Ruxolitinib + Tacrolimus + Methotrexate for Graft-versus-Host Disease Prevention in Leukemia

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

Must not be taking: Herbal medications

Disqualifiers: Prior transplant, Active infection, Thrombosis, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 31

Duration: 15 weeks

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial tests how well ruxolitinib with tacrolimus and methotrexate work to prevent the development of graft versus host disease in pediatric and young adult patients undergoing allogeneic hematopoietic cell transplant for acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome. Ruxolitinib is a type of medication called a kinase inhibitor. It works by blocking the signals of cells that cause inflammation and cell proliferation, which may help prevent graft versus host disease (GVHD). Tacrolimus is a drug used to help reduce the risk of rejection by the body of organ and bone marrow transplants by suppressing the immune system. Methotrexate stops cells from making DNA, may kill cancer cells, and also suppress the immune system, which may reduce the risk of GVHD. Giving ruxolitinib with tacrolimus and methotrexate may prevent GVHD in pediatric and young adults undergoing allogeneic hematopoietic cell transplants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude those who have had recent chemotherapy, radiation, or certain other therapies. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination Ruxolitinib, Tacrolimus, and Methotrexate for preventing graft-versus-host disease in leukemia?

Research shows that Ruxolitinib can reduce the incidence and severity of acute graft-versus-host disease (aGVHD) when used early after transplantation. Additionally, Methotrexate combined with another drug has been shown to significantly reduce the incidence of aGVHD compared to using the other drug alone, suggesting its potential effectiveness in combination therapies. ^{1 2 3 4 5}

Is the combination of Ruxolitinib, Tacrolimus, and Methotrexate safe for humans?

Tacrolimus and Methotrexate have been studied together in rheumatoid arthritis patients, showing a generally safe profile, though some side effects like gastrointestinal issues and liver enzyme changes can occur. Methotrexate alone is known to be safe in low doses, with rare serious side effects. Ruxolitinib's safety in combination with these drugs specifically for graft-versus-host disease is not detailed here, but the individual drugs have been used safely in other conditions. ^{6 7 8 9 10}

What makes the drug combination of Ruxolitinib, Tacrolimus, and Methotrexate unique for preventing graft-versus-host disease in leukemia?

This drug combination is unique because it includes Ruxolitinib, which is a JAK1/2 inhibitor that has shown effectiveness in reducing the incidence and severity of graft-versus-host disease (GVHD) by targeting specific pathways involved in immune response, potentially offering a more targeted approach compared to traditional treatments. ^{1 3 5 11 12}

Research Team

Haris Ali

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for pediatric and young adult patients aged 2-22 with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome who are in remission and planning to undergo a bone marrow transplant. They must be generally healthy with an ECOG ≤ 2 or Karnofsky/Lansky status ≥ 60%, have a matched donor, not be pregnant, agree to birth control measures, and have no recent history of certain severe health issues.

Inclusion Criteria

You or someone who can make decisions for you have signed a paper saying you agree to be in the study.

If you're under 18, you will need to agree to take part in the study.

If you are a woman who can have a baby, you need to have a negative pregnancy test before starting the study. If the urine test is positive or unclear, a blood test will be needed.

Exclusion Criteria

History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent

Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures

I am currently taking herbal medications.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive ruxolitinib orally twice daily from day -1 to day +100, tacrolimus intravenously on day -1, and methotrexate intravenously on days +1, +3, +6, and +11, and undergo hematopoietic cell transplantation on day 0

15 weeks

Multiple visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments at 30 days after the last dose of ruxolitinib and at 1 and 2 years post-transplant

2 years

Follow-up visits at 30 days, 1 year, and 2 years post-transplant

Treatment Details

Interventions

• Methotrexate
• Ruxolitinib
• Tacrolimus

Trial Overview The trial tests if ruxolitinib combined with tacrolimus and methotrexate can prevent graft versus host disease after allogeneic hematopoietic cell transplantation. Ruxolitinib is a kinase inhibitor that may reduce inflammation; tacrolimus suppresses the immune system to lower rejection risk; methotrexate stops DNA production which might also help prevent GVHD.

Participant Groups

Group I: Prevention (Ruxolitinib, tacrolimus, methotrexate) Experimental Treatment 8 Interventions

Patients receive ruxolitinib PO BID from day -1 to day +100, tacrolimus IV on day -1, and methotrexate IV on days +1, +3, +6, and +11, and undergo HCT on day 0. Patients also undergo chest CT and ECHO/MUGA at screening and undergo collection of blood samples throughout the trial.

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

Approved in United States as Trexall for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis

Approved in Canada as Mexate for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis

Approved in European Union as Methotrexate for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis
• Crohn's disease
• Ulcerative colitis

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

In a study of 57 patients undergoing alternative donor transplantation for acute leukemia, early application of ruxolitinib significantly reduced the incidence of acute graft-versus-host disease (aGVHD) compared to the control group (22% vs. 50%).

Ruxolitinib was well tolerated, with no significant differences in overall survival or disease-free survival between the ruxolitinib and control groups, indicating its safety and efficacy in preventing aGVHD without compromising other health outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib early administration reduces acute GVHD after alternative donor hematopoietic stem cell transplantation in acute leukemia. Zhang, B., Chen, L., Zhou, J., et al.[2021]

In a phase II trial involving 138 patients undergoing HLA-mismatched allogeneic stem cell transplantation, the addition of bortezomib to tacrolimus/methotrexate did not significantly reduce the incidence of grade II-IV acute graft-versus-host disease compared to conventional therapy.

Overall survival, progression-free survival, and non-relapse mortality rates were similar across all treatment groups, indicating that bortezomib-based regimens did not provide additional benefits over standard tacrolimus/methotrexate therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib-based immunosuppression after reduced-intensity conditioning hematopoietic stem cell transplantation: randomized phase II results. Koreth, J., Kim, HT., Lange, PB., et al.[2021]

Ruxolitinib prophylaxis showed a 41.2% incidence of acute graft-versus-host disease (aGVHD) in patients after modified donor lymphocyte infusion, indicating it can help reduce the severity of aGVHD in high-risk leukemia patients post-transplant.

Among the 17 patients studied, 58.8% achieved a complete response, suggesting that ruxolitinib may effectively maintain the graft-versus-leukemia (GVL) effect while managing aGVHD, despite a median follow-up of only 8 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib on acute graft-versus-host disease prophylaxis after modified donor lymphocyte infusion. Tang, Y., Yang, D., Xie, R., et al.[2023]

In a study of 93 patients with acute nonlymphoblastic leukemia or chronic myelocytic leukemia, the combination of methotrexate and cyclosporine significantly reduced the incidence of acute graft versus host disease (GVHD) compared to cyclosporine alone (33% vs. 54%).

Patients receiving both methotrexate and cyclosporine also had better long-term survival rates, with an 80% survival rate at 1.5 years compared to 55% for those on cyclosporine alone, suggesting that this combination therapy improves outcomes after marrow transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. Storb, R., Deeg, HJ., Whitehead, J., et al.[2022]

In a study of 8 patients with acute or chronic graft versus host disease (GVHD) who were unresponsive to standard treatments, ruxolitinib demonstrated a high overall response rate of 85%, with 50% achieving complete response.

Ruxolitinib was well-tolerated, indicating it could be a promising rescue therapy for patients suffering from refractory GVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Compassionate use of ruxolitinib in acute and chronic graft versus host disease refractory both to corticosteroids and extracorporeal photopheresis. Sarmiento Maldonado, M., Ramírez Villanueva, P., Bertín Cortes-Monroy, P., et al.[2022]

In a 24-week study involving 75 rheumatoid arthritis patients, tacrolimus (TAC) combined with methotrexate (MTX) was found to be non-inferior in efficacy compared to leflunomide (LEF) combined with MTX, indicating that TAC is an effective alternative treatment.

The safety profile of TAC was better than LEF, with fewer adverse events reported (49 in TAC group vs. 66 in LEF group), and lower instances of liver enzyme elevation (transaminitis) in the TAC group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of add-on tacrolimus versus leflunomide in rheumatoid arthritis patients with inadequate response to methotrexate. Shin, K., Baek, HJ., Kang, YM., et al.[2020]

In a 6-month study involving 464 patients with active rheumatoid arthritis, tacrolimus demonstrated significant efficacy as a monotherapy, with a 26.8% ACR20 response rate at the 3 mg dose compared to 10.2% for placebo.

While some patients experienced increased serum creatinine levels, these remained within the normal range for about 90% of participants, indicating that tacrolimus is generally safe for use in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of tacrolimus in patients with rheumatoid arthritis: a double-blind trial. Yocum, DE., Furst, DE., Kaine, JL., et al.[2013]

Low-dose methotrexate (MTX) is an effective second-line treatment for rheumatoid arthritis (RA) with a good safety and tolerability profile, although its risk-benefit ratio in psoriatic arthritis is less established.

Common side effects include gastrointestinal issues and elevated liver enzymes, but serious complications like severe hemocytopenia and MTX pneumonitis are rare and can often be prevented by monitoring for risk factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose methotrexate in rheumatic diseases--efficacy, side effects, and risk factors for side effects. Schnabel, A., Gross, WL.[2022]

In a study of 80 patients with active rheumatoid arthritis (RA) despite methotrexate treatment, combining tacrolimus with methotrexate resulted in a 52.5% clinical response rate, indicating significant efficacy in managing symptoms.

The treatment was generally safe, with 12.5% of patients experiencing adverse events related to tacrolimus, including one serious case of pancreatitis, and a notable increase in creatinine levels, suggesting careful monitoring is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tacrolimus in rheumatoid arthritis patients receiving concomitant methotrexate: a six-month, open-label study. Kremer, JM., Habros, JS., Kolba, KS., et al.[2013]

Tocilizumab, an anti-IL-6 receptor monoclonal antibody, has shown significant clinical efficacy in treating moderately to severely active rheumatoid arthritis, achieving disease remission in 30% of patients who did not respond to anti-TNF therapy after 24 weeks of treatment.

While tocilizumab is generally well-tolerated, common side effects include upper respiratory infections and mild liver enzyme increases, with serious risks such as infections and gastrointestinal perforations, leading to its approval in over 70 countries for rheumatoid arthritis treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tocilizumab for the treatment of rheumatoid arthritis. Tanaka, T., Ogata, A., Narazaki, M.[2016]

Ruxolitinib (RUX) was well tolerated and led to significant improvements in chronic graft-versus-host disease (GVHD) symptoms in 19 allograft recipients, with high response rates in various affected areas, such as oral (92%) and cutaneous (82%) regions.

The treatment allowed for a reduction or discontinuation of steroid use in 68% of patients, demonstrating RUX's effectiveness as a steroid-sparing agent in managing chronic GVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib: a steroid sparing agent in chronic graft-versus-host disease. Khoury, HJ., Langston, AA., Kota, VK., et al.[2021]

Ruxolitinib demonstrated high efficacy in treating steroid-refractory graft-versus-host disease (SR-GVHD), with an overall response rate of 86.9% in acute GVHD patients and 78.1% in chronic GVHD patients, indicating its potential as a salvage therapy.

The treatment was associated with a 1-year overall survival rate of 82.6% for acute GVHD responders, significantly better than non-responders, while chronic GVHD showed no significant survival difference between responders and non-responders, highlighting the need for further investigation in chronic cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib for Treatment of Steroid-Refractory Graft-versus-Host Disease: Real-World Data from Chinese Patients. Wei, C., Zhang, X., Liang, D., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Ruxolitinib early administration reduces acute GVHD after alternative donor hematopoietic stem cell transplantation in acute leukemia. [2021]

2. Italy pubmed.ncbi.nlm.nih.gov

Bortezomib-based immunosuppression after reduced-intensity conditioning hematopoietic stem cell transplantation: randomized phase II results. [2021]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Ruxolitinib on acute graft-versus-host disease prophylaxis after modified donor lymphocyte infusion. [2023]

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

Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. [2022]

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

Compassionate use of ruxolitinib in acute and chronic graft versus host disease refractory both to corticosteroids and extracorporeal photopheresis. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of add-on tacrolimus versus leflunomide in rheumatoid arthritis patients with inadequate response to methotrexate. [2020]

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

Efficacy and safety of tacrolimus in patients with rheumatoid arthritis: a double-blind trial. [2013]

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

Low-dose methotrexate in rheumatic diseases--efficacy, side effects, and risk factors for side effects. [2022]

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

Tacrolimus in rheumatoid arthritis patients receiving concomitant methotrexate: a six-month, open-label study. [2013]

10. England pubmed.ncbi.nlm.nih.gov

Tocilizumab for the treatment of rheumatoid arthritis. [2016]

11. England pubmed.ncbi.nlm.nih.gov

Ruxolitinib: a steroid sparing agent in chronic graft-versus-host disease. [2021]

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

Ruxolitinib for Treatment of Steroid-Refractory Graft-versus-Host Disease: Real-World Data from Chinese Patients. [2022]