Bevacizumab (B) plus everolimus (E) and panitumumab (P) in refractory advanced solid tumors.
3551 Background: In preclinical models, VEGF, mTOR, and EGFR inhibitors have anti-tumor and anti-angiogenesis effects as monotherapies and in combination. B inhibits VEGF; E inhibits mTOR; P inhibits EGFR. There is also potential for interaction between the pathways. Previously BE and BE + erlotinib were evaluated and showed signs of clinical activity. METHODS: Patients (pts) with refractory advanced solid tumors were accrued in a phase I dose escalation of B + E + P on a 28d cycle. Dose levels are shown in the table below. DLT was defined as any treatment-related grade 4 heme, grade 3/4 non-heme adverse event (AE), or receiving <85% any study drug in Cycle 1. Blood, skin, and tumor biopsies pre- and on-treatment were collected for correlative biomarkers of angiogenesis. RESULTS: At this time, 12 pts (3M: 9F) are evaluable for toxicity; 9 for efficacy. Median age: 54 years (range 23-72). 9 of 12 pts had prior B exposure. Dose level 1 was expanded due to 1/3 DLT, with total of 3/6 DLT (Grade (Gr) 3 mucositis (n=2), Gr3 hypokalemia (n=1)). Dose level -1 had 3/3 DLT (Gr3, Gr4 mucositis (n=2), Gr3 non-acneform rash (n=1)). Dose level -2 had 0/3 pts DLT. Gr 3-4 related toxicities in cycle 2+: hypokalemia (n=4); hypophosphatemia (n = 1); hypomagnesemia (n = 1); diarrhea (n=1); hoarseness (n=1). Other events of interest were: Gr1-2 mucositis (n=7); Gr1 hyperlipidemia (n=5); Gr1-2 hyperglycemia (n=4); Gr2 hypertension (n=2); Gr1-2 neutropenia (n=5); Gr1-2 thrombocytopenia (n=5). 8/9 evaluable pts had SD as best response (median 26 wks, range 8+ to 32+ wks): 1 pt with pancreatic cancer and progression on 2 prior EGFR inhibitors had prolonged 32+ wk SD. There was 1 minor response (23.3%) in a pt with bevacizumab-refractory ovarian cancer (32+ wks). No CR or PR were seen. CONCLUSIONS: B + E + P at full doses has dose limiting toxicities of rash and mucositis. B 10 mg/kg q2wks + E 5 mg q48h + P 4.8 mg/kg q2wks is the maximum tolerated dose. This dose is currently being expanded in 20 patients with extensive pre- and on-treatment biomarker analyses. Updated clinical and biomarker data will be presented. [Table: see text] [Table: see text].
Howard, LA; Bullock, KE; Bendell, JC; Uronis, HE; Vlahovic, G; Blobe, GC; Riedel, RF; Nixon, AB; Gockerman, JP; Hurwitz, HI
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