Cardiovascular Safety Profile of Combretastatin A4 Phosphate in a Single-Dose Phase I Study in Patients with Advanced Cancer

Cooney, Matthew M.; Radivoyevitch, Tomas; Dowlati, Afshin; Overmoyer, Beth; Levitan, Nathan; Robertson, Kelly M.; Levine, S.; DeCaro, Kathleen; Buchter, Carol; Taylor, Anne L.; Stambler, Bruce S.; Remick, Scot C.

doi:10.1158/1078-0432.ccr-0364-3

Cited by 121 publications

(92 citation statements)

References 5 publications

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“…Furthermore, in phase I studies of ASA404, the predominant cardiac AE was QTc interval prolongation (Jameson et al, 2003;, of which there was a low incidence in this study. Nonetheless, as cardiac toxicity could result from the mechanism of action of VDAs (Cooney et al, 2004), the cardiac safety profile of ASA404 should continue to be monitored in future studies.…”

Section: Discussionmentioning

confidence: 99%

Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer

et al. 2008

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ASA404 (5,6-dimethylxanthenone-4-acetic acid or DMXAA) is a small-molecule tumour-vascular disrupting agent (Tumour-VDA). This randomised phase II study evaluated ASA404 plus standard therapy of carboplatin and paclitaxel in patients with histologically confirmed stage IIIb or IV non-small cell lung cancer (NSCLC) not previously treated with chemotherapy. Patients were randomised to receive p6 cycles of carboplatin area under the plasma concentration -time curve 6 mg ml À1 min and paclitaxel 175 mg m À2 (CP, n ¼ 36) or standard therapy plus ASA404 1200 mg m À2 (ASA404-CP, n ¼ 37). There was little change in the systemic exposure of either total or free carboplatin or paclitaxel on addition of ASA404. Safety profiles were similar and manageable in both groups, with most adverse effects attributed to standard therapy. Tumour response rate (31 vs 22%), median time to tumour progression (5.4 vs 4.4 months) and median survival (14.0 vs 8.8 months, hazard ratio 0.73, 95% CI 0.39, 1.38) were improved in the ASA404 combination group compared with the standard therapy group. In conclusion, this study establishes the feasibility of combining ASA404 with carboplatin and paclitaxel in patients with previously untreated, advanced NSCLC, demonstrating a manageable safety profile and lack of adverse pharmacokinetic interactions. The results indicate that there may be a benefit associated with ASA404, but this needs to be evaluated in a larger trial.

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Section: Discussionmentioning

confidence: 99%

Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer

et al. 2008

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“…9 Combretastatin causes endothelial cell apoptosis. 10 Positron emission tomography (PET) demonstrated decreased cardiac output, attributable to increased peripheral vascular resistance induced by combretastatin and not to myocardial toxicity. 11 Combretastatin induces apoptosis of human proliferating endothelial cells and umbilical vein endothelial cells 12 and disrupts endothelial networks formed in type I collagen.…”

Section: Pathophysiologymentioning

confidence: 99%

Myocardial Stunning Following Combined Modality Combretastatin‐Based Chemotherapy: Two Case Reports and Review of the Literature

Bhakta

Flick

Cooney

et al. 2009

Clinical Cardiology

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Myocardial stunning, known as stress cardiomyopathy, broken-heart syndrome, transient left ventricular apical ballooning, and Takotsubo cardiomyopathy, has been reported after many extracardiac stressors, but not following chemotherapy. We report 2 cases with characteristic electrocardiographic and echocardiographic features following combined modality therapy with combretastatin, a vascular-disrupting agent being studied for treatment of anaplastic thyroid cancer. In 1 patient, an ECG performed per protocol 18 hours after drug initiation showed deep, symmetric T-wave inversions in limb leads I and aVL and precordial leads V 2 through V 6 . Echocardiography showed mildly reduced overall left ventricular systolic function with akinesis of the entire apex. The patient had mild elevations of troponin I. Coronary angiography revealed no epicardial coronary artery disease. The electrocardiographic and echocardiographic abnormalities resolved after several weeks. The patient remains stable from a cardiovascular standpoint and has not had a recurrence during follow-up. An electrocardiogram performed per protocol in a second patient showed deep, symmetric T-wave inversions throughout the precordial leads and a prolonged QT interval. Echocardiography showed mildly reduced left ventricular function with hypokinesis of the apical-septal wall. Acute coronary syndrome was ruled out, and both the electrocardiographic and echocardiographic changes resolved at follow-up. Although the patient remained pain-free without recurrence of anginal symptoms during long-term follow-up, the patient developed progressive malignancy and died. IntroductionMyocardial stunning, known as stress cardiomyopathy, broken heart syndrome, left ventricular apical ballooning, and Takotsubocardiomyopathyis defined as: left ventricular apical ballooning on echocardiography or ventriculography; no angiographic stenoses > 50%; and no history of known cardiomyopathy. While the patient in the first of our 2 case reports fulfills these criteria, the second patient had a positive stress test following the incident but did not undergo coronary angiography, so ischemic heart disease was not excluded.Combretastatin may precipitate acute coronary syndrome. 1 A 57-year-old male with pancreatic cancer developed chest pain 80 minutes after combretastatin, and ECG showed acute myocardial infarction. Coronary angiography demonstrated an occluded distal left anterior descending artery. A 77-year-old male developed ECG changes and elevated troponin I following combretastatin. Coronary angiography revealed 2-vessel coronary artery disease.

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“…Four small-molecule VDAs are under clinical investigation: the tubulin-depolymerizing VDAs combretastatin A4, ZD6126, and AVE8062A, and the microtubuleindependent VDA 5,6-dimethylxanthenone-4-acetic acid (DMXAA) (1). Although VDAs are showing promise in clinical trials, some have been associated with cardiovascular adverse events (2).…”

Section: à2mentioning

confidence: 99%

5,6-Dimethylxanthenone-4-Acetic Acid in the Treatment of Refractory Tumors: a Phase I Safety Study of a Vascular Disrupting Agent

McKeage

Fong

Jeffery

et al. 2006

Clinical Cancer Research

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This phase I safety study aimed to identify the optimal dose of the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) for combination studies. Using a crossover design, 15 patients with refractory tumors were allocated randomly to receive six sequential doses of DMXAA (300, 600, 1,200, 1,800, 2,400, and 3,000 mg m À2 ), each given once-weekly as a 20-minute i.v. infusion. The drug was generally well tolerated. Transient, moderate increases in the heart rate^corrected cardiac QT interval occurred at the two highest doses. DMXAA produced transient dose-dependent increases in blood pressure. Transient, dose-related visual disturbances occurred at the two highest doses. No significant changes in K trans and k ep were observed but V e , a secondary dynamic contrast^enhanced magnetic resonance imaging variable, increased significantly after giving DMXAA. At 1,200 mg m À2, the C max and the area under the concentration-time curve over 24 hours for total and free DMXAA plasma concentrations were 315 F 25.8 À2 have been selected for further studies (phase II combination studies with taxanes and platins are under way) because this dose produced no significant effect on heart rate^corrected cardiac QT interval, produced near maximum levels of 5-hydroxyindoleacetic acid, achieved DMXAA plasma concentrations within the preclinical therapeutic range, and was well tolerated.

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Cardiovascular Safety Profile of Combretastatin A4 Phosphate in a Single-Dose Phase I Study in Patients with Advanced Cancer

Cited by 121 publications

References 5 publications

Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer

Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer

Myocardial Stunning Following Combined Modality Combretastatin‐Based Chemotherapy: Two Case Reports and Review of the Literature

5,6-Dimethylxanthenone-4-Acetic Acid in the Treatment of Refractory Tumors: a Phase I Safety Study of a Vascular Disrupting Agent

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