Gemcitabine + Leflunomide for Pancreatic Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must be taking: Gemcitabine

Must not be taking: Herbal medications

Disqualifiers: HIV, Hepatitis B/C, Tuberculosis, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 33

Duration: 28 days per cycle, repeated until disease progression or unacceptable toxicity

19 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for individuals with advanced pancreatic cancer that cannot be surgically removed. Researchers are testing whether adding leflunomide, a drug used for rheumatoid arthritis, to the standard chemotherapy drug gemcitabine (Gemzar) can safely improve treatment outcomes. The goal is to enhance gemcitabine's effectiveness without increasing side effects, potentially helping patients live longer and better lives. The trial seeks participants with advanced pancreatic cancer who plan to receive gemcitabine as a single-agent treatment. 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.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, including chemotherapy, radiation, biological therapy, immunotherapy, and specific drugs metabolized by certain enzymes and transporters, at least 21 days before starting the trial. Herbal medications, except for CBD, must also be stopped.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that using gemcitabine with leflunomide might be safe for treating advanced pancreatic cancer. Gemcitabine is a common chemotherapy drug for this type of cancer. Leflunomide, originally used for rheumatoid arthritis, has shown potential in cancer treatments. Studies have not identified any long-term safety issues with leflunomide over two years.

While these findings are encouraging, further research is needed to confirm the safety of this combination for all patients. By joining clinical trials, participants help scientists evaluate the effectiveness of these treatments together. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for pancreatic cancer?

Most treatments for pancreatic cancer, like chemotherapy with gemcitabine alone, aim to slow tumor growth by interfering with cancer cell division. The new combination of gemcitabine with leflunomide is exciting because leflunomide, typically used for rheumatoid arthritis, may enhance the cancer-fighting effects by targeting cancer cells in a different way. Leflunomide works by inhibiting a specific enzyme involved in cell growth, which could make cancer cells more susceptible to gemcitabine. This dual approach has the potential to improve treatment outcomes by more effectively stopping cancer progression.

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

Research has shown that combining gemcitabine with leflunomide might help treat advanced pancreatic cancer. In this trial, participants will receive both gemcitabine, a common treatment for this cancer, and leflunomide, typically used for rheumatoid arthritis. Studies have found that leflunomide can enhance the cancer-fighting effects of gemcitabine. In lab tests, this combination slowed the growth of pancreatic cancer cells. Although these results are promising, further research is needed to confirm their benefits in people. ^{2 3 4 6 7}

Who Is on the Research Team?

Vincent Chung, MD

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for patients with advanced pancreatic cancer that has spread and cannot be removed by surgery. Participants should not have had previous chemotherapy for metastatic disease and must have acceptable organ function.

Inclusion Criteria

I can carry out all my usual activities without help.

Documented informed consent of the participant and/or legally authorized representative

I need help with my medication but have someone who can assist me.

Exclusion Criteria

Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

I have been diagnosed with Gilbert's disease.

I am not taking any herbal medications except for CBD.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive gemcitabine IV on days 1, 8, and 15 of each 28-day cycle and leflunomide PO daily. Cholestyramine is given for 11 days at the end of treatment.

28 days per cycle, repeated until disease progression or unacceptable toxicity

3 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with imaging and blood sample collection.

Up to 1 year

Follow-up at 30 days, then up to 1 year

What Are the Treatments Tested in This Trial?

Interventions

• Gemcitabine
• Leflunomide

Trial Overview The trial is testing the safety, side effects, and best dose of leflunomide combined with gemcitabine. Leflunomide is usually used for rheumatoid arthritis but may help improve the effectiveness of gemcitabine in treating pancreatic cancer without increasing side effects.

How Is the Trial Designed?

Group I: Treatment (gemcitabine, leflunomide) Experimental Treatment 7 Interventions

Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle and leflunomide PO QD on days -3 to -1 prior to cycle 1 and days 1-28 of each cycle thereafter. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive cholestyramine PO TID for 11 days at the end of treatment in the absence of unacceptable toxicity. Patients also undergo CT, MRI, or other imaging scans as clinically indicated throughout the study, as well as blood sample collection on study and during follow up.

Gemcitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in United States as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in Canada as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in Japan as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Leflunomide's active metabolite, teriflunomide, shows promise in treating pancreatic cancer by not only inhibiting cell growth on its own but also enhancing the effectiveness of the chemotherapy drug gemcitabine.

Teriflunomide directly targets the PIM-3 kinase, which is linked to pancreatic cancer development, and its inhibition leads to reduced cancer cell proliferation, suggesting a new mechanism of action beyond its known effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide Synergizes with Gemcitabine in Growth Inhibition of PC Cells and Impairs c-Myc Signaling through PIM Kinase Targeting. Buettner, R., Morales, C., Wu, X., et al.[2020]

Leflunomide is effective and well tolerated when used in combination with either sulfasalazine or methotrexate (MTX) for treating rheumatoid arthritis, based on a review of clinical studies.

An International Expert Panel supports the use of leflunomide in combination therapies, particularly with MTX and sulfasalazine, but emphasizes the need for careful monitoring of patient safety during such treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lefunomide in combination therapy. Kalden, JR., Smolen, JS., Emery, P., et al.[2018]

In a two-year study of 42 psoriatic arthritis patients treated with leflunomide (LEF), the cumulative survival rate on the medication was similar to that of 44 patients treated with methotrexate (MTX), indicating comparable long-term adherence to both treatments.

However, leflunomide had a higher discontinuation rate due to adverse events (29.2% for LEF vs. 10.8% for MTX), and a significantly greater incidence of adverse events overall, suggesting that while LEF is effective, it may have a less favorable safety profile compared to MTX.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide in psoriatic arthritis: a retrospective study of discontinuation rate in daily clinical practice compared with methotrexate. Malesci, D., Tirri, R., Buono, R., et al.[2018]

Leflunomide is as effective as methotrexate for treating rheumatoid arthritis, showing similar clinical and radiographic outcomes over trials lasting up to two years, and it may even improve quality of life more than methotrexate.

Leflunomide has a generally acceptable side effect profile compared to other DMARDs, with liver toxicity being the most significant concern, though it is rare; it is contraindicated in pregnancy and should be used cautiously in women of child-bearing age.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reappraisal of the clinical use of leflunomide in rheumatoid arthritis and psoriatic arthritis. Jones, PB., White, DH.[2020]

In a study of 40,594 rheumatoid arthritis patients, leflunomide (LEF) monotherapy showed a significantly lower incidence of serious adverse events (94 events/1000 person-years) compared to methotrexate (MTX) and other DMARDs, indicating a safer profile for LEF.

Combination therapy with LEF and MTX also resulted in lower adverse event rates than those seen with MTX alone, suggesting that LEF can be a safer option when used in conjunction with other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events with disease modifying antirheumatic drugs (DMARD): a cohort study of leflunomide compared with other DMARD. Cannon, GW., Holden, WL., Juhaeri, J., et al.[2018]

Leflunomide is an effective disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis (RA), showing superior efficacy compared to placebo and comparable results to other treatments like sulfasalazine and methotrexate in improving symptoms and quality of life.

The drug works by inhibiting dihydroorotate dehydrogenase, which limits T-cell proliferation, a key factor in RA, and while it has some mild to moderate side effects, these are generally manageable and resolve without lasting issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of leflunomide in the treatment of rheumatoid arthritis: an experimental and clinical review. Schattenkirchner, M.[2021]

Leflunomide is an effective oral DMARD for treating active rheumatoid arthritis, showing significant improvements in symptoms and slowing disease progression compared to placebo and is equivalent to other treatments like sulfasalazine and methotrexate over 26 to 52 weeks.

It works by inhibiting the synthesis of pyrimidine nucleotides in immune cells, leading to reduced inflammation and has a rapid onset of action within 4 weeks, with mild to moderate side effects that are generally well-tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide: a novel DMARD for the treatment of rheumatoid arthritis. Alldred, A., Emery, P.[2019]

Leflunomide is an effective disease-modifying anti-rheumatic drug (DMARD) for rheumatoid arthritis, showing superior efficacy compared to placebo and comparable results to other treatments like sulphasalazine and methotrexate in improving symptoms and functional ability.

In two years of treatment, leflunomide maintained its efficacy without long-term safety issues, although common side effects included gastrointestinal symptoms and elevated liver enzymes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of leflunomide in active rheumatoid arthritis. Smolen, JS., Emery, P.[2019]

Leflunomide, an immunomodulator and disease-modifying antirheumatic drug (DMARD), was approved by the FDA in 1998 for treating rheumatoid arthritis (RA) in adults, demonstrating its efficacy in managing this condition.

Despite its effectiveness, leflunomide has been associated with rare side effects, such as pancytopenia, leading to recommendations against its use during pregnancy and the establishment of a pregnancy registry to monitor potential risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide Aventis Pharma. Kaplan, MJ.[2018]

A novel algorithm was developed to predict effective drug combinations for rheumatoid arthritis, identifying Ligustrazine (LIG) as a promising partner for Leflunomide (LEF).

In a clinical trial, the combination of LEF and LIG showed a significantly higher response rate (78.7%) and reduced bone erosion compared to LEF alone (58.8% response rate), indicating improved efficacy in treating rheumatoid arthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of leflunomide combined with ligustrazine in the treatment of rheumatoid arthritis: prediction with network pharmacology and validation in a clinical trial. Zhang, C., Guan, D., Jiang, M., et al.[2022]

Citations

1. cancer.gov cancer.gov/clinicaltrials/NCI-2024-04359

Gemcitabine and Leflunomide in Patients with Advanced ... Giving gemcitabine in combination with leflunomide may be safe and effective in treating patients with advanced unresectable pancreatic cancer. Eligibility ...

2. withpower.com withpower.com/trial/phase-1-adenocarcinoma-4-2024-81cd6

Gemcitabine + Leflunomide for Pancreatic Cancer It has shown promising results when combined with gemcitabine. Giving gemcitabine in combination with leflunomide may be safe and effective in treating patients ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6562366/

Leflunomide Synergizes with Gemcitabine in Growth ... We report that Ter not only shows in vitro anti-proliferative activity in pancreatic cancer (PC) cells as a single agent but also synergizes with the ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4849685/

Systemic Chemotherapy in Advanced Pancreatic Cancer - PMC In a phase III trial, 5-FU and gemcitabine combined treatment did not improve the median survival of patients with advanced pancreatic carcinoma ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1044579X25001105

Therapeutic pancreatic cancer biomarkers and ... FOLFIRINOX and gemcitabine plus nab-paclitaxel represent the most effective chemotherapy regimens for metastatic pancreatic cancer patients ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06454383

NCT06454383 | Gemcitabine and Leflunomide in Patients ... Giving gemcitabine in combination with leflunomide may be safe and effective in treating patients with advanced unresectable pancreatic cancer. Detailed ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3118359/

Regional Chemotherapy in Locally Advanced Pancreatic ... Intravenous gemcitabine is the current standard treatment of pancreatic cancer. However, >90% of the drug is secreted unchanged affecting toxicity but not the ...