Phase I Study of NK012, a Novel SN-38–Incorporating Micellar Nanoparticle, in Adult Patients with Solid Tumors

Abstract

Purpose: We conducted a first-in-human phase I study to determine the dose-limiting toxicity (DLT), evaluate the pharmacokinetic profile, and document any antitumor activity of NK012, a novel SN-38-incorporating micellar nanoparticle.Experimental Design: Patients with solid tumors refractory to standard therapy, or for which no standard therapy is available, were enrolled. NK012 was administered as a 30-minute infusion every 3 weeks. The starting dose was 2 mg/m 2 as SN-38 equivalent, and an accelerated titration schedule was used. Pharmacokinetic analysis was conducted in cycles 1 and 2. Results: Twenty-four patients were enrolled in the study. No UGT1A1*28 homozygous patients were enrolled. Predominant toxicity was neutropenia. Nonhematologic toxicity, especially diarrhea, was mostly grade 1 or 2 during study treatments. Two of nine patients had DLT during cycle 1 at the 28 mg/m 2 dose level. DLTs were mostly neutropenia or a related event. Polymer-bound SN-38 (NK012) and SN-38 released from NK012 were slowly eliminated from the plasma, with a terminal-phase half-life of approximately 140 and 210 hours, respectively. Systemic exposure to both polymer-bound SN-38 and SN-38 increased in proportion to the dose. A refractory esophageal cancer patient and a lung carcinoid tumor patient had an objective response and continued the study treatment for 5 and 12 months, respectively.Conclusions: NK012 was well tolerated and showed antitumor activity including partial responses and several occurrences of prolonged stable disease across a variety of advanced refractory cancers. Phase II studies are ongoing. Clin Cancer Res; 16(20); 5058-66. ©2010 AACR.Irinotecan hydrochloride (CPT-11) has proven to be active against colorectal, lung, and ovarian cancers (1-5). CPT-11 is a prodrug that is converted to a biologically active metabolite, 7-ethyl-10-hydroxy-CPT (SN-38), by carboxylesterase (CE) enzymes. SN-38 is an analogue of the plant alkaloid camptothecin, which targets DNA topoisomerase I. Compared with CPT-11, SN-38 exhibits up to 1,000-fold more potent cytotoxic activity against various cancer cells in vitro (6). Although CPT-11 is converted to SN-38 in the liver and tumor, the metabolic conversion rate is <10% of the original volume of 8). Moreover, the conversion of CPT-11 to SN-38 depends on the genetic interindividual variability of CE activity (9). Thus, more efficient use of SN-38 might be highly advantageous and quite attractive for cancer treatment.Drugs categorized under the drug delivery system (DDS) are made primarily by using nanotechnology (10). In the field of oncology, DDS drugs have been produced and evaluated in preclinical or clinical trials, with some already approved for clinical use (11,12). NK012 categorized in DDS is a micelle-forming macromolecular prodrug prepared by binding SN-38 to the polyglutamate of a block copolymer via an ester bond (Fig. 1). The amphiphilic block copolymers consist of polyethylene glycol and partially SN-38-bound polyglutamate. Polyethylene glycol is hydrophilic a...

Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle

“…Likewise, the MAG-CPT gave released CPT dynamics of the same type (35,36). However, the polymeric micelle of SN-38 shows the same behavior for released SN-38 in animals (37) and humans (28), as does PEG-bound SN-38 in animals (38) and humans (39). When CPT binding to albumin is properly accounted for, the PK parameters of the unconjugated CPT in animals and humans can be correlated.…”

“…Other nanoparticles have shown this type of scaling in humans. For example, Hamaguchi et al reported from their phase 1 study that the AUC of the polymeric micelle NK105 increases linearly with dose in milligrams per square meter (28). Likewise, Lim et al reported that the AUC for the polymeric micelle Genexol-PM increases linearly with dose in milligrams per square meter (29).…”

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

“…(Nanoplain: PEG + poly-glutamic acid) [18,361] and NK012 (PEG + poly-glycolic acid) [18,362], containing cisplatin or SN38, respectively, and the phase II/III trials of the P-glycoproteintargeting pluronic micelle of doxorubicin (SP1049C) that was labeled as orphan drug by the FDA in 2008 [347,354].…”

Tissue Penetration and Activity of Camptothecins in Solid Tumor Xenografts

“…To date, two clinically approved analogues exist, topotecan and irinotecan, while there are currently efforts being made to develop a new generation of compounds that exhibit significantly longer systemic exposures (5)(6)(7)(8).…”