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Pharmacokinetics of mitomycin-c lipidic prodrug entrapped in liposomes and clinical correlations in metastatic colorectal cancer patients

Summary

Background Pegylated liposomal (PL) mitomycin-c lipidic prodrug MLP) may be a useful agent in patients with metastatic colo-rectal carcinoma (CRC). We report here on the pharmacokinetics and clinical observations in a phase 1A/B study with PL-MLP. Methods Plasma levels of MLP were examined in 53 CRC patients, who received PL-MLP either as single agent or in combination with capecitabine and/or bevacizumab. MLP was determined by an HPLC-UV assay, and its pharmacokinetics was analyzed by noncompartmental methods. The correlation between clinical and pharmacokinetic parameters was statistically analyzed. Results PL-MLP was well tolerated with a good safety profile as previously reported. Stable Disease was reported in 15/36 (42%) of efficacy-evaluable patients. Median survival of stable disease patients (14.4 months) was significantly longer than of progressive disease patients (6.5 months) and non-evaluable patients (2.3 months). MLP pharmacokinetics was stealth-like with long T½ (~1 day), slow clearance, and small volume of distribution (Vd). The addition of capecitabine and/or bevacizumab did not have any apparent effect on the pharmacokinetics of MLP and clinical outcome. High baseline neutrophil count and CEA level were correlated with faster clearance, and larger Vd. Stable disease patients had longer T½ and slower clearance than other patients. T½ and clearance were significantly correlated with survival. Conclusions PL-MLP treatment results in a substantial rate of disease stabilization in metastatic CRC, and prolonged survival in patients achieving stable disease. The correlation of neutrophil count and CEA level with pharmacokinetic parameters of MLP is an unexpected finding that needs further investigation. The association of long T½ of MLP with stable disease and longer survival is consistent with an improved probability of disease control resulting from enhanced tumor localization of long-circulating liposomes and underscores the relevance of personalized pharmacokinetic evaluation in the use of nanomedicines.

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Notes

  1. 1.

    Promitil® is a registered trademark of Lipomedix Pharmaceuticals Ltd.

  2. 2.

    Calculated for an MLP single dose of 2.5 mg/kg q4weeks and a cumulative MLP dose of 12.5 mg/kg (1 cycle of 2.5 mg/kg and 5 cycles of 2 mg/kg) to an adult patient of 70 kg weight and 170 cm height. Conversion factor: 1 mg MMC = 3.4 mg MLP.

References

  1. 1.

    Cattel L, Ceruti M, Dosio F (2004) From conventional to stealth liposomes: a new frontier in cancer chemotherapy. J Chemother (Florence, Italy) 16(Suppl 4):94–97. https://doi.org/10.1179/joc.2004.16.Supplement-1.94

    CAS  Article  Google Scholar 

  2. 2.

    Allen TM, Cullis PR (2013) Liposomal drug delivery systems: from concept to clinical applications. Adv Drug Deliv Rev 65(1):36–48. https://doi.org/10.1016/j.addr.2012.09.037

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Gabizon AA, Patil Y, La-Beck NM (2016) New insights and evolving role of pegylated liposomal doxorubicin in cancer therapy. Drug Resist Updat 29:90–106. https://doi.org/10.1016/j.drup.2016.10.003

    Article  PubMed  Google Scholar 

  4. 4.

    Glassman DC, Palmaira RL, Covington CM, Desai AM, Ku GY, Li J, Harding JJ, Varghese AM, O'Reilly EM, Yu KH (2018) Nanoliposomal irinotecan with fluorouracil for the treatment of advanced pancreatic cancer, a single institution experience. BMC Cancer 18(1):693. https://doi.org/10.1186/s12885-018-4605-1

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Prabhakar U, Maeda H, Jain RK, Sevick-Muraca EM, Zamboni W, Farokhzad OC, Barry ST, Gabizon A, Grodzinski P, Blakey DC (2013) Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. Cancer Res 73(8):2412–2417. https://doi.org/10.1158/0008-5472.can-12-4561

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Gabizon AA, Tzemach D, Horowitz AT, Shmeeda H, Yeh J, Zalipsky S (2006) Reduced toxicity and superior therapeutic activity of a mitomycin C lipid-based prodrug incorporated in pegylated liposomes. Clin Cancer Res 12(6):1913–1920

    CAS  Article  Google Scholar 

  7. 7.

    Zalipsky S, Saad M, Kiwan R, Ber E, Yu N, Minko T (2007) Antitumor activity of new liposomal prodrug of mitomycin C in multidrug resistant solid tumor: insights of the mechanism of action. J Drug Target 15(7-8):518–530. https://doi.org/10.1080/10611860701499946

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Gabizon A, Amitay Y, Tzemach D, Gorin J, Shmeeda H, Zalipsky S (2012) Therapeutic efficacy of a lipid-based prodrug of mitomycin C in pegylated liposomes: studies with human gastro-entero-pancreatic ectopic tumor models. J Control Release 160(2):245–253. https://doi.org/10.1016/j.jconrel.2011.11.019

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Golan T, Grenader T, Ohana P, Amitay Y, Shmeeda H, La-Beck NM, Tahover E, Berger R, Gabizon AA (2015) Pegylated liposomal mitomycin C prodrug enhances tolerance of mitomycin C: a phase 1 study in advanced solid tumor patients. Cancer Med 4(10):1472–1483. https://doi.org/10.1002/cam4.491

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Tahover E, Bar-Shalom R, Sapir E, Pfeffer R, Nemirovsky I, Turner Y, Gips M, Ohana P, Corn BW, Wang AZ, Gabizon AA (2018) Chemo-radiotherapy of Oligometastases of colorectal Cancer with Pegylated liposomal Mitomycin-C Prodrug (Promitil): mechanistic basis and preliminary clinical experience. Front Oncol 8:544. https://doi.org/10.3389/fonc.2018.00544

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Amitay Y, Shmeeda H, Patil Y, Gorin J, Tzemach D, Mak L, Ohana P, Gabizon A (2016) Pharmacologic studies of a Prodrug of Mitomycin C in Pegylated liposomes (Promitil((R))): high stability in plasma and rapid Thiolytic Prodrug activation in tissues. Pharm Res 33(3):686–700. https://doi.org/10.1007/s11095-015-1819-7

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Arner ES, Holmgren A (2006) The thioredoxin system in cancer. Semin Cancer Biol 16(6):420–426. https://doi.org/10.1016/j.semcancer.2006.10.009

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Soderberg A, Sahaf B, Rosen A (2000) Thioredoxin reductase, a redox-active selenoprotein, is secreted by normal and neoplastic cells: presence in human plasma. Cancer Res 60(8):2281–2289

    CAS  PubMed  Google Scholar 

  14. 14.

    Powis G, Kirkpatrick DL (2007) Thioredoxin signaling as a target for cancer therapy. Curr Opin Pharmacol 7(4):392–397. https://doi.org/10.1016/j.coph.2007.04.003

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Gabizon A, Grenader T, Tahover E, Shmeeda H, Golan T, Berger R, Geva R, Wolf I, Perets R, Amitay Y, Ohana P (2016) ESMO 2016 congress abstract: a phase 1B study of pegylated liposomal mitomycin-C prodrug with or without capecitabine and bevacizumab in third line chemotherapy of colorectal cancer. Ann Oncol 27(6):149–206. https://doi.org/10.1093/annonc/mdw370

    Article  Google Scholar 

  16. 16.

    Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A, Group RS (2015) Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 372(20):1909–1919. https://doi.org/10.1056/NEJMoa1414325

    Article  PubMed  Google Scholar 

  17. 17.

    Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouche O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D, Group CS (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381(9863):303–312. https://doi.org/10.1016/S0140-6736(12)61900-X

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372(26):2509–2520. https://doi.org/10.1056/NEJMoa1500596

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Verweij J, Pinedo HM (1990) Mitomycin C: mechanism of action, usefulness and limitations. Anti-Cancer Drugs 1(1):5–13

    CAS  Article  Google Scholar 

  20. 20.

    Chong G, Dickson JL, Cunningham D, Norman AR, Rao S, Hill ME, Price TJ, Oates J, Tebbutt N (2005) Capecitabine and mitomycin C as third-line therapy for patients with metastatic colorectal cancer resistant to fluorouracil and irinotecan. Br J Cancer 93(5):510–514. https://doi.org/10.1038/sj.bjc.6602733

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Rao S, Cunningham D, Price T, Hill ME, Ross PJ, Tebbutt N, Norman AR, Oates J, Shellito P (2004) Phase II study of capecitabine and mitomycin C as first-line treatment in patients with advanced colorectal cancer. Br J Cancer 91(5):839–843. https://doi.org/10.1038/sj.bjc.6602039

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Dimou A, Syrigos KN, Saif MW (2010) Is there a role for mitomycin C in metastatic colorectal cancer? Expert Opin Investig Drugs 19(6):723–735. https://doi.org/10.1517/13543784.2010.485191

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Tebbutt NC, Wilson K, Gebski VJ, Cummins MM, Zannino D, van Hazel GA, Robinson B, Broad A, Ganju V, Ackland SP, Forgeson G, Cunningham D, Saunders MP, Stockler MR, Chua Y, Zalcberg JR, Simes RJ, Price TJ (2010) Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian gastrointestinal trials group randomized phase III MAX study. J Clin Oncol 28(19):3191–3198. https://doi.org/10.1200/JCO.2009.27.7723

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Price TJ, Zannino D, Wilson K, Simes RJ, Cassidy J, Van Hazel GA, Robinson BA, Broad A, Ganju V, Ackland SP, Tebbutt NC (2012) Bevacizumab is equally effective and no more toxic in elderly patients with advanced colorectal cancer: a subgroup analysis from the AGITG MAX trial: an international randomised controlled trial of Capecitabine, Bevacizumab and Mitomycin C. Ann Oncol 23(6):1531–1536. https://doi.org/10.1093/annonc/mdr488

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Xu Y, Kolesar JM, Schaaf LJ, Drengler R, Duan W, Otterson G, Shapiro C, Kuhn J, Villalona-Calero MA (2009) Phase I and pharmacokinetic study of mitomycin C and celecoxib as potential modulators of tumor resistance to irinotecan in patients with solid malignancies. Cancer Chemother Pharmacol 63(6):1073–1082. https://doi.org/10.1007/s00280-008-0826-3

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Thomas SN, Zhu F, Schnaar RL, Alves CS, Konstantopoulos K (2008) Carcinoembryonic antigen and CD44 variant isoforms cooperate to mediate colon carcinoma cell adhesion to E- and L-selectin in shear flow. J Biol Chem 283(23):15647–15655. https://doi.org/10.1074/jbc.M800543200

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Konstantopoulos K, Thomas SN (2009) Cancer cells in transit: the vascular interactions of tumor cells. Annu Rev Biomed Eng 11:177–202. https://doi.org/10.1146/annurev-bioeng-061008-124949

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Giovinazzo H, Kumar P, Sheikh A, Brooks KM, Ivanovic M, Walsh M, Caron WP, Kowalsky RJ, Song G, Whitlow A, Clarke-Pearson DL, Brewster WR, Van Le L, Zamboni BA, Bae-Jump V, Gehrig PA, Zamboni WC (2016) Technetium Tc 99m sulfur colloid phenotypic probe for the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin in women with ovarian cancer. Cancer Chemother Pharmacol 77(3):565–573. https://doi.org/10.1007/s00280-015-2945-y

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Caron WP, Lay JC, Fong AM, La-Beck NM, Kumar P, Newman SE, Zhou H, Monaco JH, Clarke-Pearson DL, Brewster WR, Van Le L, Bae-Jump VL, Gehrig PA, Zamboni WC (2013) Translational studies of phenotypic probes for the mononuclear phagocyte system and liposomal pharmacology. J Pharmacol Exp Ther 347(3):599–606. https://doi.org/10.1124/jpet.113.208801

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    La-Beck NM, Zamboni BA, Gabizon A, Schmeeda H, Amantea M, Gehrig PA, Zamboni WC (2012) Factors affecting the pharmacokinetics of pegylated liposomal doxorubicin in patients. Cancer Chemother Pharmacol 69(1):43–50. https://doi.org/10.1007/s00280-011-1664-2

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Grodzinski P, Kircher M, Goldberg M, Gabizon A (2019) Integrating nanotechnology into Cancer care. ACS Nano 13(7):7370–7376. https://doi.org/10.1021/acsnano.9b04266

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Lyass O, Uziely B, Ben-Yosef R, Tzemach D, Heshing NI, Lotem M, Brufman G, Gabizon A (2000) Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer 89(5):1037–1047. https://doi.org/10.1002/1097-0142(20000901)89:5<1037::AID-CNCR13>3.0.CO;2-Z

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Amantea MA, Forrest A, Northfelt DW, Mamelok R (1997) Population pharmacokinetics and pharmacodynamics of pegylated-liposomal doxorubicin in patients with AIDS-related Kaposi's sarcoma. Clin Pharmacol Ther 61(3):301–311. https://doi.org/10.1016/S0009-9236(97)90162-4

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Rajan R, Sabnani MK, Mavinkurve V, Shmeeda H, Mansouri H, Bonkoungou S, Le AD, Wood LM, Gabizon AA, La-Beck NM (2018) Liposome-induced immunosuppression and tumor growth is mediated by macrophages and mitigated by liposome-encapsulated alendronate. J Control Release 271:139–148. https://doi.org/10.1016/j.jconrel.2017.12.023

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We are grateful to Frederic and Lisa Deutsch (BioStats Ltd., Maccabim, Israel) for their collaboration in data management and pharmacokinetic analysis, and to Jenny Gorin (Shaare Zedek MC) for her technical help with HPLC analysis of MLP.

Funding

This study was funded by Lipomedix Pharmaceuticals Ltd. (Jerusalem, Israel).

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Correspondence to Alberto A. Gabizon.

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Conflict of interest

A. Gabizon is founder, chief scientist and a director of Lipomedix; E. Tahover declares that she has no conflict of interest; T. Golan declares that she has no conflict of interest; R. Geva declares that she has no conflict of interest; R. Perets declares that she has no conflict of interest; Y. Amitay is an employee (scientist) of Lipomedix; H. Shmeeda declares that she has no conflict of interest; P. Ohana is an employee (vice-president) of Lipomedix.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional review boards and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Gabizon, A.A., Tahover, E., Golan, T. et al. Pharmacokinetics of mitomycin-c lipidic prodrug entrapped in liposomes and clinical correlations in metastatic colorectal cancer patients. Invest New Drugs 38, 1411–1420 (2020). https://doi.org/10.1007/s10637-020-00897-3

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Keywords

  • Colo-rectal cancer
  • Liposome
  • Mitomycin-c
  • Prodrug
  • Pharmacokinetics
  • Nanomedicine