Ruxolitinib for Graft-Versus-Host Disease Prevention

Recruiting in Palo Alto (17 mi)

Overseen by Ramzi Abboud, M.D.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Washington University School of Medicine

Must be taking: Tacrolimus, Mycophenolate mofetil, Cyclophosphamide

Must not be taking: Investigational drugs, Antithymocyte globulin

Disqualifiers: Prior allogeneic transplant, HIV, Hepatitis, others

No Placebo Group

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

Allogeneic hematopoietic cell transplantation (HCT) is one of the only curative intent therapies available for hematologic malignancies. HLA-matched sibling donors have historically offered the best clinical results but are unavailable for the majority of patients, while most patients do have readily available haploidentical donors. One of the risks of a haploidentical HCT is graft vs. host disease (GVHD), but it is difficult to reduce the incidence of GVHD without compromising the graft vs. leukemia (GVL) effect. The hypothesis of this study is that JAK inhibition with haploidentical HCT may mitigate GVHD and cytokine release syndrome while retaining the GVL effect and improving engraftment.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on investigational drugs or immunosuppressive doses of steroids, you may need to stop them before joining the trial.

What data supports the effectiveness of the drug Ruxolitinib for preventing graft-versus-host disease?

Research shows that Ruxolitinib can reduce the incidence and severity of acute graft-versus-host disease (aGVHD) when used early after transplantation. It has been effective in treating steroid-refractory GVHD and is approved for chronic GVHD, indicating its potential in prevention as well. ^{1 2 3 4 5}

Is Ruxolitinib safe for humans?

Ruxolitinib has been used safely in humans for conditions like myelofibrosis and graft-versus-host disease (GVHD). Studies show it is generally well-tolerated, with no significant differences in survival or infection rates compared to other treatments. ^{1 2 3 4 5}

How is the drug ruxolitinib unique for preventing graft-versus-host disease?

Ruxolitinib is unique because it targets the JAK1/2 pathways, which are involved in immune cell activation, making it effective for patients who do not respond to standard treatments like corticosteroids. It is particularly useful for both acute and chronic forms of graft-versus-host disease, offering a novel approach by modulating immune responses. ^{4 5 6 7 8}

Research Team

Ramzi Abboud, M.D.

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for adults with certain blood cancers who are in remission and have a closely related family member as a donor. They must be healthy enough for stem cell harvesting, not HIV or HTLV positive, and agree to use birth control. People can't join if they've had previous allogeneic transplants, active hepatitis or HIV, severe allergies to study drugs, or are pregnant.

Inclusion Criteria

I am scheduled for a specific type of stem cell transplant from a half-matched donor.

I am 18 years old or older.

I can take care of myself and am up and about more than 50% of my waking hours.

Exclusion Criteria

Known hypersensitivity to study agents

I have or had active tuberculosis.

I am not taking high doses of steroids that weaken my immune system.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Ruxolitinib starting on Day -3 and continuing until Day 180, with dose adjustments based on recovery criteria

26 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Expansion Phase

Continuation of Ruxolitinib treatment with dose adjustments based on patient recovery

Duration not specified

Treatment Details

Interventions

• Ruxolitinib (JAK Inhibitor)

Trial Overview The trial tests Ruxolitinib's ability to prevent graft-versus-host disease (GVHD) and cytokine release syndrome after receiving stem cells from half-matched donors. It aims to see if the drug can protect patients without harming the anti-cancer effects of the transplant.

Participant Groups

Group I: Phase I: Ruxolitinib Experimental Treatment 1 Intervention

* Ruxolitinib at 5 mg twice per day (BID) beginning on Day -3 and continuing until Day 180 followed by a taper (duration of taper depends on dose of ruxolitinib at Day 180). Once a patient's counts have reached ANC \> 1.5 K/cumm, hemoglobin \> 9.0 g/dL, and platelets \> 50 K/cumm, ruxolitinib dosing will escalate to 10 mg BID. * Ruxolitinib starting dose for patients receiving fluconazole will be 5 mg QD. Patients who remain on fluconazole and meet the target recovery criteria below can increase ruxolitinib dosing to 5 mg BID and subsequently 10 mg BID.

Group II: Expansion Phase: Ruxolitinib Experimental Treatment 1 Intervention

* Ruxolitinib at 5 mg twice per day (BID) beginning on Day -3 and continuing until Day 180 followed by a taper (duration of taper depends on dose of ruxolitinib at Day 180). Once a patient's counts have reached ANC \> 1.5 K/cumm, hemoglobin \> 9.0 g/dL, and platelets \> 50 K/cumm, ruxolitinib dosing will escalate to 10 mg BID. * Ruxolitinib starting dose for patients receiving fluconazole will be 5 mg QD. Patients who remain on fluconazole and meet the target recovery criteria below can increase ruxolitinib dosing to 5 mg BID and subsequently 10 mg BID.

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

David H. Perlmutter

Washington University School of Medicine

Chief Executive Officer since 2015

MD from Washington University School of Medicine

Paul Scheel

Washington University School of Medicine

Chief Medical Officer since 2022

MD from Washington University School of Medicine

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Findings from Research

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 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]

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 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 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]

References

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

New Indication for Ruxolitinib. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of graft-versus-host disease. [2021]

3. England pubmed.ncbi.nlm.nih.gov

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

4. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

Ruxolitinib for the Treatment of Chronic GVHD and Overlap Syndrome in Children and Young Adults. [2022]

7. Australia pubmed.ncbi.nlm.nih.gov

JAK1/2 inhibitor ruxolitinib promotes the expansion and suppressive action of polymorphonuclear myeloid-derived suppressor cells via the JAK/STAT and ROS-MAPK/NF-κB signalling pathways in acute graft-versus-host disease. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Pharmacodynamics of Ruxolitinib: A Review. [2023]