Ruxolitinib + Fostamatinib for Chronic Graft-versus-Host Disease

Overseen By Lauren Hill, BS

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Stefanie Sarantopoulos, MD, PhD.

Must be taking: Corticosteroids, Calcineurin inhibitors

Must not be taking: SYK inhibitors

Disqualifiers: Relapsed malignancy, Active infection, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: Unknown

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for individuals with chronic graft-versus-host disease (cGvHD) who haven't responded well to steroids. Researchers aim to determine a safe and effective dose of fostamatinib (also known as Tavalisse) when combined with ruxolitinib, a standard treatment for cGvHD. Participants should have cGvHD that persists despite steroid use or returns after treatment.

As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but ongoing systemic therapy for chronic GvHD other than corticosteroids, calcineurin inhibitor, or mycophenolate mofetil is not allowed, except for fewer than 3 weeks of ruxolitinib.

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

Research has shown that ruxolitinib, one of the drugs tested with fostamatinib in this study, is usually well-tolerated for treating chronic graft-versus-host disease (cGVHD). However, it can cause side effects, with the most common being low blood counts, such as anemia (low red blood cells) and thrombocytopenia (low platelets).

Fostamatinib is also part of this combination, but specific safety information for its use with cGVHD is limited. As this is an early-phase study, the main goal is to find a safe and effective dose. Researchers are still determining how well the treatment is tolerated when both drugs are used together.

Prospective participants should know that the combination is still being tested for safety, so unknown risks may exist. However, data on ruxolitinib alone provides some initial insights into what to expect. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining fostamatinib with ruxolitinib for chronic graft-versus-host disease (cGVHD) because it offers a new way to tackle this challenging condition. Most current treatments for cGVHD, like steroids and other immunosuppressants, broadly suppress the immune system. However, fostamatinib targets specific pathways involved in immune responses, potentially reducing side effects and improving efficacy. Additionally, ruxolitinib, already a staple for cGVHD, works by inhibiting different immune pathways. Together, this combination may provide a more tailored approach, potentially leading to better control of symptoms and improved patient outcomes.

What evidence suggests that this trial's treatments could be effective for chronic GvHD?

Research has shown that ruxolitinib effectively treats chronic graft-versus-host disease (cGVHD), particularly in patients unresponsive to steroids. Studies indicate that patients taking ruxolitinib are three times more likely to improve compared to those receiving the best available therapy. Specifically, ruxolitinib alone demonstrated a 33% improvement rate after six months. In this trial, participants will receive a combination of ruxolitinib and fostamatinib. When used with treatments like ruxolitinib, fostamatinib is thought to enhance effectiveness by targeting specific parts of cGVHD. This combination aims to assist those who don't respond to or rely on steroids. ^{3 6 7 8 9}

Who Is on the Research Team?

Chenyu Lin, MD

Principal Investigator

Duke Health

Are You a Good Fit for This Trial?

This trial is for individuals with chronic Graft-versus-Host Disease (cGVHD) who haven't responded well to steroids. Participants should have specific conditions like Bronchiolitis Obliterans Syndrome and be able to receive both Ruxolitinib and Fostamatinib.

Inclusion Criteria

I have received a stem cell transplant from a donor.

I have chronic GvHD that's not responding well to steroids, regardless of other treatments.

Patient is able and willing to provide written informed consent prior to any study related screening procedures are performed

Exclusion Criteria

I have had progressive multifocal leukoencephalopathy in the past.

I do not have any ongoing serious infections, or they are being treated and under control.

I do not have active significant viral infections like HIV or hepatitis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Initial dose escalation cohort employing a modified 3+3 design to investigate up to three doses of fostamatinib in combination with ruxolitinib.

6 months

Regular visits for dose escalation and monitoring

Safety Expansion

Safety expansion cohort to backfill two candidate doses up to a total of 12 patients per dose, including those in the dose escalation cohort.

6 months

Regular visits for safety and efficacy assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Fostamatinib
• Ruxolitinib

Trial Overview

The study tests the safety and effectiveness of combining two drugs, Ruxolitinib and Fostamatinib, for cGVHD patients not responding to steroids. It starts by finding a safe dose before expanding to more patients who will help determine the best dose for future studies.

How Is the Trial Designed?

Group I: Dose escalation phase: Dose level 3 Experimental Treatment 2 Interventions

Fostamatinib at dose level 3 (dose of 100mg BID) in combination with standard of care ruxolitinib 10mg BID

Group II: Dose escalation phase: Dose level 2 Experimental Treatment 2 Interventions

Fostamatinib at dose level 2 (dose of 150mg QAM) in combination with standard of care ruxolitinib 10mg BID

Group III: Dose escalation phase: Dose level 1 Experimental Treatment 2 Interventions

Fostamatinib at dose level 1 (dose of 100mg QAM) in combination with standard of care ruxolitinib 10mg BID

Group IV: Dose escalation phase: Dose level 0 Experimental Treatment 2 Interventions

Fostamatinib at dose level 0 (dose of 50mg QAM) in combination with standard of care ruxolitinib 10mg BID

Group V: Candidate Dose #2 Experimental Treatment 2 Interventions

In the safety expansion cohort, subjects will be randomized to one of two candidate doses of fostamatinib (identified from the dose escalation phase) in combination with ruxolitinib 10mg BID.

Group VI: Candidate Dose #1 Experimental Treatment 2 Interventions

In the safety expansion cohort, subjects will be randomized to one of two candidate doses of fostamatinib (identified from the dose escalation phase) in combination with ruxolitinib 10mg BID.

Fostamatinib is already approved in United States for the following indications:

Approved in United States as Tavalisse for:

• Chronic immune thrombocytopenia (ITP)

Who Is Running the Clinical Trial?

Stefanie Sarantopoulos, MD, PhD.

Lead Sponsor

Trials

2

Recruited

50+

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

Rigel Pharmaceuticals

Industry Sponsor

Trials

37

Recruited

4,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Published Research Related to This Trial

In a study of 115 patients with steroid-refractory or -dependent chronic graft versus host disease (cGVHD), ruxolitinib demonstrated an overall response rate of approximately 48.6% at 3 months, indicating its efficacy in a heavily pretreated population.

After 12 months of treatment, 37.9% of patients were able to discontinue prednisone, and 63.8% could taper their dosage to less than 0.1 mg/kg, highlighting ruxolitinib's potential to reduce steroid dependency in cGVHD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Multicenter, Retrospective Study Evaluating Clinical Outcomes of Ruxolitinib Therapy In Heavily Pretreated Chronic GVHD Patients With Steroid Failure. White, J., Elemary, M., Linn, SM., et al.[2023]

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 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]

In a study of 156 patients with steroid-refractory acute graft-versus-host disease (aGvHD), treatment with MSC-FFM showed an overall response rate of 46% in adults and 64% in children, indicating its potential effectiveness in this challenging condition.

The median overall survival for patients treated with MSC-FFM was 5.8 months, significantly better than the 28 days reported for patients not receiving MSC treatment, highlighting the potential benefit of MSC-FFM in improving survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world data suggest effectiveness of the allogeneic mesenchymal stromal cells preparation MSC-FFM in ruxolitinib-refractory acute graft-versus-host disease. Bonig, H., Verbeek, M., Herhaus, P., et al.[2023]

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, 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 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 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]

In a study of 53 pediatric patients with graft-versus-host disease (GVHD), ruxolitinib demonstrated a high overall response rate of 75.5%, with 80.6% efficacy in chronic GVHD (cGVHD) cases compared to 64.7% in acute GVHD (aGVHD).

Ruxolitinib treatment allowed 39% of patients to discontinue steroids and 22.2% to reduce their steroid dosage, although it was associated with a high incidence of adverse events (94.1%) in the aGVHD group, indicating a need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effectiveness of Ruxolitinib for Acute/Chronic Graft-versus-Host Disease in Children: A Retrospective Study. Yang, W., Zhu, G., Qin, M., et al.[2022]

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]

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.

hcp.jakafi.com

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

Efficacy of Jakafi in cGVHD

Patients treated with Jakafi were 3× more likely to achieve an overall response at week 24 vs BAT (OR, 2.99)

3.

withpower.com

withpower.com/trial/phase-1-bronchiolitis-obliterans-syndrome-5-2024-b2628

Ruxolitinib + Fostamatinib for Chronic Graft-versus-Host ...

In a study of 115 patients with steroid-refractory or -dependent chronic graft versus host disease (cGVHD), ruxolitinib demonstrated an overall response rate of ...

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11358232/

Efficacy and safety of ruxolitinib in the treatment of chronic ...

Overall, ruxolitinib was relatively well-tolerated and showed outcomes comparable to the REACH3 trial in a heavily pretreated patient population.

5.

synapse.patsnap.com

synapse.patsnap.com/disease/170144d041c9427a8cfe5e542c2014c7

Steroid Refractory Graft Versus Host Disease - Drugs, Targets, ...

A Single-arm Multi-center Study of Ruxolitinib in Chinese Participants With Corticosteroid-refractory Chronic Graft Versus Host Disease After Allogeneic ...

6.

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) ... VIEW SAFETY DATA. NCCN Guidelines® Recommend. NCCN Clinical Practice ...

7.

jakafi.com

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

Chronic Graft-Versus-Host Disease

Jakafi can cause serious side effects, including: Low blood counts: Jakafi® (ruxolitinib) may cause low platelet, red blood cell, and white blood cell counts.

8.

go.drugbank.com

go.drugbank.com/conditions/DBCOND0045787

Chronic Graft-Versus-Host Disease (DBCOND0045787)

Associated Data ; NCT06824103. Study of Efficacy and Safety of Ruxolitinib in Chinese Participants With Corticosteroid-refractory Chronic Graft vs. Host Disease.

9.

fda.gov

fda.gov/drugs/resources-information-approved-drugs/fda-approves-ruxolitinib-chronic-graft-versus-host-disease

FDA approves ruxolitinib for chronic graft-versus-host ...

In cGVHD, the most common (incidence > 35%) hematologic adverse reactions of ruxolitinib were anemia and thrombocytopenia. The most common ( ...