Ruxolitinib for Chronic Graft-versus-Host Disease

Overseen By Claire Dusa

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Children's Hospital Medical Center, Cincinnati

Must be taking: Ruxolitinib

Must not be taking: Corticosteroids

Disqualifiers: Active infection, Malignancy, Thrombosis, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of ruxolitinib (also known as Jakafi, Jakavi, or Opzelura) for treating chronic graft-versus-host disease (cGVHD), a complication that can occur after a stem cell transplant. The researchers aim to determine if ruxolitinib can serve as a first-line treatment instead of high-dose steroids. Suitable candidates for this trial have moderate to severe cGVHD, have not received prior systemic treatment for it, and can take oral medication. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

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 require that you are on a low dose of steroids or can reduce your steroid dose to a low level within a month. If you are on high-dose steroids, you may not be eligible.

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

Research has shown that ruxolitinib is generally well-tolerated by patients with chronic graft-versus-host disease (cGVHD). In one study, patients did not experience any unexpected side effects, and the safety results aligned with earlier research. Another study found that while some patients had severe cGVHD, the treatment proved effective for many, achieving a 78.3% overall response rate.

Ruxolitinib is also approved for adults and children with cGVHD when other treatments have failed, indicating its safety for these patients. However, since this study is in an early phase, it primarily explores the safety and effectiveness of using ruxolitinib as a first treatment option rather than after other treatments. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Ruxolitinib is unique because it targets chronic graft-versus-host disease (GVHD) by inhibiting specific enzymes known as Janus kinases (JAK1 and JAK2). Unlike standard treatments, which often rely on broad immunosuppression, ruxolitinib offers a more targeted approach, potentially reducing inflammation with fewer side effects. Researchers are excited about this treatment because it provides a novel mechanism of action that could improve patient outcomes and quality of life compared to conventional therapies.

What evidence suggests that ruxolitinib might be an effective treatment for chronic GVHD?

Research has shown that ruxolitinib, which participants in this trial will receive, may help treat chronic graft-versus-host disease (cGVHD). One study found that about one-third of patients (33%) improved after six months of treatment. Over a longer period, the response rate increased to 78.3%, indicating its effectiveness as a backup treatment for cGVHD. Ruxolitinib also provides longer periods without treatment failure compared to other therapies. These findings suggest ruxolitinib can effectively manage cGVHD. ^{1 3 6 7 8}

Who Is on the Research Team?

Pooja Khandelwal, MD

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Are You a Good Fit for This Trial?

This trial is for individuals who have received a stem cell transplant and are now dealing with chronic graft versus host disease (cGVHD), which can affect various organs. Participants should not have previously used high-dose steroids or other immunosuppressants for cGVHD.

Inclusion Criteria

I have not had systemic treatment for chronic GVHD but may have been treated for acute GVHD.

I have a new diagnosis of severe chronic graft versus host disease needing treatment.

I am between 12 and 30 years old.

Exclusion Criteria

I currently have a serious infection.

I have not had a clot-related event like a heart attack or stroke in the last 6 months.

My blood counts are low and not improving with standard care.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive upfront single agent ruxolitinib for chronic graft-versus-host disease

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ruxolitinib

Trial Overview The study is testing the effectiveness of Ruxolitinib as an initial, standalone treatment for cGVHD. The goal is to see if using this drug early on, without combining it with steroids, can help manage symptoms better.

How Is the Trial Designed?

Group I: Ruxolitinib Treatment Experimental Treatment 1 Intervention

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

Approved in United States as Jakafi for:

• Intermediate or high-risk myelofibrosis
• Polycythemia vera
• Steroid-refractory acute graft-versus-host disease
• Chronic graft-versus-host disease
• Vitiligo

Approved in European Union as Jakavi for:

• Intermediate or high-risk myelofibrosis
• Polycythemia vera
• Steroid-refractory acute graft-versus-host disease
• Chronic graft-versus-host disease
• Non-segmental vitiligo

Who Is Running the Clinical Trial?

Children's Hospital Medical Center, Cincinnati

Lead Sponsor

Trials

844

Recruited

6,566,000+

Published Research Related to This Trial

In a study of 20 pediatric and young adult patients with chronic graft versus host disease (cGVHD), ruxolitinib showed a 70% overall response rate, with 2 patients achieving complete response and 12 achieving partial response after a median of 48 days.

The dosing strategy of ruxolitinib was effective in inhibiting JAK signaling, as indicated by decreased phosphorylation of STAT5 in lymphocytes, although some patients experienced side effects like neutropenia and infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the Treatment of Chronic GVHD and Overlap Syndrome in Children and Young Adults. Wang, YM., Teusink-Cross, A., Elborai, Y., et al.[2022]

Ruxolitinib (Jakafi) has received approval for the treatment of chronic graft-vs-host disease, indicating its efficacy in managing this condition.

The approval of ruxolitinib highlights its role as a kinase inhibitor, which works by targeting specific pathways involved in the immune response, potentially improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Indication for Ruxolitinib. Aschenbrenner, DS.[2023]

In a study of 46 patients with steroid-refractory chronic graft-versus-host disease (cGVHD), ruxolitinib, a JAK1/2 inhibitor, showed promising results with a 1-year treatment failure-free survival probability of 54.2%.

After 12 months of treatment, 43.5% of patients achieved either a complete or partial response, and ruxolitinib was associated with a reduction in the need for prednisone, highlighting its potential as an effective second-line therapy for cGVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib as Salvage Therapy for Chronic Graft-versus-Host Disease. Modi, B., Hernandez-Henderson, M., Yang, D., et al.[2021]

Ruxolitinib, an oral JAK1/JAK2 inhibitor, was approved by the FDA for treating steroid-refractory acute graft-versus-host disease (GVHD) based on promising results from the Phase II REACH1 trial.

The drug shows potential not only for treating SR acute GVHD but also for preventing GVHD and possibly serving as a first-line therapy, highlighting its versatility in managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of graft-versus-host disease. Ali, H., Salhotra, A., Modi, B., et al.[2021]

In an expanded access program involving 609 patients (60 with acute GVHD and 549 with chronic GVHD), ruxolitinib demonstrated a tolerable safety profile, with serious adverse events (SAEs) reported in 68.3% of acute and 33.9% of chronic GVHD patients.

The most common SAEs included infections, with sepsis and respiratory failure being prevalent in acute GVHD, indicating that while ruxolitinib is generally well-tolerated, careful monitoring for infections is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety analysis of patients who received ruxolitinib for steroid-refractory acute or chronic graft-versus-host disease in an expanded access program. Schroeder, MA., Hari, PN., Blithe, A., et al.[2022]

Ruxolitinib is a well-absorbed tyrosine kinase inhibitor with 95% bioavailability, primarily metabolized in the liver, and its pharmacokinetics can vary based on factors like gender and body weight.

The drug's effectiveness can be influenced by liver and renal function, necessitating dose adjustments, and while model-informed precision dosing could enhance treatment personalization, more research is needed before it can be routinely implemented.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Pharmacodynamics of Ruxolitinib: A Review. Appeldoorn, TYJ., Munnink, THO., Morsink, LM., et al.[2023]

Ruxolitinib shows promising efficacy in treating corticosteroid-refractory graft-versus-host disease (SR-GVHD), with an 84% response rate in acute SR-GVHD and a 63% response rate in chronic SR-GVHD after 28 days of treatment among 43 patients.

Infectious complications were notably higher in patients treated for acute SR-GVHD, with 42% experiencing infections, including significant viral and bacterial events, highlighting the need for careful monitoring and possible prophylactic measures during ruxolitinib therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, Toxicity, and Infectious Complications in Ruxolitinib-Treated Patients with Corticosteroid-Refractory Graft-versus-Host Disease after Hematopoietic Cell Transplantation. Abedin, S., McKenna, E., Chhabra, S., et al.[2022]

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 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 study of 29 children with steroid-refractory acute graft-versus-host disease (aGVHD), ruxolitinib demonstrated a high overall response rate of 72.4%, with 19 patients achieving complete response by a median of 41 days after treatment initiation.

Ruxolitinib was well-tolerated, with no severe hematological adverse events reported, suggesting it is a promising second-line treatment option for this condition, although further validation in larger trials is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib in children with steroid-refractory acute graft-versus-host disease: A retrospective multicenter study of the pediatric group of SFGM-TC. Laisne, L., Neven, B., Dalle, JH., et al.[2021]

In a study of 35 patients with steroid-refractory chronic graft-versus-host disease (cGVHD), ruxolitinib demonstrated a high overall response rate of 89%, with 26% achieving complete response after a median of 4 weeks of treatment.

The long-term follow-up showed that 67% of surviving patients were free of immunosuppression, indicating ruxolitinib's potential as a safe and effective second-line therapy for cGVHD, with manageable hematologic side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Follow-Up of Ruxolitinib in the Treatment of Steroid-Refractory Chronic Graft-versus-Host Disease. Ferreira, AM., Szor, RS., Molla, VC., et al.[2021]

In a study of 29 patients with graft versus host disease (GvHD), Ruxolitinib exposure was found to be significantly higher than in myelofibrosis patients, indicating altered drug metabolism in GvHD.

Increased Ruxolitinib levels were linked to reduced drug clearance and the use of CYP3A4 or CYP2C9 inhibitors, suggesting that higher trough concentrations may indicate a risk of toxicity and necessitate careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice-a prospective single-center trial. Isberner, N., Kraus, S., Grigoleit, GU., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38916742/

Efficacy and safety of ruxolitinib in the treatment of chronic ... At the primary analysis after six months on ruxolitinib treatment, the overall response rate was 33%, and failure-free survival was 58%.

2. sciencedirect.com sciencedirect.com/science/article/pii/S2531137925001038

Long-term follow-up results of ruxolitinib as salvage ... The long-term follow-up in this study supports ruxolitinib as an effective salvage therapy for chronic graft-versus-host disease with a 78.3% overall response ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO-24-02477

3-Year Final Analysis of the Phase III REACH3 Study Ruxolitinib provided longer FFS and DOR than BAT, demonstrating sustained efficacy and manageable safety over 3 years of follow-up in patients with SR/D-cGVHD.

4. ashpublications.org ashpublications.org/blood/article/145/20/2312/536227/Low-rates-of-chronic-graft-versus-host-disease

Low rates of chronic graft-versus-host disease with ruxolitinib ... Prolonged ruxolitinib administration after allogeneic HCT is associated with low rates of clinically significant chronic GVHD.

5. nature.com nature.com/articles/s41409-024-02252-z

Ruxolitinib for the treatment of acute and chronic graft ... Overall response rate (ORR) ranged from 45% to 100% in both acute and chronic GvHD. Complete response rates (CR) varied from 9% to 67% and from ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00809

Final Analysis From the Randomized Phase III REACH2 Trial Numerically higher chronic GVHD rates were noted with ruxolitinib than with BAT from 12 months; however, 95% confidence intervals overlapped.

7. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/654/503361/Ruxolitinib-in-Patients-With-Chronic-Graft-Versus

Ruxolitinib in Patients With Chronic Graft-Versus-Host ... RUX was well tolerated with no unexpected toxicities and safety that was consistent with earlier studies. Overall, the long-term control of ...

8. hcp.jakafi.com hcp.jakafi.com/chronic-graft-versus-host-disease/

For adults with cGVHD Jakafi is indicated for treatment of chronic graft-versus-host disease (cGVHD) after failure of one or two lines of systemic therapy in adult and pediatric ...