A Study of Ruxolitinib in Combination With Corticosteroids for the Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease (REACH-1)

• ClinicalTrials.gov Identifier: NCT02953678
• Recruitment Status: Completed
• First Posted: November 3, 2016
• Results First Posted: August 20, 2019
• Last Update Posted: November 24, 2021
• Sponsor: Incyte Corporation
• Information provided by (Responsible Party): Incyte Corporation

Study Description

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).

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

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Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 71 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: December 30, 2016
• Actual Primary Completion Date: January 31, 2018
• Actual Study Completion Date: August 14, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ruxolitinib in combination with corticosteroids; Participants began oral administration of ruxolitinib at 5 mg twice daily (BID); if stable after the first 3 days of treatment, the dose could be increased to 10 mg BID.	Drug: Ruxolitinib; Other Names: Jakafi; INCB018424; Drug: Prednisone or methylprednisolone; Either oral prednisone or IV methylprednisolone may be used to begin corticosteroid treatment at the investigator's discretion.

Outcome Measures

Primary Outcome Measures :

1. Overall Response Rate (ORR) at Day 28 [ Time Frame: From baseline to Day 28 ]
   Defined as the percentage of participants demonstrating a complete response (CR), very good partial response (VGPR), or partial response (PR).

Secondary Outcome Measures :

1. Overall Response Rate (ORR) [ Time Frame: From baseline to days 14, 56, and 100 ]
   Defined as the percentage of participants demonstrating a CR, VGPR, or PR.
2. Nonrelapse Mortality (NRM) [ Time Frame: From baseline to Months 6, 9, 12, and 24 ]
   Defined as the proportion of subjects who died due to causes other than malignancy relapse.
3. Percentage of Participants With Six-month Duration of Response (DOR) [ Time Frame: From Baseline up to 6 months ]
   Defined as the time from first response until graft-versus-host disease (GVHD) progression or death. DOR was assessed when all participants who were on the study completed the Day 180 visit.
4. Percentage of Participants With Three-month DOR [ Time Frame: From Baseline up to 3 months ]
   Defined as the time from first response until GVHD progression or death. DOR was assessed when all participants who were on the study completed the Day 84 visit.
5. Relapse Rate [ Time Frame: From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months) ]
   Defined as the percentage of participants whose underlying malignancy relapsed.
6. Relapse-related Mortality Rate [ Time Frame: From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months) ]
   Defined as the percentage of participants whose malignancy relapsed and had a fatal outcome.
7. Failure-free Survival (FFS) [ Time Frame: From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months) ]
   Defined as the time from first dose of ruxolitinib to the earliest date that a participant died, had a relapse/progression of the underlying malignancy, required additional therapy for aGVHD, or demonstrated signs or symptoms of chronic graft-versus-host disease (cGVHD).
8. Overall Survival (OS) [ Time Frame: From Baseline until death, withdrawal of consent, or the end of the study, whichever occurs first (up to approximately 24 months) ]
   Defined as the time from study enrollment (first day of ruxolitinib treatment) to death due to any cause.
9. Number of Participants With Treatment-emergent Adverse Events (TEAES), Serious TEAEs, And Grade 3 or Higher TEAEs [ Time Frame: From signing the informed consent form up to 30-35 days after the last dose of study treatment (up to 24 months) ]
   AE was any unfavorable and unintended sign, symptom, or disease temporally associated with use of medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. Serious AE was any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization. TEAE was an AE that was reported for the first time, or worsening of a pre-existing event after the first dose of study drug (until 30 days after the last dose of study drug). Severity of AEs was described and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03). Grade 3 and above would constitute a severe, life-threatening, or death event.

Eligibility Criteria

• Ages Eligible for Study: 12 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Arizona

Tucson, Arizona, United States, 85719

United States, California

Duarte, California, United States, 31010

La Jolla, California, United States, 92903

Los Angeles, California, United States, 90033

Los Angeles, California, United States, 90095

Stanford, California, United States, 94306

United States, Colorado

Denver, Colorado, United States, 80218

United States, Florida

Gainesville, Florida, United States, 32610

Miami, Florida, United States, 33136

Tampa, Florida, United States, 33612

United States, Georgia

Atlanta, Georgia, United States, 30322

United States, Illinois

Chicago, Illinois, United States, 60611

Chicago, Illinois, United States, 60637

United States, Kentucky

Lexington, Kentucky, United States, 40536-0293

United States, Massachusetts

Boston, Massachusetts, United States, 02114

United States, Michigan

Grand Rapids, Michigan, United States, 49503

United States, Minnesota

Minneapolis, Minnesota, United States, 55455

United States, Missouri

Saint Louis, Missouri, United States, 63110

United States, New Jersey

Hackensack, New Jersey, United States, 07601

United States, New York

New York, New York, United States, 10022

New York, New York, United States, 10065

Rochester, New York, United States, 14642

United States, North Carolina

Charlotte, North Carolina, United States, 28204

United States, Ohio

Cincinnati, Ohio, United States, 45242

Cleveland, Ohio, United States, 44195

United States, Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

Philadelphia, Pennsylvania, United States, 19107

Pittsburgh, Pennsylvania, United States, 15224

Pittsburgh, Pennsylvania, United States, 15232

United States, Tennessee

Nashville, Tennessee, United States, 37203

Nashville, Tennessee, United States, 37232

United States, Texas

Dallas, Texas, United States, 75246

San Antonio, Texas, United States, 78229

United States, Utah

Salt Lake City, Utah, United States, 84112

United States, Washington

Seattle, Washington, United States, 98109

United States, West Virginia

Morgantown, West Virginia, United States, 26506

United States, Wisconsin

Madison, Wisconsin, United States, 53705

Milwaukee, Wisconsin, United States, 53226

Sponsors and Collaborators

Incyte Corporation

Investigators

• Study Director: Fitzroy Dawkins, MD; Incyte Corporation

  Study Documents (Full-Text)

Documents provided by Incyte Corporation:

Study Protocol  [PDF] October 4, 2016

Statistical Analysis Plan  [PDF] July 24, 2017

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: Incyte Corporation
• ClinicalTrials.gov Identifier: NCT02953678
• Other Study ID Numbers: INCB 18424-271 (REACH-1)
• First Posted: November 3, 2016
• Results First Posted: August 20, 2019
• Last Update Posted: November 24, 2021
• Last Verified: October 2021

Keywords provided by Incyte Corporation:

Graft-versus-host disease (GVHD); acute GVHD; steroid-refractory; ruxolitinib; Janus kinase inhibitor

Additional relevant MeSH terms:

Graft vs Host Disease; Immune System Diseases; Prednisone; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Neuroprotective Agents; Protective Agents