Trametinib, Fluorouracil, and Radiation Therapy Before Surgery in Treating Patients With Stage II-III Rectal Cancer

PRIMARY OBJECTIVES:

I. To identify the maximally tolerated dose and recommended phase II dose of trametinib to be
used in combination with 5FU (fluorouracil) and radiation in patients with rectal cancers.

II. To determine a recommended phase II dose of trametinib to be used with 5FU chemoradiation
in patients with locally advanced rectal cancer.

SECONDARY OBJECTIVES:

I. Evaluation of the tolerability and safety of the combination of trametinib and 5-FU
chemoradiation in locally advanced rectal cancer.

II. Evaluation of post-therapy pathologic response.

III. Evaluation of the rate of local control, disease-free survival and overall survival.

IV. Analysis of biomarkers - total mutations in v-Ki-ras2 Kirsten rat sarcoma viral oncogene
homolog (KRAS), v-raf murine sarcoma viral oncogene homolog B1(BRAF), and neuroblastoma RAS
viral (v-ras) oncogene homolog (NRAS), as well as RAS/mitogen-activated protein kinase (MAPK)
and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/v-akt murine thymoma viral oncogene
homolog 1 (AKT) pathway signaling pathways to potentially correlate with clinical benefit.

OUTLINE: This is a dose-escalation study of trametinib.

Patients receive trametinib orally (PO) once daily (QD) on days -14 to -10 and 1-38 and
fluorouracil intravenously (IV) continuously 5 days a week from days 1-38. Patients also
undergo radiation therapy 5 days a week on days 1-33. Patients then undergo surgery 6-10
weeks later.

Patients achieving negative surgical margins after complete resection of tumor receive
postoperative chemotherapy comprising leucovorin calcium IV over 2 hours and fluorouracil IV
continuously over 46 hours on days 1 and 15 OR oxaliplatin IV over 2 hours, leucovorin
calcium IV over 2 hours and fluorouracil IV continuously over 46 hours on days 1 and 15.
Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, and
then annually for 3 years.

Inclusion Criteria:

- All prior treatment-related toxicities must be Common Terminology Criteria for Adverse
Events (CTCAE) (version 4.0) =< grade 1 (except alopecia) at the time of enrollment

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

- Hemoglobin >= 9 g/dL

- Platelets >= 100 x 10^9/L

- Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 x upper limit of
normal (ULN)

- Partial thromboplastin time (PTT) =< 1.5 x ULN

- Albumin >= 2.5 g/dL

- Total bilirubin =< 1.5 x ULN

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN

- Creatinine =< 1.5 ULN or calculated creatinine clearance >= 50 mL/min or 24-hour urine
creatinine clearance >= 50 mL/min

- Left ventricular ejection fraction (LVEF) >= lower limit of normal (LLN) by
echocardiogram (ECHO) or multi gated acquisition scan (MUGA)

- Life expectancy of at least 3 months in the opinion of investigator

- Able to swallow and retain orally administered medication and does not have any
clinically significant gastrointestinal abnormalities that may alter absorption such
as malabsorption syndrome or major resection of the stomach or bowels

- Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Ability to provide written informed consent obtained prior to participation in the
study and any related procedures being performed

- Women of child-bearing potential (WOCBP) must have a negative pregnancy test within 14
days of the first administration of study treatment, and counseled on
contraception/abstinence while receiving the study treatment; urine human chorionic
gonadotropin (HCG) is an acceptable pregnancy assessment

- A histologically confirmed rectal cancer with measurable or evaluable disease on
imaging or endoscopy

- Stage II or III disease by the American Joint Committee on Cancer (AJCC) 7th edition

- Specific tumor genetic eligibility criteria include:

- Presence of KRAS gene mutation (at codon 12, 13, or 61) for patients on expansion
cohort.

- Presence of V600E BRAF gene mutation, or

- Presence of an NRAS mutation at codon 12, 13, or 61

Exclusion Criteria:

- History of another malignancy; exception: subjects who have been disease-free for 5
years, or subjects with a history of completely resected non-melanoma skin cancer or
successfully treated in situ carcinoma are eligible

- Any serious and/or unstable pre-existing medical disorder (aside from malignancy
exception above), psychiatric disorder, or other conditions that could interfere with
subject's safety, obtaining informed consent or compliance to the study procedures, in
the opinion of the Investigator

- Prior chemotherapy treatment unless > 5 years ago

- Prior treatment with a selective inhibitor of v-raf-1 murine leukemia viral oncogene
homolog 1 (RAF) or mitogen-activated protein kinase kinase 1 (MEK)

- Prior radiation therapy to the abdomen or pelvis

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

- Current use of a prohibited medication

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

- History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled
glaucoma or ocular hypertension, uncontrolled systemic disease such as
hypertension, diabetes mellitus, or history of hyperviscosity or
hypercoagulability syndromes)

- Visible retinal pathology as assessed by ophthalmic exam that is considered a
risk factor for RVO or CSR such as:

- Evidence of optic disc cupping

- Evidence of visual field defects

- Intraocular pressure > 21 mm Hg

- Known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C
virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection
which will be allowed)

- History or evidence of cardiovascular risk including any of the following:

- Bazett correction QT (QTcB) >= 480 msec

- History or evidence of current clinically significant uncontrolled arrhythmias;
exception: subjects with controlled atrial fibrillation for >30 days prior to
enrollment are eligible

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

- History or evidence of current >= class II congestive heart failure as defined by
New York Heart Association (NYHA)

- Treatment refractory hypertension defined as a blood pressure of systolic > 140
mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive
therapy

- Patients with intra-cardiac defibrillators or permanent pacemakers

- Cardiac metastases

- Pregnancy or breastfeeding: women of child-bearing potential and men must agree to use
adequate contraception (hormonal or barrier method of birth control; abstinence) prior
to study entry and for the duration of study participation; should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately; no breastfeeding while patient is on study