Chemotherapy + Binimetinib for Biliary Tract Cancer

Recruiting at 239 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: MEK inhibitors, KRAS inhibitors

Disqualifiers: Pregnancy, Hypertension, Lung disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: Up to 5 years

66 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding binimetinib (Mektovi) to the usual mFOLFOX6 chemotherapy can more effectively shrink advanced biliary tract cancers that have spread and continued to grow after initial treatments. The researchers aim to determine if this combination can stop or slow tumor growth more effectively than standard chemotherapy alone. This trial may suit individuals with advanced biliary tract cancer who have a specific genetic mutation and whose cancer has progressed after the first line of treatment. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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.

Do I need to stop my current medications to join the trial?

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 be restricted. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that binimetinib is generally well-tolerated by patients. A previous study found it effective in patients with biliary tract cancer (BTC) and noted manageable side effects. Binimetinib blocks proteins that signal cancer cells to grow, helping to slow or stop their spread.

When combined with the mFOLFOX6 chemotherapy treatment, binimetinib remains safe for patients. Past studies with similar combinations suggest this treatment does not introduce significant new risks beyond those typically associated with chemotherapy.

This trial tests binimetinib with mFOLFOX6 specifically for advanced biliary tract cancer. Binimetinib has also been studied in other cancer types, providing some confidence in its known and manageable safety profile. However, as this is a Phase 2 trial, safety continues to be evaluated. While early results are promising, ongoing trials will offer more information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about binimetinib for biliary tract cancer because it targets a specific pathway in cancer cells called the MEK pathway. This is different from the standard chemotherapy treatments like fluorouracil and oxaliplatin, which attack fast-dividing cells more generally. By combining binimetinib with traditional chemotherapy (known as mFOLFOX6), there's hope that the treatment will be more effective by both targeting and broadly attacking cancer cells. This dual approach could potentially improve outcomes for patients with this challenging type of cancer.

What evidence suggests that this trial's treatments could be effective for biliary tract cancer?

Research shows that binimetinib, when combined with mFOLFOX6 chemotherapy, may help treat advanced biliary tract cancers. In this trial, one group of participants will receive binimetinib with mFOLFOX6. Studies have demonstrated that binimetinib can fight tumors, particularly in biliary tract cancer cells. In previous studies, patients who received this combination treatment showed positive results: 13% had no detectable cancer, and 62% experienced a reduction in cancer size. Additionally, 55% of patients did not see their cancer worsen. These findings suggest that adding binimetinib to chemotherapy could potentially improve outcomes for patients with advanced biliary tract cancer. ^{1 2 3 6 7}

Who Is on the Research Team?

Ardaman Shergill

Principal Investigator

Alliance for Clinical Trials in Oncology

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive mFOLFOX6 chemotherapy with or without binimetinib in 14-day cycles

Up to 5 years

Bi-weekly visits for chemotherapy administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 8 weeks until disease progression, then every 4 months for up to 5 years

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Binimetinib
• Fluorouracil
• Oxaliplatin

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.

How Is the Trial Designed?

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 9 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

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase II study involving 34 patients with advanced biliary tract cancer who had previously failed gemcitabine treatment, modified FOLFIRINOX (mFOLFIRINOX) showed a median overall survival of 6.2 months and a median progression-free survival of 2.8 months, indicating its potential as a second-line treatment.

The treatment resulted in a disease control rate of 61.7%, although the most common adverse events were hematopoietic, suggesting that while mFOLFIRINOX can be effective, careful management of side effects is necessary for patient safety.

NCBI (Pubmed)

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. Lee, YP., Oh, SY., Kim, KM., et al.[2022]

In a study involving 28 patients with advanced biliary tract cancer, binimetinib was found to be well tolerated, with common mild side effects like rash (82%) and nausea (54%), and only two patients experienced severe adverse events.

Binimetinib demonstrated promising clinical activity, with 43% of patients achieving stable disease and two patients showing objective responses, including one complete response, suggesting its potential effectiveness in treating this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b investigation of the MEK inhibitor binimetinib in patients with advanced or metastatic biliary tract cancer. Finn, RS., Ahn, DH., Javle, MM., et al.[2019]

In a phase 1 study involving 93 patients with advanced solid tumors, binimetinib was found to have a maximum tolerated dose (MTD) of 60 mg twice daily, but the recommended dose for further studies was adjusted to 45 mg due to ocular toxicity.

Binimetinib showed a manageable safety profile with common side effects including rash and nausea, and demonstrated preliminary anti-tumor activity with three patients with biliary cancer achieving objective responses, indicating potential for further investigation in this group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor. Bendell, JC., Javle, M., Bekaii-Saab, TS., et al.[2022]

Gemcitabine plus platinum chemotherapy is the standard first-line treatment for advanced biliary tract cancers (BTC), while the FOLFOX regimen is the only validated second-line therapy, showing only modest survival benefits over best supportive care.

Recent advancements in genomic analyses have revealed the molecular diversity of BTC, paving the way for personalized targeted therapies, particularly focusing on fibroblast growth factor receptor and isocitrate dehydrogenase gene alterations, as well as combination immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Continuum of care for advanced biliary tract cancers. Vienot, A., Neuzillet, C.[2021]

The combination of binimetinib and capecitabine was well-tolerated in a phase Ib study with no dose-limiting toxicities observed, leading to a recommended phase 2 dose of 30 mg binimetinib and 1250 mg capecitabine.

In patients with biliary tract cancer who had previously been treated with gemcitabine, the treatment showed promising efficacy with a 3-month progression-free survival rate of 64%, and particularly better outcomes in those with RAS/RAF/MEK/ERK pathway mutations.

NCBI (Pubmed)

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. Kim, JW., Lee, KH., Kim, JW., et al.[2021]

A phase III trial showed that combining gemcitabine with cisplatin significantly improved overall survival and progression-free survival in patients with metastatic biliary tract cancers compared to gemcitabine alone, establishing a new standard of care.

Emerging therapies, such as epidermal growth factor receptor inhibitors, are showing promise in the treatment of biliary tract cancers, indicating a shift towards targeted agents in cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advanced biliary tract cancers. Goff, LW., Berlin, JD.[2020]

The LV5FU2-P chemotherapy regimen demonstrated a 34% objective response rate in 29 patients with advanced or metastatic biliary tract carcinoma, indicating its potential effectiveness in treating this challenging cancer.

The treatment was well-tolerated, with no treatment-related deaths and significant improvements in patient performance status and weight, although some patients experienced grade 3 toxicity.

NCBI (Pubmed)

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. Taïeb, J., Mitry, E., Boige, V., et al.[2020]

In a phase I/II trial involving 41 patients with untreated advanced biliary tract cancer, the maximum tolerated dose (MTD) of binimetinib was established at 45 mg twice daily when combined with gemcitabine and cisplatin, showing a median overall survival of 13.3 months.

Despite the treatment regimen, the combination of binimetinib with chemotherapy did not improve progression-free survival (PFS) or response rate (RR), suggesting that molecular profiling may be necessary to identify patients who could benefit from this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Binimetinib plus Gemcitabine and Cisplatin Phase I/II Trial in Patients with Advanced Biliary Cancers. Lowery, MA., Bradley, M., Chou, JF., et al.[2022]

The combination of cisplatin and gemcitabine is established as the standard first-line treatment for biliary tract cancers, but overall clinical outcomes remain poor, highlighting the need for improved therapies.

Molecular profiling can identify genetic alterations in biliary cancers, guiding targeted therapies and immunotherapy, with ongoing research into actionable targets like FGFR2 fusions and IDH1/2 mutations showing promise for better patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic therapy for biliary cancers. Jordan, E., Abou-Alfa, GK., Lowery, MA.[2017]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12272295/

Successful Treatment of BRAF V600E-Mutant Intrahepatic ... This report describes the case of a 59-year-old woman with advanced BRAF V600E-mutated IHCC (cT3N3M1c, stage IVc) treated with encorafenib, binimetinib, and

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29785570/

Phase 1b investigation of the MEK inhibitor binimetinib in ... Conclusion Binimetinib was well tolerated and showed promising evidence of activity in patients with BTC. Correlative studies suggested the ...

3. nature.com nature.com/articles/s41416-019-0523-5

Enhanced antitumor effect of binimetinib in combination ... The preclinical efficacy of binimetinib and 5-fluorouracil. a Binimetinib demonstrates antitumour activity in biliary tract cancer cell lines.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05564403

NCT05564403 | Study of Chemotherapy, With or Without ... Giving binimetinib in combination with mFOLFOX6 chemotherapy may be effective in shrinking or stabilizing advanced biliary tract cancers in the 2nd line setting ...

5. ar.iiarjournals.org ar.iiarjournals.org/content/40/6/3013

Second-line Treatment in Advanced Biliary Tract Cancer At the time of primary data cutoff, 7 patients (13%) achieved CR and 34 (62%) PR; moreover, 71% of patients had ongoing response and 55% were progression-free ...

6. aacrjournals.org aacrjournals.org/clincancerres/article/25/3/937/9754/Binimetinib-plus-Gemcitabine-and-Cisplatin-Phase-I

Binimetinib plus Gemcitabine and Cisplatin Phase I/II Trial in ... A phase II trial evaluating the MEK inhibitor selumetinib in a mixed population of pretreated and treatment-naïve patients with biliary tract cancer reported an ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS4196

Alliance EAY191-A6: FOLFOX in combination with ... In this study, we will evaluate if the combination of mFOLFOX6+binimetinib improves OS for patients with BTC and MAPK mutations compared to mFOLFOX6 alone in 2 ...