A first-in-human Phase 1 study of epirubicin-conjugated polymer micelles (K-912/NC-6300) in patients with advanced or recurrent solid tumors

  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},
  author={Hirofumi Mukai and Takahiro Kogawa and Nobuaki Matsubara and Yoichi Naito and Masaoki Sasaki and Ako Hosono},
  journal={Investigational New Drugs},
SummaryBackground 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… 
A Phase 1b Dose Escalation Trial of NC-6300 (Nanoparticle Epirubicin) in Patients with Advanced Solid Tumors or Advanced, Metastatic, or Unresectable Soft-tissue Sarcoma
NC-6300 was well tolerated with a manageable side effect profile, despite the MTD and RP2D being higher than conventional epirubicin doses, and warrants further investigation in patients with advanced solid tumors, including sarcoma.
Anthracyclines are a clinically important class of antineoplastic agents used to treat a wide variety of solid and blood cancers. The first described anthracycline, daunorubicin, was first isolated
Reinforcement of antitumor effect of micelles containing anticancer drugs by binding of an anti-tissue factor antibody without direct cytocidal effects.
Efficacy of pH-Sensitive Nanomedicines in Tumors with Different c-MYC Expression Depends on the Intratumoral Activation Profile.
Tumor-targeted nanomedicines capable of treating both tumors with high and low c-Myc levels by adjusting their ability to spatiotemporally control drug action are developed and indicate the potential of engineered nanomediines for c- myelocytomatosis inhibition and spur the idea of precision pH-sensitive nanomedicsine based on cancer biomarker levels.
Effective treatment of drug resistant recurrent breast tumors harboring cancer stem‐like cells by staurosporine/epirubicin co‐loaded polymeric micelles
RNA‐Peptide nanoplexes drug DNA damage pathways in high‐grade serous ovarian tumors
The development of a nanoscale peptide‐nucleic acid complex that facilitates tumor‐specific RNA interference therapy to chemosensitize advanced ovarian tumors to frontline platinum/taxane therapy and combined inhibition of MK2 could improve treatment outcomes in patients currently receiving frontline chemotherapy for advanced OC are reported.


NC‐6300, an epirubicin‐incorporating micelle, extends the antitumor effect and reduces the cardiotoxicity of epirubicin
NC‐6300 showed a significantly potent antitumor effect against Hep3B s.c. tumors compared with epirubicin and produced a significantly longer survival rate than epirUBicin against the liver orthotopic tumor of Hep3 B.
Improved anti‐tumor activity of stabilized anthracycline polymeric micelle formulation, NC‐6300
It is confirmed that polymeric micelles incorporating epirubicin through an acid‐labile linker improve the therapeutic index and achieve a broad range of therapeutic doses, demonstrating the advantage of NC‐6300 attributable to the efficient drug release in the tumor.
Preclinical and clinical studies of anticancer agent‐incorporating polymer micelles
The size of anticancer agent‐incorporating micelles can be controlled within the diameter range of 20–100 nm to ensure that they do not penetrate normal vessel walls to reduce the incidence of drug‐induced side‐effects.
Tumoritropic and lymphotropic principles of macromolecular drugs.
Improvements in protein drugs, after tailoring with polymers, are as follows: increased plasma half-life, loss of antigenecity, lymphotropism, and, especially, preferred tumor-targeting efficiency and long-term retention in the tumor tissues.
Preparation and biological characterization of polymeric micelle drug carriers with intracellular pH-triggered drug release property: tumor permeability, controlled subcellular drug distribution, and enhanced in vivo antitumor efficacy.
In vitro and in vivo studies show that the micelles have the characteristic properties, such as an intracellular pH-triggered drug release capability, tumor-infiltrating permeability, and effective antitumor activity with extremely low toxicity.
Kinin‐generating Cascade in Advanced Cancer Patients and in vitro Study
It is concluded that kinin generation does occur in the plasma of patients with advanced cancer, and that one of the initiation mechanisms of the kinin‐generating cascade appears to be mediated by plasmin and to depend on cancer cell‐derived PA activity.
Risk factors for doxorubicin-induced congestive heart failure.
There was a continuum of increasing risk as the cumulative amount of administered drug increased, and a weekly dose schedule of doxorubicin was associated with a significantly lower incidence of congestive heart failure than was the usually employed every 3-week schedule.
Chemotherapy-induced palmar-plantar erythrodysesthesia syndrome: etiology and emerging therapies.
Although the exact mechanism is unknown, there are several approaches to ameliorating the symptoms of this complication, including antiinflammatory agents, vitamin products, and peripheral vasoconstricting agents.
New anthracycline antibiotics.
  • T. Oki
  • Chemistry, Biology
    The Japanese journal of antibiotics
  • 1977
32 new anthracycline compounds in Streptomyces cultures are found and aclacinomycin A is under the phase II clinical study, which has aklavinone aglycone and is becoming more interesting in its low cardiac toxicity.
Congestive heart failure in patients treated with doxorubicin
Doxorubicin is a highly effective and widely used cytotoxic agent with application that is limited by cardiotoxicity related to the cumulative dose of the drug, which is reflected in the incidence in the broader clinical oncology setting.