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...

Objective: To evaluate the efficacy and safety of ulipristal acetate (UPA) for uterine fibroids (UFs), a phase III study was conducted with leuprorelin (LEU) as a comparator. This is the first confirmatory trial of UPA for UFs among Asians. Design: Multicenter, randomized, double-blind, double-dummy, parallel-group study. Setting: Thirty-two sites in Japan. Patient(s): Patients were assigned to 2 arms, with 82 patients in the UPA group and 79 patients in the LEU group. Intervention(s): In the UPA group, 10 mg of UPA was orally administered once a day for 12 weeks. In the LEU group, 1.88 mg or 3.75 mg of LEU was subcutaneously administered at weeks 0, 4, and 8. Main Outcome Measure(s): The primary endpoint was the percentage of patients with amenorrhea for 35 days. For safety evaluation, adverse events (AEs) were recorded. Result(s): The percentage of patients with amenorrhea for 35 days was 87.0% in the UPA group and 81.8% in the LEU group, and the efficacy of UPA for causing amenorrhea for 35 days was confirmed to be noninferior to that of LEU. AEs occurred in 78.0% of the patients in the UPA group and 88.8% of the patients in the LEU group. Conclusion(s): The effect of UPA on heavy menstrual bleeding was shown to be comparable with that of LEU in Japanese patients with symptomatic UFs. No notable AEs occurred because of the UPA treatment, and the incidence of AEs in the UPA group was comparable with that of AEs in the LEU group. This result demonstrates the clinical utility of UPA for Asians.

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Misfit layer compounds are another family of layered materials, which are typically described as (MX) n TX 2 (M = Sn, Pb, Bi, rare earth metals; T = Nb, Ta, Ti, V, Cr; X = S, Se; 1.08 < n < 1.23). [7][8][9] They consist of MX and TX 2 sublattices. These subsystems have a different geometry in the a-b plane. The projection of the typical crystal structure along [1 0 0] is shown in

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