Trametinib or Combination Chemotherapy in Treating Patients With Refractory or Advanced Biliary or Gallbladder Cancer or That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To assess overall survival (OS) in patients with refractory advanced biliary cancer
randomized to Arm 1: trametinib compared to those randomized to Arm 2: chemotherapy (either
5-fluorouracil [fluorouracil] and leucovorin [leucovorin calcium] or capecitabine).

SECONDARY OBJECTIVES:

I. To determine the frequency and severity of adverse events of trametinib in this patient
population.

II. To assess response rate (RR) and progression-free survival (PFS) in patients randomized
to Arm 1: trametinib and patients randomized to Arm 2: chemotherapy (fluorouracil [5-FU] or
capecitabine in this patient population).

TERTIARY OBJECTIVES:

I. To determine if a 16-gene expression signature is predictive of mitogen-activated protein
kinase kinase (MEK) efficacy as evidenced by improved RR, PFS, and OS.

II. To evaluate the effects of trametinib on the inflammatory cytokine and explore potential
associations with response rate and survival.

III. To estimate lean soft tissue and fat mass weight gain as a result of treatment with
trametinib vs. capecitabine in patients with advanced refractory biliary cancer.

IV. To bank tissue samples for other future correlative studies including next generation
sequencing and whole genome methylation assays. NOTE: These potential future correlative
studies will not be performed until an amended protocol with relevant detailed information
including specific arms and assays is approved by Cancer Therapy Evaluation Program (CTEP).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive trametinib orally (PO) once daily (QD) on days 1-21. Courses repeat
every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive 1 of 2 treatment regimens at the discretion of the investigator.

ARM IIA: Patients receive leucovorin calcium intravenously (IV) over 2 hours and
fluorouracil IV continuously over 46-48 hours on days 1 and 15. Courses repeat every 28 days
in the absence of disease progression or unacceptable toxicity.

ARM IIB: Patients receive capecitabine PO twice daily (BID) on days 1-14. Courses repeat
every 21 days in the absence of disease progression or unacceptable toxicity.

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

Inclusion Criteria:

- DISEASE RELATED CRITERIA

- Patients must have histologically or cytologically documented carcinoma primary to
the intra- or extra-hepatic biliary system or gall bladder with clinical and/or
radiologic evidence of unresectable, locally advanced or metastatic disease; patients
with ampullary carcinoma are not eligible

- Patients must have measurable disease; computed tomography (CT) scans or magnetic
resonance imaging (MRI)s used to assess measurable disease must have been completed
within 28 days prior to registration; CT scans or MRIs used to assess non-measurable
disease must have been completed within 42 days prior to registration; all disease
must be assessed and documented on the Baseline Tumor Assessment Form (Response
Evaluation Criteria in Solid Tumors [RECIST] 1.1)

- PRIOR/CONCURRENT THERAPY CRITERIA

- Patients must have completed any prior chemotherapy at least 21 days prior to
registration and have recovered from any of the effects AND

- Patients must have experienced progression to no more than 1 prior regimen of
systemic chemotherapy for advanced biliary cancer OR

- Patients who received adjuvant chemotherapy and had evidence of disease
recurrence within 6 months of completion of the adjuvant treatment are also
eligible; if patient received adjuvant treatment and had disease recurrence
after 6 months, patients will only be eligible after failing one regimen of
systemic chemotherapy used to treat the (unresectable or metastatic) disease
recurrence

- Patients must not have been treated with prior MEK inhibitors; prior 5-FU or
capecitabine treatment is allowed only if given as a radiosensitizer concurrently
with radiation therapy at least 12 weeks prior to registration or if given as part of
any adjuvant therapy regimen >= 12 months prior to study enrollment

- Patients must have no plans to receive concurrent chemotherapy, hormonal therapy,
radiotherapy, immunotherapy or any other type of therapy (including herbal or natural
supplements) for treatment of cancer while on this treatment protocol

- For patients who have received prior cryotherapy, radiation therapy, radiofrequency
ablation, therasphere, ethanol injection, transarterial chemoembolization (TACE) or
photodynamic therapy, the following criteria must be met:

- 28 days have elapsed since that therapy (lesions that have not been treated with
local therapy must be present and measureable)

- CLINICAL/LABORATORY CRITERIA

- Patients must have a Zubrod performance status of 0-1

- Absolute neutrophil count (ANC) > 1000/mcL

- Platelets > 100000/mcL

- Total bilirubin =< 2.0 x the institutional upper limit of normal limits (IULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 3 x IULN;
if liver metastases are present, AST and ALT must be =< 5 x IULN

- If the patient has had decompression of the biliary tree within the last 14 days,
stability of the bilirubin level needs to be confirmed with two measurements that are
within 5 to 7 days of each other; (the second measurement must be obtained within 7
days prior to registration;) both the first and second measurement must be =< 2.0 x
IULN; stability is defined as the second measurement being no more than one point
higher than the first

- Patients must have adequate kidney function as evidenced by at least ONE of the
following:

- Serum creatinine =< 1.5 x IULN within 28 days prior to registration

- Calculated creatinine clearance >= 50 ml/min for patients with creatinine level
of 1.0-1.5 x IULN; the serum creatinine value used in the calculation must have
been obtained within 28 days prior to registration

- Patients with known history or current evidence of retinal vein occlusion (RVO) or
retinal pigment epithelial detachment (RPED) are not eligible:

- History of RVO or RPED, or predisposing factors to RVO or RPED (e.g. such as
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 RPED such as:

- Evidence of new optic disc cupping

- Evidence of new visual field defects

- Intraocular pressure > 21 mmHg

- NOTE: ophthalmic exam is required for all patients; this exam should not be
performed until or unless it is very clear the patient is otherwise eligible for
registration; this exam should not be performed until or unless it is very clear
the patient is otherwise eligible for registration

- Patients must have echocardiogram and left ventricular ejection fraction (LVEF) >=
institutional lower limit of normal (LLN) within 28 days prior to registration; this
exam should not be performed until or unless it is very clear the patient is
otherwise eligible for registration

- Patients must not have uncontrolled or clinically significant cardiovascular disease
including: myocardial infarction within past 6 months; uncontrolled angina within
past 6 months; class II-IV New York Heart Association (NYHA) congestive heart
failure; grade 3 cardiac valve dysfunction; cardiac arrhythmia not controlled by
medication; history of stroke or transient ischemic attack within 6 months; history
of arterial thrombotic event (ATE) of any type in the past 6 months;
treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg
and/or diastolic > 90 mmHg which cannot be controlled with anti-hypertensive therapy;
known intra-cardiac defibrillators; known cardiac metastases

- Patients must have an electrocardiogram (ECG) within 28 days prior to registration;
patients must have corrected QT interval (QTc) =< 500 msec; this exam should not be
performed until or unless it is very clear the patient is otherwise eligible for
registration

- Must be 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

- Must not have a known immediate or delayed hypersensitivity reaction or idiosyncrasy
to drugs chemically related to trametinib, or excipients or to dimethyl sulfoxide
(DMSO) or other agents used in study

- Must not have active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection
(patients with chronic or cleared HBV and HCV infection are eligible)

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible

- Patients must not be pregnant or nursing; women/men of reproductive potential must
have agreed to use an effective contraceptive method while on study and for 4 months
after discontinuation of study drug; a woman is considered to be of "reproductive
potential" if she has had menses at any time in the preceding 12 consecutive months;
in addition to routine contraceptive methods, "effective contraception" also includes
heterosexual celibacy and surgery intended to prevent pregnancy (or with a
side-effect of pregnancy prevention) defined as a hysterectomy, bilateral
oophorectomy or bilateral tubal ligation; however, if at any point a previously
celibate patient chooses to become heterosexually active during the time period for
use of contraceptive measures outlined in the protocol, he/she is responsible for
beginning contraceptive measures

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
stage I or II cancer from which the patient is currently in complete remission, or
any other cancer from which the patient has been disease free for five years

- SPECIMEN SUBMISSION CRITERIA

- Patients must submit paraffin-embedded tissue and blood for banking within 28 days
after registration; paraffin-embedded tissue from prior surgical resection or from a
diagnostic biopsy is acceptable

- REGULATORY CRITERIA

- Patients or their legally authorized representative must be informed of the
investigational nature of this study and must sign and give written informed consent
in accordance with institutional and federal guidelines

- As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study has been
entered in the system