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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.

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.

Binimetinib

Biopsy

Biospecimen Collection

Bone Scan

Computed Tomography

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Leucovorin Calcium

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Multigated Acquisition Scan

Site Public Contact

Rebecca C. Arend

Ahmed Abdalla

Chukwuemeka (Emeka) V. Ikpeazu

John M. Schallenkamp

Alison K. Conlin

Thomas J. Saphner

Thomas E. Lad

Chih-Yi Liao

Suparna Mantha

Bryan A. Faller

Olivia Aranha

Joshua Lukenbill

Susanne M. Arnold

Sarah J. Sinclair

Jibran Ahmed

Anwaar Saeed

Tareq Al Baghdadi

Dana Zakalik

Daniel Almquist

Bret E. Friday

Daniel M. Anderson

Mridula Krishnan

John A. Ellerton

Ardaman Shergill

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 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.

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

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

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Defined as presence of peritoneal disease/locally advanced disease/metastatic disease, Eastern Cooperative Oncology Group (ECOG) performance status, CA19.9 level. Will fit multivariate Cox regression models including MAPK mutation status, presence of peritoneal disease/locally advance disease/metastatic disease, ECOG performance status, and CA19-9 level, stratified by treatment arm. We will calculate C-statistics with 5-fold cross-validation

Will correlate with activity of addition of binimetinib therapy to standard 2nd line chemotherapy.

Will correlate with presence of MAPK pathway mutations.

Will be used to assess determinants of response and resistance. Concordance of diagnostic tumor mutation profile generated by the Designated Laboratory, the pre-treatment biopsy mutation profile, and the pre-treatment circulating tumor deoxyribonucleic acid (ctDNA) mutation profile will be assessed. Details are provided in the statistical plan of the ComboMATCH Registration Protocol.

Will correlate changes with clinical activity, disease course as well as response/resistance to therapy.

Will 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.

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.

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.

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.

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.

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.

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.

National Cancer Institute (NCI)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study of Chemotherapy, With or Without Binimetinib in Advanced Biliary Tract Cancers in 2nd Line Setting (A ComboMATCH Treatment Trial)	NCT05564403	Recurrent Bilia... Recurrent Dista... Recurrent Gallb... Recurrent Intra... Stage III Dista... Stage III Hilar... Stage III Intra... Stage IV Distal... Stage IV Hilar ... Stage IV Intrah... Unresectable Bi... Unresectable Di... Unresectable Ga... Unresectable In...	Binimetinib Biopsy Biospecimen Col... Bone Scan Computed Tomogr... Echocardiograph... Fluorouracil Leucovorin Calc... Magnetic Resona... Multigated Acqu... Oxaliplatin	18 Years -	National Cancer Institute (NCI)
Study of Chemotherapy, With or Without Binimetinib in Advanced Biliary Tract Cancers in 2nd Line Setting (A ComboMATCH Treatment Trial)	NCT05564403	Recurrent Bilia... Recurrent Dista... Recurrent Gallb... Recurrent Intra... Stage III Dista... Stage III Hilar... Stage III Intra... Stage IV Distal... Stage IV Hilar ... Stage IV Intrah... Unresectable Bi... Unresectable Di... Unresectable Ga... Unresectable In...	Binimetinib Biopsy Biospecimen Col... Bone Scan Computed Tomogr... Echocardiograph... Fluorouracil Leucovorin Calc... Magnetic Resona... Multigated Acqu... Oxaliplatin	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for unresectable distal bile duct adenocarcinoma