Study of Trametinib in Advanced Cancer Patients With Hepatic Dysfunction

Patients will be separated into the following groups: Group A: Normal hepatic function,
Group B: Mild hepatic dysfunction, Group C: Moderate hepatic dysfunction, Group D: Severe
hepatic dysfunction

Groups of 3-6 patients to take part in each group will receive increasing doses of the study
drug to until the best dose of study drug for each hepatic function group is found.

Trametinib is an oral drug that works by blocking mitogen-activated extracellular signal
regulated kinase (MEK) 1 and MEK 2. MEK1 and MEK2 are important proteins that are needed for
the growth of cells. When these proteins are blocked, it is believed that the growth of
cancer cells will stop and the cancer cells will then die.

Inclusion Criteria:

- Histologically or cytologically confirmed solid malignancy that is metastatic or
unresectable for which standard curative or palliative treatments do not exist or are
no longer effective. Excludes: Pancreatic cancer patients, colorectal cancer
patients, or BRAF V600E melanoma patients who have failed BRAF inhibitors

- Must have completed any prior treatments 28 days or more before study entry.

- 18 years of age or older.

- ECOG performance status 2 or less.

- Life expectancy of greater than 3 months.

- Able to swallow and retain orally-administered medication and does not have any
clinically significant gastrointestinal abnormalities that may alter absorption.

- All prior treatment-related toxicities must recovered to an acceptable grade at the
time of enrollment.

- Must have normal organ (except liver function) and marrow function

- Patients with abnormal hepatic function will be eligible.

- Women of child-bearing potential must have a negative serum pregnancy test within 14
days prior to randomization. Women of child-bearing potential and men must agree to
use adequate contraception prior to study entry, during the study participation, and
for four months after the last dose of the drug.

- Ability to understand and the willingness to sign a written informed consent
document.

Exclusion Criteria:

- History of another malignancy.

- History of interstitial lung disease or pneumonitis.

- Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity,
biologic therapy, or immunotherapy within 21 days prior to enrollment and/or daily or
weekly chemotherapy without the potential for delayed toxicity within 14 days prior
to enrollment.

- Use of other investigational drugs within 28 days (or five half-lives, whichever is
shorter; with a minimum of 14 days from the last dose) preceding the first dose of
trametinib and during the study. Patients previously treated with RAF and/or MEK
inhibitors are excluded from the study.

- Symptomatic or untreated leptomeningeal or brain metastases or spinal cord
compression.

- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to trametinib or excipients or to dimethyl sulfoxide (DMSO).

- Current use of a prohibited medication. The following medications or non-drug
therapies are prohibited:

- Other anti-cancer therapy.

- Concurrent treatment with bisphosphonates is permitted; however, treatment must
be initiated prior to the first dose of study therapy. Prophylactic use of
bisphosphonates in patients without bone disease is not permitted, except for
the treatment of osteoporosis.

- Herbal supplements

- History or current evidence/risk of retinal vein occlusion (RVO) or central serous
retinopathy (CSR)

- History or evidence of cardiovascular risk

- Active Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (patients with
chronic or cleared HBV and HCV infection are eligible). Patients with known HIV
infection are eligible if not on antiviral agents and CD4 counts are adequate (500 or
greater).

- Uncontrolled intercurrent illness that would limit compliance with study
requirements.

- Pregnant women or nursing mothers.

- HIV-positive patients on combination antiretroviral therapy.

- Any condition or medical problem in addition to the underlying malignancy and organ
dysfunction which the investigator feels would pose unacceptable risk.