Study of Chemotherapy, With or Without Binimetinib in Advanced Biliary Tract Cancers in 2nd Line Setting (A ComboMATCH Treatment Trial)

Study Overview
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Brief Summary
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This phase II ComboMATCH treatment trial compares the usual treatment of modified leucovorin, fluorouracil and oxaliplatin (mFOLFOX6) chemotherapy to using binimetinib plus mFOLFOX6 chemotherapy to shrink tumors in patients with biliary tract cancers that have spread to other places in the body (advanced) and had progression of cancer after previous treatments (2nd line setting). Fluorouracil is in a class of medications called antimetabolites. It works by slowing or stopping the growth of cancer cells in the body. Oxaliplatin is in a class of medications called platinum-containing antineoplastic agents. It works by killing tumor cells. Leucovorin may help the other drugs in the mFOLFOX6 chemotherapy regimen work better by making tumor cells more sensitive to the drugs. Binimetinib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals tumor cells to multiply. This helps to stop or slow the spread of tumor cells. Giving binimetinib in combination with mFOLFOX6 chemotherapy may be effective in shrinking or stabilizing advanced biliary tract cancers in the 2nd line setting.

Detailed Description
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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 30 minutes on day 1, oxaliplatin IV over 30 minutes 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 echocardiogram (ECHO) and multigated acquisition scan (MUGA) during screening and on study, a computed tomography (CT) with contrast, magnetic resonance imaging (MRI), or a fludeoxyglucose F-18 positron emission tomography (FDG-PET) during screening, collection of blood during screening and on study, and a biopsy during screening. Patients may also undergo brain MRI or CT during screening and on study, bone scans on study, and biopsy on study if 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 ECHO and MUGA during screening and on study, a CT with contrast, MRI, or an FDG-PET during screening, collection of blood during screening and on study, and a biopsy during screening. Patients may also undergo brain MRI or CT during screening and on study, bone scans on study, and biopsy on study if 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.

Official Title
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A ComboMATCH Treatment Trial: FOLFOX in Combination With Binimetinib as 2nd Line Therapy for Patients With Advanced Biliary Tract Cancers With MAPK Pathway Alterations

Conditions
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Stage IV Distal Bile Duct Cancer AJCC v8, Stage IV Hilar Cholangiocarcinoma AJCC v8, Stage IV Intrahepatic Cholangiocarcinoma AJCC v8, Unresectable Biliary Tract Carcinoma, Unresectable Distal Bile Duct Adenocarcinoma, Unresectable Gallbladder Carcinoma, Unresectable Intrahepatic Cholangiocarcinoma, Recurrent Biliary Tract Carcinoma, Recurrent Distal Bile Duct Adenocarcinoma, Recurrent Gallbladder Carcinoma, Recurrent Intrahepatic Cholangiocarcinoma, Stage III Distal Bile Duct Cancer AJCC v8, Stage III Hilar Cholangiocarcinoma AJCC v8, Stage III Intrahepatic Cholangiocarcinoma AJCC v8

Intervention / Treatment
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* Drug: Binimetinib
* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Procedure: Bone Scan
* Procedure: Computed Tomography
* Procedure: Echocardiography
* Drug: Fluorouracil
* Drug: Leucovorin Calcium
* Procedure: Magnetic Resonance Imaging
* Procedure: Multigated Acquisition Scan
* Drug: Oxaliplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must fulfill all eligibility criteria outlined in the ComboMATCH Registration Protocol (EAY191) at the time of registration to study. This includes submission of next generation sequencing (NGS) data from one of the MATCH Designated Laboratories for all potential patients prior to treatment trial assignment. Copy number and allele frequency cutoffs as per the Registration Protocol. Patients must be enrolled on the ComboMATCH Master Registration Trial EAY191 Patients must have RAS/RAF/MEK/ERK mutations 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 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: www.ctsu.org (final uniform resource locator [URL] pending). Please note novel/Dynamic aMOI can be submitted for review per the process described in the ComboMATCH Registration Protocol 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 (tumor or ct-DNA). BRAFV600E mutations are not eligible due to other ongoing/upcoming studies in this disease cohort Measurable disease per Response Evaluation Criteria in Solid Tumors (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 randomization Progression of disease on gemcitabine based first-line regimen 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) 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 total bilirubin < 3.0 mg/dL (51 umole/L) Aspartate aminotransferase (AST) /alanine aminotransferase (ALT) =< 5.0 x upper limit of normal (ULN) Hemoglobin >= 8 g/dL, no transfusion within 14 days of 1st dose Albumin >= 3 g/dL (451 micromole/L) Creatine phosphokinase =< 2.5 x ULN 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 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. Baseline corrected QT (QTc) interval < 460ms for women and =< 450ms for men (average of triplicate readings) (CTCAE Grade 1) using Fridericia's QT correction formula. NOTE: This criterion does not apply to patients with a right or left bundle branch block. Concurrent 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 Exclusion Criteria: Patients must not have BRAF V600E as determined by the ComboMATCH screening assessment High blood pressure more than 160/90 despite treatment are ineligible 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1 (mFOLFOX6)<br>Patients receive leucovorin IV over 30 minutes on day 1, oxaliplatin IV over 30 minutes 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 ECHO and MUGA during screening and on study, a CT with contrast, MRI, or a FDG-PET during screening, collection of blood during screening and on study, and a biopsy during screening. Patients may also undergo brain MRI or CT during screening and on study, bone scans on study, and biopsy on study if clinically indicated. | Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo collection of blood<br>* Other names: Specimen Collection;Procedure: Bone Scan<br>* Undergo bone scan<br>* Other names: Bone Scintigraphy;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Drug: Leucovorin Calcium<br>* Given IV<br>* Other names: Wellcovorin;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;Drug: Oxaliplatin<br>* Given IV<br>* Other names: SR-96669;|
| Experimental: Arm 2 (binimetinib, mFOLFOX6)<br>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 ECHO and MUGA during screening and on study, a CT with contrast, MRI, or an FDG-PET during screening, collection of blood during screening and on study, and a biopsy during screening. Patients may also undergo brain MRI or CT during screening and on study, bone scans on study, and biopsy on study if clinically indicated. | Drug: Binimetinib<br>* Given PO<br>* Other names: Mektovi;Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo collection of blood<br>* Other names: Specimen Collection;Procedure: Bone Scan<br>* Undergo bone scan<br>* Other names: Bone Scintigraphy;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Drug: Leucovorin Calcium<br>* Given IV<br>* Other names: Wellcovorin;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;Drug: Oxaliplatin<br>* Given IV<br>* Other names: SR-96669;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | The primary efficacy analysis will be to compare the OS distributions between those treated with modified leucovorin, fluorouracil and oxaliplatin (mFOLFOX6) and binimetinib versus (vs.) mFOLFOX6. Despite being a randomized phase II trial, we will utilize an intent to treat approach such that patients will be analyzed based on the treatment arm to which they were randomized. As defined above, OS will be compared between the two treatment arms using Kaplan-Meier methods. The hazard ratio, median OS, and estimated OS rates at 6, 12, 18, 24, and 30 months will be estimated along with corresponding 95% confidence intervals. Anticipating that the treatment arms will be balanced in terms of the potential confounders reflect in the stratification factors, a log-rank test will be used to compare the OS distributions between the two treatment arms in this cohort. | From randomization to the time of death due to any cause, assessed up to 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response | Objective response by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria will be estimated using objective response rate (ORR) where ORR is defined as the number of evaluable patients achieving a response (partial response [PR] or complete response [CR] per RECIST v1.1) during treatment with study therapy divided by the total number of evaluable patients. Rates of response will be compared across arms using a Chi-Square Test for Proportion. Point estimates will be generated for objective response rates within each arm along with 95% confidence intervals using the Clopper-Pearson method. | Up to 5 years | 
| Progression free survival (PFS) | Disease progression will be determined based on RECIST 1.1 criteria. PFS will be estimated using the Kaplan-Meier method. The median PFS and 95% confidence interval will be reported. Patients will be censored at the last disease assessment date. | From study entry to the first of either disease progression or death from any cause, assessed up to 5 years | 
| Duration of response (DoR) | Defined for all evaluable patients who have achieved an objective response as the date at which the patient's earliest best objective status is first noted to be either a CR or PR to the earliest date progression is documented, or death if no prior evidence of disease progression. The distribution of DoR will be estimated using the method of Kaplan-Meier. | Up to 5 years | 
| Clinical benefit | Defined as achieving CR, PR, or stable disease (SD) for at least 4 months while on treatment. Disease status will be assessed using RECIST v. 1.1 criteria. Clinical benefit rate (CBR) will be calculated as the proportion of evaluable patients who achieve clinical benefit. The final CBR point estimate and corresponding 95% confidence interval calculated using Clopper-Pearson method. | Up to 5 years | 
| Incidence of adverse events | Patients will be evaluated for adverse events using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events version 5.0. Summary statistics (e.g., mean, median, standard deviation) and frequency tables will be used to describe the distributions of adverse events. Rates of adverse events occurring in the treatment arm will be compared to the control arm with chi-squared tests (or suitable alternative) used for comparisons where applicable. Tolerability will also be evaluated, summarizing rates of dose delays or modifications, reasons patients end treatment, and time to end of active treatment. | Up to 5 years |