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Biotech / Medical : Tularik Inc. (TLRK) -- Ignore unavailable to you. Want to Upgrade?

To: keokalani'nui who wrote (84)	11/7/2000 6:38:39 PM
From: keokalani'nui	Respond to of 598

[Proceedings of the 11th NCI · EORTC · AACR Symposium] Copyright © 2000 Stichting NCI-EORTC Symposium on New Drugs in Cancer Therapy Published by the AACR. 563 A phase I study of a novel antimicrotubule agent: T138067. Budman DR, Berg WB, Spriggs DR, Vongprachnach P, O'Mara V, Wright M, Walling J; North Shore University Hospital--New York University, Manhasset, NY; Memorial Sloan Kettering Cancer Center, New York, NY; Tularik Inc., San Francisco, CA. T138067 (2-fluoro-1-methoxy-4-[pentafluorophenylsuphonamide]benzene) binds to isotypes 1, 2, and 4 of tubulin and induces microtubule depolymerization. It is not a substrate for the MDR protein and has efficacy in human tumor xenografts including those resistant to paclitaxel. Preclinical studies indicated hepatic clearance via GSH conjugation, myelosuppression, and neurotoxicity associated with peak plasma concentrations in the mouse. This clinical study evaluated a 3h intravenous infusion of drug once every 3-4 weeks with a starting dose of 11 mg/m2. Initial dose escalation used a modified Fibonacci scheme, which was changed to a continual reassessment method at 55 mg/m2 after the absence of any toxicity, and subsequently to a pharmacokinetically guided method at 440 mg/m2. Twenty-eight solid tumor patients (pts) with PS 60-80, median age 62, 10 females and 18 males, normal organ function, and median of 3 (0-15) prior chemotherapies received a total of 54 infusions at 8 dose levels: 11, 22, 36, 55, 110, 220, 440 and 585 mg/m2. CTC Grade 4 (G4) neurotoxicity (hearing loss and peripheral neuropathy, acute ataxia, dysphoria, lethargy, tremulousness) occurred in one patient at 585 mg/m2. This pt has some residual hearing loss and peripheral neuropathy post-treatment. His exposure was twice the level predicted from linear pharmacokinetics (pk), which may have been attributable to reduced hepatic blood flow secondary to reduced cardiac output. All pts treated at 585 mg/m2 had G2 neutropenia and thrombocytopenia. 9 pts were treated at 440 mg/m2 and the predominant (non dose-limiting) toxicity was reversible neutropenia, which was often manifest on day 2. Additional toxicities included nausea, vomiting, and diarrhea. There was no evidence of cumulative effects. Pk parameters from pts dosed up to 440 mg/m2 (N= 24) were: clearance (SD) of 1.5 (0.44) L/h/kg, Vdss 0.6 (0.26) L/kg, and apparent elimination half-life of 0.5 (0.3) h. Suggested Phase II dosing is 440 mg/m2 q 3 weeks based upon reversible hematological toxicity.