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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for pancreatic cancer that has spread and involves a specific gene mutation called KRAS. The researchers aim to find the best dose of hydroxychloroquine when used with binimetinib. Binimetinib (also known as Mektovi) may stop tumor growth by blocking certain enzymes, while hydroxychloroquine may help kill cancer cells by preventing them from destroying treatments. The trial seeks participants with metastatic pancreatic cancer who have previously received treatment and have a confirmed KRAS mutation.

As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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

Research has shown that the combination of binimetinib and hydroxychloroquine has been tested for safety in patients with advanced pancreatic cancer. One study found no severe side effects that would prevent doctors from increasing the dose, indicating the treatment was generally well-tolerated. However, some treatment-related side effects did occur. The most serious side effects, classified as Grade 3 or higher, occurred in about 27.3% of patients. While these serious side effects were not common, they did occur.

Overall, the results suggest that although some patients might experience significant side effects, the treatment is considered safe enough for continued testing in clinical trials. Prospective participants should discuss these potential risks with their doctor. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the combination of Binimetinib and Hydroxychloroquine for pancreatic cancer because it offers a novel approach compared to current treatment options like chemotherapy. Most treatments for this cancer focus on killing rapidly dividing cells, but this combination works differently by targeting specific pathways that help cancer cells survive and grow. Binimetinib inhibits a crucial protein in the cancer's growth pathway, while Hydroxychloroquine disrupts the cancer cells' ability to recycle and manage waste, potentially making them more vulnerable to treatment. This dual-action strategy could provide a more effective way to fight pancreatic cancer, which is notoriously difficult to treat.

What evidence suggests that this treatment might be an effective treatment for pancreatic cancer?

This trial will evaluate the combination of binimetinib and hydroxychloroquine for treating pancreatic cancer. Studies suggest that combining binimetinib with hydroxychloroquine might be more effective than using binimetinib alone. Binimetinib blocks certain proteins that cancer cells need to grow, while hydroxychloroquine may inhibit autophagy, a process that can protect cancer cells. Previous research showed some positive effects with this combination, but the results were limited. It is important to note that this combination has posed challenges due to side effects. ^{1 2 4 6 7}

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 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]

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]

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]

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]

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]

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]

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 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]

Citations

1. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.2025.43.16_suppl.4152

A phase I trial of binimetinib plus hydroxychloroquine in ... Bini + HCQ demonstrated a challenging toxicity profile and limited clinical activity in a heavily pretreated cohort of metastatic PDAC pts.

2. 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. PRIMARY ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10322125/

A Phase II Open-Label Trial of Binimetinib and ... The median progression free survival (PFS) was 1.9 months, and median overall survival (OS) was 5.3 months. Overall, 5 patients (55.6%) ...

4. withpower.com withpower.com/trial/phase-1-pancreatic-neoplasms-9-2019-43890

Binimetinib + Hydroxychloroquine for Pancreatic Cancer In a study of 1102 patients with metastatic pancreatic cancer, FOLFIRINOX treatment resulted in a median overall survival of 9.27 months, significantly longer ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.4_suppl.TPS634

Phase I study of hydroxychloroquine plus binimetinib in ... This is a single arm, single center phase I trial of binimetinib plus hydroxychloroquine in patients with metastatic pancreatic cancer harboring a KRAS ...

6. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2019-0191.html

Hydroxychloroquine and binimetinib in KRASmt metastatic ... Giving hydroxychloroquine together with binimetinib may work better in treating patients with pancreatic cancer compared to binimetinib alone. Resources and ...

7. 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 ... Safety: No dose-limiting toxicity was observed, neither maximum tolerated dose (MTD) been identified. ... The TEAEs ≥Grade 3 occurred in 27.3% ...