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Where the investigators felt that specific toxicities were not of sufficient clinical concern, dose escalation continued without the dose level being expanded. One patient experienced DLT at the highest dose level and dropped one dose level for the second course, and is therefore represented twice.
The first escalation 1. Therefore, the dose was doubled for subsequent escalations. Dose escalation was not restricted by nonhaematological toxicities that technically met the protocol definition for DLT but were not considered of sufficient clinical significance such as acute onset of tremor that resolved within one hour.
Toxicities of DMXAA were markedly different from those of many cytotoxic drugs, and many patients commented that it was easier to tolerate than chemotherapy. There was no significant drug-related neutropenia, thrombocytopenia or coagulopathy, and while anaemia and lymphocytopenia were common, they were judged unrelated to DMXAA in the majority of cases.
At lower dose levels, this drug was generally well tolerated, with a minority of patients experiencing mild drug-related toxicity. Acute symptoms included venous discomfort with the infusion alleviated by application of a warm pad , increased tumour pain several hours after the drug infusion and one patient briefly developed small urticarial lesions. These included slurred speech two patients , confusion and expressive dysphasia one patient , moderate anxiety one patient , severe visual disturbance one patient , tremor two patients and urinary incontinence one patient.
Symptoms at lower dose levels included altered colour vision, blurring without impairment of visual acuity and mild photophobia. Pattern and flash electroretinogram ERG showed an acute increase in latency and reduction in amplitude of certain retinal responses following DMXAA infusion with subsequent return to baseline over several hours, and a dose—response relationship was observed.
No clear dose—response relationship was observed and no ventricular tachyarrhythmia was seen. At higher doses, acute dyspnoea at rest occurred in four patients immediately following DMXAA infusion. Clinically, she had basal pulmonary inspiratory crackles but no bronchospasm. A total of 60 patients were evaluable for response.
The response was unconfirmed because two small neck nodes increased in size transiently after the third course then subsequently regressed again and overall tumour response was maintained for eight courses Figure 3. Tumour size was calculated as the sum of the products of bidimensional measurements of three clinically measurable metastatic neck nodes. This phase I trial of DMXAA has demonstrated clinical antitumour activity and reduction in tumour blood flow at well-tolerated doses Galbraith et al, While the clinical toxicities of DMXAA and FAA showed some similarities warmth, flushing, sweating, fatigue, myalgia, nausea, vomiting and visual disturbance , the DLTs of FAA were remarkably different and included hypotension, diarrhoea, flushing, asthenia and fatigue Kerr et al, ; Weiss et al, ; Kaye et al, ; Havlin et al, ; Olver et al, Prolongation of bleeding time was described Rubin et al, and one patient presented with haemorrhage due to immune thrombocytopenia after five doses of FAA Davis et al, However, the blood flow-modifying effect of CA4P is not entirely tumour-selective Griggs et al, , and it appears to be reversible except at high doses Anderson et al, ; Murata et al, Some CA4P toxicities resembled those of DMXAA including flushing, nausea, vomiting, tumour pain and QT c prolongation , but others cardiac ischaemia and cerebellar ataxia were notably different Galbraith et al, ; Dowlati et al, This syndrome most commonly occurs when two drugs are taken, which can each increase CNS serotonin and includes alterations in cognition, behaviour, autonomic nervous system function and neuromuscular activity Sporer, The mechanism underlying the acute release of CNS serotoninis not known, but serotonin release in plasma has been observed in this study Kestell et al, , and is a feature of the antivascular activity of this drug in preclinical models Baguley et al, The latter's visual toxicities are thought to be due to inhibition of phosphodiesterase type 6 PDE6 , which exists exclusively in the retina and is responsible for modulating the transduction cascade of the photoreceptor response to light.
It is reassuring in this regard that no long-term retinal sequela of sildenafil administration is known, including data from retinal histologic studies in dogs dosed with 65 times the maximum recommended human dose daily for 12 months Wallis et al, ; Marmor and Kessler, The significance of the observed QT c prolongation in these preliminary data is uncertain given its brevity, its possible relation to autonomic changes caused by the infusion and the population of patients potentially being treated with this agent.
Moreover, the use of ad hoc heart rate correction formulae such as Bazett's may bias the result Aytemir et al, Therefore the QT c results in this trial must be regarded as indicative only. However, given the concern that QT interval prolongation may predispose to ventricular tachycardia Committee for Proprietary Medicinal Products, , it will be important to determine the dose—response relationship of QT c prolongation before deciding on the dose of DMXAA for phase II and combination studies.
In conclusion, DMXAA is well tolerated over a wide dose range and has clinical and biological features distinct from those of other antivascular drugs in clinical development. Further clinical trials with this agent are clearly warranted, particularly in combination with other treatment modalities where synergistic interactions are observed in animal tumour models. This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication.
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Br J Cancer 80 Suppl 1 : 57— Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. Please refer to this study by its ClinicalTrials. More Information. Br J Cancer. Invest Ophthalmol Vis Sci. Epub Apr National Library of Medicine U. National Institutes of Health U.
Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Solid Tumors.
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