Chemotherapy + Binimetinib for Biliary Tract Cancer

Recruiting in Palo Alto (17 mi)

+222 other locations

Overseen by Ardaman Shergill

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Waitlist Available

Sponsor: National Cancer Institute (NCI)

Must not be taking: MEK inhibitors, KRAS inhibitors

Disqualifiers: Pregnancy, Hypertension, Lung disease, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this 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.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must not have had systemic anti-cancer therapy within 4 weeks before joining the trial, and certain medications that could affect heart rhythm may not be allowed. It's best to discuss your current medications with the trial team.

What evidence supports the effectiveness of the drug combination of chemotherapy and Binimetinib for biliary tract cancer?

Research shows that Binimetinib, when combined with chemotherapy drugs like gemcitabine and cisplatin, has shown promise in treating advanced biliary tract cancer, especially in patients with specific genetic mutations. Additionally, combining chemotherapy drugs like 5-fluorouracil with platinums has been more effective than using them alone, suggesting potential benefits of combination therapies. ^{1 2 3 4 5}

Is the combination of chemotherapy and binimetinib safe for humans?

Binimetinib, when used with chemotherapy, has been studied in patients with biliary tract cancer and was generally well tolerated. Common mild side effects included rash and nausea, while more serious side effects like generalized swelling and blood clots were less common. Overall, binimetinib showed a promising safety profile in these studies. ^{2 3 4 6 7}

What makes the chemotherapy and binimetinib drug combination unique for biliary tract cancer?

This treatment combines binimetinib, a drug that targets a specific pathway (MEK1/2) often altered in biliary tract cancer, with chemotherapy drugs like fluorouracil and oxaliplatin. This combination is unique because it targets the cancer more precisely by addressing specific genetic mutations, potentially improving effectiveness compared to standard chemotherapy alone. ^{2 3 4 6 8}

Eligibility Criteria

Adults with advanced biliary tract cancers that have worsened after first-line treatment can join. They must not be pregnant, agree to use contraception, and have no history of certain eye diseases or severe allergies to trial drugs. Participants need a specific mutation in their cancer but cannot have BRAF V600E mutations or high blood pressure uncontrolled by medication.

Inclusion Criteria

My kidneys work well enough, with a creatinine clearance rate of at least 50 mL/min.

My cancer has specific genetic changes known as RAS/RAF/MEK/ERK mutations.

I have not had minor surgery in the last 2 weeks.

Exclusion Criteria

My blood pressure is controlled and below 160/90.

I can swallow pills and do not have issues absorbing them due to stomach surgery or bowel inflammation.

My cancer does not have the BRAF V600E mutation.

Treatment Details

Interventions

• Binimetinib (Kinase Inhibitor)
• Fluorouracil (Anti-metabolite)
• Oxaliplatin (Platinum-containing Antineoplastic Agent)

Trial Overview The study compares standard chemotherapy (mFOLFOX6) alone versus mFOLFOX6 combined with Binimetinib, a kinase inhibitor that may help stop cancer cells from multiplying. The goal is to see if adding Binimetinib improves outcomes for patients who've already had one round of treatment.

Participant Groups

Group I: Arm 2 (binimetinib, mFOLFOX6) Experimental Treatment 11 Interventions

Patients receive binimetinib 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 or 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.

Group II: Arm 1 (mFOLFOX6) Active Control 10 Interventions

Patients receive leucovorin 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 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.

Binimetinib is already approved in United States, European Union, Canada, Japan for the following indications:

🇺🇸 Approved in United States as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation

🇪🇺 Approved in European Union as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

🇨🇦 Approved in Canada as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation

🇯🇵 Approved in Japan as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Trinity Health Saint Joseph Mercy Hospital Ann Arbor Ann Arbor, MI

Carle Physician Group-Mattoon/Charleston Mattoon, IL

West Virginia University Healthcare Morgantown, WV

United Hospital Saint Paul, MN

More Trial Locations

Who Is Running the Clinical Trial?

National Cancer Institute (NCI) Lead Sponsor

References

1. China pubmed.ncbi.nlm.nih.gov

Systemic therapy for biliary cancers. [2017] Biliary tract cancers represent an uncommon, heterogenous malignant group of tumors that include gallbladder cancers (GBC) and cholangiocarcinomas that are frequently detected in the locally advanced or metastatic setting. The randomized phase III ABC-02 trial established the combination regimen of cisplatin plus gemcitabine as standard of care therapy. Nevertheless, despite prior and subsequent attempts utilizing a variety of treatment strategies clinical outcomes for these cancers remains disappointing, necessitating the innate call for improvements in treatment approaches. In this article, we provide an overview of prior first line studies of single, doublet and triplet systemic chemotherapy regimens as well as attempts to incorporate agents that target the EGFR and VEGF pathways in combination with a cytotoxic backbone and the current role of chemotherapy in the second line setting. Additionally, molecular profiling has the capability to identify genetic alterations to help guide rational treatment approaches; we highlight the molecular diverse profile within biliary cancer and the prior, current and emergent role of targeted therapy in biliary cancers as well as the ongoing investigational assessment of immunotherapy. Overall, combination therapy is superior to single agent therapy in the first line setting. For second line therapy, enrollment on to clinical trials is paramount as no standard of care currently exists and no specific regimen has shown a significant better outcome. Limitations of chemotherapy have been exposed and future trials must have a logical design with incorporation of biomarkers that can aid prognosis or predict benefit to therapy. Advances in genomic sequencing can allow identification of potential actionable targets that can be exploited therapeutically which is already underway with the targeting of FGFR2 fusions and IDH1/2 mutations in intrahepatic cholangiocarcinoma (IHCC). With these approaches there is potential to gain improvements in outcomes for patients affected by these adverse group of cancers.

2. England pubmed.ncbi.nlm.nih.gov

Optimization of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy with a new schedule of leucovorin, 5-FU and cisplatin (LV5FU2-P regimen) in patients with biliary tract carcinoma. [2020] Unresectable biliary tract carcinoma (BTC) is associated with a very poor prognosis. To improve efficacy and tolerance of the 5-fluorouracil (5-FU)/cisplatin combination in BTC, we designed a new therapeutic schedule, the LV5FU2-P regimen.

3. England pubmed.ncbi.nlm.nih.gov

Enhanced antitumor effect of binimetinib in combination with capecitabine for biliary tract cancer patients with mutations in the RAS/RAF/MEK/ERK pathway: phase Ib study. [2021] A phase Ib study of binimetinib and capecitabine for gemcitabine-pretreated biliary tract cancer (BTC) patients was conducted.

4. United States pubmed.ncbi.nlm.nih.gov

Binimetinib plus Gemcitabine and Cisplatin Phase I/II Trial in Patients with Advanced Biliary Cancers. [2022] Label="PURPOSE">Mutations in the RAS/RAF/MEK/ERK signaling pathway are commonly found in biliary tract cancer (BTC). Binimetinib, a selective inhibitor of MEK1/2, has single-agent activity. Preclinical data support binimetinib combination with chemotherapy, when given in an interrupted dosing schedule.Patients and Methods: A phase I/II trial evaluated binimetinib in combination with gemcitabine and cisplatin in patients with untreated advanced BTC. The primary endpoints were to determine the MTD (phase I), and PFS 6 and RR (phase II). Tumor tissue for targeted gene sequencing and blood samples for peripheral blood pERK expression were evaluated. Patients received oral binimetinib twice daily with gemcitabine and cisplatin on day 8 and 15 of a 21-day cycle. Binimetinib was held for 2 days prior to and on day of each chemotherapy treatment.

5. United States pubmed.ncbi.nlm.nih.gov

Advanced biliary tract cancers. [2020] Single-agent management of metastatic biliary tract cancers with 5-fluorouracil (5-FU) or gemcitabine has shown limited efficacy, although 5-FU has been shown to be more effective than best supportive care alone. An analysis of phase II trials has suggested that platinums enhanced the efficacy of single-agent fluoropyrimidines. In a phase III randomized trial comparing single-agent gemcitabine with gemcitabine plus cisplatin, the gemcitabine/cisplatin combination significantly improved median overall survival (OS) and progression-free survival (PFS), which established a new option for standard of care. However, the future of cancer medicine lies in newer, targeted agents. In the management of biliary tract cancers, preliminary evidence with epidermal growth factor receptor inhibitors has already demonstrated activity. This article reviews systemic therapies for metastatic biliary tract cancers as they relate to current and emerging standards of care.

6. United States pubmed.ncbi.nlm.nih.gov

Phase 1b investigation of the MEK inhibitor binimetinib in patients with advanced or metastatic biliary tract cancer. [2019] Background The MAPK pathway plays a central role in regulation of several cellular processes, and its dysregulation is a hallmark of biliary tract cancer (BTC). Binimetinib (MEK162), a potent, selective oral MEK1/2 inhibitor, was assessed in patients with advanced BTC. Patients and Methods An expansion cohort study in patients who received ≤1 line of therapy for advanced BTC was conducted after determination of the maximum tolerated dose in this Phase 1 trial. Patients received binimetinib 60 mg twice daily. The primary objectives were to characterize the safety profile and pharmacokinetics of binimetinib in advanced BTC. Secondary objectives included assessment of clinical efficacy, changes in weight and lean body mass, and pharmacodynamic effects. Tumor samples were assessed for mutations in relevant genes. Results Twenty-eight patients received binimetinib. Common adverse events (AEs) were mild, with rash (82%) and nausea (54%) being most common. Two patients experienced grade 4 AEs, one generalized edema and the other pulmonary embolism. The pharmacokinetics in this patient population were consistent with those previously reported (Bendell JC et al., Br J Cancer 2017;116:575-583). Twelve patients (43%) experienced stable disease and two had objective responses (1 complete response, 1 partial response) per Response Evaluation Criteria in Solid Tumors and stable metabolic disease by positron emission tomography/computed tomography. Most patients (18/25; 72%) did not have KRAS, BRAF, NRAS, PI3KCA, or PTEN mutations, nor was there correlation between mutation status and response. The average non-fluid weight gain was 1.3% for lean muscle and 4.7% for adipose tissue. Conclusion Binimetinib was well tolerated and showed promising evidence of activity in patients with BTC. Correlative studies suggested the potential for binimetinib to promote muscle gain in patients with BTC.

7. England pubmed.ncbi.nlm.nih.gov

A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor. [2022] Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor. This phase 1 study determined the maximum tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumour activity of binimetinib in patients with advanced solid tumours, with expansion cohorts of patients with biliary cancer or KRAS- or BRAF-mutant colorectal cancer.

8. Switzerland pubmed.ncbi.nlm.nih.gov

Modified FOLFIRINOX as a Second-Line Treatment for Patients with Gemcitabine-Failed Advanced Biliary Tract Cancer: A Prospective Multicenter Phase II Study. [2022] After the publication of the ABC-02 trial, gemcitabine and cisplatin combination therapy (GP) became the standard first-line treatment for advanced biliary tract cancer (BTC). Despite GP therapy, most patients suffer from disease progression. The ABC-06 trial recommended FOLFOX as a second-line treatment, but its efficacy was modest. In this phase II study, we looked at the efficacy and safety of a second-line modified dose of FOLFIRINOX (mFOLFIRINOX) for patients who had failed first-line gemcitabine-based treatment.