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

Trial Summary

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.

What data supports the effectiveness of the drug Gemcitabine + Leflunomide for pancreatic cancer?

Research shows that leflunomide, when combined with gemcitabine, can work together to stop the growth of pancreatic cancer cells. Leflunomide has been effective in treating rheumatoid arthritis and has shown potential in cancer treatment by targeting specific proteins involved in cancer cell growth. ^{1 2 3 4 5}

Is the combination of Gemcitabine and Leflunomide safe for humans?

Leflunomide has been used safely in over 300,000 patients with rheumatoid arthritis, with common side effects including stomach issues, allergic reactions, hair loss, and increased liver enzyme levels. No long-term safety issues were reported with leflunomide over two years. Gemcitabine is a chemotherapy drug, and while specific safety data for the combination with leflunomide in pancreatic cancer is limited, leflunomide has shown a generally safe profile in other conditions. ^{2 6 7 8 9}

What makes the drug combination of Gemcitabine and Leflunomide unique for treating pancreatic cancer?

This drug combination is unique because Leflunomide, typically used for rheumatoid arthritis, works with Gemcitabine to inhibit pancreatic cancer cell growth by targeting specific enzymes and kinases involved in cancer cell proliferation, offering a novel approach compared to standard treatments. ^{1 2 4 5 10}

What is the purpose of this trial?

This phase Ib trial tests the safety, side effects, and best dose of leflunomide in combination with gemcitabine in treating patients with pancreatic cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) and cannot be removed by surgery (unresectable). Improving the effectiveness of gemcitabine without increasing side effects could lead to a greater impact for pancreatic cancer patients' survival and quality of life. Gemcitabine is commonly used as a first-line chemotherapy treatment for pancreatic cancer. Leflunomide is a drug approved for use against rheumatoid arthritis that is being looked at as a cancer treatment option. It has shown promising results when combined with gemcitabine. Giving gemcitabine in combination with leflunomide may be safe and effective in treating patients with advanced unresectable pancreatic cancer.

Research Team

Vincent Chung, MD

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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 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 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]

References

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

Reappraisal of the clinical use of leflunomide in rheumatoid arthritis and psoriatic arthritis. [2020]

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

Leflunomide Synergizes with Gemcitabine in Growth Inhibition of PC Cells and Impairs c-Myc Signaling through PIM Kinase Targeting. [2020]

3. England 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. [2022]

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

Leflunomide Aventis Pharma. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Leflunomide: a novel DMARD for the treatment of rheumatoid arthritis. [2019]

6. Italy pubmed.ncbi.nlm.nih.gov

Leflunomide in psoriatic arthritis: a retrospective study of discontinuation rate in daily clinical practice compared with methotrexate. [2018]

7. Canada pubmed.ncbi.nlm.nih.gov

Adverse events with disease modifying antirheumatic drugs (DMARD): a cohort study of leflunomide compared with other DMARD. [2018]

8. Netherlands pubmed.ncbi.nlm.nih.gov

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

9. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of leflunomide in active rheumatoid arthritis. [2019]

10. Canada pubmed.ncbi.nlm.nih.gov

Lefunomide in combination therapy. [2018]