TNP-470 120 Hour Continuous Infusion in Advanced Cancer

Georgetown University, Washington DC

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Abstract

One unique property makes endothelial cell proliferation a promising target for the chemotherapy of malignant growth: In the adult the only physiologic conditions which require endothelial cell proliferation are wound healing and the reproductive cycle. Endothelial cell proliferation in a growing primary tumor can thus be targeted with high selectivity. Animal studies have given the best insight into the selective tumor-induced endothelial cell proliferation in vivo. This selective endothelial cell proliferation in tumors should make selective inhibitors very effective anti-cancer drugs with only few systemic effects on the host. TNP-470, an angiogenesis inhibitor, is a synthetic analogue of fumagillin, a natural product secreted by the fungus Aspergillus fumigatus fresenius. Studies demonstrating fumagillin's angioinhibitory activity were initiated in the laboratory of Judah Folkman, M.D., following observations of morphological changes in endothelial cell cultures inadvertently contaminated by this fungus. The results of these studies confirmed that fumagillin inhibited endothelial cell proliferation in vitro as well as angiogenesis and tumor growth in vivo. Animal toxicology studies show that TNP-470 behaves very differently when given as a continuous infusion instead of a weekly bolus injection, with myelosuppression and gastrointestinal epithelial toxicity being the prominent toxicities with prolonged infusion. In addition, the short half life that we have seen of the parent compound in human pharmacokinetic studies would support a continuous infusion for maximal therapeutic effect. The purpose of this study is to determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and pharmacokinetics of TNP-470 when administered as a 120 hour continuous intravenous infusion once every three weeks in patients with advanced, incurable malignancies. To document any objective antitumor responses that occur in patients treated on this protocol. TNP-470, a fumagillin analogue and potent anti-angiogenic agent, is currently in phase I/II clinical trials. Pharmacokinetic (PK) data revealed a short plasma half life of TNP-470 and its active metabolite AGM-1883 in humans. Based o this data, a 120-hour continuous infusion study of TNP-470 was initiated in pts with advaned, incurable solid tumors. The starting dose was 0.6mg/m2 over 24-hours daily x 5 days. Pts without dose limiting toxicity or evidence of disease progression were allowed to escalate to the next dose level. We also measured endothelial cell inhibitory activity in the plasma of these pts during thecourse of TNP-470 infusion using a human umbilical vein endothelial cell (HUVEC) proliferation assay. 41 pts have been treated: 21 M/20 F, median age 53 (19-76). ECOG PS 0-2. Primary tumor sites were: Lung (17), Sarcoma (7), Breast (4), Colorectal (2), Renal (2), Head and Neck (2), others (7). Eleven dose levels habe evaluated ranging from 0.6 to 20mg/m2/day. Preliminary data reveal rare adverse events (AEs) up to a dose of 5.65mg/m2/day. Between the doses of 7.51 and 20mg/m2/day, the following AEs have been observed: fatigue (gr 1-2), nausea (gr 1-2), vomiting (gr 1), diaarrhea (gr 1-2), anorexia (mild), weight loss (gr 1-2), and neurologic symptoms (lightheadedness, dizziness, ataxia, insomnia, nightmares). Preliminary PK reveal extremely low levels of TNP-470 and AGM-1883 at a dose of 3.2mg/m2/day. Howeverm significant bioactivity was seen at this dose level, with nearly complete inhibition of HUVEC proliferation (in response to bFGF) by patients' plasma in vitro. Analysis of samples from higher dose levels is ongoing. Pts are currently being accrued at a dose of 20mg/m2/day. A pt with small cell lung cancer who started treatment at 7.51mg/m2/day had a partial response (>50% reduction) and has received treatment for >6 months. Overall, these data indicate that TNP-470 is well tolerated up to a dose of 13.27mg/m2/day. However, significant endothelial cell inhibitory activity is seen in plasma of pts at lower dose levels, indicating that lower doses of TNP-470 may be adequate to achieve the desired biologic effect.