[Proceedings of the 11th NCI · EORTC · AACR Symposium]
Copyright © 2000 Stichting NCI-EORTC Symposium on New Drugs in Cancer Therapy
Published by the AACR.
564 Phase I and pharmacokinetic study of T138067 administered as a weekly 3-hour infusion. Donehower RC, Schwartz G, Wolf AC, Olivo N, Burks KL, Wright M, Walling J, Rowinsky EK, Johns Hopkins Oncology Center, Baltimore, MD, Brooke Army Medical Center, Cancer Therapy and Research Center, San Antonio, TX, Tularik Inc., South San Francisco, CA.
T138067 is a novel antimicrotubule depolymerizing agent that binds to cysteine 239 on tubulin causing depolymerization. It is not a substrate for Pgp, and is hepatically metabolized. Myelosuppression and CNS toxicity were dose limiting in animals, but the CNS toxicity could be avoided by slowly infusing the compound, thereby avoiding peak plasma levels. The current clinical study investigates the feasibility of a weekly 3 hour infusional schedule. The starting dose of 110 mg/m2 was determined from an ongoing q 3 week study. Sixteen patients with the following characteristics (range) have been treated at dose levels of 110, 220, 330, 385 and 440 mg/m2: 10 males, 6 females, median age 61 (30 - 83), median number of prior chemotherapeutic regimens 2 (2 -12). One patient treated with a hepatocellular carcinoma (HCC) at 110 mg/m2 who had progressed through prior doxorubicin, gemcitabine + 5FU, and an experimental pyrimidine antimetabolite, had a durable (9+ months) PR concomitant with symptomatic improvement. At 440 mg/m2, 2 patients had DLTs: a neutrophil count that failed to return to 1000/mm3 on the day of planned dosing resulting in a dose omission and CTC grade 3 reversible ataxia. The recommended phase II dose is being defined in two groups of patients: HCC and non-HCC. Treatment in HCC patients has been limited by mild reversible thrombocytopenia and the current dose is 220 mg/m2. In the non-HCC group, at doses below 440 mg/m2, no acute CNS toxicity has been seen and the current dose level is 385 mg/m2. Toxicities include neutropenia, diarrhea, fatigue and peripheral neuropathy. Pharmacokinetics are linear up to 330 mg/m2. Data are available for 16 patients to date (±SD): clearance = 1.11 (0.26) L/h/kg, Vdss = 0.39 (0.17) L/kg, apparent terminal half-life = 0.52 (0.24) h. Patients with HCC have a trend towards lower clearance, but this is not statistically significant. Conclusion: the weekly schedule of T138067 has been well tolerated, with evidence of activity, and is therefore recommended for evaluation in phase II. |
