Trametinib and TAS-102 in Treating Patients With Colon or Rectal Cancer That is Advanced, Metastatic, or Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) for the combination of trametinib and
trifluridine/tipiracil hydrochloride combination agent TAS-102 (TAS-102) in patients with
chemotherapy-resistant metastatic colorectal cancer.

SECONDARY OBJECTIVES:

I. Describe the safety of the combination of trametinib and TAS-102 across all investigated
dose levels.

II. Describe the clinical activity including objective response rate (ORR), progression-free
survival (PFS), and overall survival (OS) of the combination in an expansion cohort using
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

OUTLINE:

Patients receive trifluridine/tipiracil hydrochloride combination agent TAS-102 orally (PO)
twice daily (BID) on days 1-5 and 8-12 and trametinib PO once daily (QD) on days 1-28.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then bi-annually
thereafter.

Inclusion Criteria:

- All subjects must have the ability to understand and the willingness to sign a written
informed consent

- All patients must be able to take oral medications

- All patients must be deemed by investigator to have the initiative and means to be
compliant with the study protocol (treatment and follow-up)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Pathologically confirmed advanced, unresectable, or metastatic colon or rectal cancer
who have had intolerance to or progression after a fluoropyrimidine, oxaliplatin,
irinotecan, and cetuximab or panitumumab in the event of wild-type RAS/BRAF tumors

* Of note, prior bevacizumab or regorafenib exposure is not mandated as some patients
are deemed poor candidates for anti-angiogenesis therapy and never receive these
agents

- Tumors must have undergone expanded molecular profiling with a Clinical Laboratory
Improvement Act (CLIA)-certified platform that evaluates, at a minimum, RAS, PIK3CA,
PTEN and BRAF mutations status

- Documented RAS-mutated tumor without activating PIK3CA mutations or PTEN mutation
(loss of PTEN or silencing)

- Measurable disease by RECIST 1.1 guidelines

- Last chemotherapy at least 3 weeks from initiation of study treatment

- No investigational agents within 4 weeks from initiation of study treatment

- Negative serum or urine beta-human chorionic gonadotropin (HcG) test (female patient
of childbearing potential only) performed within 72 hours of prior to first study dose

- To be performed within 28 days prior to day 1 of protocol therapy: Absolute neutrophil
count (ANC) >= 1500/mm^3

* NOTE: Growth factor is not permitted within 14 days of ANC assessment unless
cytopenia is secondary to disease involvement

- To be performed within 28 days prior to day 1 of protocol therapy: Platelets >=
75,000/mm^3 without transfusions

- To be performed within 28 days prior to day 1 of protocol therapy: Hemoglobin (Hgb) >=
8 g/dL without transfusions

- To be performed within 28 days prior to day 1 of protocol therapy: Total serum
bilirubin < upper limit of normal (ULN)

- To be performed within 28 days prior to day 1 of protocol therapy: Aspartate
aminotransferase (AST) =< 2.5 x ULN if no liver metastases or =< 5 x ULN if liver
metastases

- To be performed within 28 days prior to day 1 of protocol therapy: Alanine
aminotransferase (ALT) =< 2.5 x ULN if no liver metastases or =< 5 x ULN if liver
metastases

- To be performed within 28 days prior to day 1 of protocol therapy: Creatinine < 1.5 x
ULN or creatinine clearance of >=60 mL/min per the Cockcroft-Gault formula

- To be performed within 28 days prior to day 1 of protocol therapy: Female of
childbearing potential: negative urine or serum pregnancy test

* If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required

- To be performed within 28 days prior to day 1 of protocol therapy: Corrected QT (QTc)
interval =< 480 ms (12 lead-electrocardiography [ECG])

- To be performed within 28 days prior to day 1 of protocol therapy: Left ventricular
ejection >= 50% as determined by multigated acquisition (MUGA) scan or echocardiogram

- To be performed within 28 days prior to day 1 of protocol therapy: Normal eye
examination

- Women of childbearing potential must use highly effective methods of contraception
throughout the study and for 4 months after study drug discontinuation

- Sexually active men must use a condom during intercourse while taking study drug and
for 60 days after study drug discontinuation; a condom is required for vasectomized
men to prevent delivery of study drug via seminal fluid

Exclusion Criteria:

- Prior chemotherapy, biologic, targeted, or radiotherapy within 3 weeks prior to
entering study or not recovered from grade >= 2 adverse events (AEs) due to agents
administered more than 4 weeks earlier (except alopecia or neuropathy)

- Prior MEK inhibitor or prior TAS-102 therapy

- Use of other investigational drugs

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

- History of retinal degenerative disease

- History of Gilbert's syndrome

- Previous or concurrent malignancy with the following exceptions:

- Adequately treated basal cell or squamous cell carcinoma of skin with adequate
wound healing prior to study entry

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

- Primary malignancy completely resected and in complete remission >= 1 year

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

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

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

- Neuromuscular disorders associated with elevated creatine kinase (CK, e.g.,
inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, or spinal
muscular atrophy)

- Started or planning to start on strenuous exercise regimen after first dose of study
treatment (i.e., muscular activities, such as strenuous exercise, that can result in
significant increase in plasma CK levels should be avoided while on trametinib
treatment)

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

- Prior major surgery =< 3 weeks before study drug or not recovered from side effects of
such procedure

- Ongoing grade >= 3 neuropathy

- Known hypersensitivity to any components of study drugs

- Prior intolerance to a fluoropyrimidine

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

- Prospective participants who, in the opinion of the investigator, may not be able to
comply with all study procedures (including compliance issues related to
feasibility/logistics)