1. Phase I Trial Of FOLFIRI In Combination With Sorafenib And Bevacizumab In Patients With Advanced Gastrointestinal Malignancies Background: Background: Sorafenib inhibits various pro- angiogenesis pathways including PDGFR-B, a factor associated with resistance to anti-VEGF therapy. A previous phase II trial in patients with chemorefractory metastatic CRC demonstrated a 63% disease control rate with a combination of bevacizumab (BEV) and sorafenib. This phase I trial sought to determine the MTD of BEV and sorafenib combined with standard cytotoxic therapy for advanced gastrointestinal (GI) cancers. Methods: Patients with advanced GI malignancies appropriate for irinotecan-based therapy were enrolled (14 with CRC, 3 gastroesophageal). A standard 3 + 3 design was used with 3 escalating sorafenib dose levels (DL): (1) 200 mg po daily, days 3- 7, 10-14; (2) 200 mg po twice daily, days 3-6, 10-13; and (3) 200 mg po twice daily, days 3-7, 10-14. FOLFIRI: irinotecan 180 mg/m 2 d1, leucovorin 400 mg/m2 d1, 5-fluorouracil (FU) bolus 400 mg/m 2 d1, 5-FU infusion 2400 mg/m 2 d1-2 and BEV 5 mg/kg d1. 1 cycle = 14 days. Results: Seventeen pts were enrolled, median age of 56 (range 32 and 81). Two pts were replaced, as they did not complete DLT evaluation, leaving 15 evaluable pts. Four evaluable pts at DL1 and 6 pts at DL2 had no DLTs. At DL 3, the first cohort of 3 pts did not experience any DLTs. In the second cohort of 3 pts, 2 pts experienced DLTs (asymptomatic G3 hypophosphatemia, G3 dehydration and diarrhea). MTD was determined to be DL2: sorafenib 200 mg PO twice daily, days 3-6, 10-13 combined with FOLFIRI and BEV at standard doses. Of the 15 evaluable pts, 4 pts had PR, 8 pts had SD as best response, 1 pt had PD, and 2 pts discontinued treatment prior to first tumor assessment. The median number of cycles was 10 (range 1 -37). Three pts with CRC had disease control > 12 months. Conclusions: The MTD of this regimen is sorafenib 200 mg PO twice daily, Days 3-6,10-13 combined with standard doses of FOLFIRI and BEV. Dual VEGF inhibition combined with cytotoxic therapy may provide prolonged disease stabilization for select patients with advanced GI malignancies. Supported by CA69912 and CA15083 Abstract Patients with advanced gastrointestinal malignancies deemed appropriate for irinotecan-based therapy were enrolled on the study Inclusion criteria: ≥18 years of age Adequate hematologic function (ANC ≥ 1500/μL, PLT ≥ 100,000/μL, Hgb ≥ 9.0 gm/dL) Alkaline phosphatase ≤ 3 x ULN AST ≤ 3 x ULN or AST ≤ 5 x ULN if liver involvement INR < 1.5 or INR ≤ 3.0 on anticoagulation UPC ratio < 1 or urine dipstick < 2+ Creatinine ≤ 1.5 x ULN (CrCl ≥ 45 ml/min) ECOG PS 0 or 1 Life expectancy > 3 months Exclusion criteria: Prior sorafenib use (prior FOLFIRI + bev allowed) Inadequately controlled hypertension, recent aterial thrombotic event, recent hemorrahge or bleeding diasthesis, nonhealing wound, h/o fiistula, perforation, or abscess within 6 months, recent surgical procedure, known brain metastasis Study Population Figure 3 Standard 3 + 3 Dose escalation phase I design Chemotherapy consisted of standard doses of FOLFIRI + bevacizumab: irinotecan 180 mg/m 2 day 1 leucovorin 400 mg/m 2 day 1 5-FU bolus 400 mg/m 2 day 1 5-FU 46 hour infusion 2400 mg/m2 days 1-2 bevacizumab 5 mg/kg day 1 sorafenib per dose cohort 1 Cycle = 2 weeks Patients were monitored for 2 cycles (28 days) to assess for dose-limiting toxicity (DLT) prior to dose escalation Safety Dual VEGF inhibition (bevacizumab + sorafenib) can safely be combined with cytotoxic chemotherapy (FOLFIRI) The MTD was determined to be dose level 2: FOLFIRI + bevacizumab + sorafenib 200 mg bid, days 3-6, 10-13 The majority of adverse events can be explained by FOLFIRI and/or bevacizumab alone Several patients received sustained benefit for a prolonged duration greater than 1 year Continued research is warranted to identify biomarkers to predict which patients may benefit from antiangiogenesis therapy and whether dual VEGF inhibition plays a role in the prevention or treatment of bevacizumab resistance Conclusions Patient CharacteristicsBackground: © 2014 Mayo Foundation for Medical Education and Research Objectives The primary objective of this study: To determine the maximally tolerated dose of the combination of FOLFIRI plus sorafenib plus bevacizumab Secondary objectives of this study: To assess the safety of FOLFIRI plus sorafenib plus bevacizumab To assess the feasibility of the proposed combination To evaluate the response rate and identify any activity of the proposed combination Joleen Hubbard 1, George Kim 2, Mitesh Borad 3, Rui Qin 1, Janet Lensing 1, John Wright 4, Charles Erlichman 1, Axel Grothey 1 1 Mayo Clinic Rochester, MN, 2 Mayo Clinic Jacksonville, FL, 3 Mayo Clinic Scottsdale, AZ, 4 Investigational Drug Branch CTEP First line therapy for metastatic colorectal cancer (mCRC) frequently consists of FOLFOX + bevacizumab Second line therapy for mCRC commonly consists of FOLFIRI + continued VEGF inhibition (with bevacizumab or aflibercept), especially for RAS mutant tumors that are unresponsive to EGFR antibodies Mechanisms of resistance in response to treatment with bevacizumab include upregulation of non-VEGF pro-angiogenesis pathways including PDGRF-B and FGF (Kopetz JCO 2010) Sorafenib is a multikinase inhibitor targeting several serine/threonine and receptor tyrosine kinases including all VEGF- receptors, Raf, PDGFR-B, and FGFR-1. Dual VEGF inhibition therapy with bevacizumab and sorafenib may have several effects: Completing VEGF blockade by targeting all 3 VEGF-receptors Targeting mechanisms of VEGF resistance (PDGF, FGF) Downstream antiproliferative effects (Ras-Raf-MEK pathway) A previous phase II trial (N054C) testing combination bevacizumab and sorafenib demonstrated a mPFS 3.5 months and mOS 8.3 months in patients with chemorefractory mCRC Study Design 17 patients enrolled between August 2011 and February 2013 14 patients with mCRC 2 patients with metastatic esophageal adenocarcinoma 1 patient with metastatic gall bladder adenocarcinoma 15 patients were evaluable for DLT evaluation 4 patients were enrolled at dose level 1 (1 experienced dehydration & hospitalization prior to 1 st dose of sorafenib and replaced). No DLTs in remaining 3 patients. No DLTs in 3 patients enrolled at dose level 2, cohort 1. The first 4 patients at dose level 3 had no DLTs (one replaced due to incorrect dosing), 2 patients experienced DLTs in the 2 nd cohort at dose level 3 (see chart) No patients experienced DLT in the 2 nd cohort of dose level 2 The MTD was determined to be dose level 2: FOLFIRI + bevacizumab + sorafenib 200 mg bid, days 3-6, 10-13 MTD Determination Median 12 cycles received (range 1 - 46) 3 patients remained on study for > 1 year 1 patient remains on study at cycle 46 on bevacizumab + sorafenib maintenance Efficacy and Follow-up 13 (76.5%) of patients experienced grade 3+ adverse events that were at least possibly related to treatment *This patient had prior radiation therapy for esophageal adenocarcinoma