UAB - Center for Clinical and Translational Science

Conditions

• Advanced Biliary Tract Carcinoma
• Advanced Gallbladder Carcinoma
• Advanced Intrahepatic Cholangiocarcinoma
• Recurrent Biliary Tract Carcinoma
• Recurrent Gallbladder Carcinoma
• Recurrent Intrahepatic Cholangiocarcinoma
• Stage III Distal Bile Duct Cancer AJCC v8
• Stage III Gallbladder Cancer AJCC v8
• Stage III Hilar Cholangiocarcinoma AJCC v8
• Stage III Intrahepatic Cholangiocarcinoma AJCC v8
• Stage IV Distal Bile Duct Cancer AJCC v8
• Stage IV Gallbladder Cancer AJCC v8
• Stage IV Hilar Cholangiocarcinoma AJCC v8
• Stage IV Intrahepatic Cholangiocarcinoma AJCC v8
• Unresectable Biliary Tract Carcinoma
• Unresectable Gallbladder Carcinoma
• Unresectable Intrahepatic Cholangiocarcinoma

Eligibility

Eligible Ages

Over 18 Years

Eligible Genders

All

Accepts Healthy Volunteers

No

Criteria

Inclusion Criteria:

- Patient must have enrolled onto EAY191 and must have been given a treatment
assignment to ComboMATCH to EAY191-A6 based on the presence of an actionable
mutation as defined in EAY191

- GENERAL COMBOMATCH EAY191:

- Patients must be registered to the ComboMATCH Registration Protocol (EAY191)

- Patients must have RAS/RAF/MEK/ERK mutations as determined by the ComboMATCH
screening assessment

- Patients must not have BRAF V600E as determined by the ComboMATCH screening
assessment

- Patients must have disease that can be safely biopsied and agree to a pre-treatment
biopsy or have archival tissue available from within 12 months prior to registration
on the ComboMATCH Registration Trial (EAY191).

- Please note the current actionable marker of interest (aMOI)/actionable alteration
list for this treatment trial can be found on the Cancer Trials Support Unit (CTSU)
website

- Please note novel/Dynamic aMOI can be submitted for review per the process described
in the ComboMATCH Registration Protocol

- EAY191-A6 REGISTRATION:

- Participants must have histologically confirmed BTC (intrahepatic cholangiocarcinoma
[IHC], extrahepatic cholangiocarcinoma [EHC] or gallbladder cancer [GBC]) that is
unresectable or recurrent with a confirmed RAS/RAF/MEK/ERK pathway mutation via any
Clinical Laboratory Improvement Act (CLIA)-certified method. BRAFV600E mutations are
not eligible due to other ongoing/upcoming studies in this disease cohort

- Tumor tissue must be available:

- Adequate archival tumor specimen (obtained within 12 months of EAY191
registration which has not had a Response Evaluation Criteria in Solid Tumors
(RECIST) response, complete response (CR) or partial response (PR), to any
intervening therapy after collection of the tissue) must be available with
formalin-fixed paraffin-embedded tumor tissue (blocks or slides) OR

- Consent to a new tumor tissue biopsy which is not a representative target
lesion. This lesion must be amenable to a minimal risk image-guided or direct
vision biopsy

- A new biopsy is preferred but is not required for enrollment in EAY191-A6
if sufficient archival tissue is available as described above.

- Measurable disease per RECIST 1.1 Of note, in the case when a baseline biopsy is
done after scans are obtained, a lesion separate from one that is biopsied needs to
be measurable per RECIST 1.1. All radiologic studies must be performed within 28
days prior to registration

- Progression of disease on gemcitabine based first-line regimen (i.e. only one prior
line of therapy is permitted)

- No systemic anti-cancer therapy within 4 weeks of registration to EAY191-A6

- No prior MEK inhibitor therapy

- No prior history of treatment with a direct and specific inhibitor of KRAS

- Patients who only received radio-sensitizing chemotherapy with fluorouracil (5-FU)
or capecitabine are eligible, but need to have received and failed first-line
systemic chemotherapy upon recurrence. Peri-operative systemic 5-FU/capecitabine
and/or oxaliplatin, is allowed if it's been more than 12 months of registration to
EAY191-A6

- No major surgery within 4 weeks (excluding placement of vascular access) of
registration to EAY191-A6

- No minor surgery within 2 weeks of registration to EAY191-A6

- No palliative radiotherapy within 1 week of registration to EAY191-A6

- Not pregnant and not nursing, because this study involves an investigational agent
whose genotoxic, mutagenic and teratogenic effects on the developing fetus and
newborn are unknown

- Therefore, for women of childbearing potential only, a negative pregnancy test
done =< 14 days prior to registration is required

- Adequate contraception is needed for at least 30 days after the last dose of
binimetinib and breastfeeding should be discontinued for at least 3 days after
the last dose of binimetinib. For FOLFOX regimen, 9 months is recommended for
contraception after last dose of oxaliplatin for females of childbearing
potential and 6 months for males

- Age >= 18 years

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Absolute neutrophil count (ANC) >= 1,000/mm^3, no growth factor within 14 days of
1st dose

- Platelet count >= 75,000/mm^3

- Creatinine < 1.6 x upper limit of normal (ULN) OR

- Calculated (Calc.) creatinine clearance >= 50 mL/min, as calculated by the
Cockcroft-Gault formula

- Total bilirubin =< 2.0 x upper limit of normal (ULN); Patients with Gilbert syndrome
may enroll if < 3.0 x ULN

- Aspartate aminotransferase (AST) /alanine aminotransferase (ALT) =< 5.0 x upper
limit of normal (ULN)

- Hemoglobin >= 8 g/dL, no transfusion within 7 days of 1st dose

- Creatine phosphokinase =< 2.5 x ULN

- High blood pressure more than 160/90 despite treatment are ineligible

- No history of interstitial lung disease. No history of idiopathic pulmonary
fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced
pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on
screening chest computed tomography (CT) scan

- Patients should not have history of bowel perforation or intestinal fistulas in the
last 6 months

- Patients with the inability to swallow oral medications or impaired gastrointestinal
absorption due to gastrectomy or active inflammatory bowel disease are ineligible

- Must have adequate cardiac function with left ventricular ejection fraction >= 50%
by echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan. Patients with
congenital long QT syndrome are not permitted

- No history of prolonged QTc or at risk for prolonged QTc due to any reason (for
example, concomitant medications during or before chemotherapy that may increase the
risk of prolonged QTc), uncontrolled congestive heart failure, prior history of
class III/ IV cardiac disease (New York Heart Association [NYHA]), myocardial
infarction within the last 6 months, unstable arrhythmias, unstable angina or severe
obstructive pulmonary disease

- No active skin disorder that has required systemic therapy within the past 1 year

- No history of rhabdomyolysis

- No concurrent ocular disorders, including:

- Patients with history of glaucoma, history of retinal vein occlusion (RVO),
predisposing factors for RVO, including but not limited to uncontrolled
hypertension, uncontrolled diabetes

- Patients with history of retinal pathology or evidence of visible retinal
pathology that is considered a risk factor for RVO, intraocular pressure > 21
mm Hg as measured by tonometry, or other significant ocular pathology, such as
anatomical abnormalities that increase the risk for RVO

- Patients with a history of corneal erosion (instability of corneal epithelium),
corneal degeneration, active or recurrent keratitis, and other forms of serious
ocular surface inflammatory conditions

- Patients with known or at risk for retinopathies, uveitis or retinal vein
occlusion

- No patients with a history of hypersensitivity to any of the inactive ingredients in
binimetinib, nor known severe allergic reactions or hypersensitivity of 5-FU,
leucovorin (LV) or oxaliplatin will be allowed to participate in this study for
safety concerns

- No other medical condition (e.g. cardiac, gastrointestinal, pulmonary, psychiatric,
neurological, genetic, etc.) that in the opinion of the investigator would places
the subject at unacceptably high risk for toxicity

- No prior allogeneic stem cell or solid organ transplantation

- Central nervous system (CNS) metastases must have been treated with local therapy
(surgery, radiation, ablation) with systemic steroids tapered to a physiologic dose
(10 mg or prednisone equivalent or less)

- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial

- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable on suppressive therapy, if indicated

- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load

- Patients must not have grade 2 neuropathy or greater, within 14 days prior to
registration

Recruiting Locations

Study Contact

Detailed Description

PRIMARY OBJECTIVE: I. To determine whether binimetinib and mFOLFOX6 combination therapy improves overall survival (OS) compared to mFOLFOX6 alone in patients with advanced/recurrent biliary tract cancer (BTC) and with alterations in RAS/RAF/MEK/ERK pathway, who have progressed on one prior line of therapy. SECONDARY OBJECTIVES: I. To determine whether binimetinib and mFOLFOX6 combination therapy improves objective response rate (ORR) compared to FOLFOX alone. II. To determine if clinical outcomes including progression free survival (PFS), duration of response (DOR), and disease control rate (DCR) are improved with combination treatment of binimetinib and mFOLFOX6 compared to FOLFOX alone in patients with advanced/recurrent BTC and with alterations in RAS/RAF/MEK/ERK pathway who have progression on one prior line of therapy. III. Toxicity and tolerability will be evaluated within and between the two treatment arms, where frequency, type, and severity of adverse events will be assessed per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v)5.0. IV. Collect tissue and provide it to the ComboMATCH Registration Protocol to assess concordance between the diagnostic tumor mutation profile generated by the Designated Laboratories, the pre-treatment biopsy mutation profile, and the pre-treatment circulating tumor deoxyribonucleic acid (ctDNA) mutation profile from plasma, as described in ComboMATCH Registration Protocol. EXPLORATORY OBJECTIVES: I. Generate a prognostic model of MAPK mutations for this patient population using clinical, laboratory and molecular features of their disease and clinical outcome to validate on future samples. II. Correlation of outcome with albumin. III. Assess the correlation between the presence of MAPK pathway mutations and activity of addition of binimetinib therapy to standard 2nd line chemotherapy. IV. Conduct whole-exome sequencing and ribonucleic acid (RNA)-sequencing at baseline, and on optional biopsy upon progression to assess determinants of response and resistance. V. Explore changes in plasma MAPK mutations allelic burden and other molecular findings at baseline and upon progression using ctDNA and correlate changes with clinical activity, disease course as well as response/resistance to therapy. VI. Evaluate if our machine learning algorithm for RAS/RAF/MEK/ERK pathway mutations correlates with detection of mutations as well as prediction of outcomes from samples obtained in this study. OUTLINE: Patients are randomized to 1 of 2 arms. ARM 1: Patients receive leucovorin intravenously (IV) over 2 hours and oxaliplatin IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-2. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo collection of blood during screening and on study, and undergo computed tomography (CT) with contrast, magnetic resonance imaging (MRI), or fludeoxyglucose F-18 positron emission tomography (FDG-PET) throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated. ARM 2: Patients receive binimetinib orally (PO) on days 1-14, and leucovorin IV, oxaliplatin IV, and fluorouracil IV as in Arm 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiogram (ECHO) or multigated acquisition scan (MUGA) and collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated. After completion of study treatment, patients are followed up every 8 weeks until disease progression, thereafter patients are followed for survival every 4 months for up to 5 years following registration.