Reference Detail

Ref Type

Journal Article

PMID

(15136596)

Authors

Raymond E, Alexandre J, Faivre S, Vera K, Materman E, Boni J, Leister C, Korth-Bradley J, Hanauske A, Armand JP

Title

Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of clinical oncology : official journal of the American Society of Clinical Oncology	22	12	2004 Jun 15	2336-47	J Clin Oncol

URL

Abstract Text

To establish the safety, tolerability, and pharmacokinetic parameters of CCI-779, a selective inhibitor of the mammalian target of rapamycin, in patients with advanced cancer.Using a modified continuous reassessment method, we performed a phase I with pharmacokinetic study of CCI-779 given as a weekly 30 minutes intravenous (I.V.) infusion.Twenty-four patients received CCI-779 at doses ranging 7.5 to 220 mg/m(2). No immunosuppressive effect was reported. Dose-limiting thrombocytopenia occurred in two patients at 34 or 45 mg/m(2). At 220 mg/m(2), dose-limiting toxicities consisted of manic-depressive syndrome, stomatitis, and asthenia in two of nine patients, preventing further dose escalation. The most frequent drug-related toxicities were acne-like, maculopapular rashes and mucositis or stomatitis. All toxicities were reversible on treatment discontinuation. Maximum concentration and area under the concentration-time curve increase sub-proportionally with dose. Mean steady-state volume of distribution ranged from 127 to 385L. Sirolimus was a major metabolite (metabolite-to-parent ratio range, 2.5 to 3.5). Whole blood clearance was nonlinear, ranging from 19 to 51 L/h (34 to 220 mg/m(2)). Variability predicted with flat doses appears comparable with data based on body-surface area-normalized treatment. Partial responses were observed in one patient with renal clear-cell carcinoma and in one patient with breast adenocarcinoma.CCI-779 displayed no immunosuppressive effects with manageable and reversible adverse events at doses up to 220 mg/m(2), the highest dose tested. Based on our results, weekly doses of 25, 75, and 250 mg CCI-779 not based on classical definitions of maximum-tolerated dose are being tested in phase II trials in patients with breast and renal cancer.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References