial of Dasatinib in Patients with Metastatic Breast Cancer Using Real-Time Pharmacodynamic Tissue Biomarkers of Src Inhibition to Escalate Dosing

“…Week 4 biopsy (25) PD (2), toxicity (2), withdrew (2) Dose escalation (15) No dose escalation due to toxicity (10) Correlative science All 31 patients had a baseline biopsy; 25 of these patients also had metastatic biopsy at week 4. Of these 25 patients, 20 of the paired metastatic biopsies were evaluable and 5 were not because of insufficient tissue quality.…”

“…12, 13). In the phase I setting investigating the use of dasatinib in advanced solid tumors, dasatinib showed a generally tolerable safety profile, with a doselimiting toxicity of pleural effusions, as well as preliminary evidence of efficacy (14,15).…”

Chemotherapy-related cardiotoxicity

“…Yeh and Bickford reported a 2-4% incidence of left ventricular dysfunction (about half were grade 3-4 heart failures) related to dasatinib therapy after reviewing phase III clinical data [Yeh and Bickford, 2009]. Asymptomatic QT prolongation and pericardial effusion have also been reported with the use of dasatinib [Johnson et al 2010]. No cardiac events have been reported with nilotinib, except for QT prolongation on electrocardiogram [Wolf et al 2011].…”