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

Alejandro D. Ricart, Edward A. Ashton, Matthew M. Cooney, John Sarantopoulos, Joanna M. Brell, Maria A. Feldman, Kale E. Ruby, Kazuko Matsuda, Mark S. Munsey, Gerardo Medina, Angela Zambito, Anthony W. Tolcher, Scot C. Remick

Research output: Contribution to journalArticle

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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/m 2) 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/m 2 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/m 2, 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/m 2.

Original languageEnglish (US)
Pages (from-to)959-970
Number of pages12
JournalCancer Chemotherapy and Pharmacology
Volume68
Issue number4
DOIs
StatePublished - Oct 2011

Fingerprint

Proxy
Blood Vessels
Tumors
Neoplasms
Toxicity
Pharmacokinetics
Stomatitis
Maximum Tolerated Dose
denibulin
Transient Ischemic Attack
Alopecia
Endothelial cells
Anorexia
Cytoskeleton
Titration
Microtubules
Nausea
Area Under Curve
Vomiting
Fatigue

Keywords

  • MN-029
  • Phase I
  • Vascular-disrupting agent

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

A phase i study of MN-029 (denibulin), a novel vascular-disrupting agent, in patients with advanced solid tumors. / Ricart, Alejandro D.; Ashton, Edward A.; Cooney, Matthew M.; Sarantopoulos, John; Brell, Joanna M.; Feldman, Maria A.; Ruby, Kale E.; Matsuda, Kazuko; Munsey, Mark S.; Medina, Gerardo; Zambito, Angela; Tolcher, Anthony W.; Remick, Scot C.

In: Cancer Chemotherapy and Pharmacology, Vol. 68, No. 4, 10.2011, p. 959-970.

Research output: Contribution to journalArticle

Ricart, AD, Ashton, EA, Cooney, MM, Sarantopoulos, J, Brell, JM, Feldman, MA, Ruby, KE, Matsuda, K, Munsey, MS, Medina, G, Zambito, A, Tolcher, AW & Remick, SC 2011, 'A phase i study of MN-029 (denibulin), a novel vascular-disrupting agent, in patients with advanced solid tumors', Cancer Chemotherapy and Pharmacology, vol. 68, no. 4, pp. 959-970. https://doi.org/10.1007/s00280-011-1565-4
Ricart, Alejandro D. ; Ashton, Edward A. ; Cooney, Matthew M. ; Sarantopoulos, John ; Brell, Joanna M. ; Feldman, Maria A. ; Ruby, Kale E. ; Matsuda, Kazuko ; Munsey, Mark S. ; Medina, Gerardo ; Zambito, Angela ; Tolcher, Anthony W. ; Remick, Scot C. / A phase i study of MN-029 (denibulin), a novel vascular-disrupting agent, in patients with advanced solid tumors. In: Cancer Chemotherapy and Pharmacology. 2011 ; Vol. 68, No. 4. pp. 959-970.
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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/m 2) 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/m 2 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/m 2, 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/m 2.",
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AU - Sarantopoulos, John

AU - Brell, Joanna M.

AU - Feldman, Maria A.

AU - Ruby, Kale E.

AU - Matsuda, Kazuko

AU - Munsey, Mark S.

AU - Medina, Gerardo

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AU - Remick, Scot C.

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