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

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.

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.