A dose‐escalation study of combretastatin A4‐phosphate in healthy dogs

Abstract

Combretastatin A4-Phosphate (CA4P) is a vascular disrupting agent revealing promising results in cancer treatments for humans. The aim of this study was to investigate the safety and adverse events of CA4P in healthy dogs as a prerequisite to application of CA4P in dogs with cancer.Ten healthy dogs were included. The effects of escalating doses of CA4P on physical, haematological and biochemical parameters, systolic arterial blood pressure, electrocardiogram, echocardiographic variables and general wellbeing were characterised. Three different doses were tested: 50, 75 and 100 mg m −2 .At all 3 CA4P doses, nausea, abdominal discomfort as well as diarrhoea were observed for several hours following administration. Likewise, a low-grade neutropenia was observed in all dogs. Doses of 75 and 100 mg m −2 additionally induced vomiting and elevation of serum cardiac troponine I levels. At 100 mg m −2 , low-grade hypertension and high-grade neurotoxicity were also observed.In healthy dogs, doses up to 75 mg m −2 seem to be well tolerated. The severity of the neurotoxicity observed at 100 mg m −2 , although transient, does not invite to use this dose in canine oncology patients. K E Y W O R D Santicancer therapy, combretastatin A4-phosphate, dogs, dose-escalation, vascular disrupting agent

A single dose of intravenous combretastatin A4‐phosphate is reasonably well tolerated and significantly reduces tumour vascularization in canine spontaneous cancers

“…Although not all tumours responded to the same extent, CA4P treatment resulted in an overall significant decrease in tumour vascularization and a significant increase of tumour necrosis, suggesting that 75 mg m −2 can be considered as an effective therapeutic dose. In accordance with the dose of 52 to 75 mg m −2 recommended in our previous toxicity study in healthy dogs, the results of the present study suggest that 75 mg m −2 is reasonably well tolerated by dogs with spontaneous cancer. Apart from one case of severe (but temporary) neurotoxicity, AEs were generally mild and transient and comparable to the side effects described in healthy dogs …”

“…In accordance with the dose of 52 to 75 mg m −2 recommended in our previous toxicity study in healthy dogs, the results of the present study suggest that 75 mg m −2 is reasonably well tolerated by dogs with spontaneous cancer. Apart from one case of severe (but temporary) neurotoxicity, AEs were generally mild and transient and comparable to the side effects described in healthy dogs …”

“…While 3 dogs maintained a stable HR, 2 patients developed tachycardia and 3 bradycardia, of which 2 had concurrent clinical hypertension. An increase in SABP after CA4P administration has been described in humans, dogs, rats and mice . CA4P causes vasoconstriction not only in tumours, but also in non‐tumour vascular beds .…”

“…Neurotoxicity after administration of tubulin‐binding agents has been reported in both human cancer patients and in healthy dogs; even so, its aetiology is still unclear . Further diagnostic work‐up in the most severely affected dog failed to identify the underlying cause.…”

“…In rodent models, vascular shutdown has been observed within 1 hour after injection . CA4P‐induced adverse events (AEs) in healthy dogs and human cancer patients are reported to be typically mild and transient, with nausea and vomiting seen most commonly, followed by tumour pain, neurotoxicity and hypertension …”