Topical Ruxolitinib for Cutaneous Chronic Graft Versus Host Disease (cGVHD)
- Conditions
- Graft Versus Host DiseaseJNS KinaseTopical Administration
- Interventions
- Drug: vehicle cream
- Registration Number
- NCT03395340
- Lead Sponsor
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
- Brief Summary
Background:
About half the people who have a hematopoietic stem cell transplant using donor cells get Chronic Graft Versus Host Disease (cGVHD). This is chronic graft versus host disease. Immune cells from the donor may see the body tissues in the person as foreign and attack, causing damage. The skin is the most commonly affected organ. Most cGVHD therapies have serious side effects. The cream ruxolitinib inhibits proteins that may play a role in cGVHD.
Objective:
To test the safety and effectiveness of topical ruxolitinib 1.5 percent cream in people with cGVHD of the skin.
Eligibility:
People ages 12 and older with epidermal skin cGVHD
Design:
Participants will be screened with:
Medical history
Physical exam
Blood and urine tests
Skin sample taken (biopsy) to confirm the diagnosis.
At the baseline visit, participants will have:
Skin disease measured with rulers, photographs, and tracing the outline of skin lesions
To complete questionnaires about their symptoms
Blood and urine tests
Some participants will also have a skin biopsy, or total body photographs while they wear only underwear.
Participants will get the ruxolitinib cream and a placebo cream to apply to 2 separate areas of disease. They will do this twice a day for 6 weeks, if they do not have serious side effects. Neither the study team nor the participant will know which area will get ruxolitinib cream and the placebo cream.
Participants will write down:
* When they apply the creams
* Any side effects
* Any medications they take
Most participants will have 4 visits during the 6 weeks they use the creams. Some will have 3 visits and a phone call to see how they are doing. All participants will get a call 4-6 weeks after they stop. Visits include physical exams, blood tests, skin disease measurements, questionnaires, and photos.
- Detailed Description
Background:
* Chronic graft-versus-host disease (cGVHD) develops in approximately half of individuals who undergo allogeneic hematopoietic cell transplant (HCT) and is the leading cause of non-relapse mortality.
* There are no skin-targeted therapies for cutaneous cGVHD that are directed to the pathogenesis of cGVHD.
* Many inflammatory cytokines involved in the pathogenesis of cGVHD signal through the Janus kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) pathway.
* Systemic JAK inhibitors have been studied in GVHD murine models and in humans with improvement at the cellular and clinical level.
* Topical JAK inhibitors have not been studied in cutaneous cGVHD but have demonstrated the ability to decrease inflammatory markers as well as improve clinical findings of psoriasis.
Objectives:
* To determine the safety and tolerability of topical ruxolitinib 1.5% cream in patients with cutaneous cGVHD with epidermal involvement (non-sclerotic form)
* To determine the efficacy of topical ruxolitinib 1.5% cream in patients with cutaneous cGVHD with epidermal involvement (non-sclerotic form)
Eligibility:
Inclusion:
* Age greater than or equal to 12 years old
* Histologically confirmed epidermal cGVHD (including lichen planus-like, papulosquamous, erythematous) involving at least 2 separate, non-ulcerated sites that can be delineated by body region (e.g., right forearm and left forearm)
* Stable systemic cGVHD treatment including immunosuppressant therapy for 4 weeks prior to enrollment
* Karnofsky or Lansky score greater than or equal to 60%
Exclusion:
* Concurrent use of JAK inhibitors (topical or systemic), fluconazole, or strong Cytochrome P450 3A4 (CYP3A4) inhibitors
* Known hypersensitivity to JAK inhibitors or their components
* Active infection including cytomegalovirus (CMV), Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV)
* Recurrent or progressive malignancy requiring anticancer treatment
* Patients receiving other investigational agents
* Pregnancy
Design:
* This is a Phase II, placebo-controlled, double-blinded study to determine the safety, tolerability and efficacy of topical ruxolitinib in patients with epidermal cGVHD.
* Participants with at least 2 non-ulcerated sites of epidermal cGVHD will apply topical ruxolitinib 1.5% cream to 1 prespecified site and vehicle cream to the second prespecified site twice a day for 6 weeks.
* Safety will be assessed according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria. Assessments will occur during visits and/or phone follow-up every 2 weeks during treatment.
* Efficacy will be assessed at 6 weeks. The initial surface areas of the 2 target lesions will be measured at baseline, week 2, and week 6 on evaluable patients, with the option for an in-person assessment at week 4. The percent decline in the surface area of the 2 lesions will be determined, and the difference in decline between the 2 lesions will be calculated, expressed consistently as ruxolitinib decline minus placebo decline.
* A skin biopsy and peripheral blood samples will be collected prior to treatment and at week 6 to evaluate the cutaneous immune compartment cellular infiltrate, cytokine profiling, signal transducer and activator of transcription (STAT) phosphorylation, and in situ cGVHD biomarkers.
* Pharmacokinetic studies will be performed at week 2.
* Up to 15 patients will be enrolled to achieve 10 evaluable patients, defined as participants who remain active at the time of the primary endpoint. 10 evaluable patients will provide 80% power to detect whether these paired differences in the changes from baseline are equal to one standard deviation (SD) of the difference of the changes (effect size=1.0) using a two-tailed 0.05 significance level paired t-test. In practice, a Wilcoxon signed rank test may be used instead of a t-test if the differences are not consistent with a normal distribution (p\<0.05 by a Shapiro-Wilks test).
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 1
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Ruxolitinib cream Ruxolitinib 1.5% cream Investigational cream to 1 location; vehicle cream to 2nd location Vehicle cream vehicle cream Investigational cream to 1 location; vehicle cream to 2nd location
- Primary Outcome Measures
Name Time Method Percent Change in the Surface Area Measurement of the Target Lesions for Ruxolitinib Treated Versus Placebo Treated Lesions Baseline to week 6 The surface area will be measured by tracing the lesion on transparency paper and measuring the area from the transparency. Differences in remaining active surface area at 6 weeks from baseline between the treated and placebo sites were compared to calculate efficacy. A decrease in active surface area would signify improvement in skin disease.
Number of Participants With Grade 3 and Grade 4 Adverse Events date on study, up to approximately 2 months and 12 days. Adverse events were measured by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 3 is severe. Grade 4 is life-threatening.
- Secondary Outcome Measures
Name Time Method Change in Overall Severity Visual Analog Scale (VAS) Baseline and week 6 The Overall Severity VAS is a psychometric response questionnaire to measure subjective characteristics or attitudes that cannot be directly measured on a scale of 0-10; a participants assessment of degree of disease activity on the skin. 0=none and 10 = worst imaginable.
Change in Pain Visual Analog Scale (VAS) Baseline and week 6 The Pain VAS is a psychometric response questionnaire to measure subjective characteristics or attitudes that cannot be directly measured on a scale of 0 (no pain) -10 (worst imaginable pain). The participant draws a line on the scale representing how they feel between 0 (none) and 10 (worst). That line is measured and assigned a value. Scores from Baseline and week 6 will be reported. A change is considered a higher number (worsening of disease) or a lower number (improvement of disease) from baseline.
Change in Pruritus Visual Analog Scale (VAS) Baseline and week 6 The pruritus VAS is a psychometric response questionnaire to measure subjective characteristics or attitudes that cannot be directly measured on a scale of 0 (no itching) -10 (worst imaginable itching). Scores from Baseline and week 6 will be reported. A change is considered a higher number (worsening of disease) or a lower number (improvement of disease) from baseline.
Area Under the Serum Concentration Versus Time Curve (AUC) of Ruxolitinib A pre-dose trough sample will be collected prior to application of the treatment on the day of the follow up visit. After application in clinic, blood samples will be collected at 1 hour, 2 hour and 4 hours. The AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption.
Total Clearance (CL) of Ruxolitinib A pre-dose trough sample will be collected prior to application of the treatment on the day of the follow up visit. After application in clinic, blood samples will be collected at 1 hour, 2 hour and 4 hours. The CL is a quantitative measure of the rate at which a drug substance is removed from the body.
Half-Life of Ruxolitinib A pre-dose trough sample will be collected prior to application of the treatment on the day of the follow up visit. After application in clinic, blood samples will be collected at 1 hour, 2 hour and 4 hours. Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States
National Institutes of Health Clinical Center🇺🇸Bethesda, Maryland, United States