Binimetinib + Hydroxychloroquine for Pancreatic Cancer

Overseen By Shubham Pant

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Anticancer drugs, Steroids, Antiepileptics, others

Disqualifiers: Other pancreatic tumors, Cardiovascular disease, Gastrointestinal impairment, others

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

Compensation: Varies

Number of Visits: 30

Duration: Up to 1 year

39 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the best dose of hydroxychloroquine combined with binimetinib for treating advanced pancreatic cancer with a KRAS mutation. Binimetinib stops cancer cells from growing, while hydroxychloroquine prevents them from protecting themselves. The goal is to find a more effective treatment for these patients.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, certain medications like digoxin, methotrexate, and some others are not allowed during the trial. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

Is the combination of Binimetinib and Hydroxychloroquine safe for humans?

Binimetinib, when used in combination with other drugs, has been associated with serious side effects like peripheral neuropathies (nerve damage) and renal disorders (kidney problems). Hydroxychloroquine is generally considered safe but can have side effects like vision changes and heart issues. It's important to discuss potential risks with your doctor. ^{1 2 3 4 5}

How is the drug combination of Binimetinib and Hydroxychloroquine unique for treating pancreatic cancer?

The combination of Binimetinib and Hydroxychloroquine is unique because it targets specific pathways involved in cancer cell growth and survival, potentially offering a new approach for pancreatic cancer treatment where standard options are limited, especially in later stages. ^{1 6 7 8 9}

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

A case report showed that a patient with a difficult-to-treat type of colorectal cancer experienced a rapid improvement and a 17% reduction in tumor size within six weeks when treated with a combination of binimetinib, hydroxychloroquine, and another drug. This suggests potential effectiveness of the combination in similar cancers. ^{1 10 11 12 13}

Who Is on the Research Team?

Shubham Pant, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with metastatic pancreatic cancer that has a KRAS mutation. They must have had at least one prior treatment, be in good physical condition (ECOG 0 or 1), and meet certain blood criteria. Women of childbearing age need a negative pregnancy test and agree to use contraception, as do men.

Inclusion Criteria

You need to have certain levels of blood cells and chemicals in your blood.

Ability to be compliant with scheduled visits, treatment plan, and study procedures

Willing and able to provide written informed consent for the trial

Exclusion Criteria

You have been using steroids for a long time to manage pain or nausea.

You have certain liver diseases, active tuberculosis, or can't handle imaging tests.

Participation in or use of investigational agent within 2 weeks prior to the anticipated first dose of study treatment

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive binimetinib and hydroxychloroquine orally twice daily on days 1-14, with cycles repeating every 14 days in the absence of disease progression or unacceptable toxicity

Up to 1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 1 year

Follow-up every 30 days

What Are the Treatments Tested in This Trial?

Interventions

• Binimetinib
• Hydroxychloroquine

Trial Overview The trial is testing the combination of Binimetinib, which blocks enzymes for cell growth, with Hydroxychloroquine, which may disrupt tumor cells' survival mechanisms. It aims to find the best dose when used together against advanced pancreatic cancer.

How Is the Trial Designed?

Group I: Treatment (binimetinib, hydroxychloroquine) Experimental Treatment 2 Interventions

Patients receive binimetinib PO BID and hydroxychloroquine PO BID on days 1-14. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

The combination of gemcitabine and chloroquine was well tolerated in a phase I study involving nine patients with metastatic pancreatic cancer, with no dose-limiting toxicities observed.

Three patients showed a partial response to the treatment, and the median overall survival was 7.6 months, suggesting that this combination may enhance the effectiveness of chemotherapy and warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of a chloroquine-gemcitabine combination in patients with metastatic or unresectable pancreatic cancer. Samaras, P., Tusup, M., Nguyen-Kim, TDL., et al.[2022]

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 I study involving 26 patients with metastatic colorectal cancer, the combination of oral binimetinib and FOLFOX was found to have a maximum tolerated dose of 45 mg taken twice daily, with no dose-limiting toxicities observed.

The treatment showed some antitumor activity, with 9 out of 13 patients on continuous dosing achieving stable disease after 2 months, and a median progression-free survival of 3.5 months, indicating potential efficacy in heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I clinical trial of binimetinib in combination with FOLFOX in patients with advanced metastatic colorectal cancer who failed prior standard therapy. Cho, M., Gong, J., Frankel, P., et al.[2022]

A review of 11,721 serious adverse event reports from patients treated with BRAF and MEK inhibitors revealed that different combinations have unique safety profiles, with V+C showing a high incidence of skin toxicities like Stevens-Johnson syndrome.

The combination E+B was notably associated with an increased risk of peripheral neuropathies and renal disorders, as well as a significant rise in reports of Guillain-Barré syndrome, indicating that while these treatments improve survival in melanoma, they also carry serious risks that need careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of BRAF+MEK Inhibitor Combinations: Severe Adverse Event Evaluation. Meirson, T., Asher, N., Bomze, D., et al.[2020]

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]

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]

In a study of 13 patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) receiving trametinib combined with hydroxychloroquine or CDK4/6 inhibitors, only one patient achieved stable disease, indicating limited efficacy of this treatment regimen.

The median overall survival for patients treated with trametinib plus hydroxychloroquine was 4.2 months, and 4.7 months for those treated with CDK4/6 inhibitors, with 50% of patients experiencing significant adverse events, suggesting safety concerns alongside limited effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world analysis of trametinib in combination with hydroxychloroquine or CDK4/6 inhibitor as third- or later-line therapy in metastatic pancreatic adenocarcinoma. Tang, H., Ge, Y., You, T., et al.[2023]

In a study of 1102 patients with metastatic pancreatic cancer, FOLFIRINOX treatment resulted in a median overall survival of 9.27 months, significantly longer than the 6.87 months observed with gemcitabine plus nab-paclitaxel (P < 0.001).

Patients receiving FOLFIRINOX also experienced 17.3% fewer posttreatment hospitalizations and 20% lower posttreatment costs compared to those treated with gemcitabine plus nab-paclitaxel, indicating better safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of FOLFIRINOX vs Gemcitabine Plus Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Ductal Adenocarcinoma. Klein-Brill, A., Amar-Farkash, S., Lawrence, G., et al.[2023]

Citations

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. Switzerland pubmed.ncbi.nlm.nih.gov

Rapid Improvement of the Performance Status and Reduction of the Tumor Size in KRAS-Mutated Colorectal Cancer Patient Receiving Binimetinib, Hydroxychloroquine, and Bevacizumab. [2020]

3. Germany pubmed.ncbi.nlm.nih.gov

Phase I study of a chloroquine-gemcitabine combination in patients with metastatic or unresectable pancreatic cancer. [2022]

4. England pubmed.ncbi.nlm.nih.gov

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

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

A phase I clinical trial of binimetinib in combination with FOLFOX in patients with advanced metastatic colorectal cancer who failed prior standard therapy. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Safety of BRAF+MEK Inhibitor Combinations: Severe Adverse Event Evaluation. [2020]

7. India pubmed.ncbi.nlm.nih.gov

Sorafenib and sunitinib: A dermatologist's perspective. [2021]

8. 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]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Tubulointerstitial Nephritis in an Advanced Melanoma Patient Treated with Encorafenib plus Binimetinib Combination Therapy. [2022]

10. 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]

11. England pubmed.ncbi.nlm.nih.gov

A real-world analysis of trametinib in combination with hydroxychloroquine or CDK4/6 inhibitor as third- or later-line therapy in metastatic pancreatic adenocarcinoma. [2023]

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

Comparison of FOLFIRINOX vs Gemcitabine Plus Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Ductal Adenocarcinoma. [2023]

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

Sintilimab Plus Modified FOLFIRINOX in Metastatic or Recurrent Pancreatic Cancer: The Randomized Phase II CISPD3 Trial. [2023]