A phase II clinical trial of BMS-247550 (ixabepilone), a microtubule-stabilizing agent in renal cell cancer

Abstract

4550 Background: No chemotherapy has been proven effective in renal cell cancer (RCC). The epothilones are a new generation of potent microtubule-stabilizing agents that are not P-glycoprotein substrates and active in taxane-resistant cells. We conducted a phase II trial of BMS-247550, an epothilone B analogue in metastatic RCC. Methods: Patients with metastatic RCC received BMS-247550 (6 mg/m2/day), daily for 5 consecutive days every 3 weeks. All patients had been previously treated with, been ineligible for, or refused IL-2 treatment. BMS-247550 was continued until progression or unacceptable toxicities. Results: 214 cycles have been administered in 39 patients. Treatment was well tolerated. 11 patients are still on study. A PR has been confirmed in 4 patients (10%) with clear cell RCC. 5 additional patients have had minor or mixed responses. Several post-translational modifications on a-tubulin have been shown to correlate with the extent of microtubule stability. A carboxypeptidase-catalyzed removal of the C-terminal tyrosine exposing a glutamic acid as the new C-terminal residue is one such modification. Using an antibody that recognizes glutamic acid terminated a-tubulin, we showed that the level of glu-terminated tubulin provides a reliable measure of microtubule stability. Furthermore, we were able to show an increase in glu-terminated tubulin in 6 of 12 serial tumor biopsies obtained from patients treated with BMS-247550. 50–70% of sporadic clear cell carcinomas have Von Hippel-Lindau (VHL) gene abnormalities. Consistent with previous studies reporting microtubule-stabilization by wild type VHL protein, we found that sensitivity to BMS-247550 correlates with VHL protein levels in 8 clear cell RCC cell lines. Studies using paraffin-embedded tumor are ongoing to determine if clinical response to BMS-247550 in study patients correlates with VHL gene status and protein levels. Conclusions: BMS-247550 has shown some activity against RCC. Glu-terminated tubulin level is a simple and reliable surrogate for its pharmacodynamic effects. Sensitivity of clear cell RCC to BMS-247550 is associated with VHL protein levels in cultured cells. No significant financial relationships to disclose.