title: A first-in-human Phase 1 study of epirubicin-conjugated polymer micelles (K-912/NC-6300) in patients with advanced or recurrent solid tumors.
abstract: Background K-912 also known as NC-6300 is a novel epirubicin pro-drug conjugate developed using micellar nanoparticle technology. We conducted a first-in-human, Phase 1, open-label, non-randomized dose escalation study to evaluate the safety, tolerability, efficacy, and pharmacokinetics of K-912 administered as monotherapy in patients with advanced or recurrent solid tumors. Methods Patients aged 41 to 72 years with histologically or cytologically confirmed advanced or recurrent malignant solid tumors either refractory to standard therapy or had no other viable treatment options were enrolled. K-912 was administered as a 10-min intravenous infusion every three weeks. Doses were increased in a step-wise manner based on a predetermined series: 15, 30, 60, 80, 100, 130, 170, and 225 mg/m2. The appropriateness of doses above 60 mg/m2was assessed using a Bayesian continual reassessment model. Treatment-emergent adverse events and tumor response were evaluated according to internationally accepted criteria. Results Nineteen patients were treated with K-912. No additional adverse events expected with anthracyclines were observed. While the number of patients treated at the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) were small, MTD and RP2D were established to be 170 mg/m2. Partial response was observed in one patient with breast cancer treated at 100 mg/m2, yielding an objective response rate of 5% (1/19). Stable disease was observed in 10 patients. The human pharmacokinetic profile of K-912 was consistent with that observed from nonclinical studies in rats and monkeys. Conclusions This study showed that K-912 was well tolerated in patients with various solid tumors and exhibited less toxicity than conventional epirubicin formulations.
authors.affiliation: Division of Breast and Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa City, Chiba Prefecture, 277-8577, Japan. hrmukai@east.ncc.go.jp.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Mukai
authors.affiliation: Division of Breast and Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa City, Chiba Prefecture, 277-8577, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kogawa
authors.affiliation: Division of Breast and Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa City, Chiba Prefecture, 277-8577, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Matsubara
authors.affiliation: Division of Breast and Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa City, Chiba Prefecture, 277-8577, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Naito
authors.affiliation: Division of Breast and Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa City, Chiba Prefecture, 277-8577, Japan.
authors.forename: Masaoki
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: Division of Breast and Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa City, Chiba Prefecture, 277-8577, Japan.
authors.forename: Ako
authors.initials: A
authors.lastname: Hosono
mesh_terms: D000328:Adult; D000368:Aged; D015251:Epirubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D020714:Maximum Tolerated Dose; D008823:Micelles; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011108:Polymers / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011506:Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D012166:Retinal Hemorrhage / Q000139:chemically induced; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D008823:Micelles; C555062:NC 6300; D011108:Polymers; D011506:Proteins; D015251:Epirubicin
keywords: Drug delivery system; Epirubicin; K-912; Micelle; NC-6300; Polymer