Phase I Clinical and Pharmacokinetic Evaluation of the Vascular-Disrupting Agent OXi4503 in Patients with Advanced Solid Tumors

Abstract

Purpose: Preclinical studies show that OXi4503 (combretastatin A1 diphosphate, CA1P) is more potent than other clinically evaluated vascular-disrupting agents.Experimental Design: Escalating doses of OXi4503 were given intravenously over 10 minutes on days 1, 8, and 15 every 28 days to patients with advanced solid tumors.Results: Doses were escalated in single-patient cohorts from 0.06 to 1.92 mg/m 2 , then expanded cohorts to 15.4 mg/m 2 in 43 patients. Common adverse drug reactions were hypertension, tumor pain, anemia, lymphopenia, and easily controllable nausea/vomiting and fatigue. Five patients experienced different drugrelated dose-limiting toxicities, atrial fibrillation, increased troponin, blurred vision, diplopia, and tumor lysis. Prophylactic amlodipine failed to prevent adverse events. Pharmacokinetics showed dose-dependent linear increases in peak plasma concentrations and area under the curve value of OXi4503. One partial response was seen in a heavily pretreated patient with ovarian cancer. Dynamic contrast-enhanced MRI confirmed a dose effect and showed significant antivascular effects in 10 of 13 patients treated at doses of 11 mg/m 2 or higher. Conclusions:The maximum tolerated dose was 8.5 mg/m 2 but escalation to 14 mg/m 2 was possible with only temporary reversible cerebrovascular toxicity by excluding hypertensive patients. As a tumor response was seen at 14 mg/m 2 and maximum tumor perfusion reductions were seen at doses of 11 mg/m 2 or higher, the recommended phase II dose is from 11 to 14 mg/m 2 .

The Vascular Disrupting Agent STA-9584 Exhibits Potent Antitumor Activity by Selectively Targeting Microvasculature at Both the Center and Periphery of Tumors

“…Taken together, these findings show that cardiac toxicity is not likely to be dose-limiting for STA-9584. This represents an important discriminating feature of the compound, because both hypertension (as a common adverse drug reaction) and atrial fibrillation (as a dose-limiting toxicity) have recently been reported in a phase I evaluation of Oxi4503 (Patterson et al, 2012).…”

The changing paradigm of tumour response to irradiation

“…A major difference between these two pathways is new vessels sprouting from existing vessels (angiogenesis) vs the influx of cells from other parts of the body or bone marrow, which can build or rebuild vessels (vasculogenesis). 115 Various vascular disrupting agents are also in clinical development, 116 and pre-clinical studies have suggested that these agents have potential to be combined with radiation, but apart from anecdotal observations in early stage trials, it is unclear if these will prove to be any more beneficial than antiangiogenic agents.…”

Combretastatins: More Than Just Vascular Targeting Agents?

“…Current clinical data suggest that CA-1P is now the most potent clinically evaluated VTA (Patterson et al, 2012). Intriguingly, the vast majority of synthetic combretastatins are analogous to CA-4 despite emerging data demonstrating the superior therapeutic efficacy of CA-1 (Hua et al, 2003;Patterson et al, 2012). Similarly, combretastatin signaling pathways are primarily investigated using CA-4 and associated analogs.…”

“…The combretastatin A-1 diphosphate (CA-1P) and combretastatin A-4 phosphate (CA-4P) prodrugs were converted into their active counterparts over 7 times faster in tumor and liver preparations than in blood (Kirwan et al, 2004). The prodrugs soon became the preferred structures to progress to clinical trials (Young and Chaplin, 2004;Chaplin et al, 2006;Patterson et al, 2012).…”