Detail of "289499-45-2"

Reference

A Phase I Clinical and Pharmacokinetic Study of Oral CI-1033 in Combination with Docetaxel in Patients with Advanced Solid Tumors

All Rights Reserved. A Phase I Clinical and Pharmacokinetic Study of Oral CI-1033 in Combination with Docetaxel in Patients with Advanced Solid Tumors. Garland, Linda L.; Hidalgo, Manuel; Mendelson, David S.; Ryan, David P.; Arun, Banu K.; Lovalvo, Jennifer L.; Eiseman, Irene A.; Olson, Stephen C.; Lenehan, Peter F.; Eder, Joseph P. (Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA). Clinical Cancer Research, 12(14, Pt. 1), 4274-4282 (English) 2006 American Association for Cancer Research. CODEN: CCREF4. ISSN: 1078-0432. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) CI-1033 is an orally available 4-anilinoquinazolone irreversible tyrosine kinase inhibitor of erbB-1, erbB-2, and erbB-4. We conducted a dose escalation study of CI-1033 with docetaxel to assess the safety profile and pharmacokinetics of the combination and to establish the max. tolerated dose. Twenty-six patients with advanced solid tumors were treated on four dosing cohorts starting at CI-1033 (50 mg/d) + docetaxel (75 mg/m2). An intermittent dosing schedule avoided concurrent drug dosing. CI-1033 alone was escalated from 50 to 75 mg/d (dose level 2), where diarrhea was dose limiting; a 38% incidence of cycle 1 febrile neutropenia prompted dose de-escalation of both CI-1033 and docetaxel for dose level 3, where dose-limiting toxicities prompted further de-escalation of CI-1033 to 45 mg/d. Given equiv. safety profiles for dose level 1 [CI-1033 (50 mg/d) + docetaxel (75 mg/m2)] and dose level 4 [CI-1033 (45 mg/d) + docetaxel (60 mg/m2)], the former was detd. to be the recommended phase II dose, given greater dose intensity of both drugs. Antitumor activity was noted in three patients, including a complete response in a patient with cervix uteri cancer. Pharmacokinetic anal.There are some commonly used reagents with their cas registry numbers 114977-28-5 and 289499-45-2 in this article. showed a possible effect of docetaxel on CI-1033 pharmacokinetics. It is feasible to combine the irreversible pan-erbB tyrosine kinase inhibitor CI-1033 with docetaxel on an intermittent dosing schedule in advanced cancer patients. We established the max. tolerated dose and recommended phase II dose for the combination. Further investigation of this combination should include a rigorous anal. of the effect of docetaxel on CI-1033 pharmacokinetics. .

Increased Bioavailability of Intravenous Versus Oral CI-1033, a Pan erbB Tyrosine Kinase Inhibitor: Results of a Phase I Pharmacokinetic Study

All Rights Reserved. Increased Bioavailability of Intravenous Versus Oral CI-1033, a Pan erbB Tyrosine Kinase Inhibitor: Results of a Phase I Pharmacokinetic Study. Simon, George R.; Garrett, Christopher R.; Olson, Stephen C.; Langevin, Michael; Eiseman, Irene A.; Mahany, John J.; Williams, Charles C.; Lush, Richard; Daud, Adil; Munster, Pamela; Chiappori, Alberto; Fishman, Mayer; Bepler, Gerold; Lenehan, Peter F.; Sullivan, Daniel M. (H. Lee Moffitt Cancer Center, Tampa, FL, USA). Clinical Cancer Research, 12(15), 4645-4651 (English) 2006 American Association for Cancer Research. CODEN: CCREF4. ISSN: 1078-0432. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Section cross-reference(s): 63 Purpose: In phase I studies with oral CI-1033, dose-limiting toxicities were primarily gastrointestinal, supporting the exploration of i.v. dosing to achieve optimal drug exposures by increasing bioavailability. Exptl. Design: Fifty-three patients with advanced nonhematol. malignancies received i.There are some reagents like 289499-45-2 is used in this study.v. CI-1033 via 30-min infusions (10-500 mg) on a thrice-weekly schedule. Pharmacokinetic samples were collected on days 1 and 8 and evaluated using noncompartmental anal. Results: Dose levels evaluated were 10, 20, 30, 45, 67.5, 100, 150, 225, 337.5, and 500 mg. The max. administered dose was 500 mg, whereas the max. tolerated dose was 225 mg. The most common treatment-related grade 1 to 2 adverse events were rashes (38% of patients), nausea (17%), vomiting (17%), stomatitis (14%), and diarrhea (13%). Most common grade 3 adverse events were hypersensitivity reactions (7.5%), rashes (3.8%), and diarrhea (3.8%). No grade 4 toxicities were obsd. Ten of the 53 (19%) patients had disease stabilization at their first efficacy evaluation visit (including two with minor responses). A 5- to 10-fold increase in i.v. Cmax was noted with a 3-fold increase in AUC compared with oral CI-1033 at equiv. doses. Treatment-related gastrointestinal adverse events were notably less frequent with this i.v. regimen. Conclusions: CI-1033 was safely given i.v. up to 225 mg/dose on a thrice-weekly schedule, with evidence of antitumor activity. At equivalent doses, the bioavailability of i.v. CI-1033 is thrice that of the oral formulation. Treatment with i.v. CI-1033 is feasible and may be warranted when increased drug exposures are desired. .