Loading…
A Phase I Trial to Determine the Safety, Tolerability, and Maximum Tolerated Dose of Deforolimus in Patients with Advanced Malignancies
Purpose: This was a phase I trial to determine the maximum tolerated dose and toxicity of deforolimus (AP23573, MK-8669), an inhibitor of mammalian target of rapamycin (mTOR). The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied. Experimental Design: Deforolimus was a...
Saved in:
Published in: | Clinical cancer research 2009-02, Vol.15 (4), p.1428-1434 |
---|---|
Main Authors: | , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Summary: | Purpose: This was a phase I trial to determine the maximum tolerated dose and toxicity of deforolimus (AP23573, MK-8669), an inhibitor
of mammalian target of rapamycin (mTOR). The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied.
Experimental Design: Deforolimus was administered intravenously over 30 min every 7 days according to a flat dosing schedule. Dose was escalated
according to an accelerated titration design. Patients remained on study until disease progression as long as they tolerated
the drug without significant toxicities.
Results: Forty-six patients were enrolled on the study. Common side effects included fatigue, anorexia, and mucositis. The maximum
tolerated dose was 75 mg and mucositis was the dose-limiting toxicity. Similar to other mTOR inhibitors, deforolimus exhibited
nonlinear pharmacokinetics and a prolonged half-life. Among 34 patients evaluable for response, 1 patient had a partial response,
21 patients had stable disease, and 12 had progressed. Percent change in tumor size was significantly associated with AUC
( P = 0.015). A significant association was also detected for maximum change in cholesterol within the first two cycles of therapy
and change in tumor size ( r = â0.38; P = 0.029).
Conclusions: Deforolimus was well tolerated on the schedule tested in this trial with toxicity and pharmacokinetic profiles that were
similar to that of other mTOR inhibitors. Additional phase II studies are needed to determine if deforolimus is superior to
other mTOR inhibitors in terms of efficacy. The change in serum cholesterol as a potential biomarker of activity should be
studied further. |
---|---|
ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-08-2076 |