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Ruxolitinib for the Treatment of Acute Graft versus Host Disease
Trial Status: active
This phase II trial tests the safety, side effects, and effect of ruxolitinib alone and in combination with corticosteroids in treating patients with acute graft versus host disease (GVHD). Acute GVHD occurs when donor cells attack the healthy tissue of the body. The standard treatment for GVHD is corticosteroids such as methylprednisolone, which suppresses the donor cells, but sometimes there can be either no response or the response does not last. In these cases, the GVHD can become dangerous or even life threatening. Researchers have developed a system to help predict how well the GVHD will respond to steroids based on the symptoms present at the time of diagnosis, including standard risk and high risk. Patients classified as standard risk usually respond well to steroid treatment, however, steroid treatment can cause many complications. Only about a half of patients considered high risk respond to steroids and the risk for death is about one in three. Ruxolitinib blocks a protein called Janus kinase (JAK), which may help keep abnormal blood cells or cancer cells from growing. It may also lower the body’s immune response. Ruxolitinib is a type of tyrosine kinase inhibitor. Anti-inflammatory drugs, such as corticosteroids, lower the body’s immune response and are used with other drugs in the treatment of some types of cancer. For standard risk patients, giving ruxolitinib alone may work as well as corticosteroids alone and with fewer side effects in treating acute GVHD. For high risk patients, giving ruxolitinib in combination with corticosteroids may be safe, tolerable, and/or more effective than giving corticosteroids alone in treating acute GVHD.
Inclusion Criteria
LOW RISK COHORT: Minnesota standard risk GVHD (except patients with grade I [< 50% BSA rash]) that is also Ann Arbor 1 by biomarkers
HIGH RISK COHORT: Minnesota high risk GVHD or Minnesota standard risk GVHD that is also Ann Arbor 2/3 by biomarkers
GVHD that developed after donor lymphocyte infusion (DLI) for mixed chimerism or poor graft function is allowed (provided that hematologic parameters are met)
No prior systemic acute GVHD treatment. Topical or non-absorbed steroids are permitted
All donor types, human leukocyte antigen (HLA)-matches, conditioning regimens, or GVHD prophylaxis strategies are acceptable
≥ 18 years of age
LOW RISK COHORT: Hematopoietic engraftment with absolute neutrophil count (ANC) ≥ 1000/uL
* Use of growth factor supplementation and transfusions to maintain adequate hematologic parameters are allowed
LOW RISK COHORT: Hematopoietic engraftment with platelet count ≥ 20,000
* Use of growth factor supplementation and transfusions to maintain adequate hematologic parameters are allowed.
HIGH RISK COHORT: Hematopoietic engraftment with ANC ≥ 500/uL
* Use of growth factor supplementation and transfusions to maintain adequate hematologic parameters are allowed
HIGH RISK COHORT: Hematopoietic engraftment with platelet count ≥ 20,000
* Use of growth factor supplementation and transfusions to maintain adequate hematologic parameters are allowed
Exclusion Criteria
Systemic treatment with ruxolitinib or any other JAK inhibitor within 7 days of study entry
Prior use of ruxolitinib to treat GVHD at any time
Relapsed, progressing or persistent malignancy requiring withdrawal of systemic immunosuppression
Relapse prior to development of GVHD unless subsequently in remission for at least 3 months
GVHD that developed after DLI for relapse is not allowed without study principal investigator (PI) or medical monitor approval
Uncontrolled infection (i.e., progressive symptoms related to infection despite treatment or persistently positive microbiological cultures despite treatment or any other evidence of severe sepsis)
Severe organ dysfunction within 3 days of enrollment including requirement for dialysis, mechanical ventilation, continuous bilevel positive airway pressure (BiPAP), or continuous high flow oxygen by nasal cannula, or total bilirubin ≥ 3 x upper limit of normal not due to GVHD
A clinical presentation resembling de novo chronic GVHD or overlap syndrome developing before or present at the time of enrollment (except for mild oral or ocular GVHD)
Corticosteroids > 10 mg/day methylprednisolone (or other methylprednisolone equivalent, MPE) for any indication within 5 days before the onset of acute GVHD except for adrenal insufficiency or premedication for transfusions/IV meds
Participation in clinical trials using experimental agents not approved by the Food and Drug Administration (FDA) for any indication within 14 days of enrollment or five half-lives, whichever is longer provided any prior adverse events have improved to ≤ grade 1
Patients who are pregnant or nursing
History of allergic reaction to ruxolitinib or any JAK inhibitor
Additional locations may be listed on ClinicalTrials.gov for NCT06936566.
I. To determine the effectiveness of ruxolitinib as single agent primary treatment for newly diagnosed, low risk acute GVHD (excluding patients with grade I GVHD [< 50% body surface area (BSA) rash]).
II. To determine the effectiveness of ruxolitinib plus high dose systemic corticosteroids (SCS) for the treatment of newly diagnosed, high risk acute GVHD.
SECONDARY OBJECTIVES:
I. To assess the safety of ruxolitinib monotherapy as the primary treatment for newly diagnosed, low risk acute GVHD (excluding patients with grade I GVHD [< 50% BSA rash]).
II. To determine the incidence of steroid refractory (SR) GVHD in patients with low risk GVHD whose GVHD is not responsive to ruxolitinib monotherapy.
III. To assess the safety of ruxolitinib plus high dose SCS as the primary treatment for newly diagnosed, high risk acute GVHD.
EXPLORATORY OBJECTIVES:
I. To analyze the safety and effectiveness of ruxolitinib 5 mg twice daily monotherapy and ruxolitinib 10 mg twice daily monotherapy for low risk GVHD in comparison to each other and to a matched synthetic control group treated with SCS.
II. To analyze the safety and effectiveness of ruxolitinib 10 mg twice daily plus high dose SCS for high risk GVHD in comparison to a matched synthetic control group treated with high dose SCS alone.
III. To retrospectively correlate novel risk classification systems that use clinical and/or biomarker data such as Manhattan risk and Mount Sinai Acute GVHD International Consortium (MAGIC) composite scores at start of treatment with clinical outcomes such as day 28 (D28) overall response and six-month non-relapse mortality (NRM).
IV. To retrospectively correlate novel endpoints that use both clinical and/or biomarker data at different timepoints, such as MAGIC integrated response at D14 with short and long-term treatment outcomes, such as D28 response and six-month NRM.
V. To assess patient reported outcomes in patients treated with ruxolitinib-based therapy for acute GVHD.
OUTLINE: Low risk patients are randomized to 1 of 2 arms. High risk patients are assigned to arm 3.
ARM I: Patients receive lower dose ruxolitinib orally (PO) twice daily (BID) for 56 days then begin taper PO once daily (QD) for 1 week in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection throughout the study.
ARM II: Patients receive higher dose ruxolitinib PO BID for 56 days then begin taper PO BID for 1 week, followed by PO QD for 1 week in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection throughout the study.
ARM III: Patients receive higher dose ruxolitinib PO BID for 56 days then begin taper PO BID for 1 week, followed by PO QD for 1 week in the absence of disease progression or unacceptable toxicity. Patients also receive systemic corticosteroid (methylprednisolone or similar) for a minimum of 3 days, then taper dose every 3-5 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection throughout the study.
After completion of study treatment, patients are followed up at 30 days then at days 90, 180, and 365.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationIcahn School of Medicine at Mount Sinai
