Phase Ib/II Trial of NC-6004 (Nanoparticle Cisplatin) Plus Gemcitabine in Patients with Advanced Solid Tumors

Abstract

Purpose: NC-6004, a novel cisplatin nanoparticle developed using micellar technology exhibits sustained release of cisplatin and selective distribution to tumors. Preclinical data demonstrated a favorable tolerability profile and preserved or improved antitumor activity compared with cisplatin across animal models. We evaluated the safety and tolerability of NC-6004 and gemcitabine using a Bayesian continual reassessment model (N-CRM) to determine the optimal dose.Experimental Design: Patients with advanced solid tumors received NC-6004 at 60 to 180 mg/m 2 on day 1 and gemcitabine at 1,250 mg/m 2 on days 1 and 8 every 3 weeks. Dose escalation of NC-6004 began with a single patient run-in until a dose-limiting toxicity occurred at 180 mg/m 2 . Cohorts of four patients were enrolled at doses predicted by the N-CRM. The maximum tolerated dose (MTD) was defined as having the greatest probability of target toxicity <25%. Quality of life was assessed using EORTC-QLQ-C30.Results: Among 22 patients, the most common grade III/IV hematologic adverse events were leukopenia (68%) and thrombocytopenia (59%). Of 20 pretreated patients evaluable for response, half were previously exposed to a platinum agent. The MTD was 135 mg/m 2 . Nine patients were treated at the MTD with median treatment duration of 15 weeks (range, 3-50). Tumor shrinkage occurred in 11 (55%), partial responses in 3 (15%), and stable disease in 14 (70%). Most patients reported stable or improved EORTC QLQ-C30 scores.Conclusions: Greater cisplatin equivalent doses were achieved with no clinically significant neuro-, oto-, or nephrotoxicity. These data demonstrate tolerability and promising activity of NC-6004 in combination with gemcitabine.

Cancer Extracellular Vesicles: Next-Generation Diagnostic and Drug Delivery Nanotools

“…Besides the cited pharmacological properties, the nanoformulation also improved the physicochemical properties of drugs and could be engineered in order to modify their surface for active targeting [258][259][260]. Several nanoparticle formulations, such as lipids and polymer-based materials, have already been approved and are in use [20,261,262]. Although such nanocarriers show good pharmacokinetic and safety profiles, together with enhanced bioavailability, the use of naturally occurring EEVs could be of help in overcoming the off-target effects of lipidand polymer-based nanocarriers since EEVs are naturally covered with several biomolecules useful for tumor targeting [263,264].…”

Recent Advances in Nanocarrier-Assisted Therapeutics Delivery Systems

“…Moving forward, some areas need further investigation in order to overcome currently poor translational outcomes of nanomedicine, such as identifying the mechanisms of nanoparticles' interaction with different tissues and their uptake in the body [191]. [194] Squamous Cell Carcinoma of the Head and Neck…”

A multicenter, single-arm, basket design, phase II study of NC-6004 plus gemcitabine in patients with advanced unresectable lung, biliary tract, or bladder cancer

“…The MTD of NC-6004 was 135 mg/m 2 , which is 50% higher than the MTD determined using a traditional 3+3 modified Fibonacci dose escalation design in a previous trial of NC-6004 that reported no clinically significant neuro, oto, or nephrotoxicity. In the Phase II portion of this study, which is reported here, an adaptive, open-label expansion trial was conducted at the MTD dose identified in the first phase in patients with squamous NSCLC, biliary tract, or bladder cancer; treatment efficacy, safety, and tolerability were assessed [9].…”