Researchers at City of Hope in Duarte, Calif., are now enrolling patients for a new trial that is evaluating whether leflunomide can be repurposed for treating severe COVID-19 in patients with cancer (NCT04532372). Leflunomide is an inexpensive oral generic drug that has been used since the 1990s to treat rheumatoid arthritis, with few serious side effects in these patients.
"Leflunomide is anti-inflammatory and has an excellent safety profile with rare liver toxicity. It is approved for the therapy of autoimmune diseases and has been used successfully with some viruses," co-principal investigator Steven T. Rosen, MD, told Oncology Times. He is Provost and Chief Scientific Officer of City of Hope.
Because leflunomide may have antiviral properties, it has been used to treat cytomegalovirus infection in patients with cancer (Immunotherapy 2010; doi: 10.2217/imt.10.52). It may also decrease the expression of the ACE2 receptor, which the coronavirus uses to infect cells, according to Rosen.
Research Details
In vitro laboratory experiments using human cells infected with COVID-19 have shown that leflunomide inhibits RNA formation and may decrease the ability of the coronavirus to replicate. A small study of 10 people without cancer and moderate COVID-19 in Wuhan, China, found that patients given leflunomide had shorter viral shedding time and lower levels of the inflammatory marker CRP, compared to patients who did not receive leflunomide. No obvious adverse effects were noted (Virol Sin 2020; doi: 10.1007/s12250-020-00258-7).
"Leflunomide has multiple other effects that impact the dysregulated immune response related to COVID-19. By combining leflunomide with remdesivir, we are exploring the possibility of addressing COVID-19 disease by attacking the virus and the inflammatory cascade," said principal investigator Sanjeet Dadwal, MD, Chief of the Division of Infectious Diseases at City of Hope.
Researchers plan to enroll a total of 30 patients in the Phase I study, which will include patients who are receiving care at City of Hope as well as USC. City of Hope may also work with other local medical centers to enroll patients in the trial. Patients will be eligible to participate if they have severe COVID-19 requiring supplemental oxygen and if they currently have cancer or have had cancer in the past 2 years. Patients who are critically ill with COVID-19, have no history of cancer, have had chemotherapy within the past 30 days, and/or have had a stem cell transplant within the past 120 days will not be able to participate.
For the Phase I trial, patients will receive leflunomide in addition to standard of care drugs, including the antiviral remdesivir, the steroid dexamethasone, and the IL-6 inhibitor tocilizumab.
If results from the Phase I trial demonstrate safety and tolerability of leflunomide in patients with cancer and COVID-19, then a Phase II randomized, double-blind trial is planned for a later date. In that study, roughly half of patients will receive leflunomide while the other half will receive placebo, both added to standard of care.
"There are currently few effective drugs against COVID-19, and our clinical trial targets a critical high-risk group," said Rosen.
Cancer patients may be at increased risk for severe COVID-19 infection due to weakened immune systems, either from the cancer itself or from cancer treatment. One recent analysis of 22 different studies about cancer and COVID-19 found that patients with cancer may have nearly 4 times the increased risk of severe COVID-19, and about 3 times the increased risk of death from COVID-19, compared to patients without cancer (Hematol Oncol Stem Cell Ther 2020; doi:10.1016/j.hemonc.2020.07.005).
"Our hope is that leflunomide will eradicate COVID-19 in cancer patients, providing the medical community with an effective therapy against this devastating virus," Rosen said.
Veronica Hackethal is a contributing writer.
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