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

Yoshitaka Seki, Noboru Yamamoto, Yosuke Tamura, Yasushi Goto, Takashi Shibata, Maki Tanioka, Hajime Asahina, Hiroshi Nokihara, Yasuhide Yamada, Takashi Shimamoto, Kazuo Noguchi, Tomohide Tamura, Yoshitaka Seki, Noboru Yamamoto, Yosuke Tamura, Yasushi Goto, Takashi Shibata, Maki Tanioka, Hajime Asahina, Hiroshi Nokihara, Yasuhide Yamada, Takashi Shimamoto, Kazuo Noguchi, Tomohide Tamura

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.

Figures

Fig. 1
Fig. 1
CT scans showing a partial response (in Patient 13). a Baseline, longest diameter of 42 mm; and b Day 28, longest diameter of 21 mm

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