MedKoo product information:

  NK-012

Description of NK-012:  NK-012 is a SN-38-loaded polymeric micelles, which is a formulation consisting of polymeric micelles loaded with the irinotecan metabolite SN-38 with potential antineoplastic activity. SN-38-loaded polymeric micelles NK012 is an SN-38-releasing nanodevice constructed by covalently attaching SN-38 to the block copolymer PEG-PGlu, followed by self-assembly of amphiphilic block copolymers in an aqueous milieu. SN-38 (7-ethyl-10-hydroxy-camptothecin), a biological active metabolite of the prodrug irinotecan (CPT-11), binds to and inhibits topoisomerase I by stabilizing the cleavable complex between topoisomerase I and DNA, resulting in DNA breaks, inhibition of DNA replication, and apoptosis. SN-38 has been reported to exhibit up to 1,000-fold more cytotoxic activity against various cancer cells in vitro than irinotecan. This formulation increases the water-solubility of SN-38 and allows the delivery of higher doses of SN-38 than those achievable with SN-38 alone. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    Nippon Kayaku, Japan.

NK012 is a 'nanodevice' formulation of SN-38 (an irinotecan metabolite). NK012 is an SN-38-releasing nanodevice constructed by covalently attaching SN-38 to the block copolymer PEG-PGlu, followed by self-assembly of amphiphilic block copolymers in aqueous media. It has entered phase II clinical trials for triple-negative breast cancer and relapsed small cell lung cancer.

Phase I study of NK012: Japan scientist recently reported Phase I study of NK012. The results are the following. Twenty-four patients were enrolled in the study. 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. (source: Clin Cancer Res. 2010 Oct 15;16(20):5058-66.)

1: Hamaguchi T, Doi T, Eguchi-Nakajima T, Kato K, Yamada Y, Shimada Y, Fuse N, Ohtsu A, Matsumoto S, Takanashi M, Matsumura Y. Phase I study of NK012, a novel SN-38-incorporating micellar nanoparticle, in adult patients with solid tumors. Clin Cancer Res. 2010 Oct 15;16(20):5058-66. Epub 2010 Oct 13. PubMed PMID: 20943763.

2: Takahashi A, Ohkohchi N, Yasunaga M, Kuroda J, Koga Y, Kenmotsu H, Kinoshita T, Matsumura Y. Detailed distribution of NK012, an SN-38-incorporating micelle, in the liver and its potent antitumor effects in mice bearing liver metastases. Clin Cancer Res. 2010 Oct 1;16(19):4822-31. Epub 2010 Aug 31. PubMed PMID: 20807756.

3: Kenmotsu H, Yasunaga M, Goto K, Nagano T, Kuroda J, Koga Y, Takahashi A, Nishiwaki Y, Matsumura Y. The antitumor activity of NK012, an SN-38-incorporating micelle, in combination with bevacizumab against lung cancer xenografts. Cancer. 2010 Oct 1;116(19):4597-604. PubMed PMID: 20572031.

4: Matsumura Y. Preclinical and clinical studies of NK012, an SN-38-incorporating polymeric micelles, which is designed based on EPR effect. Adv Drug Deliv Rev. 2011 Mar 18;63(3):184-92. Epub 2010 May 31. Review. PubMed PMID: 20561951.

5: Nagano T, Yasunaga M, Goto K, Kenmotsu H, Koga Y, Kuroda J, Nishimura Y, Sugino T, Nishiwaki Y, Matsumura Y. Synergistic antitumor activity of the SN-38-incorporating polymeric micelles NK012 with S-1 in a mouse model of non-small cell lung cancer. Int J Cancer. 2010 Dec 1;127(11):2699-706. PubMed PMID: 20198621.

6: Kuroda J, Kuratsu J, Yasunaga M, Koga Y, Kenmotsu H, Sugino T, Matsumura Y. Antitumor effect of NK012, a 7-ethyl-10-hydroxycamptothecin-incorporating polymeric micelle, on U87MG orthotopic glioblastoma in mice compared with irinotecan hydrochloride in combination with bevacizumab. Clin Cancer Res. 2010 Jan 15;16(2):521-9. Epub 2010 Jan 12. PubMed PMID: 20068081.

7: Saito Y, Yasunaga M, Kuroda J, Koga Y, Matsumura Y. Antitumour activity of NK012, SN-38-incorporating polymeric micelles, in hypovascular orthotopic pancreatic tumour. Eur J Cancer. 2010 Feb;46(3):650-8. Epub 2009 Dec 16. PubMed PMID: 20015633.

8: Nagano T, Yasunaga M, Goto K, Kenmotsu H, Koga Y, Kuroda J, Nishimura Y, Sugino T, Nishiwaki Y, Matsumura Y. Antitumor activity of NK012 combined with cisplatin against small cell lung cancer and intestinal mucosal changes in tumor-bearing mouse after treatment. Clin Cancer Res. 2009 Jul 1;15(13):4348-55. Epub 2009 Jun 9. PubMed PMID: 19509138.

9: Kuroda J, Kuratsu J, Yasunaga M, Koga Y, Saito Y, Matsumura Y. Potent antitumor effect of SN-38-incorporating polymeric micelle, NK012, against malignant glioma. Int J Cancer. 2009 Jun 1;124(11):2505-11. PubMed PMID: 19189401.

10: Nakajima TE, Yanagihara K, Takigahira M, Yasunaga M, Kato K, Hamaguchi T, Yamada Y, Shimada Y, Mihara K, Ochiya T, Matsumura Y. Antitumor effect of SN-38-releasing polymeric micelles, NK012, on spontaneous peritoneal metastases from orthotopic gastric cancer in mice compared with irinotecan. Cancer Res. 2008 Nov 15;68(22):9318-22. PubMed PMID: 19010905.

11: Matsumura Y. Polymeric micellar delivery systems in oncology. Jpn J Clin Oncol. 2008 Dec;38(12):793-802. Epub 2008 Nov 6. Review. PubMed PMID: 18988667.

12: Saito Y, Yasunaga M, Kuroda J, Koga Y, Matsumura Y. Enhanced distribution of NK012, a polymeric micelle-encapsulated SN-38, and sustained release of SN-38 within tumors can beat a hypovascular tumor. Cancer Sci. 2008 Jun;99(6):1258-64. Epub 2008 Apr 21. PubMed PMID: 18429960.

13: Matsumura Y. Poly (amino acid) micelle nanocarriers in preclinical and clinical studies. Adv Drug Deliv Rev. 2008 May 22;60(8):899-914. Epub 2008 Feb 9. Review. PubMed PMID: 18406004.

14: Sumitomo M, Koizumi F, Asano T, Horiguchi A, Ito K, Asano T, Kakizoe T, Hayakawa M, Matsumura Y. Novel SN-38-incorporated polymeric micelle, NK012, strongly suppresses renal cancer progression. Cancer Res. 2008 Mar 15;68(6):1631-5. PubMed PMID: 18339841.

15: Nakajima TE, Yasunaga M, Kano Y, Koizumi F, Kato K, Hamaguchi T, Yamada Y, Shirao K, Shimada Y, Matsumura Y. Synergistic antitumor activity of the novel SN-38-incorporating polymeric micelles, NK012, combined with 5-fluorouracil in a mouse model of colorectal cancer, as compared with that of irinotecan plus 5-fluorouracil. Int J Cancer. 2008 May 1;122(9):2148-53. PubMed PMID: 18196580.

16: Koizumi F, Kitagawa M, Negishi T, Onda T, Matsumoto S, Hamaguchi T, Matsumura Y. Novel SN-38-incorporating polymeric micelles, NK012, eradicate vascular endothelial growth factor-secreting bulky tumors. Cancer Res. 2006 Oct 15;66(20):10048-56. PubMed PMID: 17047068.