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.

Simona Ruxandra Volovat,Atsushi Osada,Piotr Koralewski,Giulio Cerea,Juneko E Grilley Olson,Adina Croitoru,Tudor-Eliade Ciuleanu,Krassimir Koynov,Iulian Bobe,Constantin Volovat,Stefano Stabile

doi:10.18632/oncotarget.27684

Abstract

NC-6004 is a nanoparticle developed using micellar technology that can improve release of cisplatin, a standard treatment for many cancer types, and achieve selective distribution to tumors. Here, in the Phase II portion of this study, the activity, safety, tolerability, and effects on quality of life of NC-6004 in combination with gemcitabine was examined in 34 squamous non-small cell lung carcinoma (NSCLC) patients, 50 biliary tract cancer patients, and 13 bladder cancer patients. All patients received 135 mg/m2 NC-6004 on day one and 1,250 mg/m2 gemcitabine on days one and eight. The median progression-free survival was 3.9 months in NSCLC patients, 4.3 months in biliary tract cancer patients, and 6.8 months in bladder cancer patients fit for cisplatin treatment. The most frequently reported Grade 3 Treatment Emergent Adverse Events across all cohorts were nausea, anemia and neutropenia, and hyponatremia. Quality of life measures for patients who received the combined therapy were generally consistent with expectations for patients undergoing chemotherapy. Overall, combined NC-6004 and gemcitabine treatment resulted in long-lasting antitumor activity and had a favorable safety profile, suggesting that it should be investigated further as a therapy for various types of cancer.

Highlights

Platinum-based therapy is widely used to treat many types of cancer
In the presence of chloride in the bloodstream, the NC-6004 micelle formulation is gradually disassembled and releases cisplatin [4]. This sustained release feature of NC-6004 results in a lower maximum cisplatin concentration (Cmax) with a higher area under the curve (AUC); together with preferential distribution to tumors, this reduces toxicity and increases antitumor activity compared to conventional cisplatin at equivalent doses [5]
In an NC-6004 phase I clinical trial completed in the United Kingdom, administration of NC-6004 in patients with advanced solid tumors was associated with significantly prolonged half-life (230-fold increase) and greater AUC (8.5-fold increase) compared to equivalent cisplatin dose levels. These results indicated that antitumor activity at the maximum tolerated dose (MTD) for NC6004 may be greater than that of cisplatin, and the NC6004 dose of 90 mg/m2 was determined to be well tolerated [7]

Summary

Introduction

Platinum-based therapy is widely used to treat many types of cancer. cumulative doselimiting toxicity (DLT) is a common problem with cisplatin treatment [1]. NC-6004, a nanoparticle that encapsulates cisplatin, was developed to reduce DLTs while maintaining or increasing antitumor activity due to its unique pharmacokinetic characteristics. In the presence of chloride in the bloodstream, the NC-6004 micelle formulation is gradually disassembled and releases cisplatin [4]. This sustained release feature of NC-6004 results in a lower maximum cisplatin concentration (Cmax) with a higher area under the curve (AUC); together with preferential distribution to tumors, this reduces toxicity and increases antitumor activity compared to conventional cisplatin at equivalent doses [5]. Stability studies demonstrated that, when 5% dextrose in water is used to reconstitute NC-6004, more than 50% of the cisplatin released from nanoparticles due to the presence of chloride is stable after 120 hours [4]

Methods

Results

Conclusion