MEK Inhibitor MEK162 in Combination With Leucovorin Calcium, Fluorouracil, and Oxaliplatin in Treating Patients With Advanced Metastatic Colorectal Cancer

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) for the combination of MEK162 (MEK inhibitor
MEK162) plus leucovorin calcium, fluorouracil, oxaliplatin (FOLFOX) in patients with
metastatic colorectal cancer.

SECONDARY OBJECTIVES:

I. Describe the safety of the combination of MEK162 across all investigated dose levels.

II. Describe the pharmacokinetics of MEK162 and FOLFOX in 6 patients in the expanded MTD
cohort.

III. Describe any clinical activity to the combination using Response Evaluation Criteria in
Solid Tumors (RECIST) 1.1 criteria.

IV. Determine the recommended Phase II dose (RP2D) which may be less than the MTD for both
intermittent and continuous dosing of MEK162.

OUTLINE: This is a dose-escalation study of MEK inhibitor MEK162. Patients are assigned to 1
of 2 treatment arms.

ARM I: Patients receive MEK inhibitor MEK162 orally (PO) twice daily (BID) on days 1-14, and
leucovorin calcium intravenously (IV) over 2 hours, oxaliplatin IV over 2 hours, and
fluorouracil IV continuously over 46 hours on days 1 and 2. Courses repeat every 14 days in
the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive MEK inhibitor MEK162 PO BID on days 1-5, and leucovorin calcium IV
over 2 hours, oxaliplatin IV over 2 hours, and fluorouracil IV continuously over 46 hours on
days 6 and 7. Courses repeat every 14 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Patients with pathologically confirmed colon or rectal cancer who have received and
progressed or failed following a fluoropyrimidine, irinotecan, and oxaliplatin based
chemotherapy regimens will be eligible for this study; patients who have a known
Kirsten rat sarcoma viral oncogene homolog (KRAS)/v-raf murine sarcoma viral oncogene
homolog B (BRAF) wild type tumor should have progressed or failed following cetuximab
or panitumumab based chemotherapy; prior bevacizumab or regorafenib exposure is not
mandated on this study as some patients are deemed poor candidates for
anti-angiogenesis therapy and never receive these agents

- Patients should have measurable disease defined as a minimum of one tumor measuring >=
10 mm on computed tomography (CT) scans

- Signed written informed consent

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

- Hemoglobin (Hgb) >= 9 g/dL without transfusions

- Platelets (PLT) >= 100 x 10^9/L without transfusions

- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =< 2.5 × upper
limit of normal (ULN); patient with liver metastases =< 5 ×ULN

- Total bilirubin =< ULN

- Creatinine =< 1.5 mg/dL

- Left ventricular ejection fraction (LVEF) >= 50% as determined by a multigated
acquisition (MUGA) scan or echocardiogram

- Corrected QT (QTc) interval =< 480 ms

- Able to take oral medications

- Patient is deemed by the investigator to have the initiative and means to be compliant
with the protocol (treatment and follow-up)

- Negative serum beta-human chorionic gonadotropin (HCG) test (female patient of
childbearing potential only) performed locally within 72 hrs prior to first dose

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1

Exclusion Criteria:

- History or current evidence of retinal vein occlusion (RVO) or current risk factors
for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity
or hypercoagulability syndromes)

- Patients who have had chemotherapy, biologic, targeted, or radiotherapy within 4 weeks
prior to entering the study or those who have not recovered from grade 2 and above
adverse events due to agents administered more than 4 weeks earlier (with the
exception of alopecia or neuropathy)

- History of retinal degenerative disease

- History of Gilbert's syndrome

- Previous or concurrent malignancy with the following exceptions:

- Adequately treated skin basal cell or squamous cell carcinoma (adequate wound
healing is required prior to study entry)

- In situ carcinoma of the cervix, treated curatively and without evidence of
recurrence

- A primary malignancy which has been completely resected and in complete remission
for >= 1 years

- Prior therapy with a MEK- inhibitor

- History of acute coronary syndromes (including myocardial infarction, unstable angina,
coronary artery bypass grafting [CABG], coronary angioplasty, or stenting) < 6 months
prior to screening

- Impaired cardiovascular function or clinically significant cardiovascular diseases,
including any of the following: symptomatic chronic heart failure; evidence of
clinically significant cardiac arrhythmias and/or conduction abnormalities < 6 months
prior to screening except atrial fibrillation and paroxysmal supraventricular
tachycardia

- Uncontrolled arterial hypertension despite appropriate medical therapy (defined as
systolic blood pressure > 160 or diastolic blood pressure > 100)

- Known positive serology for human immunodeficiency virus (HIV), active hepatitis B,
and/or active hepatitis C infection

- Patients who have neuromuscular disorders that are associated with elevated creatine
kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral
sclerosis, spinal muscular atrophy)

- Patients who are planning on embarking on a new strenuous exercise regimen after first
dose of study treatment; NB: muscular activities, such as strenuous exercise, that can
result in significant increases in plasma CK levels should be avoided while on MEK162
treatment

- Impairment of gastrointestinal function or gastrointestinal disease (e.g., active
ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome,
small bowel resection)

- Any other condition that would, in the investigator's judgment, contraindicate the
patient's participation in the clinical study due to safety concerns or compliance
with clinical study procedures, e.g., infection/inflammation, intestinal obstruction,
unable to swallow medication, social/ psychological issues, etc.

- Patients who have undergone major surgery =< 3 weeks prior to starting study drug or
who have not recovered from side effects of such procedure

- Pregnant or nursing (lactating) women confirmed by a positive hCG laboratory test

- Women of child-bearing potential unless they are using highly effective methods of
contraception throughout the study and for 60 days after study drug discontinuation

- Sexually active males unless they use a condom during intercourse while taking the
drug and for 60 days after stopping treatment and should not father a child in this
period; a condom is required to be used also by vasectomized men

- Medical, psychiatric, cognitive or other conditions that may compromise the patient's
ability to understand the patient information, give informed consent, comply with the
study protocol or complete the study

- Current grade 3 or higher neuropathy

- Use of other investigational drugs

- Known hypersensitivity to any components of the study drugs

- Prior intolerance to fluorouracil (5-FU) or oxaliplatin, excluding severe neuropathy
that reversed to grade 2 or less