Clinical trial NCT02953678: A Study of Ruxolitinib in Combination With Corticosteroids for the Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease (REACH-1)
Official title: A Single-Cohort, Phase 2 Study of Ruxolitinib in Combination With Corticosteroids for the Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease (REACH-1)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Graft-versus-host Disease (GVHD)
Keywords: Graft-versus-host disease (GVHD)
acute GVHD
steroid-refractory
ruxolitinib
Janus kinase inhibitor
Lead sponsor: Incyte Corporation
Sponsor class: INDUSTRY
First posted: 2016-11-03
Enrollment: 71
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to assess the efficacy of ruxolitinib in combination with corticosteroids in subjects with Grades II to IV steroid-refractory acute graft-versus-host disease (GVHD).


Eligibility criteria: Inclusion Criteria:

* Have undergone first allogeneic hematopoietic stem cell transplantation (allo-HSCT) from any donor source using bone marrow, peripheral blood stem cells, or cord blood for hematologic malignancies. Recipients of nonmyeloablative and myeloablative conditioning regimens are eligible.
* Clinically suspected Grades II to IV acute GVHD as per MAGIC guidelines, occurring after allo-HSCT with any conditioning regimen and any anti-GVHD prophylactic program.
* Subjects with steroid-refractory acute GVHD, defined as any of the following:

  * Subjects with progressive GVHD (ie, increase in stage in any organ system or any new organ involvement) after 3 days of primary treatment with methylprednisolone ≥ 2 mg/kg per day (or equivalent).
  * Subjects with GVHD that has not improved (ie, decrease in stage in at least 1 involved organ system) after 7 days of primary treatment with methylprednisolone ≥ 2 mg/kg per day (or equivalent).
  * Subjects who previously began corticosteroid therapy at a lower dose (at least 1 mg/kg per day methylprednisolone) but develop new GVHD in another organ system.
  * Subjects who cannot tolerate a corticosteroid taper, that is, begin corticosteroids at 2.0 mg/kg per day, demonstrate response, but progress before a 50% decrease from the initial starting dose of corticosteroids is achieved.
* Evidence of myeloid engraftment (eg, absolute neutrophil count ≥ 0.5 × 10\^9/L for 3 consecutive days if ablative therapy was previously used). Use of growth factor supplementation is allowed.
* Be willing to avoid pregnancy or fathering children

Exclusion Criteria:

* Has received more than 1 allo-HSCT.
* Has received more than 1 systemic treatment in addition to corticosteroids for acute GVHD.
* Presence of GVHD overlap syndrome as per NIH guidelines.
* Subjects who have had a splenectomy.
* Presence of an active uncontrolled infection. An active uncontrolled infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs, or radiographic findings attributable to infection. Persisting fever without signs or symptoms will not be interpreted as an active uncontrolled infection.
* Known human immunodeficiency virus infection.
* Active hepatitis B virus (HBV) or hepatitis C virus infection that requires treatment or at risk for HBV reactivation. Subjects whose immune status is unknown or uncertain must have results confirming immune status before enrollment.
* Serum creatinine \> 2.0 mg/dL or creatinine clearance \< 40 mL/min measured or calculated by Cockcroft-Gault equation.
* Subjects with evidence of relapsed primary disease, or subjects who have been treated for relapse after the allo-HSCT was performed.
* Unresolved toxicity or complications (other than acute GVHD) due to previous allo-HSCT.
* Any corticosteroid therapy for indications other than GVHD at doses of methylprednisolone or equivalent \> 1 mg/kg per day within 7 days of enrollment.
* Severe organ dysfunction unrelated to underlying GVHD, including:

  * Cholestatic disorders or unresolved veno-occlusive disease of the liver (defined as persistent bilirubin abnormalities not attributable to GVHD and ongoing organ dysfunction).
  * Clinically significant or uncontrolled cardiac disease including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, New York Heart Association Class III or IV congestive heart failure, circulatory collapse requiring vasopressor or inotropic support, or arrhythmia that requires therapy.
  * Clinically significant respiratory disease that requires mechanical ventilation support or 50% oxygen.
* Currently breast feeding.
* Received Janus kinase inhibitor (JAK) therapy after allo-HSCT for any indication. Treatment with a JAK inhibitor before allo-HSCT is permitted.
* Treatment with any other investigational agent, device, or procedure, within 21 days (or 5 half-lives, whichever is greater) of enrollment. Subjects participating in a GVHD prophylaxis study or conditioning regimen should be discussed with the sponsor's medical monitor before enrollment.
* Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the subject; or interfere with interpretation of study data.
* Known allergies, hypersensitivity, or intolerance to any of the study medications, excipients, or similar compounds.

Primary outcomes:
measure: Overall Response Rate (ORR) at Day 28
timeFrame: From baseline to Day 28
Secondary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: From baseline to days 14, 56, and 100
measure: Nonrelapse Mortality (NRM)
timeFrame: From baseline to Months 6, 9, 12, and 24
measure: Percentage of Participants With Six-month Duration of Response (DOR)
timeFrame: From Baseline up to 6 months
measure: Percentage of Participants With Three-month DOR
timeFrame: From Baseline up to 3 months
measure: Relapse Rate
timeFrame: From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months)
measure: Relapse-related Mortality Rate
timeFrame: From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months)
measure: Failure-free Survival (FFS)
timeFrame: From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months)
measure: Overall Survival (OS)
timeFrame: From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months)
measure: Number of Participants With Treatment-emergent Adverse Events (TEAES), Serious TEAEs, And Grade 3 or Higher TEAEs
timeFrame: From signing the informed consent form up to 30-35 days after the last dose of study treatment (up to 24 months)
Other outcomes:
Locations:
city: Tucson
country: United States
state: Arizona
city: Duarte
country: United States
state: California
city: La Jolla
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Stanford
country: United States
state: California
city: Denver
country: United States
state: Colorado
city: Gainesville
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Chicago
country: United States
state: Illinois
city: Chicago
country: United States
state: Illinois
city: Lexington
country: United States
state: Kentucky
city: Boston
country: United States
state: Massachusetts
city: Grand Rapids
country: United States
state: Michigan
city: Minneapolis
country: United States
state: Minnesota
city: Saint Louis
country: United States
state: Missouri
city: Hackensack
country: United States
state: New Jersey
city: New York
country: United States
state: New York
city: New York
country: United States
state: New York
city: Rochester
country: United States
state: New York
city: Charlotte
country: United States
state: North Carolina
city: Cincinnati
country: United States
state: Ohio
city: Cleveland
country: United States
state: Ohio
city: Philadelphia
country: United States
state: Pennsylvania
city: Philadelphia
country: United States
state: Pennsylvania
city: Pittsburgh
country: United States
state: Pennsylvania
city: Pittsburgh
country: United States
state: Pennsylvania
city: Nashville
country: United States
state: Tennessee
city: Nashville
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Salt Lake City
country: United States
state: Utah
city: Seattle
country: United States
state: Washington
city: Morgantown
country: United States
state: West Virginia
city: Madison
country: United States
state: Wisconsin
city: Milwaukee
country: United States
state: Wisconsin
Study officials:
affiliation: Incyte Corporation
name: Fitzroy Dawkins, MD
role: STUDY_DIRECTOR
References:
citation: Jagasia M, Perales MA, Schroeder MA, Ali H, Shah NN, Chen YB, Fazal S, Dawkins FW, Arbushites MC, Tian C, Connelly-Smith L, Howell MD, Khoury HJ. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood. 2020 May 14;135(20):1739-1749. doi: 10.1182/blood.2020004823.
citation: Jagasia M, Zeiser R, Arbushites M, Delaite P, Gadbaw B, Bubnoff NV. Ruxolitinib for the treatment of patients with steroid-refractory GVHD: an introduction to the REACH trials. Immunotherapy. 2018 Apr;10(5):391-402. doi: 10.2217/imt-2017-0156. Epub 2018 Jan 10.