Background: Combined targeting of ERBB receptors and VEGF-dependent signaling pathways has proven to be a successful strategy in preclinical studies. L is a dual HER2/EGFR tyrosine kinase inhibitor, S is an oral multikinase inhibitor (VEGFR-2,3, PDGFR-b, Flt-3, Raf-1 and c-KIT). We conducted a phase I dose-escalation study to assess the maximum tolerated dose (MTD), safety/tolerability, PK, PD and preliminary antitumor activity of the combination of these two agents. Methods: Patients (pts) with advanced malignancies refractory to standard therapy were eligible. A traditional 3+3 dose escalation schema was employed. Dose levels (DL) were 1) L 750 mg + S 200 mg BID; 2) L 1000 mg + S 200 mg BID; 3) L 1000 mg + S 400 mg BID; 4) L 1250 mg+ S 400 mg BID. L and S were given together on a continuous schedule with a 28-day cycle. Once the MTD has been determined, additional 9 patients were enrolled in the PK part of the study and received L alone during a “running-in” period for two weeks before starting with the combined schedule. Results: 30 pretreated pts (median 3 previous lines, range 1-6) were enrolled, M/F: 19/11, median age: 65 yrs (25-76), PS: 0/1=15/15. DLTs were observed in 2 pts, one at DL 2 [grade (G) 3 fatigue] and one at DL 3 (G3 rash). The MTD was reached at DL4. The most common toxicities were fatigue (64%), diarrhea (61%), anemia (61%), rash (43%), and hand-foot syndrome (29%). G3 treatment-related AEs were reported in 9 pts (32%) (anemia, fatigue, diarrhea, hyponatremia, hypokalemia, rash, LDH and phosphatase alkaline increase) and G4 AST/ALT increase in one pt. Pts received a median of 2 cycles (1-14). Among 28 evaluable pts (5 ongoing), 5 had PR (prostate, colorectal, breast, and 2 thymic cancers), 12 SD (4 colorectal, 3 gastric, 2 pancreatic, 1 prostate, 1 breast, 1 bladder cancers) with a DCR of 61%. Median clinical benefit duration was 8 wks (2-43). Preliminary PK data suggest that S may alter L concentrations. Conclusions: The combination of L + S is safe and well tolerated. L 1250 mg + S 400 mg BID is the recommended dose for phase II trials. Preliminary evidence of anticancer activity has been observed. Updated clinical and biological data will be presented at the meeting.