Combination Therapy for Graft-versus-Host Disease

Overseen By Cancer Center Clinical Trials Office

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

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

Compensation: Varies

Number of Visits: 2

Duration: 8 weeks

55 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for individuals with high-risk acute graft-versus-host disease (aGVHD), which can occur after a stem cell transplant. The researchers aim to find the lowest effective dose of corticosteroids (a type of anti-inflammatory drug) to use alongside ruxolitinib (an oral tablet) and a novel therapy called uhCG/EGF, without compromising the treatment's effectiveness. The trial will first determine the optimal steroid dose and then assess the safety and early effectiveness of this treatment combination. Individuals diagnosed with high-risk aGVHD within the last week may be suitable candidates for this study. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking advancements in aGVHD treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have shown that ruxolitinib, one of the drugs being tested, can cause some side effects. These include an increased risk of low blood platelets, a slight rise in anemia (low red blood cell count), and a possible increase in certain viral infections. However, these side effects are usually manageable.

Corticosteroids, another part of the treatment, are commonly used in medical care. Many people tolerate them well, though some might experience weight gain or mood changes.

The third treatment, uhCG/EGF, is still under study, so less is known about its side effects. It aims to reduce the amount of steroids needed, potentially leading to fewer steroid-related side effects.

Overall, the combination of these treatments is being tested to find the safest and most effective dose. This research is in the early stages, focusing on ensuring safety and determining the right doses. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this combination therapy for graft-versus-host disease (GVHD) because it brings together treatments with unique mechanisms and potential synergistic effects. Ruxolitinib, a JAK inhibitor, targets specific pathways involved in immune responses, offering a different approach compared to traditional corticosteroids. The addition of human chorionic gonadotropin (hCG) could enhance immune modulation and improve outcomes. This combination aims to offer a more effective and potentially faster way to manage GVHD symptoms compared to standard treatments like corticosteroids alone.

What evidence suggests that this trial's treatments could be effective for high-risk aGVHD?

In this trial, participants will receive a combination of treatments for graft-versus-host disease (GVHD), including Ruxolitinib, human chorionic gonadotropin (hCG), and corticosteroids. Research has shown that Ruxolitinib is promising for treating acute graft-versus-host disease (aGVHD). Specifically, studies found that two-thirds of patients using Ruxolitinib could stop taking corticosteroids and were likely to be alive three years after starting treatment. The success rate of Ruxolitinib for chronic GVHD is about 78.3%, indicating strong effectiveness. Additionally, hCG has been effective in about 50% of aGVHD patients. Low-dose corticosteroids work as well as high-dose ones for most GVHD outcomes and may offer survival benefits. This combination of treatments could be a promising way to manage high-risk aGVHD. ^{6 7 8 9 10}

Who Is on the Research Team?

Sherman Holtan, MD

Principal Investigator

Masonic Cancer Center, University of Minnesota

Are You a Good Fit for This Trial?

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

Pregnancy

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

I cannot or will not stop taking supplemental sex hormones.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Corticosteroids
• hCG
• Ruxolitinib 10 MG Oral Tablet

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7388928/

Corticosteroid regimens for treatment of acute and chronic ... This review highlights the paucity of information on the role of corticosteroids in treatment of Graft versus Host Disease. Also, there was a lack of evidence ...

2. haematologica.org haematologica.org/article/view/8291

Steroid treatment of acute graft-versus-host disease grade I Steroid treatment of acute grade I GvHD prevents progression to grade II but not to grade III–IV GvHD, and there is no effect on non-relapse mortality and ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1465324923009568

Corticosteroids as graft-versus-host disease prophylaxis for ... Allogeneic HCT recipients with CNI intolerance are at increased risks of acute GVHD and poor outcomes despite institution of corticosteroid prophylaxis.

4. astctjournal.org astctjournal.org/article/S1083-8791(13)00054-2/fulltext

Current Practice in Diagnosis and Treatment of Acute Graft ... To assess current clinical practice in diagnosis and treatment of acute graft-versus-host disease (aGVHD), we performed a survey among German, Austrian, ...

5. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/7695/528686/Safety-and-Efficacy-of-Low-Dose-Versus-High-Dose

Safety and Efficacy of Low Dose Versus High Dose ... Low-dose prednisone showed similar efficacy to standard-dose for most GVHD outcomes (relapse risk, mortality), with potential benefits on survival.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05123040

Ruxolitinib, Human Chorionic Gonadotropin (uhCG/EGF ... This is a single arm study designed to determine the lowest dose of corticosteroids required (toxicity endpoint) without impairing GVHD complete response or ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11305901/

New Investigational drugs for Steroid-Refractory Acute ... A single-center study of combining ruxolitinib with ECP in 18 patients with severe GI SR-aGVHD demonstrated promising results, with CR in 44% ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S0952791525001256

Emerging novel therapies for steroid-refractory acute graft- ... Standard treatment of aGVHD involves systemic corticosteroids, but many patients do not respond adequately, with 30%–50% of patients being steroid refractory ( ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8791180/

Acute GVHD: think before you treat - PMC 001). Ruxolitinib was associated with a higher incidence of thrombocytopenia and a modest increase in anemia and cytomegalovirus infection. In ...

10. studyfinder.umn.edu studyfinder.umn.edu/studies/24841

A Phase I/II Study - StudyFinder: UMN. - University of Minnesota The purpose of this study is to learn whether the use of Pregnyl with the drug ruxolitinib is able to reduce the need for high dose steroids to treat severe ...