Weekly nab-Rapamycin in patients with advanced nonhematologic malignancies: final results of a phase I trial

Abstract

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 (Cmax) 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.

Conflict of interest statement

Conflict of Interest Statement

Drs Gonzalez-Angulo, Blumenschein, and Meric-Bernstam received research funding from Celgene. Drs Li, Elias, and Desai are employee of Celgene.

©2013 AACR.

Figures

Figure 1

nab-Rapamycin plasma concentration by time

Figure 2

Waterfall plot showing percent change of target lesion from baseline by patient and tumor types

Figure 3

Regulation of mTOR signaling in PBMCs. A) Levels of 4EBP1 T70, S6K T389, S6 S235/236 and S6 S240/244 were assessed during cycle 1 of nab-rapamycin treatment, on D1(pre-treatment), D2, D4 and D8 (trough). Protein expression is expressed in Log2 scale. Red line depicts average expression levels. B) Expression of S6K T389 in PBMCs at different timepoints in different dose cohorts. C) Expression of 4EBP1 T70 in PBMCs at different timepoints in different dose cohorts.