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A phase I study of MN-029 (denibulin), a novel vascular-disrupting agent, in patients with advanced solid tumors

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Abstract

Purpose

MN-029 (denibulin HCl) is a novel vascular-disrupting agent that reversibly inhibits microtubule assembly, resulting in disruption of the cytoskeleton of tumor vascular endothelial cells. This study determined the safety, pharmacokinetics, and acute anti-vascular effects of MN-029.

Methods

Patients were treated with escalating doses of MN-029 (4.0–225 mg/m2) administered IV at 3-week intervals. This first-in-human study followed an accelerated titration design, with intra-patient dose escalation. Plasma samples were assayed to determine PK parameters. DCE-MRI scans were acquired at baseline and at 6–8 h post-dose.

Results

Thirty-four patients received 151 infusions of MN-029. The most common toxicities of MN-029 included nausea and vomiting (which appeared to be dose related), diarrhea, fatigue, headache, and anorexia. No clinically significant myelotoxicity, stomatitis or alopecia was observed. There was no evidence of cumulative toxicity in patients receiving multiple courses of therapy. The cohort at 180 mg/m2 was expanded to six patients due to a reversible episode of acute coronary ischemia, without sequelae and with preservation of myocardial function. Two dose-limiting toxicities occurred at 225 mg/m2, a transient ischemic attack and grade 3 transaminitis, thus ending dose escalation. Pharmacokinetic data indicated dose-related increases in C max and AUC values, although substantial inter-subject variability was observed. No objective responses were noted; however, five patients had stable disease ≥6 months. A significant linear correlation was found between reduction in K trans and exposure to MN-029.

Conclusions

MN-029 was generally well tolerated and showed decrease in tumor vascular parameters. The maximum tolerated dose was 180 mg/m2.

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Acknowledgments

We thank Ana Ruiz-Garcia and Louis Lazo Radulovic for helpful discussions and technical assistance. This work was supported by MediciNova, Inc.

Conflicts of interest

Alejandro D Ricart is compensated as an employee of Pfizer Inc and owns stock/stock options in Pfizer Inc. Edward A. Ashton, Matthew M. Cooney, John Sarantopoulos, Joanna M. Brell, Gerardo Medina, Angela Zambito: no disclosures. Maria A. Feldman, Kale E. Ruby, Kazuko Matsuda, Mark S. Munsey are compensated as employees of MediciNova Inc. Anthony W. Tolcher’s institution has received research funding from Abbott, Ambit, Amgen, Array BioPharma, Astellas, AVEO/Schering/Plough, Azaya Therapeutics, Bayer, Biogen Idec, BiPar, Bristol-Myers Squibb, Calando, Cougar, Dendreon, Eli Lilly, Enzon, Exelixis, Five Prime, Genentech, Genta, Glaxo Smith Kline, Hana Biosciences, Hoffman-La Roche, Merck, Merrimack, MethylGene, Myriad, Nektar, Nerviano, Proteolix, Sanofi-Aventis, Spectrum, Symphogen; he has also received payment for consulting and advisory agreements from Abbott, Abgenomics, Abraxis, ACT Biotech, Actavis, Adnexus, Adventrx Pharmaceuticals, Ambit, Amgen, Ariad Pharmaceuticals, Arresto Biosciences, Astellas, AstraZeneca, AVEO, Bayer, Bind Bio, Biogen Idec, BiPar, Calando, Calistoga, Chemokine, Curis, Daiichi Sankyo, Dendreon, Dicerna, Eli Lilly, EMTx, Endo, Enzon, Exelixis, Five Prime, Genentech, Genta, Geron, Glaxo Smith Kline, HUYA Bioscience, Intellikine, Johnson & Johnson, Merck, MethylGene, Micromet, Myriad, Nektar, Nerviano, Neumedicines, Onyx, Otsuka, Pfizer, ProNai, Regeneron, Sanofi-Aventis, Santaris, Schering Plough, Seattle Genetics, Semophore, Spectrum, Supergen, Symphogen, Vaccinex, and Veeda. Scot C. Remick has received a clinical research grant from MediciNova Inc.

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Authors and Affiliations

  1. Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA

    Alejandro D. Ricart, John Sarantopoulos, Gerardo Medina & Anthony W. Tolcher

  2. VirtualScopics, Inc., Rochester, NY, USA

    Edward A. Ashton

  3. Developmental Therapeutics Program, CASE Comprehensive Cancer Center, Cleveland, OH, USA

    Matthew M. Cooney, Angela Zambito & Scot C. Remick

  4. Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA

    Joanna M. Brell

  5. MediciNova, Inc., San Diego, CA, USA

    Maria A. Feldman, Kale E. Ruby, Kazuko Matsuda & Mark S. Munsey

  6. Oncology Development, Pfizer Inc., 10646, Science Center Drive, San Diego, CA, 92121, USA

    Alejandro D. Ricart

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  1. Alejandro D. Ricart
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  2. Edward A. Ashton
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Corresponding author

Correspondence to Alejandro D. Ricart.

Additional information

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2–6, 2006, Atlanta, GA and at the 18th European Organization for Research and Treatment of Cancer-National Cancer Institute-American Association for Cancer Research Symposium on Molecular Targets and Cancer Therapeutics, November 7–10, 2006, Prague, Czech Republic.

Appendix

Appendix

See Table 6.

Table 6 Validated LC–MS/MS method summary for the simultaneous quantitation of MN-029, MN-022, and N-acetyl MN-022 in human plasma
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Ricart, A.D., Ashton, E.A., Cooney, M.M. et al. A phase I study of MN-029 (denibulin), a novel vascular-disrupting agent, in patients with advanced solid tumors. Cancer Chemother Pharmacol 68, 959–970 (2011). https://doi.org/10.1007/s00280-011-1565-4

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