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Topical Ruxolitinib for Cutaneous Chronic Graft Versus Host Disease (cGVHD)

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ClinicalTrials.gov Identifier: NCT03395340
Recruitment Status : Recruiting
First Posted : January 10, 2018
Last Update Posted : September 12, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) )

Tracking Information
First Submitted Date  ICMJE January 9, 2018
First Posted Date  ICMJE January 10, 2018
Last Update Posted Date September 12, 2019
Actual Study Start Date  ICMJE November 19, 2018
Estimated Primary Completion Date October 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 9, 2018)
  • Counts of the grades of adverse events noted [ Time Frame: continuous ]
    CTCAE 4 will be used for grade of adverse events and each AE will bedocumented in C3D.
  • Surface area measurement [ Time Frame: 6 weeks ]
    The surface area will be measured by tracing the lesion ontransparency paper and measuring the area from the transparency.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03395340 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 9, 2018)
  • Pain, pruritus, and overall severity VAS [ Time Frame: 6 weeks ]
  • pharmacokinetics [ Time Frame: 2 weeks ]
  • pharmacodynamics [ Time Frame: 6 weeks ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Topical Ruxolitinib for Cutaneous Chronic Graft Versus Host Disease (cGVHD)
Official Title  ICMJE Phase II Study of Topical Ruxolitinib for Cutaneous Chronic Graft Versus Host Disease (cGVHD)
Brief Summary

Background:

About half the people who have a hematopoietic stem cell transplant using donor cells get 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 CYP3A4 inhibitors
  • Known hypersensitivity to JAK inhibitors or their components
  • Active infection including CMV, EBV, HIV, HBV, and/or 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 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, 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 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).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Graft Versus Host Disease
  • JNS Kinase
  • Topical Administration
Intervention  ICMJE
  • Drug: Ruxolitinib 1.5% cream
    Ruxolitinib cream 1.5% applied as a thin film twice daily (BID)
  • Drug: Vehicle cream
    Matching vehicle cream applied as a thin film BID
Study Arms  ICMJE
  • Experimental: Ruxolitinib Cream
    Intervention: Drug: Ruxolitinib 1.5% cream
  • Placebo Comparator: Vehicle cream
    Intervention: Drug: Vehicle cream
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 9, 2018)
15
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 1, 2020
Estimated Primary Completion Date October 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:
  • Patients must have histologically confirmed epidermal cGVHD including lichen planus-like, papulosquamous, and erythematous cGVHD with clinical involvement at 2 separate body regions (e.g. right forearm and left forearm).
  • Patients must have measurable disease, defined as at least 2 areas of cutaneous, nonulcerated, epidermal cGVHD involvement. Each site must involve at least 0.5% body surface area (1 palm equivalent) and cannot be a site of current or previous nonmelanoma skin cancer (NMSC).
  • Stable immunosuppressant or immunomodulatory systemic cGVHD treatment, including phototherapy and extracorporeal photopheresis, for 4 weeks prior to enrollment.
  • Age greater than or equal to 12 years. There is no available safety or adverse events data available for children younger than 12 years of age.
  • Karnofsky or Lansky greater than or equal to 60
  • Patients must have normal organ and marrow function as defined below:

    • absolute neutrophil count greater than or equal to 1,000/mcL
    • platelets greater than or equal to 50,000/mcL
    • hemoglobin > 9 g/dL
    • total bilirubin <1.5X institutional upper limit of normal except if known history of Gilbert's disease
    • AST(SGOT)/ALT(SGPT) less than or equal to 5X institutional upper limit of normal
    • creatinine clearance greater than or equal to 50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
  • Willingness to comply with twice daily application of 2 different creams to 2 separate, prespecified sites.
  • The effects of ruxolitinib on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  • Ability of subject or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

  • Patients concurrently receiving a JAK inhibitor (topical or systemic).
  • Patients receiving any other investigational agents.
  • Patients concurrently taking oral fluconazole.
  • Patients concurrently taking strong CYP3A4 inhibitors.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ruxolitinib or other agents used in study.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection including EBV, CMV, HIV, HBV, and HCV, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant women are excluded from this study because ruxolitinib is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ruxolitinib, breastfeeding should be discontinued if the mother is treated with ruxolitinib. These potential risks may also apply to other agents used in this study.
  • Recurrent or progressive malignancy requiring anticancer treatment.
  • Other cancer (except that for which HCT was performed) within 2 years of study entry, except nonmelanoma skin cancer or carcinoma in situ of the breast, uterus, or cervix.
  • History of cutaneous malignancy at target lesion site.
  • Any participant who, in the investigator s opinion, would be unable to comply with study requirements or for whom participation may pose a greater medical risk.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years to 100 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Michelle O'Brien, R.N. (301) 496-2237 obrienm@mail.nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03395340
Other Study ID Numbers  ICMJE 180035
18-AR-0035
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) )
Study Sponsor  ICMJE National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Dominique C Pichard, M.D. National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date September 10, 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP