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Realizing the Full Potential of Vascular Targeted Therapy In Orphan Oncology Indications

Publications

The following select publications are from the peer-reviewed literature and discuss the scientific data surrounding the use of VDAs in various oncology indications.

CA4P (combretastatin A4-phosphate/fosbretabulin)

Review:

Siemann DW, Chaplin DJ, Walicke PA. A review and update of the current status of the vasculature-disabling agent combretastatin A4-phosphate (CA4P). Expert Opin Investig Drugs. 2009;18(2):189-197.

Clinical—Phase 2/3 Studies:

Garon EB, Kabbinavar FF, Neidhart JA, Neidhart JD, Gabrail NY, Oliveira MR, et al. Randomized phase II trial of a tumor vascular disrupting agent fosbretabulin tromethamine (CA4P) with carboplatin (C), paclitaxel (P), and bevacizumab (B) in stage IIIb/IV nonsquamous non-small cell lung cancer (NSCLC): The FALCON trial [abstract]. J Clin Oncol. 2010;28:15s (suppl; abstr 7587).

Libutti SK, Anthony L, Sosa JA, Kunz P, Thomas J, Cruikshank SA, et al. Phase 2 study (OX4218s) of fosbretabulin tromethamine (CA4P) for the treatment of well-differentiated, low-to-intermediate-grade unresectable, recurrent or metastatic pancreatic or gastrointestinal neuroendocrine tumors/carcinoid (PNETs or GI-NETs) with elevated biomarkers [poster]. NANETS Annual Symposium October 15-17, 2015 (Austin, Texas).

Monk BJ, Sill MW, Walker JL, Darus CJ, Sutton G, Tewari KS, et al. Randomized phase II evaluation of bevacizumab versus bevacizumab plus fosbretabulin in recurrent ovarian, tubal, or peritoneal carcinoma: an NRG oncology/gynecologic oncology group studyJ Clin Oncol. 2016;34(19):2279-86.

Sosa JA, Elisei R, Jarzab B, Balkissoon J, Lu SP, Bal C, et al. Randomized safety and efficacy study of fosbretabulin with paclitaxel/carboplatin against anaplastic thyroid carcinoma. Thyroid. 2014;24(2):232-240.

Zweifel M, Jayson GC, Reed NS, Osborne R, Hassan B, Ledermann J, et al. Phase II trial of combretastatin A4 phosphate, carboplatin, and paclitaxel in patients with platinum-resistant ovarian cancer. Ann Oncol. 2011;22(9):2036-2041.

Clinical—Phase 1 Studies:

Anderson HL, Yap JT, Miller MP, Robbins A, Jones T, Price PM. Assessment of pharmacodynamic vascular response in a phase I trial of combretastatin A4 phosphate. J Clin Oncol. 2003;21(15):2823-2830.

Cooney MM, Radivoyevitch T, Dowlati A, Overmoyer B, Levitan N, Robertson K, et al. Cardiovascular safety profile of combretastatin A4 phosphate in a single-dose phase I study in patients with advanced cancer. Clin Cancer Res. 2004;10(1 Pt 1):96-100.

Dowlati A, Robertson K, Cooney M, Petros WP, Stratford M, Jesberger J, et al. 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. 2002;62(12):3408-3416.

Nathan P, Zweifel M, Padhani AR, Koh DM, Ng M, Collins DJ, et al. Phase I trial of combretastatin A4 phosphate (CA4P) in combination with bevacizumab in patients with advanced cancer. Clin Cancer Res. 2012;18(12):3428-3439.

Rustin GJ, Galbraith SM, Anderson H, Stratford M, Folkes LK, Sena L, et al. Phase I clinical trial of weekly combretastatin A4 phosphate: clinical and pharmacokinetic results. J Clin Oncol. 2003;21(15):2815-2822.

Rustin GJ, Shreeves G, Nathan PD, Gaya A, Ganesan TS, Wang D, et al. A phase Ib trial of CA4P (combretastatin A-4 phosphate), carboplatin, and paclitaxel in patients with advanced cancer. Br J Cancer. 2010;102(9):1355-1360.

Stevenson JP, Rosen M, Sun W, Gallagher M, Haller DG, Vaughn D, et al. 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. 2003;21(23):4428-4438.

Preclinical:

Dark GG, Hill SA, Prise VE, Tozer GM, Pettit GR, Chaplin DJ. Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature. Cancer Res. 1997;57(10):1829-1834.

Landuyt W, Verdoes O, Darius DO, Drijkoningen M, Nuyts S, Theys J, et al. Vascular targeting of solid tumours: a major ‘inverse’ volume-response relationship following combretastatin A-4 phosphate treatment of rat rhabdomyosarcomas. Eur J Cancer. 2000;36(14):1833-1843.

Siemann DW, Shi W. Dual targeting of tumor vasculature: combining Avastin and vascular disrupting agents (CA4P or OXi4503). Anticancer Res. 2008;28(4B):2027-2031.

Tozer GM, Prise VE, Wilson J, Locke RJ, Vojnovic B, Stratford MR, et al. Combretastatin A-4 phosphate as a tumor vascular-targeting agent: early effects in tumors and normal tissues. Cancer Res. 1999;59(7):1626-1634.

Vincent L, Kermani P, Young LM, Cheng J, Zhang F, Shido K, et al. Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelial-cadherin signaling. J Clin Invest. 2005;115(11):2992-3006.

OXi4503 (Combretastatin A1-Phosphate/CA1P)

Clinical—Phase 1 Studies:

Bosse RC, Wasserstrom B, Wise E, Meacham A, Cogle CR. Chemosensitizing leukemia by targeting the leukemia microenvironment with vascular disrupting combretastatins [abstract]. Blood. 2014;124(21):2315.

Cummings J, Zweifel M, Smith N, Ross P, Peters J, Rustin G, et al. Evaluation of cell death mechanisms induced by the vascular disrupting agent OXi4503 during a phase I clinical trialBr J Cancer. 2012;106(11):1766-1771.

Patterson DM, Zweifel M, Middleton MR, Price PM, Folkes LK, Stratford MR, et al. Phase I clinical and pharmacokinetic evaluation of the vascular-disrupting agent OXi4503 in patients with advanced solid tumors. Clin Cancer Res. 2012;18(5):1415-1425.

Turner D, Gonzalez A, Pettiford L, Meacham A, Wise E, Bosse RC, et al. A phase I study of the vascular disrupting combretastatin, OXi4503, in patients with relapsed and refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) [abstract]. Blood. 2013;122(21):1463.

Preclinical:

Benezra M, Phillips E, Tilki D, Ding BS, Butler J, Dobrenkov K, et al. Serial monitoring of human systemic and xenograft models of leukemia using a novel vascular disrupting agent. Leukemia. 2012;26(8):1771-1778.

Bosse RC, Wasserstrom B, Meacham A, Wise E, Drusbosky L, Walter GA, et al. Chemosensitizing AML cells by targeting bone marrow endothelial cells. Exp Hematol. 2016;44(5):363-377.

Hill SA, Toze GM, Pettit GR, Chaplin DJ. Preclinical evaluation of the antitumour activity of the novel vascular targeting agent Oxi 4503. Anticancer Res. 2002;22(3):1453-1458.

Hua J, Sheng Y, Pinney KG, Garner CM, Kane RR, Prezioso JA, et al. Oxi4503, a novel vascular targeting agent: effects on blood flow and antitumor activity in comparison to combretastatin A-4 phosphate. Anticancer Res. 2003;23(2B):1433-1440.

Madlambayan GJ, Meacham AM, Hosaka K, Mir S, Jorgensen M, Scott EW, et al. Leukemia regression by vascular disruption and antiangiogenic therapy. Blood. 2010;116(9):1539-1547.

Siemann DW, Shi W. Dual targeting of tumor vasculature: combining Avastin and vascular disrupting agents (CA4P or OXi4503). Anticancer Res. 2008;28(4B):2027-2031.

Siim B, Walicke P, Chaplin D. Activity of the vascular disrupting agent Oxi4503 against an acute myelogenous leukemia xenograft model [abstract]. Cancer Res. 2009;69:5640.