Trametinib in Treating Patients With Progressive Metastatic Hormone-Resistant Prostate Cancer

PRIMARY OBJECTIVES I. To assess the activity of trametinib in metastatic castration resistant
prostate cancer (mCRPC) that has progressed on either enzalutamide or abiraterone acetate.

SECONDARY OBJECTIVES I. Durability of prostate specific antigen (PSA) response as measured by
the time to PSA progression as defined by Prostate Cancer Working Group 2 guidelines for PSA
progression.

II. Maximal PSA response. III. Quality of life by Functional Assessment of Cancer Therapy-
Prostate (FACT-P).

IV. Time to initiation of alternative antineoplastic therapy. V. Time to radiographic
progression. VI. Objective response rate according to Response Evaluation Criteria in Solid
Tumors (RECIST) guidelines.

VII. Overall survival measured as time from enrollment until death. VIII. Safety and
tolerability. IX. Analysis of trametinib target engagement of mitogen-activated extracellular
signal-related kinase (MEK1/2) is assessed by presence of p-ERK, the primary phosphorylation
target of activated MEK1/2, in pre-treatment and at progression radiographically directed
metastatic tumor biopsies by immunohistochemistry evaluation of p-ERK. Markers of cell
proliferation (Ki67) and apoptosis (p27) will also be assessed.

XI. Investigation of molecular correlates to resistance and sensitivity to trametinib using
pre-treatment and at progression metastatic biopsies.

XII. Discovery of one or a set of possible discriminative networks that are associated with a
response to trametinib.

XII. Enrichment for patients in the second phase who have tumors exhibiting genomic features
associated with a response to trametinib.

XIV. Analyses of circulating tumor deoxyribonucleic acid (ctDNA) for genomic aberrations
correlated to treatment response.

OUTLINE:

Patients receive trametinib orally (PO) once daily (QD). Treatment continues in the absence
of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 2 and 4 weeks, and then
every 4 weeks thereafter.

Inclusion Criteria:

- Willing and able to give informed consent

- Histologically confirmed prostate cancer (not exclusive of adenocarcinoma)

- mCRPC that has progressed on at least 1 therapy progression (defined as Prostate
Cancer Working Group 2 [PCWG2] or at investigators' discretion) approved for treatment
of mCRPC, one of which must include abiraterone acetate and/or enzalutamide

- Metastatic tumor that has been biopsied

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

- Willing to undergo biopsy of a metastatic lesion at the time of progression

- Patients must have ongoing therapy to maintain serum testosterone < 50 ng/dL

- Absolute neutrophil count > 1,500/uL during screening evaluation

- Platelet count > 100,000/uL during screening evaluation

- Hemoglobin > 9 g/dL during screening evaluation

- Total bilirubin within the reference range during screening evaluation

- Alanine aminotransferase (ALT) within the reference range during screening evaluation

- Aspartate aminotransferase (AST) within the reference range during screening
evaluation

- Creatinine < (1.5 mg/dL) during screening evaluation (> 1.5 is allowed if epidermal
growth factor receptor [EGFR] > 45 mL/min/1.73 m^2)

- International normalized ratio (INR) < 1.3 (or < 3 if on warfarin or other
anticoagulants) during screening evaluation

- Left ventricular ejection fraction (LVEF) >= 45% as measured by echocardiogram during
screening evaluation

- Electrocardiogram (EKG) without clinically significant abnormality

Exclusion Criteria:

- A history of retinal vein occlusion (RVO) or risks factors for RVO

- A history of retinal pigment epithelial detachment (RPED) or risk factors for RPED

- Clinically significant abnormality on ophthalmologic examination during screening
evaluation

- Clinically significant cardiovascular disease including:

- LVEF < 45% measured by echocardiogram

- History of acute coronary syndromes (including myocardial infarction and unstable
angina), coronary angioplasty, or stenting within 6 months

- Uncontrolled angina within 3 months

- New York Heart Association (NYHA) class III or IV congestive heart failure

- Clinically significant abnormality on EKG

- History of clinically significant ventricular arrhythmias (e.g., ventricular
tachycardia, ventricular fibrillation, torsades de pointes)

- Patients with intra-cardiac defibrillators or permanent pacemakers

- Presence of a comorbid disease or medical condition that would impair the ability of
the patient to receive or comply with the study protocol

- History of interstitial lung disease or pneumonitis

- Use of any medication or herbal products that may have hormonal anti-prostate cancer
activity and/or are known to modulate PSA levels (e.g., saw palmetto) or systemic
corticosteroids greater than the equivalent of 10 mg of prednisone per day within 4
weeks of enrollment

- Prior use of trametinib or other mitogen activated protein kinase (MAPK) inhibitor in
any context

- Known or suspected brain metastasis or active leptomeningeal disease or spinal cord
compression

- Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer
disease within last 3 months, inflammatory bowel disease)

- Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity,
biologic therapy, or immunotherapy within 30 days of enrollment and/or daily or weekly
chemotherapy without the potential for delayed toxicity within 14 days of enrollment

- Hospitalization within 30 days of enrollment for cancer related events

- History of another malignancy within the previous 5 years other than curatively
treated non-melanoma skin cancer

- Use of an investigational agent within 4 weeks of enrollment

- Use of any medications known to affect the serum androgen level

- Any condition or reason that, in the opinion of the investigator, interferes with the
ability of the patient to participate in the trial, which places the patient at undue
risk, or complicates the interpretation of safety data