Top

Published in:

01-10-2020 | Pharmacokinetics | PHASE I STUDIES

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

Authors: Alberto A. Gabizon, Esther Tahover, Talia Golan, Ravit Geva, Ruth Perets, Yasmine Amitay, Hilary Shmeeda, Patricia Ohana

Published in: Investigational New Drugs | Issue 5/2020

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.

Available only for authorised users

Promitil® is a registered trademark of Lipomedix Pharmaceuticals Ltd.

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.

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-1.94CrossRef

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.2012.09.037CrossRefPubMed

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.2016.10.003CrossRefPubMed

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/s12885-018-4605-1CrossRefPubMedPubMedCentral

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-12-4561CrossRefPubMedPubMedCentral

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):1913–1920CrossRef

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/10.1080/10611860701499946CrossRefPubMed

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.2011.11.019CrossRefPubMed

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/cam4.491CrossRefPubMedPubMedCentral

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.2018.00544CrossRefPubMedPubMedCentral

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/s11095-015-1819-7CrossRefPubMed

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.2006.10.009CrossRefPubMed

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):2281–2289PubMed

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.2007.04.003CrossRefPubMed

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/mdw370CrossRef

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/NEJMoa1414325CrossRefPubMed

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-XCrossRefPubMed

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/NEJMoa1500596CrossRefPubMedPubMedCentral

19.

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

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.6602733CrossRefPubMedPubMedCentral

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.6602039CrossRefPubMedPubMedCentral

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/10.1517/13543784.2010.485191CrossRefPubMed

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.2009.27.7723CrossRefPubMed

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/mdr488CrossRefPubMed

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/s00280-008-0826-3CrossRefPubMed

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.M800543200CrossRefPubMedPubMedCentral

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-061008-124949CrossRefPubMed

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-yCrossRefPubMed

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.113.208801CrossRefPubMedPubMedCentral

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/s00280-011-1664-2CrossRefPubMed

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.9b04266CrossRefPubMed

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-ZCrossRefPubMed

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)90162-4CrossRefPubMed

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.2017.12.023CrossRefPubMed

Title: Pharmacokinetics of mitomycin-c lipidic prodrug entrapped in liposomes and clinical correlations in metastatic colorectal cancer patients
Authors: Alberto A. Gabizon
Esther Tahover
Talia Golan
Ravit Geva
Ruth Perets
Yasmine Amitay
Hilary Shmeeda
Patricia Ohana
Publication date: 01-10-2020
Publisher: Springer US
Keywords: Pharmacokinetics
Bevacizumab
Colorectal Cancer
Colorectal Cancer
Published in: Investigational New Drugs / Issue 5/2020
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-020-00897-3

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Summary

Please log in to get access to this content

Other articles of this Issue 5/2020

A multi-center phase II trial evaluating the efficacy of palbociclib in combination with carboplatin for the treatment of unresectable recurrent or metastatic head and neck squamous cell carcinoma

Combination of a novel microtubule inhibitor MBRI-001 and gemcitabine synergistically induces cell apoptosis by increasing DNA damage in pancreatic cancer cell lines

Phase I dose escalation study of BI 836826 (CD37 antibody) in patients with relapsed or refractory B-cell non-Hodgkin lymphoma

Structure-based design, synthesis, and evaluation of the biological activity of novel phosphoroorganic small molecule IAP antagonists

Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma

Phase I study of metformin in combination with carboplatin/paclitaxel chemotherapy in patients with advanced epithelial ovarian cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer