Clinical aspects of a phase I trial of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent

M B Jameson, P I Thompson, B C Baguley, B D Evans, V J Harvey, D J Porter, M R McCrystal, M Small, K Bellenger, L Gumbrell, G W Halbert, P Kestell, Phase I/II Trials Committee of Cancer Research UK, M B Jameson, P I Thompson, B C Baguley, B D Evans, V J Harvey, D J Porter, M R McCrystal, M Small, K Bellenger, L Gumbrell, G W Halbert, P Kestell, Phase I/II Trials Committee of Cancer Research UK

Abstract

The antitumour action of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is mediated through tumour-selective antivascular effects and cytokine induction. This clinical phase I trial was conducted to examine its toxicity, maximum tolerated dose, pharmacokinetics (PK) and pharmacodynamics (PD). A secondary objective was to assess its antitumour efficacy. DMXAA was administered every 3 weeks as a 20-min i.v. infusion. Dose escalation initially followed a modified Fibonacci schema but was also guided by PK and toxicity. A total of 63 patients received 161 courses of DMXAA over 19 dose levels ranging from 6 to 4900 mg m(-2). DMXAA was well tolerated at lower doses and no drug-related myelosuppression was seen. Rapidly reversible dose-limiting toxicities were observed at 4900 mg m(-2), including confusion, tremor, slurred speech, visual disturbance, anxiety, urinary incontinence and possible left ventricular failure. Transient prolongation of the corrected cardiac QT interval was seen in 13 patients evaluated at doses of 2000 mg m(-2) and above. A patient with metastatic cervical carcinoma achieved an unconfirmed partial response at 1100 mg m(-2), progressing after eight courses. The results of PK and PD studies are reported separately. DMXAA has antitumour activity at well-tolerated doses.

Figures

Figure 1
Figure 1
Structure of DMXAA.
Figure 2
Figure 2
Change in corrected QT interval after DMXAA administration at 3700 mg m−2.
Figure 3
Figure 3
Tumour response in a patient with metastatic squamous carcinoma of cervix treated with DMXAA 1100 mg m−2. Tumour size was calculated as the sum of the products of bidimensional measurements of three clinically measurable metastatic neck nodes.

References

    1. Algire GH, Legallais FY, Park HD (1947) Vascular reactions of normal and malignant tissues in vivo. II. The vascular reaction of normal and neoplastic tissues of mice to a bacterial polysaccharide from Serratia marcescens (Bacillus prodigiosus) culture filtrates. J Natl Cancer Inst 8: 53–62
    1. Anderson H, Jap J, Price P (2000) Measurement of tumour and normal tissue (NT) perfusion by positron emission tomography (PET) in the evaluation of antivascular therapy: results in the phase I study of combretastatin A4 phosphate (CA4P). Proc Annu Meet Am Soc Clin Oncol 19: 179
    1. Aytemir K, Maarouf N, Gallagher MM, Yap YG, Waktare JE, Malik M (1999) Comparison of formulae for heart rate correction of QT interval in exercise electrocardiograms. Pacing Clin Electrophysiol 22: 1397–1401
    1. Baguley BC, Zhuang L, Kestell P (1997) Increased plasma serotonin following treatment with flavone-8-acetic acid, 5,6-dimethylxanthenone-4-acetic acid, vinblastine, and colchicine–relation to vascular effects. Oncol Res 9: 55–60
    1. Bibby MC (1991) Flavone acetic acid–an interesting novel therapeutic agent or just another disappointment. Br J Cancer 63: 3–5
    1. Brown TM, Skop BP, Mareth TR (1996) Pathophysiology and management of the serotonin syndrome. Ann Pharmacother 30: 527–533
    1. Cao Z, Joseph WR, Browne WL, Mountjoy KG, Palmer BD, Baguley BC, Ching LM (1999) Thalidomide increases both intra-tumoural tumour necrosis factor-alpha production and anti-tumour activity in response to 5,6-dimethylxanthenone-4-acetic acid. Br J Cancer 80: 716–723
    1. Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 25: 3666–3670
    1. Chaplin DJ, Dougherty GJ (1999) Tumour vasculature as a target for cancer therapy. Br J Cancer 80(Suppl 1): 57–64
    1. Ching LM, Baguley BC (1987) Induction of natural killer cell activity by the antitumour compound flavone acetic acid (NSC 347 512). Eur J Cancer Clin Oncol 23: 1047–1050
    1. Ching LM, Joseph WR, Crosier KE, Baguley BC (1994) Induction of tumor necrosis factor-alpha messenger RNA in human and murine cells by the flavone acetic acid analogue 5,6-dimethylxanthenone-4-acetic acid (NSC 640488). Cancer Res 54: 870–872
    1. Ching LM, Wilson WR, Baguley BC (1999) Inhibition of tumour blood flow, In Methods in Molecular Medicine, Vol. 25, Drug Targeting, Francis, GE, Delgado, C (eds), Chapter 9, pp 1–26. Totowa, NJ: Humana Press Inc.
    1. Cliffe S, Taylor ML, Rutland M, Baguley BC, Hill RP, Wilson WR (1994) Combining bioreductive drugs (SR 4233 or SN 23862) with the vasoactive agents flavone acetic acid or 5,6-dimethylxanthenone acetic acid. Int J Radiat Oncol Biol Phys 29: 373–377
    1. Coley-Nauts H, Fowler GA, Bogatko FH (1953) A review of the influence of bacterial infection and bacterial products (Coley's toxins) on malignant tumours in man. Acta Med Scand 145: 5–97
    1. Committee for Proprietary Medicinal Products (1997) Points to consider: the assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products, CPMP/986/96:1-6, URL:
    1. Council on Pharmacy and Chemistry (1934) Erysipelas and prodigiosus toxins (Coley). JAMA 103: 1067–1069
    1. Davis HP, Newlands ES, Allain T, Hegde U (1988) Immune thrombocytopenia caused by flavone-8-acetic acid. Lancet 1(8582): 412
    1. DeVore RF, Hellerqvist CG, Wakefield GB, Wamil BD, Thurman GB, Minton PA, Sundell HW, Yan HP, Carter CE, Wang YF, York GE, Zhang MH, Johnson DH (1997) Phase I study of the antineovascularization drug CM101. Clin Cancer Res 3: 365–372
    1. 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: 3408–3416
    1. Eggermont AM, ten Hagen TL (2001) Isolated limb perfusion for extremity soft-tissue sarcomas, in-transit metastases, and other unresectable tumors: credits, debits, and future perspectives. Curr Oncol Rep 3: 359–367
    1. Finlay GJ, Smith GP, Fray LM, Baguley BC (1988) Effect of flavone acetic acid on Lewis lung carcinoma: evidence for an indirect effect. J Natl Cancer Inst 80: 241–245
    1. Galbraith SM, Lodge MA, Taylor NJ, Maxwell R, Tozer GM, Prise V, Wilson I, Sena L, Robbins A, Padhani A, Rustin G (2001) Combretastatin A4 phosphate (CA4P) reduces tumor blood flow in animals and man, demonstrated by MRI. Proc Annu Meet Am Soc Clin Oncol 20: 278a
    1. Galbraith SM, Rustin GJ, Lodge MA, Taylor NJ, Stirling JJ, Jameson M, Thompson P, Hough D, Gumbrell L, Padhani AR (2002) Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging. J Clin Oncol 20: 3826–3840
    1. Griggs J, Hesketh R, Smith GA, Brindle KM, Metcalfe JC, Thomas GA, Williams ED (2001) Combretastatin-A4 disrupts neovascular development in non-neoplastic tissue. Br J Cancer 84: 832–835
    1. Havlin KA, Kuhn JG, Craig JB, Boldt DH, Weiss GR, Koeller J, Harman G, Schwartz R, Clark GN, Von Hoff DD (1991) Phase I clinical and pharmacokinetic trial of flavone acetic acid. J Natl Cancer Inst 83: 124–128
    1. Horsman MR, Murata R, Overgaard J (1999) Improving conventional cancer therapy by targeting tumour vasculature. Br J Cancer 80: 90 (P247)
    1. Kanwar JR, Kanwar RK, Pandey S, Ching LM, Krissansen GW (2001) Vascular attack by 5,6-dimethylxanthenone-4-acetic acid combined with B7.1 (CD80)-mediated immunotherapy overcomes immune resistance and leads to the eradication of large tumors and multiple tumor foci. Cancer Res 61: 1948–1956
    1. Kaye SB, Clavel M, Dodion P, Monfardini S, ten Bokkel Huinink WW, Wagener DT, Gundersen S, Stoter G, Smith J, Renard J, Vanglabbeke M, Cavalli F (1990) Phase-II trials with flavone acetic acid (NSC-347512, LM975) in patients with advanced carcinoma of the breast, colon, head and neck and melanoma. Invest New Drugs 8: S95–S99
    1. Kerr DJ, Kaye SB (1989) Flavone acetic acid–preclinical and clinical activity. Eur J Cancer Clin Oncol 25: 1271–1272
    1. Kerr DJ, Kaye SB, Cassidy J, Bradley C, Rankin E, Adams L, Setanoians A, Young T, Forrest G, Soukop M, Clavel M (1987) Phase I and pharmacokinetic study of flavone acetic acid. Cancer Res 47: 6776–6781
    1. Kestell P, Zhao L, Jameson MB, Stratford MR, Folkes LK, Baguley BC (2001) Measurement of plasma 5-hydroxyindoleacetic acid as a possible clinical surrogate marker for the action of antivascular agents. Clin Chim Acta 314: 159–166
    1. Kligfield P, Lax KG, Okin PM (1996) QT interval–heart rate relation during exercise in normal men and women: definition by linear regression analysis. J Am Coll Cardiol 28: 1547–1555
    1. Lash CJ, Li AE, Rutland M, Baguley BC, Zwi LJ, Wilson WR (1998) Enhancement of the anti-tumour effects of the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by combination with 5-hydroxytryptamine and bioreductive drugs. Br J Cancer 78: 439–445
    1. Lejeune FJ, Ruegg C, Lienard D (1998) Clinical applications of TNF-alpha in cancer. Curr Opin Immunol 10: 573–580
    1. Lew YS, Brown SL, Griffin RJ, Song CW, Kim JH (1999) Arsenic trioxide causes selective necrosis in solid murine tumors by vascular shutdown. Cancer Res 59: 6033–6037
    1. Marmor MF, Kessler R (1999) Sildenafil (Viagra) and ophthalmology. Surv Ophthalmol 44: 153–162
    1. Murata R, Overgaard J, Horsman MR (2001) Comparative effects of combretastatin A-4 disodium phosphate and 5,6-dimethylxanthenone-4-acetic acid on blood perfusion in a murine tumour and normal tissues. Int J Radiat Biol 77: 195–204
    1. O'Dwyer PJ, Shoemaker D, Zaharko S, Grieshaber C, Plowman J, Corbett T, Valeriote F, King SA, Cradock J, Hoth F, Leyland-Jones B (1987) Flavone acetic acid (LM 975, NSC 347512), a novel antitumor agent. Cancer Chemother Pharmacol 19: 6–10
    1. Old LJ (1985) Tumor necrosis factor (TNF). Science 230: 630–632
    1. Olver IN, Webster LK, Bishop JF, Stokes KH (1992) A phase I and pharmacokinetic study of 12-h infusion of flavone acetic acid. Cancer Chemother Pharmacol 29: 354–360
    1. Otto F, Schmid P, Mackensen A, Wehr U, Seiz A, Braun M, Galanos C, Mertelsmann R, Engelhardt R (1996) Phase II trial of intravenous endotoxin in patients with colorectal and non-small cell lung cancer. Eur J Cancer 32A: 1712–1718
    1. Pedley RB, Boden JA, Boden R, Boxer GM, Flynn AA, Keep PA, Begent RH (1996) Ablation of colorectal xenografts with combined radioimmunotherapy and tumor blood flow-modifying agents. Cancer Res 56: 3293–3300
    1. Pedley RB, Sharma SK, Boxer GM, Boden R, Stribbling SM, Davies L, Springer CJ, Begent RH (1999) Enhancement of antibody-directed enzyme prodrug therapy in colorectal xenografts by an antivascular agent. Cancer Res 59: 3998–4003
    1. Philpott M, Baguley BC, Ching LM (1995) Induction of tumour necrosis factor-α by single and repeated doses of the antitumour agent 5,6-dimethylxanthenone-4-acetic acid. Cancer Chemother Pharmacol 36: 143–148
    1. Philpott M, Joseph WR, Crosier KE, Baguley BC, Ching LM (1997) Production of tumour necrosis factor-alpha by cultured human peripheral blood leucocytes in response to the anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid (NSC 640488). Br J Cancer 76: 1586–1591
    1. Pruijn FB, van Daalen M, Holford NH, Wilson WR (1997) Mechanisms of enhancement of the antitumour activity of melphalan by the tumour-blood-flow inhibitor 5,6-dimethylxanthenone-4-acetic acid. Cancer Chemother Pharmacol 39: 541–546
    1. Rewcastle GW, Atwell GJ, Li ZA, Baguley BC, Denny WA (1991) Potential antitumor agents. 61. Structure–activity relationships for in vivo colon 38 activity among disubstituted 9-oxo-9H-xanthene-4-acetic acids. J Med Chem 34: 217–222
    1. Rewcastle GW, Kestell P, Baguley BC, Denny WA (1990) Light-induced breakdown of flavone acetic acid and xanthenone analogues in solution. J Natl Cancer Inst 82: 528–529
    1. Rubin J, Ames M, Schutt AJ, Nichols WL, Bowie EJ, Kovach JS (1987) Flavone-8-acetic acid inhibits ristocetin-induced platelet agglutination and prolongs bleeding time. Lancet 2(8567): 1081.
    1. Ruegg C, Yilmaz A, Bieler G, Bamat J, Chaubert P, Lejeune FJ (1998) Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma. Nat Med 4: 408–414
    1. Rustin GJS, Galbraith SM, Taylor NJ, Maxwell R, Tozer G, Baddeley H, Wilson I, Prise V (1999) Combretastatin A4 phosphate (CA4P) selectively targets vasculature in animal and human tumors. Clin Cancer Res 5: 14
    1. Rustin GJ, Bradley C, Galbraith S, Stratford M, Loadman P, Waller S, Bellenger K, Gumbrell L, Folkes L, Halbert G (2003) 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent: phase I clinical and pharmacokinetic study. Br J Cancer 88: 1160–1167
    1. Siim BG, Lee AE, Shalal-Zwain S, Pruijin FB, McKeage MJ, Wilson WR (2003) Marked potentiation of the antitumour activity of chemotherapeutic drugs by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Cancer Chemother Pharmacol 51: 43–52
    1. Siim BG, Pruijn FB, Shalal-Zwain S, McKeage MJ, Wilson WR (2002) Marked potentiation of the antitumour activity of chemotherapeutic drugs by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Cancer Chemother Pharmacol
    1. Smith GP, Calveley SB, Smith MJ, Baguley BC (1987) Flavone acetic acid (NSC 347512) induces haemorrhagic necrosis of mouse colon 26 and 38 tumours. Eur J Cancer Clin Oncol 23: 1209–1211
    1. Sporer KA (1995) The serotonin syndrome. Implicated drugs, pathophysiology and management. Drug Saf 13: 94–104
    1. Spriggs DR, Yates SW (1992) Cancer chemotherapy; experiences with TNF administration in humans, In Tumor Necrosis Factors: The Molecules and Their Emerging Role in Medicine, Beutler B (ed) pp 383–406. New York: Raven Press
    1. Stücker O, Vicaut E, Teisseire B (1992) Specific response to 5-HT2 agonists by arterioles linked to Meth A tumors in mice. Am J Physiol 262: H704–H709
    1. Van de Kar LD, Rittenhouse PA, Li Q, Levy AD (1996) Serotonergic regulation of renin and prolactin secretion. Behav Brain Res 73: 203–208
    1. Wallis RM, Leishman D, Pullman L, Graepel P, Heywood R (1998) Effects of sildenafil on retinal histopathology and electroretinogram (ERG) in dogs. Ophthalmic Res 30: S68
    1. Weiss RB, Green RF, Knight RD, Collins JM, Pelosi JJ, Sulkes A, Curt GA (1988) Phase I and clinical pharmacology study of intravenous flavone acetic acid (NSC 347512). Cancer Res 48: 5878–5882
    1. Wilson WR, Baguley BC (2000) Combination of the antivascular agent DMXAA with radiation and chemotherapy. Int J Radiat Oncol Biol Phys 46: 706
    1. Wilson WR, Li AE, Cowan DS, Siim BG (1998) Enhancement of tumor radiation response by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid. Int J Radiat Oncol Biol Phys 42: 905–908
    1. Zwi LJ, Baguley BC, Gavin JB, Holdaway KM, Wilson WR (1992) The role of immune effector cells in flavone acetic acid-induced injury to tumor cells in EMT6 spheroids. Oncol Res 4: 333–339
    1. Zwi LJ, Baguley BC, Gavin JB, Wilson WR (1989) Blood flow failure as a major determinant in the antitumor action of flavone acetic acid (NSC 347512). J Natl Cancer Inst 81: 1005–1013
    1. Zwi LJ, Baguley BC, Gavin JB, Wilson WR (1990) Necrosis in non-tumour tissues caused by flavone acetic acid and 5,6-dimethylxanthenone acetic acid. Br J Cancer 62: 932–934

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