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

¹Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University (CWRU), School of Medicine, Cleveland, Ohio;² Developmental Therapeutics Program, Comprehensive Cancer Center at University Hospitals of Cleveland and CWRU, Cleveland, Ohio;³ Department of Epidemiology and Biostatistics, CWRU, School of Medicine, Cleveland, Ohio;⁴ General Clinical Research Center, University Hospitals of Cleveland and CWRU School of Medicine, Cleveland, Ohio;⁵ Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington;⁶ Division of Cardiology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota; and⁷ Division of Cardiology, Department of Medicine, University Hospitals of Cleveland, Cleveland Veterans Affairs Medical Center, CWRU, Cleveland, Ohio

Purpose: The purpose of our study was to review and determine the cardiovascular safety profile of combretastatin A4 phosphate (CA4P) in a Phase I study in 25 patients with advanced solid tumors.

Experimental Design: CA4P was administered in a dose-escalating fashion starting at 18 mg/m² i.v. every 21 days, and the maximal dosage was 90 mg/m². Continuous evaluation included bedside blood pressure and pulse monitoring, 12-lead electrocardiogram (ECG) at fixed time points for measured QT interval determination, determination of the corrected QT interval (QTc) using Bazett’s formula QTc = QT/(R-R interval)^1/2, and chart review. Pharmacodynamic correlations of CA4P dose, CA4P/CA4 area under the curve, and C_max versus heart rate (HR), blood pressure, QT, and QTc intervals, over the first 4 h postdosing were analyzed.

Results: After CA4P administration, there were significant increases in QTc interval at the 3-h and 4-h time points [27.2 ms (P < 0.0001) and 30.8 ms (P < 0.0001), respectively] and HR at the 3- and 4-h time points [13.2 beats per minute (bpm; P < 0.01) and 15.1 bpm (P < 0.001), respectively]. Three of 25 patients had prolonged QTc intervals at baseline, whereas 15 (60%) of 25 and 18 (75%) of 24 patients had prolonged QTc intervals at 3 and 4 h. The slope of HR and QTc increasing as a function of time during the first 4 h was correlated to dose (in milligrams) of CA4P (P = 0.01 and r = 0.49 for HR, P = 0.005 and r = 0.55 for QTc) and to CA4 area under the curve (P = 0.04 and r = 0.41 for HR, P = 0.02 and r = 0.44 for QTc); blood pressure and uncorrected QTc interval dose-response correlations were not significant. Two patients had ECG changes consistent with an acute coronary syndrome within 24 h of CA4P infusion.

Conclusions: CA4P prolongs the QTc interval. There was a temporal relationship with the CA4P infusion and with ECG changes consistent with an acute coronary syndrome in two patients. It is advisable that future trials with CA4P have eligibility guidelines limiting patients with known coronary artery disease or those with multiple coronary artery disease risk factors until more experience is gained regarding potential cardiovascular toxicity with this agent.

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