Phase I study of sunitinib in combination with gemcitabine/capecitabine for the first-line treatment of metastatic or unresectable renal cell carcinoma.

Abstract

e15095 Background: Gemcitabine (G) plus Capecitabine (C) have demonstrated a modest activity in metastatic renal cell cancer (mRCC) patients (pts). The combination of Sunitinib (S) and C resulted in an acceptable safety profile in pts with advanced solid tumors. We hypothesized that the addition of S to G+C in advanced/mRCC would be synergistic and could increase the therapeutic efficacy. Methods: This is an open-label, phase I, dose-escalation study to assess the maximum-tolerated dose (MTD), safety and antitumor activity (in terms of response rate) of S in combination with C and G in naive pts with advanced mRCC. Advanced RCC pts with adequate organ function, performance status (ECOG 0-1), age >18 years, were eligible. Treatment consisted on iv G day 1 and 8, oral C bid days 1–14, and oral S continuous daily dosing (CDD) schedule, for six cycles (21 days per cycle), followed by sunitinib monotherapy, at the investigator’s discretion if clinical benefit was maintained. Dose level 1 G 1000 C 850 S 37.5; dose level 0 G 1000 C 650 S 37.5 (dose level -1 G 850 C 500 S 37.5). Results: 16 pts were enrolled in the study, median age: 67 yrs, histology: 9 clear cell, 4 papillar and 1 sarcomatoid have been treated at the first two dose levels. In DL1, two out of 4 pts had DLT, consisting on G3 diarrhea and mucositis, and G4 thrombocytopenia. Decision was made to reduce down to level 0; only 1/12 pts experienced DLT at this DL (mucositis G3 and thrombocytopenia G3). Other non-DLTs adverse events were asthenia, hand-foot syndrome, mucositis, diarrhea, infection, neutropenia, epistaxis, low gastrointestinal tract bleeding and hypertension. Dose reductions were frequent (58% of pts) and only 7 pts were able to receive the 3 drugs for > 3 cycles. One death was reported as possibly related to study drugs. A partial response was achieved in 3 pts, and stable disease in 6 patients. Conclusions: Although a low rate of DLT were observed at dose level 0, the safety profile of the combination does not seem to be manageable in most patients. In this trial there are no signs of a synergistic activity for the combination therapy of S plus G/C in therapy naïve pts with mRCC.