Palbociclib + Binimetinib for Pancreatic Cancer

Recruiting at 286 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

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

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This phase II ComboMATCH treatment trial evaluates the effectiveness of palbociclib and binimetinib in treating patients with RAS-mutated cancers. Palbociclib and binimetinib are both in a class of medications called kinase inhibitors. They work by blocking the action of abnormal proteins that signals cancer cells to multiply. This trial may help researchers understand if giving the combination of palbociclib and binimetinib can help improve the amount of time before the cancer grows in patients with patients with low grade serous ovarian cancer who have certain changes in the tumor DNA. This trial may also help researchers understand if giving the combination of palbociclib and binimetinib can help improve outcomes among patients with low grade serous ovarian cancer who have previously received a MEK inhibitor. For patients with other tumors, with the exception of lung cancer, colon cancer, melanoma and low grade serous ovarian cancers, this trial may help researchers understand if giving the combination of palbociclib and binimetinib can improve the clinical outcome of survival without progression in patients who have certain changes in their tumor's DNA.

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.

What data supports the effectiveness of the drug combination of Palbociclib and Binimetinib for pancreatic cancer?

Research shows that binimetinib, a MEK inhibitor, has shown effectiveness in treating certain cancers like melanoma and colorectal cancer, especially when combined with other targeted therapies. Additionally, a case report indicated a positive tumor response in pancreatic cancer when a similar MEK inhibitor was used with a BRAF inhibitor. ^{1 2 3 4 5}

Is the combination of Palbociclib and Binimetinib safe for humans?

Binimetinib has been studied for safety in humans, particularly in patients with advanced solid tumors, and its maximum tolerated dose was determined in a phase 1 study. However, specific safety data for the combination of Palbociclib and Binimetinib in humans is not provided in the available research. ^{2 3 6 7 8}

What makes the drug combination of Palbociclib and Binimetinib unique for treating pancreatic cancer?

The combination of Palbociclib and Binimetinib is unique because it targets specific pathways involved in cancer cell growth, with Palbociclib inhibiting cell cycle progression and Binimetinib blocking MEK enzymes, which are part of a signaling pathway often active in cancers. This dual approach may offer a novel way to tackle pancreatic cancer compared to standard treatments. ^{1 2 3 9 10}

Research Team

Geoffrey I Shapiro

Principal Investigator

Alliance for Clinical Trials in Oncology

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Binimetinib (Kinase Inhibitor)
• Palbociclib (Kinase Inhibitor)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Findings from Research

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]

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]

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 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]

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]

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]

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]

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]

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]

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]

References

1. England 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. [2023]

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

The discovery and development of binimetinib for the treatment of melanoma. [2021]

3. 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]

4. France pubmed.ncbi.nlm.nih.gov

Molecular Targeting of a BRAF Mutation in Pancreatic Ductal Adenocarcinoma: Case Report and Literature Review. [2021]

5. England 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. [2023]

6. Australia pubmed.ncbi.nlm.nih.gov

Pancreatic adverse events in patients treated with immune checkpoint inhibitors. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Pancreatic Adverse Events Associated With Immune Checkpoint Inhibitors: A Large-Scale Pharmacovigilance Analysis. [2022]

8. United States 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. [2021]

9. United States 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. [2021]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Encorafenib and Binimetinib: First Global Approvals. [2019]