Skip to main content
Erschienen in: Investigational New Drugs 4/2010

01.08.2010 | PHASE I STUDIES

A dose escalation, safety, and tolerability study of MN-029 in patients with advanced solid tumors

verfasst von: Anne M. Traynor, Michael S. Gordon, Dona Alberti, David S. Mendelson, Mark S. Munsey, George Wilding, Richard E. Gammans, William L. Read

Erschienen in: Investigational New Drugs | Ausgabe 4/2010

Einloggen, um Zugang zu erhalten

Summary

Purpose: To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and tolerability of MN-209, a novel vascular disrupting agent, in patients with advanced solid tumors. Study Design: MN-029 was administered weekly for three consecutive weeks out of four; two cycles were planned. Dose escalation proceeded by 100% per toxicity criteria. Intra-patient dose escalation was permitted. Results: Twenty patients received a total of 151 infusions of MN-029. No DLTs or grade 4 toxicities occurred. The most common adverse events were nausea, vomiting, arthralgias, and headache. One patient developed acute substernal chest pain 4 days after his first dose of MN-029 and was removed from the study. An MTD was not determined. The recommended phase II dose was identified as 180 mg/m2/week. One patient with advanced pancreatic cancer attained a partial response lasting 10 weeks. Conclusions: MN-029 was well tolerated in this schedule. Further development of this class of agents is warranted, especially in combination with other anti-cancer treatments.
Literatur
6.
Zurück zum Zitat Rustin GJ, Galbraith SM, Anderson H, Stratford M, Folkes LK, Sena L, Gumbrell L, Price PM (2003) Phase I clinical trial of weekly combretastatin A4 phosphate: clinical and pharmacokinetic results. J Clin Oncol 21:2815–2822. doi:10.1200/JCO.2003.05.185 CrossRefPubMed Rustin GJ, Galbraith SM, Anderson H, Stratford M, Folkes LK, Sena L, Gumbrell L, Price PM (2003) Phase I clinical trial of weekly combretastatin A4 phosphate: clinical and pharmacokinetic results. J Clin Oncol 21:2815–2822. doi:10.​1200/​JCO.​2003.​05.​185 CrossRefPubMed
7.
Zurück zum Zitat Stevenson JP, Rosen M, Sun W, Gallagher M, Haller DG, Vaughn D, Giantonio B, Zimmer R, Petros WP, Stratford M, Chaplin D, Young SL, Schnall M, O’Dwyer PJ (2003) Phase I trial of the antivascular agent combretastatin A4 phosphate on a 5-day schedule to patients with cancer: magnetic resonance imaging evidence for altered tumor blood flow. J Clin Oncol 21:4428–4438. doi:10.1200/JCO.2003.12.986 CrossRefPubMed Stevenson JP, Rosen M, Sun W, Gallagher M, Haller DG, Vaughn D, Giantonio B, Zimmer R, Petros WP, Stratford M, Chaplin D, Young SL, Schnall M, O’Dwyer PJ (2003) Phase I trial of the antivascular agent combretastatin A4 phosphate on a 5-day schedule to patients with cancer: magnetic resonance imaging evidence for altered tumor blood flow. J Clin Oncol 21:4428–4438. doi:10.​1200/​JCO.​2003.​12.​986 CrossRefPubMed
8.
Zurück zum Zitat Dowlati A, Robertson K, Cooney M, Petros WP, Stratford M, Jesberger J, Rafie N, Overmoyer B, Makkar V, Stambler B, Taylor A, Waas J, Lewin JS, McCrae KR, Remick SC (2002) A phase I pharmacokinetic and translational study of the novel vascular targeting agent combretastatin a-4 phosphate on a single-dose intravenous schedule in patients with advanced cancer. Cancer Res 62:3408–3416PubMed Dowlati A, Robertson K, Cooney M, Petros WP, Stratford M, Jesberger J, Rafie N, Overmoyer B, Makkar V, Stambler B, Taylor A, Waas J, Lewin JS, McCrae KR, Remick SC (2002) A phase I pharmacokinetic and translational study of the novel vascular targeting agent combretastatin a-4 phosphate on a single-dose intravenous schedule in patients with advanced cancer. Cancer Res 62:3408–3416PubMed
9.
Zurück zum Zitat LoRusso PM, Gadgeel SM, Wozniak A, Barge AJ, Jones HK, DelProposto ZS, DeLuca PA, Evelhoch JL, Boerner SA, Wheeler C (2008) Phase I clinical evaluation of ZD6126, a novel vascular-targeting agent, in patients with solid tumors. Invest New Drugs 26:159–167. doi:10.1007/s10637-008-9112-9 CrossRefPubMed LoRusso PM, Gadgeel SM, Wozniak A, Barge AJ, Jones HK, DelProposto ZS, DeLuca PA, Evelhoch JL, Boerner SA, Wheeler C (2008) Phase I clinical evaluation of ZD6126, a novel vascular-targeting agent, in patients with solid tumors. Invest New Drugs 26:159–167. doi:10.​1007/​s10637-008-9112-9 CrossRefPubMed
10.
Zurück zum Zitat Beerepoot LV, Radema SA, Witteveen EO, Thomas T, Wheeler C, Kempin S, Voest EE (2006) Phase I clinical evaluation of weekly administration of the novel vascular-targeting agent, ZD6126, in patients with solid tumors. J Clin Oncol 24:1491–1498. doi:10.1200/JCO.2005.02.7458 CrossRefPubMed Beerepoot LV, Radema SA, Witteveen EO, Thomas T, Wheeler C, Kempin S, Voest EE (2006) Phase I clinical evaluation of weekly administration of the novel vascular-targeting agent, ZD6126, in patients with solid tumors. J Clin Oncol 24:1491–1498. doi:10.​1200/​JCO.​2005.​02.​7458 CrossRefPubMed
11.
Zurück zum Zitat van Heeckeren WJ, Bhakta S, Ortiz J, Duerk J, Cooney MM, Dowlati A, McCrae K, Remick SC (2006) Promise of new vascular-disrupting agents balanced with cardiac toxicity: is it time for oncologists to get to know their cardiologists? J Clin Oncol 24:1485–1488. doi:10.1200/JCO.2005.04.8801 CrossRefPubMed van Heeckeren WJ, Bhakta S, Ortiz J, Duerk J, Cooney MM, Dowlati A, McCrae K, Remick SC (2006) Promise of new vascular-disrupting agents balanced with cardiac toxicity: is it time for oncologists to get to know their cardiologists? J Clin Oncol 24:1485–1488. doi:10.​1200/​JCO.​2005.​04.​8801 CrossRefPubMed
12.
Zurück zum Zitat Shi W, Siemann DW (2005) Preclinical studies of the novel vascular disrupting agent MN-029. Anticancer Res 25:3899–3904PubMed Shi W, Siemann DW (2005) Preclinical studies of the novel vascular disrupting agent MN-029. Anticancer Res 25:3899–3904PubMed
13.
Zurück zum Zitat Ricart AD, Cooney M, Sarantopoulos J, Brell J, Locke KW, Gammans RE, Medina G, Zambito A, Tolcher AW, Remick SC (2006) A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of MN-029, a novel vascular disrupting agent (VDA), in patients (pts) with advanced solid tumors. J Clin Oncol 24:June 20 Suppl; abstr 3096 Ricart AD, Cooney M, Sarantopoulos J, Brell J, Locke KW, Gammans RE, Medina G, Zambito A, Tolcher AW, Remick SC (2006) A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of MN-029, a novel vascular disrupting agent (VDA), in patients (pts) with advanced solid tumors. J Clin Oncol 24:June 20 Suppl; abstr 3096
14.
Zurück zum Zitat Gould S, Westwood FR, Curwen JO, Ashton SE, Roberts DW, Lovick SC, Ryan AJ (2007) Effect of pretreatment with atenolol and nifedipine on ZD6126-induced cardiac toxicity in rats. J Natl Cancer Inst 99:1724–1728. doi:10.1093/jnci/djm202 CrossRefPubMed Gould S, Westwood FR, Curwen JO, Ashton SE, Roberts DW, Lovick SC, Ryan AJ (2007) Effect of pretreatment with atenolol and nifedipine on ZD6126-induced cardiac toxicity in rats. J Natl Cancer Inst 99:1724–1728. doi:10.​1093/​jnci/​djm202 CrossRefPubMed
16.
Zurück zum Zitat Rini BI, Schiller JH, Fruehauf JP, Cohen EE, Tarazi JC, Rosbrook B, Ricart AD, Olszanski S, Spano KJ (2008) Association of diastolic blood pressure (dBP) ≥ 90 mmHg with overall survival (OS) in patients treated with axitinib (AG- 013736). J Clin Oncol 26:May 20 suppl; abstr 3543 Rini BI, Schiller JH, Fruehauf JP, Cohen EE, Tarazi JC, Rosbrook B, Ricart AD, Olszanski S, Spano KJ (2008) Association of diastolic blood pressure (dBP) ≥ 90 mmHg with overall survival (OS) in patients treated with axitinib (AG- 013736). J Clin Oncol 26:May 20 suppl; abstr 3543
18.
Zurück zum Zitat Goto H, Yano S, Matsumori Y, Ogawa H, Blakey DC, Sone S (2004) Sensitization of tumor-associated endothelial cell apoptosis by the novel vascular-targeting agent ZD6126 in combination with cisplatin. Clin Cancer Res 10:7671–7676. doi:10.1158/1078-0432.CCR-04-1171 CrossRefPubMed Goto H, Yano S, Matsumori Y, Ogawa H, Blakey DC, Sone S (2004) Sensitization of tumor-associated endothelial cell apoptosis by the novel vascular-targeting agent ZD6126 in combination with cisplatin. Clin Cancer Res 10:7671–7676. doi:10.​1158/​1078-0432.​CCR-04-1171 CrossRefPubMed
19.
Zurück zum Zitat Ng QS, Goh V, Carnell D, Meer K, Padhani AR, Saunders MI, Hoskin PJ (2007) Tumor antivascular effects of radiotherapy combined with combretastatin a4 phosphate in human non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 67:1375–1380. doi:10.1016/j.ijrobp. 2006.11.028 PubMed Ng QS, Goh V, Carnell D, Meer K, Padhani AR, Saunders MI, Hoskin PJ (2007) Tumor antivascular effects of radiotherapy combined with combretastatin a4 phosphate in human non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 67:1375–1380. doi:10.​1016/​j.​ijrobp.​ 2006.​11.​028 PubMed
21.
Zurück zum Zitat O’Connor JP, Jackson A, Asselin MC, Buckley DL, Parker GJ, Jayson GC (2008) Quantitative imaging biomarkers in the clinical development of targeted therapeutics: current and future perspectives. Lancet Oncol 9:766–776. doi:10.1016/S1470-2045(08) 70196-7 CrossRefPubMed O’Connor JP, Jackson A, Asselin MC, Buckley DL, Parker GJ, Jayson GC (2008) Quantitative imaging biomarkers in the clinical development of targeted therapeutics: current and future perspectives. Lancet Oncol 9:766–776. doi:10.​1016/​S1470-2045(08) 70196-7 CrossRefPubMed
22.
Zurück zum Zitat Dowlati A, Gray R, Sandler AB, Schiller JH, Johnson DH (2008) Cell adhesion molecules, vascular endothelial growth factor, and basic fibroblast growth factor in patients with non-small cell lung cancer treated with chemotherapy with or without bevacizumab—an Eastern Cooperative Oncology Group Study. Clin Cancer Res 14:1407–1412. doi:10.1158/1078-0432.CCR-07-1154 CrossRefPubMed Dowlati A, Gray R, Sandler AB, Schiller JH, Johnson DH (2008) Cell adhesion molecules, vascular endothelial growth factor, and basic fibroblast growth factor in patients with non-small cell lung cancer treated with chemotherapy with or without bevacizumab—an Eastern Cooperative Oncology Group Study. Clin Cancer Res 14:1407–1412. doi:10.​1158/​1078-0432.​CCR-07-1154 CrossRefPubMed
Metadaten
Titel
A dose escalation, safety, and tolerability study of MN-029 in patients with advanced solid tumors
verfasst von
Anne M. Traynor
Michael S. Gordon
Dona Alberti
David S. Mendelson
Mark S. Munsey
George Wilding
Richard E. Gammans
William L. Read
Publikationsdatum
01.08.2010
Verlag
Springer US
Erschienen in
Investigational New Drugs / Ausgabe 4/2010
Print ISSN: 0167-6997
Elektronische ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-009-9264-2

Weitere Artikel der Ausgabe 4/2010

Investigational New Drugs 4/2010 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.