A Phase I Study of MEK162 and FOLFOX in chemotherapy-resistant metastatic colorectal cancer May Cho, Dean Lim, Timothy Synold, Paul Frankel, Lucille Leong, Joseph Chao, Vincent Chung, Yuan Chen, Stephen Sentovich, Eloise Luevanos and Marwan Fakih City of Hope National Medical Center, Duarte, CA. Purpose: Pre-clinical studies have shown that the combination of MEK inhibitors and 5-FU improves antitumor activity and that MEK inhibition overcomes both 5FU and platinum resistance. This phase I study was conducted to determine the maximum tolerated dose (MTD) of the combination MEK162 and FOLFOX. Patients and Methods: Patients (pts) with metastatic colon or rectal cancer who progressed or failed prior 5FU, irinotecan, oxaliplatin and anti-EGFR therapy (in cases of RAS wild type tumors) received twice daily MEK162 in combination with every-2-week FOLFOX. Two dose levels of MEK162 (30mg and 45mg) were investigated in a standard escalation design in combination with standard doses of FOLFOX without bolus 5-FU. Dose limiting toxicity (DLT) was defined as any treatment-related grade (G) 3 or 4 non-hematological toxicity (with the exception of G3 diarrhea or vomiting < 48 hrs) or G 4 neutropenia or thrombocytopenia within the first 2 cycles (4 weeks) of the treatment. Limited pharmacokinetic (PK) analysis of 5FU, oxaliplatin and MEK162 was performed at the MTD level. Results: 16 pts were enrolled in the continuous arm (median age (range) 53 yrs (49-78); 11 men; ECOG 0/1 in 9/7 patients). No DLT was noted on the study. The MTD of MEK162 was 45 mg PO BID. An additional 6 pts (for a total of 12) were enrolled at the MTD for PK analysis and none of them developed DLT defining toxicities. A median of 8 cycles (range 1-19) was administered. Treatment- related ≥ grade 3 toxicities included anaphylaxis due to oxaliplatin (n=1), CPK elevation (n=2), neutropenia (n=1), peripheral neuropathy (n=3), thrombocytopenia (n=1), retinal vascular disorder (n=1), and acneiform rash (n=1). 10 pts had SD at 2 months (m) by radiographic assessment, 5 of whom with stabilizations of > 4 months (4-10 months). Conclusions: The combination of continous MEK162 and FOLFOX has a manageable toxicity profile and promising antitumor activity in heavily pretreated metastatic colorectal cancer patients. INTRODUCTION ABSTRACT RESULTS  MEK162 is a potent and selective allosteric, ATP non-competitive inhibitor of Mek1/2 that is active in inhibiting pERK and growth of BRAF mutant cancer cells in the low nanomolar range.  FOLFOX chemotherapy is one of the most commonly used first line chemotherapy regimen and has proven efficacy in first, second and third line settings. However, the development of eventual refractoriness to this combination is common and strategies to improve FOLFOX efficacy and reverse FOLFOX resistance are needed.  Preclinical studies have shown that the combination of MEK inhibitors and platinum improves tumor kill and overcomes platinum resistance.  Platinum resistance has been shown to be associatated with ERCC-1 over-expression and Epithelial Mesenchemal Transformation (EMT), both of which are reversed with MEK inhibition in pre-clinical models.  The combination of MEK162 with 5-FU and oxaliplatin chemotherapy in colorectal xenograft models has been associated with increased antitumor activity in comparison to 5-FU and oxaliplatin alone (Investigator Brochure), adding further support to the investigation of this combination.  The goal of the study is to determine the feasibility of combining MEK162 and FOLFOX and to determine the maximum tolerated dose of this combination. METHODS  Patients with metastatic colon or rectal cancer who progressed or failed prior 5FU, irinotecan, oxaliplatin and anti-EGFR therapy (in cases of RAS wild type tumors) received twice daily MEK162 in combination with every-2-week FOLFOX.  Two dose levels of MEK162 (30mg and 45mg) were investigated in a standard escalation design in combination with standard doses of FOLFOX without bolus 5-FU.  Once the MTD was defined, an itermittant MEK162 dosing regimen was investigated.  Dose limiting toxicity (DLT) was defined as any treatment-related grade (G) 3 or 4 non-hematological toxicity (with the exception of G3 diarrhea or vomiting < 48 hrs) or G 4 neutropenia or thrombocytopenia within the first 2 cycles (4 weeks) of the treatment.  Limited pharmacokinetic (PK) analysis of 5FU, oxaliplatin and MEK162 was performed at the MTD level. Total Mean Age years (49- 78) ECOG Sex Female Male 5 11 Race Asian African American White Hispanic Pacific Islander Primary lesion Rectal Left colon Right colon RAS status Wild type Mutant 7979 Table 1. Baseline characteristics of metastatic colorectal cancer patients Table 2. Toxicities Figure 1. RAS status and PFS in days  No DLT was noted on the study.  The MTD of MEK162 was 45 mg PO BID.  A median of 8 cycles (range 1-19) was administered for continuous MEK dosing arm.  Treatment-related ≥ grade 3 toxicities included anaphylaxis due to oxaliplatin (n=1), CPK elevation (n=2), neutropenia (n=1), peripheral neuropathy (n=3), thrombocytopenia (n=1), retinal vascular disorder (n=1), and acneiform rash (n=1).  10 pts had SD at 2 months (m) by radiographic assessment, 5 of whom with stabilizations of > 4 months (4-10 months).  There were no significant differences in either 5-FU or oxaliplatin PK's with versus without MEK162. In addition, the data for both 5-FU and oxaliplatin are similar to previously published results with FOLFOX alone.  The combination of continuous MEK162 and FOLFOX has a manageable toxicity profile and promising antitumor activity in heavily pretreated metastatic colorectal cancer patients. CONCLUSION Table 3. Pharmacokinetics of 5FU and Oxaliplatin without MEK (cycle 1) and with MEK162 (cycle 2) PFS (days) N=16Grade(1-2)Grade(3-4) Peripheral neuropathy73 CPK elevation62 Retinal vascular disorder01 Mucositis40 Nausea and vomiting60 Diarrhea50 Rash71 Anaphylaxis01 Fatigue70 Renal Toxicity20 Hepatotoxicity80 Infection10 Neutropenia31 Anemia50 Thrombocytopenia61 Hypertension40 Cycle 1Cycle 2 Pt#1 Pt#2 Pt#3 Pt#4 Pt#5 Pt# ND Avg SD Cycle1 Cmax AUC T 1/2 (ug/L) (ug/L xhr) (hr) Cycle1 Cmax AUC T 1/2 (ug/L) (ug/L xhr) (hr) Pt#1 Pt#2 Pt#3 Pt#4 Pt#5 Pt# ND ND ND Avg SD FU Steady-State levels (ng/ml) Total Oxaliplatin Pharmacokinetics