Antitumor activity observed in a phase I drug–drug interaction study of cabozantinib (XL184) and rosiglitazone in patients (pts) with renal cell carcinoma (RCC) and differentiated thyroid cancer (DTC).

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e13042 Background: Cabozantinib is an oral, potent inhibitor of MET and VEGFR2 that is currently undergoing clinical efficacy evaluation in several oncology indications. In parallel, clinical pharmacology studies are being performed, including assessment of potential drug-drug interactions (DDIs). Renal cell carcinoma (RCC) and differentiated thyroid cancer (DTC) were chosen as indications in this study based on involvement of the MET and VEGFR signaling pathways in these indications. The primary objective of this study is to determine the effect of cabozantinib on single dose PK of the CYP2C8 substrate rosiglitazone. The exploratory objective of this study is to evaluate the preliminary antitumor activity of cabozantinib in pts with RCC and DTC. Methods: Approximately 35 cancer pts initially limited to DTC or RCC may be enrolled to this study. On study Day 1, pts receive a 4 mg tablet of rosiglitazone; PK sampling is completed on Day 2. On Days 2 (post PK sampling) through 21, cabozantinib is administered daily at a starting dose of 175 mg. On study Day 22 pts receive rosiglitazone 4 mg tablet and complete PK assessments. On study Day 57 and every 8 weeks thereafter subjects undergo tumor assessments by mRECIST. Results: To date, 10 pts (9 RCC; 1 DTC) have been enrolled (20 pts anticipated by May 2011). All pts had measurable disease. Median number of prior regimens was 3 (7/9 RCC pts with ≥ 2 lines of prior therapy and 6/9 with at least 1 VEGF pathway inhibitor and 1 mTOR inhibitor). No marked differences in concentration profiles, Tmax, Cmax, or AUC0-24h values were observed in 4 pts who completed the PK portion. Overall, 4/9 RCC pts had a confirmed partial response; 7/10 pts experienced tumor regression (16-49%). Related AEs ≥Grade 3 severity: fatigue (1 pt), amylase and lipase increased and hypophosphatemia (1 pt), and hyponatremia and hypophosphatemia (1 pt). Conclusions: Preliminary data suggests no drug-drug interactions between cabozantinib and rosiglitazone (CYP2C8 substrate). Cabozantinib demonstrates anti-tumor activity in heavily pretreated pts with RCC.