Combination Therapy for Graft-versus-Host Disease

Overseen by Sherman Holtan, MD

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Masonic Cancer Center, University of Minnesota

Must be taking: Corticosteroids

Must not be taking: Sex hormones

Disqualifiers: Progressive malignancy, Uncontrolled infection, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests a mix of anti-inflammatory drugs and immune response controllers for patients with severe immune reactions after a transplant. The treatment aims to reduce harmful immune attacks and inflammation.

Will I have to stop taking my current medications?

The trial requires participants to stop taking supplemental sex hormone therapy and certain hormone-related medications. If you are on these medications, you will need to stop them to participate in the trial.

What data supports the effectiveness of the drug combination therapy for graft-versus-host disease?

Research shows that ruxolitinib, a part of the combination therapy, is effective in treating chronic graft-versus-host disease (cGVHD), especially in patients who do not respond well to corticosteroids. Studies indicate that ruxolitinib can improve symptoms and reduce the need for steroids, making it a promising option for managing cGVHD. ^{1 2 3 4 5}

Is the combination therapy for graft-versus-host disease safe for humans?

Ruxolitinib, a part of the combination therapy, has been used safely in both adults and children for treating graft-versus-host disease, although it was initially used for other conditions like myelofibrosis. It has shown to be effective and safe at lower doses for treating graft-versus-host disease, with some side effects noted at higher doses. ^{2 3 6 7 8}

What makes the combination therapy for graft-versus-host disease unique?

This combination therapy is unique because it includes ruxolitinib, a JAK1/2 inhibitor, which is promising for patients who do not respond to standard steroid treatments. Ruxolitinib has shown effectiveness in treating steroid-refractory chronic graft-versus-host disease, offering a new option for patients with limited alternatives. ^{2 3 6 9 10}

Research Team

Sherman Holtan, MD

Principal Investigator

Masonic Cancer Center, University of Minnesota

Eligibility Criteria

This trial is for HCT recipients over 12 years old with high-risk aGVHD, or standard risk aGVHD plus certain biomarkers. Participants need functioning kidneys and hearts, and must consent to the study. Excluded are those with current severe infections, hormone-responsive cancers, thrombosis, or unwilling to stop hormone therapies or avoid pregnancy.

Inclusion Criteria

I am over 12 and starting treatment for severe aGVHD within 7 days.

Voluntary written consent (adult or parent/guardian with minor assent for 12 through 17-year-olds).

My kidney function, measured by creatinine, is within the normal range.

Exclusion Criteria

I cannot or will not stop taking hormone therapy for cancer.

Pregnancy

I cannot or will not stop taking supplemental sex hormones.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ruxolitinib, uhCG/EGF, and corticosteroids with dose adjustments to determine the lowest effective dose

8 weeks

Weekly visits for monitoring and dose adjustments

Follow-up

Participants are monitored for safety and effectiveness after treatment, including adverse events and response evaluation

4 weeks

2 visits (in-person)

Phase II Extension

Continuation of treatment to confirm safety and preliminary efficacy of the drug combination

Long-term

Treatment Details

Interventions

• Corticosteroids (Corticosteroid)
• hCG (Other)
• Ruxolitinib 10 MG Oral Tablet (Other)

Trial Overview The study tests the lowest effective dose of corticosteroids combined with ruxolitinib and uhCG/EGF for treating high-risk acute Graft-versus-Host Disease (aGVHD). It's a single-arm phase I/II trial aiming to find this dose without affecting response rates at day 28.

Participant Groups

Group I: Ruxolitinib;hCG (Pregnyl®) ;Corticosteroids Experimental Treatment 3 Interventions

* Ruxolitinib 10 mg by mouth twice daily (with dose adjustments as indicated) through day 56, followed by taper * hCG (Pregnyl®) 2,000 units/m2 SQ every other day x 3 doses, followed by twice weekly x 14 doses (total 17 doses through day 56) * Corticosteroids (Prednisone, or IV methylprednisolone equivalent) * Dose level 1 (starting dose) = 1 mg/kg * Dose level 2 = 0.5 mg/kg * Dose level 3 = 0.25 mg/kg * Dose level 4 = 0.1 mg/kg * Dose level 5 = 0 mg/kg

Who Is Running the Clinical Trial?

Masonic Cancer Center, University of Minnesota

Lead Sponsor

Trials

285

Recruited

15,700+

Dr. Melissa A. Geller

Masonic Cancer Center, University of Minnesota

Chief Medical Officer since 2022

MD from University of Minnesota

Dr. Jeffrey Miller

Masonic Cancer Center, University of Minnesota

Chief Executive Officer

MD from University of Minnesota

Findings from Research

The combination of donor-derived regulatory T lymphocytes and the JAK1/2 inhibitor ruxolitinib shows a synergistic effect in treating chronic graft versus host disease (cGvHD), as demonstrated in both in vitro studies and a GvHD mouse model.

This combination therapy not only reduced the incidence and severity of cGvHD but also improved survival rates without compromising the graft versus leukemia effect, indicating a promising therapeutic strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined treatment of graft versus host disease using donor regulatory T cells and ruxolitinib. Rodríguez-Gil, A., Escamilla-Gómez, V., Nufer, M., et al.[2022]

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]

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 13 pediatric patients with steroid-refractory acute graft-versus-host disease (GVHD) treated with ruxolitinib, the overall response rate was 45%, with 1 complete response and 4 partial responses observed after 4 weeks of treatment.

Ruxolitinib was associated with significant adverse effects, including elevated liver enzymes and neutropenia, but these effects were mostly reversible, indicating that while ruxolitinib shows promise as a salvage therapy, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib as Salvage Therapy in Steroid-Refractory Acute Graft-versus-Host Disease in Pediatric Hematopoietic Stem Cell Transplant Patients. Khandelwal, P., Teusink-Cross, A., Davies, SM., et al.[2022]

Ruxolitinib, a JAK1/2 inhibitor, has been FDA-approved for treating acute steroid-refractory graft-versus-host disease (SR-aGVHD), demonstrating its efficacy in managing this serious immune condition.

Initial high-dose use of ruxolitinib caused hematological toxicity, but lower doses have shown to be effective and safe, particularly in pediatric patients, suggesting a promising therapeutic strategy for GVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Applications of JAK/STAT Inhibitors in Pediatrics: Current Use of Ruxolitinib. Marcuzzi, A., Rimondi, E., Melloni, E., et al.[2022]

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 14 pediatric patients with steroid-refractory graft-versus-host disease (SR-GVHD) treated with ruxolitinib, the overall response rate was 64.3%, indicating that ruxolitinib is an effective treatment option for children after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

While ruxolitinib showed promising efficacy, 64.3% of patients experienced adverse effects, including cytopenia and infections, suggesting that while it is effective, monitoring for side effects is important in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib Treatment of Steroid-Refractory Graft-versus-Host Disease in Children: A Case Series and Review of the Literature. Yan, WL., Zhao, FY., Gu, ME., et al.[2023]

References

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

Combined treatment of graft versus host disease using donor regulatory T cells and ruxolitinib. [2022]

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

Ruxolitinib as Salvage Therapy for Chronic Graft-versus-Host Disease. [2021]

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

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

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

New Indication for Ruxolitinib. [2023]

5. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

Ruxolitinib as Salvage Therapy in Steroid-Refractory Acute Graft-versus-Host Disease in Pediatric Hematopoietic Stem Cell Transplant Patients. [2022]

7. England pubmed.ncbi.nlm.nih.gov

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

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

New Applications of JAK/STAT Inhibitors in Pediatrics: Current Use of Ruxolitinib. [2022]

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

Long-Term Follow-Up of Ruxolitinib in the Treatment of Steroid-Refractory Chronic Graft-versus-Host Disease. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Ruxolitinib Treatment of Steroid-Refractory Graft-versus-Host Disease in Children: A Case Series and Review of the Literature. [2023]