Malhotra, Usha

609 Background: Targeting MEK is of interest in the development of novel agents for treatment of many malignancies. However, better strategies are needed to overcome acquired resistance to MEK inhibitors. Preclinical studies have shown Wnt pathway overexpression in KRAS mutant cell lines resistant to the MEK inhibitor, Selumetinib. The combination of selumetinib and cyclosporin A (CsA), a non-canonical WnT pathway modulator, demonstrated antitumor activity in patient-derived xenograft (PDX) models. We are conducting an NCI CTEP-approved Phase I/IB trial (NCI # 9571/COMIRB # 13-2628) of selumetinib and CsA combination. Biomarkers of response to therapy are being co-developed. We hypothesize that this combination will be safe and potentially effective in patients with mCRC and that upregulation of FZD2 may predict for sensitivity. Methods: Phase I trial with initial dose escalation investigating the combination of selumetinib and CsA in patients with advanced solid tumors (n = 18) followed by an expansion cohort in patients with irinotecan and oxaliplatin-refractory mCRC (n = 20). The expansion cohort utilizes a selumetinib “run-in” to evaluate efficacy in RAS-WT and RAS-MT mCRC to identify those patients most likely to respond to the combination. Results: 18 patients were enrolled in the dose escalation phase and 10 patients have been enrolled in the dose expansion phase as of September 2016. Grade 1 or 2 nausea and rash were reported as the most common AEs. Most commonly reported Grade 3 or 4 toxicities were hypertension, elevated liver enzymes and rash. Three DLTs were reported with Grade 3 hypertension noted at dose level 1 and 2 and grade 3 rash reported at dose level 2. The maximum tolerated dose was defined as Selumetinib 75 mg BID and CsA 2 mg/kg BID on a 28-day cycle. Two partial responses and sixteen stable disease responses have been observed. Six patients have exhibited progressive disease. Conclusions: Selumetinib in combination with cyclosporin A appears to be well-tolerated with evidence of activity in solid tumors. Expansion cohort will complete enrollment this month. Clinical trial information: NCT02188264.

Objectives: Vascular endothelial growth factor overexpression, seen in 42% to 76% of biliary tract cancers (BTCs), correlates with poor survival. We explored the safety/efficacy and potential biomarkers for bevacizumab in combination with gemcitabine-capecitabine in advanced BTCs. Patients and Methods: Inoperable stage III/IV BTC patients in our prospective study were given 1000 mg/m 2 of gemcitabine (on days 1, 8), 650 mg/m 2 of capecitabine (on days 1 to 14), and 15 mg/kg of bevacizumab (on day 1) in 21-day cycles. Circulating tumor cells and quality of life were assessed at baseline and before cycle 2 and 3. Results: In total, 50 patients with gallbladder cancer (22%), intrahepatic (58%), and extrahepatic (20%) cholangiocarcinoma, received a median of 8 treatment cycles for median treatment duration of 5.8 months. Common grade 3/4 toxicities were neutropenia (36%), thrombocytopenia (16%), fatigue (20%), infections (14%), and hand-foot syndrome (10%). There were 12 partial response (24%), 24 stable disease (48%) with clinical benefit rate of 72%. Median progression-free survival was 8.1 months (95% confidence interval, 5.3-9.9). Median overall survival was 10.2 months (95% confidence interval, 7.5-13.7). Circulating tumor cells were identified at baseline in 21/46 patients (46%), who had lower median overall survival compared with those without (9.4 vs. 13.7 mo; P =0.29). Patients with quality of life scores greater than the group median by the end of first cycle of treatment had improved survival compared with those who did not (13.3 vs. 9.4 mo; P =0.39). Conclusions: Addition of bevacizumab to gemcitabine/capecitabine did not improve outcome in an unselected group of patients with advanced BTC compared with historical controls. The selective benefit of vascular endothelial growth factor inhibition in BTC remains to be explored.