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 is an open-label phase I study of fostamatinib in combination with ruxolitinib for the treatment of chronic GvHD with a suboptimal response to corticosteroids. The primary objective is to identify a minimum safe and biologically effective dose of fostamatinib when combined with standard of care ruxolitinib for the treatment of steroid refractory and steroid dependent cGVHD. The secondary objective is to estimate the efficacy of the combination of ruxolitinib and fostamatinib for the treatment of steroid refractory and steroid dependent cGVHD. The target enrollment is 24-30 subjects. The study will begin with an initial dose escalation cohort employing a modified 3+3 design to investigate up to three doses of fostamatinib. Using safety, efficacy, pharmacodynamic (PD), and pharmacokinetic data (PK), an interim assessment will be performed to determine two candidate doses of the biologically optimal dose to investigate further. A safety expansion cohort will be opened to backfill these two candidate doses up to a total 12 patients per dose, including those in the dose escalation cohort who received the candidate doses. Patients will then be randomized to one of these two candidate doses in the expansion. If there is an imbalance in the two expansion cohorts, the remaining patient slots after 1:1 randomization will be sequentially backfilled to a total of 12 patients per cohort. A final analysis of safety, efficacy, and PK/PD data in patients who received the two candidate doses will be conducted to determine a minimum safety and biologically effective dose, which will be the recommended phase II dose (RP2D). The primary hypothesis is that Fostamatinib combined with ruxolitinib is a safe therapy for and has synergistic activity in cGvHD. The recommended phase II dose will be determined by the study investigators in collaboration with the sponsors. The decision to select the recommended phase II dose will occur only after all patients in the part 1 have completed at least 28 days of therapy. The decision will be based on the valuation of all relevant, available data, and not solely on dose-limiting toxicities.

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 the combination of Ruxolitinib and Fostamatinib safe for treating chronic graft-versus-host disease?

Ruxolitinib has been used in patients with chronic graft-versus-host disease, and while it is generally tolerated, some serious side effects like infections, sepsis (a severe infection), and respiratory issues have been reported. There is no specific safety data available for the combination with Fostamatinib in this context. ^{1 2 3 4 5}

What makes the drug combination of Ruxolitinib and Fostamatinib unique for treating chronic graft-versus-host disease?

The combination of Ruxolitinib and Fostamatinib is unique because Ruxolitinib, a JAK1/2 inhibitor, is already a promising second-line treatment for steroid-refractory chronic graft-versus-host disease, and adding Fostamatinib, which has a different mechanism of action, may enhance treatment effectiveness and offer a novel approach for patients who do not respond to standard therapies. ^{1 6 7 8 9}

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

Ruxolitinib has shown effectiveness in treating chronic graft-versus-host disease (cGVHD), especially in patients who do not respond to steroids. Studies have reported that it helps reduce symptoms and allows some patients to lower or stop their steroid use, with a significant number experiencing clinical benefits over time. ^{1 5 6 8 10}

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

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 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 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 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]

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]

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 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]

Citations

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

New Indication for Ruxolitinib. [2023]

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

A Multicenter, Retrospective Study Evaluating Clinical Outcomes of Ruxolitinib Therapy In Heavily Pretreated Chronic GVHD Patients With Steroid Failure. [2023]

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

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

4. New Zealand pubmed.ncbi.nlm.nih.gov

The Effectiveness of Ruxolitinib for Acute/Chronic Graft-versus-Host Disease in Children: A Retrospective Study. [2022]

5. 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]

6. England pubmed.ncbi.nlm.nih.gov

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

7. England 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. [2022]

8. United States 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. [2021]

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

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

10. England 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. [2023]