Phase I study of BMS-599626, an oral pan-HER tyrosine kinase inhibitor, in patients with advanced solid tumors
2005; Lippincott Williams & Wilkins; Volume: 23; Issue: 16_suppl Linguagem: Inglês
10.1200/jco.2005.23.16_suppl.3152
ISSN1527-7755
AutoresLinda L. Garland, M. Pegram, Si Young Song, David S. Mendelson, Kizzy Parker, Robert E. Martell, Michael Gordon,
Tópico(s)Cancer Treatment and Pharmacology
Resumo3152 Background: BMS-599626 is an orally bioavailable inhibitor of the HER1, HER2 and HER4 tyrosine kinases (IC50=22, 32 and 190 nM, respectively). Methods: Patients (pts) with advanced solid tumors were administered BMS-599626 orally once daily, 21-days on, 7-days off per cycle. Initial eligibility requirements included tumor expression of HER2 by immunohistochemistry; after 6 pts were enrolled, this criterion was modified to include all pts regardless of HER2 status. Seven pts have been treated on 3 dose levels of 100, 200 and 320 mg/day. Results: As of November 22, 2004, safety and PK data are available for pts treated in the 100 and 200mg cohorts (3 pts per dose level). No dose limiting toxicities have been observed during cycle 1. Grade 1 or 2 at least possibly drug-related adverse events have been reported and include: diarrhea (1), nausea (3), vomiting (1), rash (1), fatigue (3), musculoskeletal pain/cramp (3), cough (3). In cohort 1 (100 mg dose), BMS-599626 had Tmax ranging from 1 to 8h (median 2h). Following single dose, geomean Cmax =162 ng/ml, mean AUC0-∞=2920 ng/ml hr. A healthy volunteer study revealed similar results following a single 100 mg dose, with Tmax, Cmax and AUC of 2 h, 120 ng/ml and 2610 ng/ml hr respectively. Day 8 and day 21 PK revealed similar Cmax and AUC0-∞ with respective geomean values of Cmax =352, and 377 ng/ml, and AUC0-∞=9050 and 8300 ng/ml hr, suggesting no significant accumulation in exposure over time. Terminal half-life was about 20 hrs. Exposure increase was linear from 100 mg to 200 mg dose levels. Conclusion: To date, BMS-599626 has been well tolerated and has a favorable PK profile for daily dosing. Dose escalation is ongoing. HER2 positivity will be reinstated as an eligibility criterion once the MTD has been established for further study in a dose expansion cohort. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb
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