Weekly nab-Rapamycin in Patients with Advanced Nonhematologic Malignancies: Final Results of a Phase I Trial

Purpose: This dose-finding phase I study investigated the maximum-tolerated dose (MTD) and safety of weekly nanoparticle albumin-bound rapamycin ( nab -rapamycin) in patients with untreatable advanced nonhematologic malignancies. Experimental Design: nab -Rapamycin was administered weekly for 3 weeks followed by 1 week of rest, with a starting dose of 45 mg/m 2 . Additional doses were 56.25, 100, 150, and 125 mg/m 2 . Results: Of 27 enrolled patients, 26 were treated. Two dose-limiting toxicities (DLT) occurred at 150 mg/m 2 [grade 3 aspartate aminotransferase (AST) elevation and grade 4 thrombocytopenia], and two DLTs occurred at 125 mg/m 2 (grade 3 suicidal ideation and grade 3 hypophosphatemia). Thus, the MTD was declared at 100 mg/m 2 . Most treatment-related adverse events (TRAE) were grade 1/2, including thrombocytopenia (58%), hypokalemia (23%), mucositis (38%), fatigue (27%), rash (23%), diarrhea (23%), nausea (19%), anemia (19%), hypophosphatemia (19%), neutropenia (15%), and hypertriglyceridemia (15%). Only one grade 3 nonhematologic TRAE (dyspnea) and one grade 3 hematologic event (anemia) occurred at the MTD. One patient with kidney cancer had a partial response and 2 patients remained on study for 365 days (patient with mesothelioma) and 238 days (patient with neuroendocrine tumor). The peak concentration ( C max ) and area under the concentration–time curve (AUC) of rapamycin increased with dose between 45 and 150 mg/m 2 , except for a relatively low AUC at 125 mg/m 2 . nab -Rapamycin significantly inhibited mTOR targets S6K and 4EBP1. Conclusions: The clinical dose of single-agent nab -rapamycin was established at 100 mg/m 2 weekly (3 of 4 weeks) given intravenously, which was well tolerated with preliminary evidence of response and stable disease, and produced a fairly dose-proportional pharmacokinetic profile in patients with unresectable advanced nonhematologic malignancies. Clin Cancer Res; 19(19); 5474–84. ©2013 AACR .