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

McKeage, Mark J.; Fong, Peter; Jeffery, Mark; Baguley, Bruce C.; Kestell, Phil; Ravic, Miroslav; Jameson, Michael B.

doi:10.1158/1078-0432.ccr-05-1939

Cited by 90 publications

(78 citation statements)

References 35 publications

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“…Among the identified studies, QTc prolongation was seen in 14% of patients treated with cediranib101, 102, 103, 104 and 21% of patients treated with vadimezan (ASA404) 108, 109, 175. Caution and periodic ECG monitoring is advised during the treatment with these agents.…”

Section: Resultsmentioning

confidence: 99%

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

Porta‐Sánchez

Gilbert

Spears

et al. 2017

JAHA

154

142

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BackgroundThe cardiovascular complications of cancer therapeutics are the focus of the burgeoning field of cardio‐oncology. A common challenge in this field is the impact of cancer drugs on cardiac repolarization (ie, QT prolongation) and the potential risk for the life‐threatening arrhythmia torsades de pointes. Although QT prolongation is not a perfect marker of arrhythmia risk, this has become a primary safety metric among oncologists. Cardiologists caring for patients receiving cancer treatment should become familiar with the drugs associated with QT prolongation, its incidence, and appropriate management strategies to provide meaningful consultation in this complex clinical scenario.Methods and ResultsIn this article, we performed a systematic review (using Preferred Reporting Items of Systematic Reviews and Meta‐Analyses (PRISMA) guidelines) of commonly used cancer drugs to determine the incidence of QT prolongation and clinically relevant arrhythmias. We calculated summary estimates of the incidence of all and clinically relevant QT prolongation as well as arrhythmias and sudden cardiac death. We then describe strategies to prevent, identify, and manage QT prolongation in patients receiving cancer therapy. We identified a total of 173 relevant publications. The weighted incidence of any corrected QT (QTc) prolongation in our systematic review in patients treated with conventional therapies (eg, anthracyclines) ranged from 0% to 22%, although QTc >500 ms, arrhythmias, or sudden cardiac death was extremely rare. The risk of QTc prolongation with targeted therapies (eg, small molecular tyrosine kinase inhibitors) ranged between 0% and 22.7% with severe prolongation (QTc >500 ms) reported in 0% to 5.2% of the patients. Arrhythmias and sudden cardiac death were rare.ConclusionsOur systematic review demonstrates that there is variability in the incidence of QTc prolongation of various cancer drugs; however, the clinical consequence, as defined by arrhythmias or sudden cardiac death, remains rare.

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Section: Resultsmentioning

confidence: 99%

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

Porta‐Sánchez

Gilbert

Spears

et al. 2017

JAHA

154

142

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“…Severe cardiotoxicity was infrequent and generally transient with rapid recovery, with only one grade 4 event (myocardial infarction). Given the QTc interval prolongations seen with combretastatin and ASA404 (19,20), we analyzed QTcF which is considered more appropriate than the Bazzett's formula in cases of increased heart rate, as is often associated with this class of drugs. However the maximal mean QTcF prolongation at the ombrabulin RP2D (4.1 milliseconds; 90% CI 0.94-7.3) was well below the 20-millisecond threshold recommended for the registration of oncology agents, suggesting its effect on ventricular repolarization in humans is acceptable according to the ICH E14 guideline.…”

Section: Discussionmentioning

confidence: 99%

Phase I Safety, Pharmacokinetic and Pharmacodynamic Evaluation of the Vascular Disrupting Agent Ombrabulin (AVE8062) in Patients with Advanced Solid Tumors

Sessa

LoRusso

Tolcher

et al. 2013

Clinical Cancer Research

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Purpose: The vascular disrupting agent ombrabulin rapidly reduces tumor blood flow and causes necrosis in vivo. A phase I dose-escalation study was designed to determine the recommended phase II dose (RP2D) of single-agent ombrabulin administered once every three weeks in patients with advanced solid malignancies.Experimental Design: Ombrabulin (30-minute infusion) was escalated from 6 to 60 mg/m 2 , with RP2D cohort expansion. Safety, tumor response, pharmacokinetics, and pharmacodynamic biomarkers were evaluated.Results: Eleven dose levels were evaluated in 105 patients. Two patients had dose-limiting toxicities in cycle 1 during escalation: grade 3 abdominal pain at 50 mg/m 2 , grade 3 tumor pain/grade 3 hypertension at 60 mg/m 2 , and the RP2D was 50 mg/m 2 (39 patients). Common toxicities were headache, asthenia, abdominal pain, nausea, diarrhea, transient hypertension, anemia, and lymphopenia. No clinically significant QTc prolongations or left ventricular ejection fraction (LVEF) decreases occurred. Ombrabulin was rapidly converted to its active metabolite RPR258063 (half-life 17 minutes and 8.7 hours, respectively), both having dose-proportional exposure. Weak inhibition of CYP2C19-mediated metabolism occurred at the clinical doses used and there was no effect on CYP1A2 and CYP3A4. A patient with rectal cancer had a partial response and eight patients had stable disease lasting four months or more. Circulating endothelial cells (CEC), VEGF, and matrix metalloproteinase (MMP)-9 levels increased significantly six to 10 hours postinfusion in a subset of patients. Conclusions:The recommended schedule for single-agent ombrabulin is 50 mg/m 2 every 3 weeks. CECs, VEGF, and MMP-9 are potential biomarkers of ombrabulin activity.

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“…5,6‐dimethylxanthenone (DMXAA or ASA404), flavone acetic acid analog, is a potent vascular disrupting agent that has completed multiple clinical trials, including a large scale phase III trial of carboplatin and paclitaxel with or without ASA404 in advanced non‐small‐cell lung cancer (NSCLC) 165, 166, 167, 168, 169…”

Section: Combining Phototherapy With Novel Anti‐cancer Agentsmentioning

confidence: 99%

Chemophototherapy: An Emerging Treatment Option for Solid Tumors

et al. 2016

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Near infrared (NIR) light penetrates human tissues with limited depth, thereby providing a method to safely deliver non‐ionizing radiation to well‐defined target tissue volumes. Light‐based therapies including photodynamic therapy (PDT) and laser‐induced thermal therapy have been validated clinically for curative and palliative treatment of solid tumors. However, these monotherapies can suffer from incomplete tumor killing and have not displaced existing ablative modalities. The combination of phototherapy and chemotherapy (chemophototherapy, CPT), when carefully planned, has been shown to be an effective tumor treatment option preclinically and clinically. Chemotherapy can enhance the efficacy of PDT by targeting surviving cancer cells or by inhibiting regrowth of damaged tumor blood vessels. Alternatively, PDT‐mediated vascular permeabilization has been shown to enhance the deposition of nanoparticulate drugs into tumors for enhanced accumulation and efficacy. Integrated nanoparticles have been reported that combine photosensitizers and drugs into a single agent. More recently, light‐activated nanoparticles have been developed that release their payload in response to light irradiation to achieve improved drug bioavailability with superior efficacy. CPT can potently eradicate tumors with precise spatial control, and further clinical testing is warranted.

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

Cited by 90 publications

References 35 publications

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

Phase I Safety, Pharmacokinetic and Pharmacodynamic Evaluation of the Vascular Disrupting Agent Ombrabulin (AVE8062) in Patients with Advanced Solid Tumors

Chemophototherapy: An Emerging Treatment Option for Solid Tumors

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