A Study of ARRY-438162 (MEK162) in Patients With Advanced Cancer

• Establish the maximum tolerated dose (MTD) of the study drug. [ Time Frame: Part 1, one year ] [ Designated as safety issue: Yes ]
• Characterize the safety profile of the study drug in terms of adverse events, clinical laboratory tests and electrocardiograms. [ Time Frame: Parts 1, 2 and 3: two years ] [ Designated as safety issue: Yes ]
• Characterize the pharmacokinetics (PK) of the study drug and metabolite. [ Time Frame: Parts 1, 2 and 3: two years ] [ Designated as safety issue: No ]

• Characterize the safety profile of study drug [ Time Frame: 1 year, all patients will remain on study until progression of disease, unacceptable toxicity, or another discontinuation criterion is met ] [ Designated as safety issue: Yes ]
• Characterize the plasma PK of study drug and a metabolite [ Time Frame: 1 year, all patients will remain on study until progression of disease, unacceptable toxicity, or another discontinuation criterion is met ] [ Designated as safety issue: No ]
• Determine the maximum tolerated dose (MTD) of study drug through review of all available Cycle 1 data and assessment of dose limiting toxicities (DLTs) [ Time Frame: 1 year, all patients will remain on study until progression of disease, unacceptable toxicity, or another discontinuation criterion is met ] [ Designated as safety issue: Yes ]

• Assess the efficacy of the study drug in terms of tumor response, duration of response, duration of stable disease, progression-free survival and overall survival. [ Time Frame: Parts 1, 2 and 3: two years ] [ Designated as safety issue: No ]
• Assess possible PK/pharmacodynamic (PD) or PK/efficacy and safety correlations. [ Time Frame: Parts 1, 2 and 3: two years ] [ Designated as safety issue: No ]

• Obtain preliminary estimates of efficacy of study drug [ Time Frame: 1 year, all patients will remain on study until progression of disease, unacceptable toxicity, or another discontinuation criterion is met ] [ Designated as safety issue: No ]
• Assess body weight changes as a measure of clinical benefit of study drug [ Time Frame: 1 year, all patients will remain on study until progression of disease, unacceptable toxicity, or another discontinuation criterion is met ] [ Designated as safety issue: Yes ]
• Assess PD effects of study drug in pre- and post-dose serum, skin and hair follicle samples as feasible [ Time Frame: 1 year, all patients will remain on study until progression of disease, unacceptable toxicity, or another discontinuation criterion is met ] [ Designated as safety issue: No ]
• Assess mRNA and protein expression levels and mutation status in archival or fresh predose tumor tissue as feasible [ Time Frame: 1 year, all patients will remain on study until progression of disease, unacceptable toxicity, or another discontinuation criterion is met ] [ Designated as safety issue: No ]
• Assess possible PK/PD or PK/efficacy and safety correlations [ Time Frame: 1 year, all patients will remain on study until progression of disease, unacceptable toxicity, or another discontinuation criterion is met ] [ Designated as safety issue: No ]
• Characterize the metabolite profile of study drug in plasma [ Time Frame: 1 year, all patients will remain on study until progression of disease, unacceptable toxicity, or another discontinuation criterion is met ] [ Designated as safety issue: No ]
• Assess lean body mass changes as a potential measure of clinical benefit of study drug [ Time Frame: 1 year, all patients will remain on study until progression of disease, unacceptable toxicity, or another discontinuation criterion is met ] [ Designated as safety issue: No ]

This is a Phase 1 study during which patients with advanced solid tumors will receive investigational study drug ARRY-438162 (MEK162).

This study has 3 parts. In the first part, patients with advanced solid tumors will receive increasing doses of study drug in order to achieve the highest dose of the study drug possible that will not cause unacceptable side effects. Approximately 30 patients from the US will be enrolled in Part 1. (Active, not recruiting)

In the second part of the study, patients with advanced or metastatic biliary cancer will receive the best dose of study drug determined from the first part of the study and will be followed to see what side effects and effectiveness the study drug has, if any, in treating the cancer. Approximately 25 patients from the US will be enrolled in Part 2. (Active, not recruiting)

In the third part of the study, patients with metastatic colorectal cancer (CRC) will receive the best dose of the study drug determined from the first part of the study and will be followed to see what side effects and effectiveness the study drug has, if any, in treating the cancer. Approximately 25 patients with KRAS mutation (Active, not recruiting) and 15 patients with BRAF mutation (Active, not recruiting) from the US will be enrolled in Part 3.

• Advanced Solid Tumors
• Advanced or Metastatic Biliary Cancer
• Metastatic Colorectal Cancer

Key Inclusion Criteria (for Part 3):

• A histologically or cytologically confirmed diagnosis of colorectal adenocarcinoma which is metastatic (measurable disease).
• Documented KRAS- or BRAF- tumor mutation.
• Previously treated with or unsuitable for treatment with 5-Fluorouracil (5-FU), oxaliplatin, irinotecan and, if available, bevacizumab.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
• Additional criteria exist.

Key Exclusion Criteria (for Part 3):

• Uncontrolled or symptomatic brain metastases (if the patient has brain metastases and is on steroids, the steroid dose must have been stable for at least 30 days).
• History of central serous retinopathy, retinopathy visible at baseline that would be considered a risk factor for central serous retinopathy or retinal vein occlusion.
• Concomitant malignancies or previous malignancies with less than a 2-year disease free interval at the time of enrollment; patients with adequately resected basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or stage A low grade prostate cancer may enroll irrespective of the time of diagnosis.
• Prior treatment with a MEK inhibitor.
• Treatment with prior chemotherapy, anticancer immunotherapy, monoclonal antibodies or other protein or peptide therapeutics within 21 days of the first dose of study drug.
• Treatment with a small molecule targeted agent or anticancer hormonal therapy within 14 days of the first dose of study drug.
• Treatment with prior radiotherapy within 28 days of initiating study drug (if the radiation portal covered ≤ 10% of the bone marrow reserve, the patient may be enrolled irrespective of the end date of radiotherapy).
• Major surgery within 4 weeks or minor surgery within 7 days prior to the first dose of study drug.
• Known positive serology for the human immunodeficiency virus (HIV), hepatitis C, and/or active hepatitis B.
• Additional criteria exist.