Study of Ruxolitinib for Acute and Chronic Graft Versus Host Disease

Study Overview
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Brief Summary
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While hematopoietic stem cell transplant (HSCT) is an effective therapy, graft versus host disease (GVHD) is the most significant complication after HSCT. Both acute GVHD and chronic GVHD are leading causes of non-relapse morbidity and mortality. Patients with solid organ transplants may participate in this study as well because these patients occasionally develop acute GVHD, which is biologically similar to acute GVHD after an HSCT. Acute graft versus host disease usually occurs within the first 100 days of transplant and can involve the skin, gut, or liver. Chronic graft versus host disease usually occurs after the first 100 days of transplant and can involve skin, eyes, mouth, joints, liver, intestines commonly. These two diseases are different, but both happen due to the imbalance of the donor immune system in the host. The purpose of this research is to learn more about ruxolitinib as a treatment for both acute and chronic GVHD. Specifically, the investigators would like to learn more about the pharmacokinetics (PK - the process of absorption, distribution, metabolism, and elimination from the body - meaning how the drug moves through the body) and the pharmacodynamics (PD - the body's biological response to the drug) of ruxolitinib.

Official Title
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Pharmacokinetics and Pharmacodynamic Study of Ruxolitinib for the Management of Acute and Chronic Graft Versus Host Disease

Conditions
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Acute-graft-versus-host Disease, Chronic Graft-versus-host-disease, Solid Organ Transplant

Intervention / Treatment
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* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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ARM 1 Inclusion Criteria: Established diagnosis of chronic GVHD (all grades eligible) Currently on treatment with ruxolitinib for chronic GVHD for a minimum of 3 weeks No changes in doses of ruxolitinib or concurrent azoles (if present) one week prior to obtaining ruxolitinib levels Ages eligible for enrollment (0-≤18 years at time of enrollment) Exclusion Criteria: Clinical presentation resembling overlap syndrome with both acute and chronic GVHD features ARM 2 Inclusion Criteria: Ages <12 years status post allogeneic hematopoietic stem cell transplant or solid organ transplant Any underlying diagnoses, preparative regimen, stem cell source or acute GVHD prophylaxis are eligible Diagnosis of acute GVHD which is refractory to steroids (defined as lack of improvement to 2 mg/kg/day of methylprednisolone or bioequivalent oral steroids, for 7 days or progression of acute GVHD within 72 hours at 2 mg/kg/day of Methylprednisolone or bioequivalent oral doses) Able to take enteral medications Clinically diagnosed Grades II to IV acute GVHD as per modified Glucksberg criteria occurring after allogeneic HSCT requiring systemic immune suppressive therapy. Biopsy of involved organs with acute GVHD is encouraged but not required for study enrollment. Blood counts at decision to initiate ruxolitinib: absolute neutrophil count (ANC) > 1000/mm3* AND platelets ≥ 20,000/mm3 (*Use of growth factor supplementation and transfusion support is allowed to achieve these above defined hematological parameters) Estimated GFR by cystatin C of >30 mL/min Prior systemic treatments for acute GVHD are allowed. Once ruxolitinib is initiated, no further doses of these agents will be allowed. Calcineurin inhibitors are allowed throughout the duration of study and may be discontinued per treating physician discretion. Additionally dose adjustments to maintain target blood levels of calcineurin inhibitors may proceed per routine clinical practice. Exclusion Criteria: Clinical presentation resembling de novo chronic GVHD or GVHD overlap syndrome with both acute and chronic GVHD features Presence of an active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment. Infections are considered controlled if appropriate therapy has been instituted and no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection. Evidence of uncontrolled viral reactivation (Adenovirus, CMV, EBV, BK virus). If patients are on appropriate antiviral therapy or have received virus specific T-cells (either donor derived or third-party) then the viral reactivation is not considered uncontrolled. Presence of relapsed primary malignancy. ARM 3 Inclusion Criteria: 0-≤18 years of age are eligible Any underlying diagnosis, preparative regimen, stem cell source or prior acute GVHD prophylaxis are eligible Diagnosis of chronic GVHD as per 2014 NIH consensus criteria (any organ involvement is eligible) Any GVHD global severity is eligible Patients may have received methylprednisolone or oral bioequivalent steroids at a dose of 1 mg/kg/day (or greater) for up to 28 days prior to enrollment but may be enrolled anytime between diagnosis of chronic GVHD and day 28 of systemic steroids Concurrent local therapies ( including but not limited to topical steroids, topical calcipotriene, ocular drops such as restasis, autologous serum eye drops, artificial tears, triamcinolone ointment for vulvar GVHD, Fluticasone Azithromycin and Singulair) are allowed at anytime while on ruxolitinib . Additional therapies may also be considered with PI review and approval As children may not meet criteria for lung GVHD due to inability to perform PFTs we will establish the diagnosis of lung GVHD for children as defined by any of the following criteria listed below. However, the participants do not need to have lung involvement to be eligible to receive ruxolitinib. >10% decrease in FEV1 or FVC from baseline or 25% of FEF 25-75 Active GVHD in another organ system + pulmonary symptoms (Tachypnea without wheezing, new oxygen requirement, cough) Increased R5 by 50% by Impulse oscillometry Air trapping on high resolution CT scan, small airway thickening, or bronchiectasis in the absence of infection Negative urine or serum pregnancy test for females of childbearing age Estimated GFR by cystatin C > 30 mL/min Able to take enteral medications Exclusion Criteria: Clinical presentation resembling overlap syndrome with both acute and chronic GVHD features Presence of an active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment. Infections are considered controlled if appropriate therapy has been instituted and no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection. Evidence of uncontrolled viral reactivation (Adenovirus, CMV, EBV, BK virus). If patients are on appropriate antiviral therapy or have received virus specific T-cells (either donor derived or third-party) then the viral reactivation is not considered uncontrolled. Presence of relapsed primary malignancy.

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Arm 1: Existing patients with chronic GVHD<br>Participants with established diagnosis of chronic GVHD and currently on treatment with ruxolitinib for chronic GVHD for at least 3 weeks. Participants in this arm are receiving ruxolitinib clinically and will not receive ruxolitinib as part of this research study. | |
| Experimental: Arm 2: Acute GVHD ages 0-<12 years<br>Participants with acute GVHD will receive ruxolitinib on this arm. | Drug: Ruxolitinib<br>* Ruxolitinib will be given by mouth or enteral tube (if applicable).<br>|
| Experimental: Arm 3: New onset chronic GVHD ages 0-≤18 years<br>Participants with new onset chronic GVHD will receive ruxolitinib on this arm. | Drug: Ruxolitinib<br>* Ruxolitinib will be given by mouth or enteral tube (if applicable).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of ruxolitinib in existing patients with chronic GVHD (Arm 1) | Maximum Plasma Concentration of ruxolitinib | 1 week | 
| Cmax of ruxolitinib in patients with acute GVHD (Arm 2) | Maximum Plasma Concentration of ruxolitinib | 30 days | 
| Cmax of ruxolitinib in patients with new onset chronic GVHD (Arm 3) | Maximum Plasma Concentration of ruxolitinib | 6 months | 
| To measure phosphorylation of STAT5 on lymphocytes as a functional measure of JAK inhibition (Arms 1, 2, and 3) | A blood sample will be collected at the specified time point and pharmacodynamics will be measured by PSTAT5 | Approximately 2 hours after the ruxolitinib dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with overall survival (Arm 3) |  | 6 months after ruxolitinib initiation | 
| Number of participants with complete response to ruxolitinib (Arm 2) | Complete response is defined as resolution of acute GVHD | 30 days after ruxolitinib initiation | 
| Number of participants with partial response to ruxolitinib (Arm 2) | Partial response is defined as improvement in stage of at least one organ involved in acute GVHD without worsening in additional organs | 30 days after ruxolitinib initiation | 
| Number of participants with no response to ruxolitinib (Arm 2) | No response is defined as lack of improvement or worsening of acute GVHD | 30 days after ruxolitinib initiation | 
| Number of participants with response to ruxolitinib (Arm 3) | Response is defined as resolution of chronic GVHD in at least one organ without worsening in additional organs | 6 months after ruxolitinib initiation | 
| Number of participants with relapse free survival at 6 months (Arm 3) |  | 6 months after ruxolitinib initiation | 
| Number of participants with relapse free survival at 6 months (Arm 1) | Relapse free survival at 6 months for participants on Arm 1 only if participant has been on ruxolitinib clinically for 6 months | 6 months after ruxolitinib initiation | 
| Incidence of infections (Arm 1) | Infections defined as bacterial, parasitic, fungal, new viral reactivation or disease | through study completion, average of 7 days | 
| Incidence of infections (Arm 2) | Infections defined as bacterial, parasitic, fungal, new viral reactivation or disease | 30 days after ruxolitinib initiation | 
| Incidence of infections (Arm 3) | Infections defined as bacterial, parasitic, fungal, new viral reactivation or disease | 6 months after ruxolitinib initiation | 
| Incidence of known side effects (Arm 1) | Known side effects are defined as the side effects included in the Investigator's Brochure | through study completion, average of 7 days | 
| Incidence of known side effects (Arm 2) | Known side effects are defined as the side effects included in the Investigator's Brochure | 30 days after ruxolitinib initiation | 
| Incidence of known side effects (Arm 3) | Known side effects are defined as the side effects included in the Investigator's Brochure | 6 months after ruxolitinib initiation | 
| Incidence of unknown side effects (Arm 1) | Unknown side effects are defined as the side effects not included in the Investigator's Brochure | through study completion, average of 7 days | 
| Incidence of unknown side effects (Arm 2) | Unknown side effects are defined as the side effects not included in the Investigator's Brochure | 30 days after ruxolitinib initiation | 
| Incidence of unknown side effects (Arm 3) | Unknown side effects are defined as the side effects not included in the Investigator's Brochure | 6 months after ruxolitinib initiation | 
| Number of participants who were weaned off steroids (Arm 2) | Participants will be considered weaned off steroids if the steroid dose has been decreased | 30 days after ruxolitinib initiation | 
| Number of participants who were weaned off steroids (Arm 3) | Participants will be considered weaned off steroids if the steroid dose has been decreased | 6 months after ruxolitinib initiation |