Leflunomide for Solid Tumors

Overseen By Natalie Lucas, DNP

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Deborah Doroshow

Must not be taking: Investigational agents

Disqualifiers: Primary CNS tumors, Hepatitis B/C, 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: Unknown

Duration: 1 month

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests leflunomide to determine its safety and effectiveness for individuals with certain advanced solid tumors or HER2-negative breast cancer. The goal is to assess how well leflunomide works and identify potential side effects. This trial may suit individuals with advanced cancer who have specific tumor characteristics and have not responded to previous treatments. Participants should have cancer with specific genetic changes or be HER2-negative and must be eligible for a clinical study. 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 treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must be at least 4 weeks from your last systemic therapy, surgery, or radiation. You also cannot be on any other investigational agents.

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

Research has shown that leflunomide has been used in other medical situations, such as aiding organ transplant patients, indicating some known safety. However, its safety for treating solid tumors remains under investigation. Most individuals who have used leflunomide reported mild to moderate side effects, including nausea, diarrhea, and an increased risk of infections due to its impact on the immune system. Serious side effects, such as liver problems, are rare but have been observed.

As this trial is in its early stage, it primarily aims to determine the safety and tolerability of leflunomide for cancer treatment. Researchers are specifically examining how patients respond to the treatment. Although leflunomide is not new to medicine, its application for solid tumors is still being tested to ensure safety for this new purpose. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for solid tumors, which often involve chemotherapy or targeted therapies, Leflunomide is unique because it traditionally treats autoimmune conditions like rheumatoid arthritis. Researchers are excited about Leflunomide because it inhibits a different pathway, targeting the de novo pyrimidine synthesis pathway, which is crucial for rapidly dividing tumor cells. This alternative mechanism has the potential to overcome resistance seen in other treatments and provides a novel approach to tackling solid tumors.

What evidence suggests that leflunomide might be an effective treatment for advanced solid tumors or HER2 negative breast cancer?

Research has shown that leflunomide, the treatment under study in this trial, can significantly shrink tumors. One study found that tumor size decreased by 27.7%, 38.8%, and 66.6%, depending on the dose. This suggests leflunomide might effectively slow tumor growth. Although primarily used to treat rheumatoid arthritis by improving symptoms and slowing disease progression, its potential to reduce tumor size is promising. These findings support further research into using leflunomide for treating certain types of cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Deborah Doroshow, MD, PhD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Are You a Good Fit for This Trial?

Adults with advanced solid tumors lacking PTEN protein, as confirmed by a specific test. They must have measurable disease, be at least 4 weeks out from prior treatments, and not require immediate brain metastasis treatment. Participants need to be in fair health (ECOG 0-2), have good organ function, and agree to use contraception. Those with HIV can join if their viral load is undetectable.

Inclusion Criteria

Patients must have measurable disease per RECIST 1.1 criteria

My cancer did not respond or worsened after standard treatment, or I couldn't tolerate it.

My doctor thinks I don't need immediate brain treatment for my cancer.

Exclusion Criteria

I do not have a primary brain tumor.

I haven't had chemotherapy or radiotherapy in the last 4 weeks and have recovered from most side effects.

I have a history of Hepatitis B or C.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Leflunomide, 20-50mg PO daily to determine safety, tolerability, and MTD

1 month

Dose Expansion

Participants are monitored for overall response rate using RECIST v1.1

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Leflunomide

Trial Overview The trial tests Leflunomide's safety and maximum tolerated dose in patients whose tumors don't express the PTEN protein. It also looks for any signs that the drug might help control the cancer.

How Is the Trial Designed?

Group I: Leflunomide Experimental Treatment 1 Intervention

Leflunomide, 20-50mg PO daily

Leflunomide is already approved in European Union, United States, United Kingdom for the following indications:

Approved in European Union as Arava for:

• Rheumatoid arthritis
• Psoriatic arthritis

Approved in United States as Arava for:

• Rheumatoid arthritis
• Psoriatic arthritis

Approved in United Kingdom as Arava for:

• Rheumatoid arthritis
• Psoriatic arthritis

Who Is Running the Clinical Trial?

Deborah Doroshow

Lead Sponsor

Trials

1

Recruited

20+

Published Research Related to This Trial

A 64-year-old woman developed a lichenoid drug reaction after two months of treatment with leflunomide for rheumatoid arthritis, indicating a potential adverse effect of this immunomodulator.

The reaction improved significantly after stopping the medication and using colestyramine and topical corticosteroids, suggesting that leflunomide can cause serious skin reactions, although such side effects are generally rare and benign.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Lichenoid drug reaction to leflunomide]. Canonne-Courivaud, D., Carpentier, O., Dejobert, Y., et al.[2018]

In a study of 7 pediatric kidney transplant patients, leflunomide effectively controlled BK virus viremia, with 67% achieving complete viral clearance, even with reduced immunosuppressive therapy.

No serious adverse effects like graft rejection or hepatotoxicity were observed, although some patients experienced mild issues like hemolytic anemia and pancreatitis, suggesting leflunomide may be a safe option for managing BK virus in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide for BKvirus: Report of Seven Kidney-Transplanted Children. Launay, M., Baudouin, V., Guillemain, R., et al.[2022]

Leflunomide shows significant immunosuppressive effects in liver and kidney transplant recipients, allowing for reductions in conventional immunosuppressive drugs like cyclosporine and prednisone without evidence of acute rejection.

The drug was well tolerated in patients with lower serum creatinine levels, but those with higher levels experienced more side effects, highlighting the importance of monitoring serum drug levels for safe and effective dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experiences with leflunomide in solid organ transplantation. Williams, JW., Mital, D., Chong, A., et al.[2022]

LFM-A13, a metabolite analog of leflunomide, is a designed inhibitor of Bruton's tyrosine kinase (BTK) and shows potential as a dual-function anticancer drug with both apoptosis-promoting and anti-thrombotic properties.

The drug was produced under current Good Manufacturing Practice (cGMP) conditions, ensuring its quality and safety for further development and testing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Large-scale synthesis of GMP grade alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl) propenamide (LFM-A13), a new anti-cancer drug candidate. DuMez, D., Venkatachalam, TK., Uckun, FM.[2013]

In a study of 32 sarcoidosis patients, leflunomide was found to be effective, with a complete or partial response in 12 out of 17 patients treated with leflunomide alone and 13 out of 15 patients receiving it alongside methotrexate.

Leflunomide was well tolerated, with only three patients experiencing nausea, and no serious adverse reactions reported, suggesting it may be a safer alternative to methotrexate for patients who cannot tolerate it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide for chronic sarcoidosis. Baughman, RP., Lower, EE.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04997993

NCT04997993 | Leflunomide in Patients With PTEN- ... Phase 1A objectives are to determine the safety, tolerability, and the MTD of leflunomide in patients with PTEN-Altered advanced solid malignancies and HER2 ...

2. ard.bmj.com ard.bmj.com/content/62/10/944.short

Survival and effectiveness of leflunomide compared with ... Matched survival analysis showed better retention rates for MTX (mean (SEM) survival 28 (1) months) than for LEF (20 (1) months; p=0.001), whereas retention ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0024320515300291

Effect on EGF and EGFR expression and tumor proliferation Treatment with leflunomide (3, 10 or 30 mg/kg/day) for 14 days reduced the tumor mass (27.7%, 38.8% and 66.6% reduction in tumor mass, respectively) compared to ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/7488280/

Safety and effectiveness of leflunomide in the treatment ... Results: Statistically significant improvement in primary and secondary outcome measures, as well as by responder analyses, occurred in the 10-mg and 25-mg ...

5. researchgate.net researchgate.net/publication/10728251_Leflunomide_for_the_treatment_of_rheumatoid_arthritis_A_systematic_review_and_metaanalysis

Leflunomide for the treatment of rheumatoid arthritis Leflunomide improves all clinical outcomes and delays radiographic progression at 6 and 12 months of RA treatment compared to placebo. Its ...

6. medsafe.govt.nz medsafe.govt.nz/profs/datasheet/a/aravatab.pdf

Arava Data Sheet The increase in the development of malignant lymphomas was probably due to the immunosuppressant effect of leflunomide. A no-effect dose or AUC for the ...

7. go.drugbank.com go.drugbank.com/drugs/DB01097

Leflunomide: Uses, Interactions, Mechanism of Action Has also been used for the prevention of acute and chronic rejection in recipients of solid organ trasnplants and is designated by the FDA as an orphan drug for ...

8. medcentral.com medcentral.com/drugs/monograph/16551-300032/leflunomide-oral

Leflunomide: uses, dosing, warnings, adverse events, ... Although safety and efficacy of leflunomide in transplant recipients have not been established, the drug is designated an orphan drug by FDA for the prevention ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT04997993

NCT04997993 | Leflunomide in Patients With PTEN- ... Phase 1A objectives are to determine the safety, tolerability, and the MTD of leflunomide in patients with PTEN-Altered advanced solid malignancies and HER2 ...

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5947549/

Safety profile of avelumab in patients with advanced solid ... Avelumab generally was found to be well tolerated and to have a manageable safety profile. A minority of patients experienced grade ≥3 TRAEs or irAEs, and ...