Phase I study for ridaforolimus, an oral mTOR inhibitor, in Japanese patients with advanced solid tumors.

Abstract

PURPOSE:

Ridaforolimus is a non-prodrug mTOR inhibitor. The safety, pharmacokinetics (PK), and antitumor activity of oral ridaforolimus were assessed in Japanese patients with refractory solid tumors.

METHODS:

Ridaforolimus (20 or 40 mg) was administered as a single dose on Day 1, followed by once daily dosing five times a week for a 3-week cycle beginning on Day 8. Full PK sampling was performed on Days 1 and 26.

RESULTS:

Thirteen patients (7 at 20 mg and 6 at 40 mg) were enrolled. The median treatment duration was 82 days. The most common drug-related adverse events were stomatitis, hypertriglyceridemia, and proteinuria. Two patients had dose-limiting toxicities (grade 3 stomatitis at 20 mg, and grade 3 anorexia and vomiting at 40 mg). Four patients had grade 1 interstitial pneumonitis. Ridaforolimus in the whole blood was rapidly absorbed and slowly eliminated with a half-life of approximately 56-58 h after a single dose. Two patients (with non-small cell lung cancer and angiosarcoma, respectively) achieved a partial response, and five patients (one with thymic cancer and four with soft tissue sarcomas) had a stable disease for ≥ 16 weeks.

CONCLUSIONS:

Ridaforolimus was well tolerated up to a dose of 40 mg in Japanese patients. Preliminary evidence of antitumor activity was observed for patients with solid tumors. Further investigation at this dose is warranted.

• Authors: Yoshitaka Seki, Noboru Yamamoto, Yosuke Tamura, Yasushi Goto, Takashi Shibata, Maki Tanioka, Hajime Asahina, Hiroshi Nokihara, Yasuhide Yamada, Takashi Shimamoto, Kazuo Noguchi, Tomohide Tamura
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 69 Issue 4 Pg. 1099-105 (Apr 2012) ISSN: 1432-0843 [Electronic] Germany
• PMID: 22143378 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• ridaforolimus
• MTOR protein, human
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Adult
• Aged
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Humans
• Japan
• Male
• Middle Aged
• Neoplasms (drug therapy, pathology)
• Protein Kinase Inhibitors (adverse effects, pharmacokinetics, therapeutic use)
• Sirolimus (adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)