Palbociclib + Binimetinib for Pancreatic Cancer

Not currently recruiting at 302 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Strong CYP3A4 inhibitors, Strong CYP3A4 inducers, P-gp inhibitors, P-gp inducers

Disqualifiers: Pregnancy, Interstitial lung disease, Bowel perforation, 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: 4

Duration: Up to 3 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of two drugs, palbociclib and binimetinib, to determine if they can slow the growth of pancreatic cancer and other RAS-mutated cancers. These drugs are kinase inhibitors, blocking proteins that signal cancer cells to multiply. The trial aims to extend the time before cancer resumes growing. It seeks patients with specific mutations in their cancer, particularly those who have progressed after previous treatments and lack effective standard options. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you stop taking any cancer-directed therapy at least 28 days before joining, except for hormonal therapy, which can be taken up to 14 days before. Additionally, you must stop taking strong CYP3A4 inhibitors or inducers and P-glycoprotein inhibitors or inducers 14 days before starting the trial.

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

Research shows that the combination of palbociclib and binimetinib can cause some side effects, but they are usually manageable. Common side effects of binimetinib include rash and nausea. When combined with palbociclib, some toxicity has been observed, a common occurrence in cancer treatments.

Other studies have shown that patients taking binimetinib with another drug generally experience a good safety profile, meaning many can handle the treatment without serious problems. However, there has been a rare report of pancreatitis (inflammation of the pancreas) with binimetinib when used with other drugs.

This trial is in Phase 2, indicating that researchers are still gathering information on the treatment's safety and effectiveness. Earlier phases typically focus on safety, so by this stage, the treatment is considered relatively safe for testing on more patients. However, participants might still experience side effects, which researchers will monitor closely. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of palbociclib and binimetinib for pancreatic cancer because this treatment targets cancer cells in a unique way compared to standard treatments like chemotherapy. Palbociclib is a CDK4/6 inhibitor that helps stop cancer cells from dividing, while binimetinib blocks the MEK pathway, which is often overactive in cancer cells. This dual approach aims to tackle the cancer more effectively by disrupting two critical pathways that fuel tumor growth. By using this combination, there's potential for a more targeted attack on the cancer, possibly leading to better outcomes with fewer side effects than traditional chemotherapy alone.

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

Research shows that binimetinib, which participants in this trial may receive as monotherapy, may help treat certain cancers, including pancreatic cancer. Studies have found that binimetinib can slow tumor growth in early tests, potentially delaying cancer progression. Additionally, palbociclib, part of the combination treatment arm in this trial, almost doubled the time patients lived without their cancer worsening, from 5.6 to 9.5 months. When used together in the combination cohort, these two drugs target different pathways of cancer cell growth, which might lead to better outcomes for patients with RAS-mutated cancers. Early studies in similar cancer types have shown some success with this combination, but more research is needed to confirm these results in pancreatic cancer. ^{2 6 7 8 9}

Who Is on the Research Team?

Geoffrey I Shapiro

Principal Investigator

Alliance for Clinical Trials in Oncology

Are You a Good Fit for This Trial?

This trial is for patients with RAS-mutated cancers, such as low grade serous ovarian cancer and pancreatic cancer, who have no curable treatment options. Participants must have measurable disease, be able to undergo a biopsy, and not have had prior MEK inhibitor or CDK4/6 inhibitor therapy (with exceptions for certain mutations). They should also meet all ComboMATCH Registration Protocol criteria.

Inclusion Criteria

My cancer cannot be cured with surgery or other common treatments.

I meet all requirements of the ComboMATCH study and have submitted my genetic testing data.

Participants need to be signed up for the ComboMATCH Master Registration Trial EAY191.

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 palbociclib and binimetinib in combination therapy or binimetinib monotherapy, with cycles repeating every 28 days for up to 3 years

Up to 3 years

Monthly visits for cycle assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Up to 3 years

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Binimetinib
• Palbociclib

Trial Overview The effectiveness of combining two kinase inhibitors, palbociclib and binimetinib, is being tested in this phase II trial. The study aims to see if this drug combo can delay cancer growth in patients with specific tumor DNA changes and improve survival without progression in various cancers excluding lung, colon cancer, melanoma.

How Is the Trial Designed?

Group I: Monotherapy Cohort 1 (binimetinib) Experimental Treatment 6 Interventions

Patients receive binimetinib PO BID daily, in the absence of disease progression or unacceptable toxicity, for up to 3 years. Patients who experience disease progression may elect to migrate to the combination cohort. Patients may also undergo biopsy at screening and undergo MRI, CT, bone scan, and collection of blood samples during screening, on study, and/or during follow up.

Group II: Combination Cohorts 1, 2, 3, 4 (palbociclib, binimetinib) Experimental Treatment 7 Interventions

Patients receive palbociclib PO QD on days 1-21 and binimetinib PO BID on days 1-28 of each cycle. throughout the trial. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity for up to 3 years. Patients may also undergo biopsy at screening and undergo MRI, CT, bone scan, and collection of blood samples during screening, on study, and/or during follow up.

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 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]

A study analyzing 2,364 cases of pancreatic adverse events (AEs) linked to immune checkpoint inhibitors (ICIs) found significant associations, particularly with ICI-associated pancreatitis and diabetes mellitus, indicating a notable risk for patients undergoing ICI treatment.

Combination therapy with ICIs showed a higher frequency of pancreatic AEs compared to monotherapy, suggesting that while the risk of these adverse events increases, the fatality rate remains lower, highlighting the importance of patient awareness regarding these potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreatic Adverse Events Associated With Immune Checkpoint Inhibitors: A Large-Scale Pharmacovigilance Analysis. Zhang, Y., Fang, Y., Wu, J., et al.[2022]

In a case series of seven patients treated with immune checkpoint inhibitors (ICIs), two developed diabetic ketoacidosis (DKA) and five experienced pancreatitis, highlighting the potential for serious pancreatic adverse events associated with ICI therapy.

Pancreatitis was often asymptomatic and could be managed effectively by holding the ICI treatment and administering steroids, with some patients able to safely resume ICI therapy after recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreatic adverse events in patients treated with immune checkpoint inhibitors. Hana, C., Rehman, T., Park, K., et al.[2023]

In a phase Ib trial involving 22 patients with metastatic pancreatic ductal adenocarcinoma, combinations of avelumab or talazoparib with binimetinib showed higher-than-expected rates of dose-limiting toxicity (DLT), particularly at the 45 mg dose, leading to dose adjustments.

Despite the safety concerns, the overall safety profiles of the combinations were consistent with those of the individual drugs, but no objective tumor responses were observed in the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial. Rodon Ahnert, J., Tan, DS., Garrido-Laguna, I., et al.[2023]

In a phase II trial involving 46 patients with advanced pancreatic ductal adenocarcinoma, the combination of selumetinib (a MEK inhibitor) and erlotinib showed modest antitumor activity, with 41% of patients experiencing stable disease for at least 6 weeks and a median overall survival of 7.3 months.

Patients with tumors that had a high level of E-cadherin expression were more likely to respond to the treatment, suggesting that specific molecular subtypes may benefit more from this dual-targeted therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Multicenter, Open-Label Phase II Clinical Trial of Combined MEK plus EGFR Inhibition for Chemotherapy-Refractory Advanced Pancreatic Adenocarcinoma. Ko, AH., Bekaii-Saab, T., Van Ziffle, J., et al.[2021]

In a phase Ib study involving 89 patients with advanced solid tumors, the combination of binimetinib (a MEK inhibitor) and buparlisib (a PI3K inhibitor) showed some efficacy, particularly in RAS/BRAF-mutant ovarian cancer, where 12% of patients achieved a partial response.

However, the treatment was associated with significant toxicities, leading to a lower than expected dose intensity, suggesting that alternative dosing strategies, like pulsatile dosing, may be necessary to improve safety and tolerability in future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase Ib Study of Combination Therapy with MEK Inhibitor Binimetinib and Phosphatidylinositol 3-Kinase Inhibitor Buparlisib in Patients with Advanced Solid Tumors with RAS/RAF Alterations. Bardia, A., Gounder, M., Rodon, J., et al.[2023]

Binimetinib, an uncompetitive inhibitor of MEK1/2, has shown significant efficacy in treating metastatic melanoma, particularly in combination with encorafenib, resulting in a progression-free survival (PFS) of 14.9 months compared to 7.3 months with vemurafenib alone in Phase 3 trials.

While binimetinib has a tolerable safety profile, there is currently no long-term data on durable responses or overall survival benefits compared to other treatments, highlighting the need for individualized treatment plans for patients with BRAF-mutated metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The discovery and development of binimetinib for the treatment of melanoma. Tran, B., Cohen, MS.[2021]

Encorafenib and binimetinib, a combination of a BRAF inhibitor and a MEK inhibitor, received FDA approval in June 2018 for treating patients with unresectable or metastatic melanoma that has specific BRAF mutations (V600E or V600K).

The combination therapy is also being explored in ongoing phase III clinical trials for metastatic colorectal cancer, indicating its potential broader application beyond melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib and Binimetinib: First Global Approvals. Shirley, M.[2019]

The combination of encorafenib and binimetinib was found to be safe and showed promising activity in patients with BRAF V600E-mutant solid tumors, with a recommended phase 2 dose established for further studies.

In phase II, the treatment resulted in confirmed responses in 67% of BRAFi-naïve melanoma patients, indicating significant efficacy, while the most common serious side effect was increased alanine aminotransferase levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib/II Study of the BRAF Inhibitor Encorafenib Plus the MEK Inhibitor Binimetinib in Patients with BRAFV600E/K -mutant Solid Tumors. Sullivan, RJ., Weber, J., Patel, S., et al.[2021]

A patient with advanced pancreatic ductal adenocarcinoma harboring a V600E BRAF mutation showed an objective tumor response to a combination treatment of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib.

This case highlights the potential for targeted therapy in a small subset of pancreatic cancer patients, suggesting that BRAF mutations, although rare, may offer a new avenue for treatment beyond conventional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular Targeting of a BRAF Mutation in Pancreatic Ductal Adenocarcinoma: Case Report and Literature Review. Seghers, AK., Cuyle, PJ., Van Cutsem, E.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11558618/

Encorafenib, binimetinib and cetuximab in BRAF V600E- ... We report the case of a 51-year-old woman with advanced BRAF-V600E-mutated pancreatic ductal adenocarcinomas (PDAC) who exhibited an exceptional response to ...

2. oncodaily.com oncodaily.com/drugs/binimetinib-mektovi

Binimetinib (Mektovi): Uses in Cancer, Side effects, ... After 7 years, progression-free survival (PFS) was 21.2% and overall survival (OS) was 27.4% in the combination therapy group, compared to 6.4% ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS3188

Phase II trial of binimetinib in patients with BRAF fusion- ... MEK inhibitors have been reported to show anti-tumor effects against BRAF fusion-positive cell lines. Phase I/II trials with selumetinib or ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2059702923008177

Avelumab or talazoparib in combination with binimetinib ... Furthermore, in preclinical studies, binimetinib inhibited the growth of tumor xenograft models, including pancreatic cancer. Binimetinib is approved in ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04132505

NCT04132505 | Binimetinib and Hydroxychloroquine in ... Giving hydroxychloroquine together with binimetinib may work better in treating patients with pancreatic cancer compared to binimetinib alone. Detailed ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11089837/

Pancreatitis After Treatment With Encorafenib, Binimetinib ... We report a case of grade 3 pancreatitis that emerged after treatment with ENCO, BINI, and CET in a patient with BRAF-mutant colorectal cancer.

7. jto.org jto.org/article/S1556-0864(25)00753-1/fulltext

Updated Efficacy and Safety From the Phase 2 PHAROS ... The PHAROS primary analysis revealed robust antitumor activity and acceptable safety with encorafenib plus binimetinib in patients with BRAF V600E-mutant ...

8. researchgate.net researchgate.net/publication/392301247_A_phase_I_trial_of_binimetinib_plus_hydroxychloroquine_inpatients_with_previously_treated_metastatic_pancreatic_cancer

A phase I trial of binimetinib plus hydroxychloroquine ... Overall, out of 31 response-evaluable pts, 2 pts achieved a partial response (lasting 6.9 and 4.7 mos, both at DL -1.5) and 9 pts achieved ...

9. braftovi.pfizerpro.com braftovi.pfizerpro.com/mektovi-m/overall-survival

Overall survival (OS) Review overall survival (OS) data from the COLUMBUS trial with BRAFTOVI® (encorafenib) + MEKTOVI® (binimetinib) and vemurafenib. See safety information.