As of June 1
#43 (EORTC)
A phase I study examining weekly weight based or fixed dosing and pharmacokinetics (PK) of a novel spectrum kinase inhibitor, XL999, in patients (pts) with advanced solid malignancies (ASM)
Citation: European Journal of Cancer Supplements, Volume 4, No.12, page 29
M. Mita1, J. Cooper1, A. Ricart1, A. Mita1, C. Takimoto1, S. Britt1, A. Tolcher1, A. Dowlati1, K. Papadopoulos1
1Cancer Therapy And Research Center, Institute For Drug Development, San Antonio, USA
2Case Western Reserve University, Cleveland, Ohio, USA
Background: XL999 is a small molecule inhibitor of multiple kinases involved in tumor cell growth, angiogenesis, and metastasis, including VEGFR2 (KDR), PDGFRa/ß, FGFR1/3, FLT-3, and SRC. A phase I study of XL999 administered as a 4 hr infusion every 2 weeks in pts with ASM showed that the maximum tolerated dose (MTD) was 3.2 mg/kg and the plasma t1/2 was approximately 24 hrs. Three pts dosed at 0.2–1.6 mg/kg had partial responses and 9 pts had stable disease (SD) >3 months. Based on these data, a weekly (wkly) weight based and fixed dosing schedule with PK monitoring was further explored.
Methods: XL999 at 2.4 mg/kg or 200 mg was administered to pts as a 4 hr infusion on day (d) 1 and d8 with toxicity assessment. PK sampling was performed on d1 & d15. Pts received further doses of XL999 wkly in the absence of unacceptable toxicity, disease progression, or accumulation based on PK results.
Results: As of June 1, 2006, 12 pts were enrolled and received XL999 weekly as initial treatment at 2.4 mg/kg or 200 mg fixed dose. Of 8 pts treated at 2.4 mg/kg, none had experienced any G2 or worse drug related adverse events. One asymptomatic pt at 2.4 mg/kg with non-specific ECG changes after d1 was discontinued from study. One pt receiving 200 mg experienced symptomatic hypotension and non-specific ECG changes on d1 and was discontinued. Four of 8 evaluable pts had SD for >2 months. In patients with complete d1 & d15 PK at 2.4 mg/kg (n = 5) or 200 mg (n = 4), there was moderate interpatient and intrapatient variability, with no evidence of drug accumulation on repeat dosing.
Averages for weekly dosing PK parametersa
Dose level Cycle t 1/2 (hr) Cmax (ng/mL) AUC0–inf pred (hr ng/mL) CL pred (L/hr)
2.4 mg/kg 1 20.8 (16%) 513 (34%) 5939 (45%) 40.9 (36%)
2 23.2 (28%) 670 (41%) 7359 (35%) 32.8 (41%)
200 mg 1 36.1 (54%) 528 (44%) 7737 (52%) 32.1 (51%)
2 29.2 (11%) 491 (42%) 6476 (44%) 34.6 (32%)
a%CV in parentheses.
Conclusions: XL999 administered wkly as a 4 hr infusion at a dose of 2.4 mg/kg or 200 mg appears to be well tolerated with no evidence of drug accumulation. Drug clearance appears independent of weight and supports the use of fixed dosing.
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