TNP 470 and Taxol in Advanced Cancer--Phase I Study

Georgetown University, Washington DC

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Abstract

Although mechanisms driving angiogenesis are not fully understood, it is clear that a variety of growth factors and cytokines are capable of stimulating agiogenesis. Prominent among those are FGF (acidic and basic), VEGF, PD-ECGF, TGFa and TNFa. Therefore, it may be possible to achieve a more effective control of angiogenesis by inhibiting multiple growth factors or pathways that stimulate angiogenesis. Taxol has demonstrated anti-angiogenic properties in different assay systems such as the CAM assay and the rat corneal micropocket assay. Taxol (6mg/kg i.p. daily for 5 consecutive days) inhibited bFGF and VEGF induced corneal neovascularization by 45% and 37% respectively in C57BL/6 mice. The exact mechanism by which taxol inhibits angiogenesis is unclear, but it is suspected that its effects on microtubule assembly may play an important role. TNP-470 and Taxol probably inhibit angiogenesis by distinct mechanisms, and when used together, would be expected to have an additive anti-angiogenic effect. In a study using AGM-1470 (TNP-470) in combination with Taxol in a CIA (collagen induced arthritis) model in rats, combination therapy resulted in significantly reduced clinical arthritis compared to either agents used alone. Combination therapy was significantly better than single-agent AGM-1470 or taxol in inhibiting clinical inflammation and bone destruction associated with the arthritis. It was also demonstrated that the two agents could be used together safely in rats, although adverse effects of taxol (transient weight loss, diarrhea, reversible granulocytopenia) appeared to be enhanced by the concurrent use of AGM-1470 thus necessitating a reduction of taxol dose by 25% for wubsequent cycles. The information above concerning the potential interaction of TNP-470 and taxol, both on a pharmacokinetic and mechanistic level, strongly justify clinical testing of the two agents in patients with advanced cancer. The initial phase I trial will determine the maximum dose and safety of this combination. Once this dose is determined, we then plan to perform a phase 2 randomized trial comparing TNP-470 and taxol to taxol alone in patients with advanced breast cancer. I this trial we will also obtain quality of life and cost analysis data to fully analyze the impact of adding TNP-47- to taxol. In this phase I trial, we will begin to collect pilot quality of life and cost data to validate the tools we are using in this population. TNP-470 [T], a fumagillin derivative, and Pacllitaxel [P], a cytotoxic agent, possess potent anti-angiogenic and anti-tumor activity. The activity of T is believed to be mediated via inhibition of the enzyme methionine aminopeptidase-2, while P is a microtubule stabilizing agent. Preclinical data suggest that P may prolong the half-life of AGM-1883, an active metabolite of T, through inhibition of its metabolism. Based on different mechanisms of anti-angiogenic activity and potentially beneficial metabolic interaction, a trial was conducted using a combination of T and P in patients (pts) with advanced, incurable solid tumors. T was administered as a 4-hour IV infusion on day 1; P was started on day 8 as a 1-hour IV infusion, immediately followed by T.