Abstract

ZD6474 targets angiogenesis by inhibiting VEGFR TK and also affects EGFR signaling by inhibiting EGFR TK activity. This oral agent showed dose-related tumor growth inhibition in a broad range of in vivo xenograft models. In Phase I studies, drug- and dose-related adverse events included rash, diarrhea, hypertension, and asymptomatic QT/QTc prolongation. Four patients with NSCLC included in the phase I studies exhibited partial responses. Because MM is a disease in which angiogenesis is postulated to be a relevant target for therapy, we conducted a phase II trial of ZD6474 100 mg p.o. daily in patients with MM who had relapsed following either high-dose chemotherapy and stem cell transplantation, or following non-high-dose chemotherapy. Although a higher dose was recommended for solid tumour trials, a dose of 100 mg p.o. daily produced plasma levels in phase I in excess of the IC50 for in vitro inhibition of VEGF-stimulated HUVEC proliferation and seemed well tolerated. For the study reported here, patients all had a measurable M protein in the serum or urine and were required to have an ECOG PS of 0, 1 or 2. Patients were excluded if they had any of: AGC <1.0x109/L or platelet count <50x109/L; bilirubin, AST and/or ALT >1.5xUNL; creatinine >2xUNL; K+ <4.0mmol/L; abnormal Ca2+ or Mg2+ levels, prior thalidomide treatment or pre-existing cardiac dysfunction. The primary efficacy endpoint was objective response as assessed by reduction in M protein. Following written, informed consent, 18 patients were entered into the study from five centers (9 male/9 female; mean age 64 yrs [35– 81]). Fourteen patients had relapsed following high-dose chemotherapy with stem cell transplant. One patient was ineligible due to elevated baseline calcium and one was not evaluable (off study due to non drug-related infection with < 14 days of therapy) . Patients were treated for 3.0– 29.4 weeks (mean 9.8 weeks). Overall, ZD6474 was well tolerated with only three patients missing doses of ZD6474. The most common drug-related adverse events were nausea, vomiting, fatigue, rash, pruritis, headache, diarrhea, dizziness, and sensory neuropathy, all of which were Grade I – II in severity. There were no drug-related serious adverse events. Laboratory adverse events were infrequent: one patient had Grade III anemia, and there were no Grade III changes in biochemistry. No significant QTc interval changes were seen. Fifteen patients had plasma samples obtained for at least 4 weeks after starting treatment. Trough levels of ZD6474 achieved or exceeded the IC50 for inhibition of VEGF-stimulated HUVEC proliferation in 13 of the 15 patients by day 28. There were no responses in M protein levels. In conclusion, ZD6474 was well tolerated at a dose of 100 mg per day and achieved plasma levels predicted to inhibit VEGF signaling. However, this was not reflected in clinical benefit since none of the patients had a reduction in M protein. ZD6474 development in solid tumors is continuing in a series of Phase II trials.

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