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

Abstract

Purpose This dose-finding phase 1 study investigated the maximum tolerated dose (MTD) and safety of weekly 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 45mg/m2. Additional doses were 56.25, 100, 150, and 125 mg/m2. Results Of 27 enrolled patients, 26 were treated. Two dose-limiting toxicities (DLTs) occurred at 150mg/m2 (grade 3 AST elevation and grade 4 thrombocytopenia), and 2 DLTs occurred at 125mg/m2 (grade 3 suicidal ideation and grade 3 hypophosphatemia). Thus, the MTD was declared at 100mg/m2. Most treatment-related adverse events (TRAEs) 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 1 grade 3 nonhematologic TRAE (dyspnea) and 1 grade 3 hematologic event (anemia) occurred at the MTD. One patient with kidney cancer had a partial response. The longest clinical benefits were observed in 2 patients: 1 patient with mesothelioma (SD: 365 days) and 1 patient with neuroendocrine tumor (SD: 238 days). The Cmax and AUC increased with dose between 45–150mg/m2, except for a relatively low AUC at 125 mg/m2. nab-Rapamycin significantly inhibited mTOR targets S6K and 4EBP1. Conclusions The clinical dose of single agent nab-rapamycin was established at 100 mg/m2, which was well tolerated with preliminary evidence of response and SD, and produced a fairly dose proportional pharmacokinetic profile in patients with unresectable advanced nonhematologic malignancies.

Clinical Translation of Nanomedicine

“…222 A phase I dose-finding study of q3 week ABI-009 in patients with advanced solid tumor malignancies was undertaken. 223 Dose was escalated from 45 to 125 mg/m 2 . Treatment was overall well tolerated.…”

Silk nanoparticles: proof of lysosomotropic anticancer drug delivery at single-cell resolution

“…Biopolymer-based constructs (e.g. cyclodextrin CRLX-101) [11], mannose and diethylenetriaminepentaacetic acid 99m Tc-functionlised dextran [12] and proteins [13,14] are especially appealing because their inherent biodegradability renders them less likely to disrupt lysosomal function [3]. One important protein in this respect is silk, which has recently been proposed for use in drug delivery applications [15,16].…”

The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer

“…However, despite showing good tolerability profiles when used alone or combined with other treatments, little anti-tumor activity has been reported in the clinic [ 40 , 41 , 42 , 241 , 242 , 243 , 244 , 245 , 246 , 247 , 248 , 249 ]. Efforts to improve the bioavailability and performance of these agents through nanoparticle encapsulation and binding are ongoing, although whether this improves their anti-tumor effects remains to be determined [ 250 , 251 ]. Nonetheless, early reports from a separate study have indicated promising responses in patients with PTEN-deficient mCRPC (NCT00976755).…”