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Study of Ruxolitinib in Sclerotic Chronic Graft-Versus-Host Disease After Failure of Systemic Glucocorticoids

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03616184
Recruitment Status : Recruiting
First Posted : August 6, 2018
Last Update Posted : October 2, 2019
Information provided by (Responsible Party):
Vijaya Bhatt, University of Nebraska

Brief Summary:
The primary objective of the study is to examine the efficacy of ruxolitinib in patients with sclerotic chronic graft-versus-host disease (GVHD).

Condition or disease Intervention/treatment Phase
Graft-versus-host-disease (GVHD) Drug: Ruxolitinib Phase 2

Detailed Description:
Chronic graft-versus-host-disease (GVHD) is a major complication of allogeneic hematopoietic cell transplant that impairs quality of life, and is associated with significant morbidity and mortality. Management of chronic GVHD with prednisone is associated with an overall response rate of approximately 60%, and a complete response rate of approximately 30% but sclerotic features do not respond as well. Based on the biology of chronic GVHD and available preliminary evidence, the investigators hypothesize that ruxolitinib will be effective in the management of sclerotic chronic GVHD. The study is an open label, phase II multicenter trial designed to evaluate the efficacy of ruxolitinib as a salvage treatment for patients with sclerotic GVHD (sclerosis or fasciitis). The primary objective is to determine the proportion of patients with response rate (complete and partial responses) in skin and/or joint, as determined by 2014 NIH (National Institutes of Health) consensus criteria, at 6 months of therapy with ruxolitinib. Eligibility criteria includes adult patients with chronic GVHD and skin, joint and/or fascia sclerosis, who have received systemic corticosteroids for >12 months and at least one additional line of therapy OR systemic corticosteroids and at least two additional lines of therapy for chronic GVHD. A sample size of 47 patients (43 evaluable patients and estimated 10% dropout) will allow an α of 0.044 and a power of 84% to test the null hypothesis response rate of 25% compared to an alternative of 45%. Subjects will receive ruxolitinib for 6 months for the treatment of sclerotic chronic GVHD. Subjects will be evaluated for GVHD status as well as non-relapse mortality, relapse of underlying malignancy and quality of life/functional status. Plasma cytokine levels and T/Natural Killer (NK) cell subset in peripheral blood will be measured at various time points. The response rate will be reported as a proportion and 95% exact confidence interval. If positive, the trial results will support other ongoing studies to establish the role of ruxolitinib in chronic GVHD in general and specifically in sclerotic chronic GVHD.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 47 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Single Arm, Open Label, Phase II Study of Ruxolitinib in Sclerotic Chronic Graft-Versus-Host Disease After Failure of Systemic Glucocorticoids
Actual Study Start Date : September 5, 2018
Estimated Primary Completion Date : April 2023
Estimated Study Completion Date : April 2024

Arm Intervention/treatment
Experimental: Ruxolitinib
Patients will receive oral ruxolitinib at a dose of 10 mg twice daily.
Drug: Ruxolitinib
Patients with sclerotic chronic graft-versus-host disease (GVHD) will receive oral ruxolitinib at a dose of 10 mg twice daily. Doses may not exceed 10 mg twice daily. Ruxolitinib will be continued for 6 months. Patients who continue to have stable disease, mixed responses or partial/complete responses at the end of 6 months may continue the drug for a total of 12 months.

Primary Outcome Measures :
  1. Proportion of patients with complete and partial responses in skin and/or joint [ Time Frame: 6 months ]
    This outcome will examine the efficacy of ruxolitinib in patients with sclerotic chronic graft-versus-host disease (GVHD) as determined by 2014 NIH Criteria.

Secondary Outcome Measures :
  1. Proportion of patients with complete or partial responses overall [ Time Frame: 6 months ]
    As determined by 2014 NIH Criteria.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Sclerotic chronic GVHD (classic chronic or overlap syndrome) that meets 2014 NIH Consensus Criteria. Eligible patients will have superficial or deep skin sclerosis, fasciitis or joint contractures.
  2. The subject must have received the following therapy for chronic GVHD (not necessarily for sclerotic manifestations): A - Systemic corticosteroids for >12 months and at least one additional line of systemic therapy OR B - Systemic corticosteroids and at least two additional lines of systemic therapy. For the purpose of this study, fluticasone, azithromycin and montelukast ("FAM") therapy for lung GVHD will be considered a topical therapy. Investigators are encouraged but not mandated to use ibrutinib for appropriate patients prior to enrollment in this trial.
  3. Adults, Age ≥18 years (state of Nebraska, Age ≥19 years)
  4. Karnofsky performance status ≥60% at the time of enrollment
  5. All allogeneic donor sources and all conditioning regimens are allowed.
  6. Absolute neutrophil count (ANC) greater than 1000/µL, and platelet count ³50,000/µL without the use of growth factors or platelet transfusion.
  7. Able to take orally-administered medication.
  8. Female patient of reproductive potential must have a negative serum or urine pregnancy test ≤7 days prior to starting the study drug. Women are considered NOT to have reproductive potential if they have had 12 months of amenorrhea with an appropriate clinical profile (i.e. ≥51 years, history of vasomotor symptoms, OR supportive hormone levels such as low estrogen and high follicle-stimulating hormone levels), OR surgical sterilization.
  9. Male and female patients of reproductive potential must be willing to avoid pregnancy or fathering children from enrollment to one month after the end of study treatment. This will require either a total abstinence, OR exclusively non-heterosexual activity (when this is in line with the preferred and usual lifestyle of the subject), OR two methods of contraception (male or female condom with or without a spermicidal agent, diaphragm or cervical cap with spermicide, or hormonal based contraception including intrauterine device).
  10. Life expectancy greater than 6 months
  11. Written informed consent to participate in the study.

Exclusion Criteria:

  1. Fibrosis of internal organs such as gut, liver or lung as the sole manifestation of sclerosis.
  2. Fluconazole at a dose more than 200 mg daily. Patients should stop fluconazole or lower dose to less than or equal to 200 mg daily before starting ruxolitinib.
  3. Current evidence of malignancy after allogeneic transplant.
  4. History of progressive multifocal leuko-encephalopathy (PML)
  5. Active uncontrolled bacterial, fungal, parasitic, or viral infection. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of infection 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
  6. Presence of known HIV infection, active hepatitis B or C infection.
  7. Active tuberculosis infection that developed after allogeneic hematopoietic cell transplant (HCT)
  8. Total bilirubin 1.5 ´ the upper limit of the normal range
  9. Creatinine clearance <30 mL/min
  10. 10. Presence of uncontrolled cardiopulmonary conditions such as ongoing cardiac arrhythmias, unstable angina or myocardial infarction, uncontrolled hypertension (e.g. blood pressure higher than 150/90 for patients 60 years or older, or higher than 140/90 for patients younger than 60 years, or those with diabetes and chronic kidney disease), New York Heart Association class III/IV congestive heart failure, or requirement of supplemental oxygen at rest or having a resting O2 saturation <90% by pulse oximetry.
  11. Any other condition that is judged by the physician to potentially interfere with compliance to the study protocol or pose a significant risk to the patient.
  12. Pregnancy, breastfeeding or planning to be pregnant.
  13. Exposure to Janus kinase inhibitors (JAK) inhibitor therapy for any indication after allogeneic transplant
  14. Initiation of a new systemic immunosuppressant for management of chronic GVHD within 8 weeks prior to enrollment. However, patients who develop disease progression can enroll as early as 4 weeks after initiation of a new systemic immunosuppressant. Also, patients who are unable to tolerate current therapy can enroll any time after initiation of a new systemic immunosuppressant, as long as the "new" immunosuppressant is stopped in these cases prior to initiation of ruxolitinib. Initiation of any new topical therapy (including FAM or intra-oral narrow-band UVB phototherapy) and changes in dose of existing immunosuppressive agents such as corticosteroids, sirolimus, calcineurin inhibitors or other agents are acceptable at any time prior to enrollment. The use of immunosuppressants for short term period, for example 7 days, for indications other than GVHD will be acceptable.
  15. Treatment with any other investigational agent, device, or procedure, within 21 days (or 5 half-lives, whichever is greater)
  16. Known allergies, hypersensitivity, or intolerance to any of the study medications, excipients, or similar compounds.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03616184

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Contact: Denise Kreski, M.A. 402-559-8504
Contact: April Winchester, B.S. 402-559-0963

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United States, Nebraska
University of Nebraska Medical Center Recruiting
Omaha, Nebraska, United States, 68198
Contact: Penny Nurse Coordinator, RN    402-559-4596      
United States, Ohio
Cleveland Clinic Recruiting
Cleveland, Ohio, United States, 44195
Contact: Betty Hamilton, MD         
Ohio State University Recruiting
Columbus, Ohio, United States, 43210
Contact: Ayman Saad, MD, MSc         
United States, Washington
Fred Hutchinson Cancer Research Center Recruiting
Seattle, Washington, United States, 98109
Contact: Stephanie J Lee, MD         
Sponsors and Collaborators
University of Nebraska
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Principal Investigator: Vijaya Bhatt, M.D. University of Nebraska

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Responsible Party: Vijaya Bhatt, Assistant Professor, Internal Medicine Oncology/Hematology, University of Nebraska Identifier: NCT03616184     History of Changes
Other Study ID Numbers: 333-18
First Posted: August 6, 2018    Key Record Dates
Last Update Posted: October 2, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs