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NCT03112603 Clinical Trial

A Study of Ruxolitinib vs Best Available Therapy (BAT) in Patients With Steroid-refractory Chronic Graft vs. Host Disease (GvHD) After Bone Marrow Transplantation (REACH3)

Graft-versus-host Disease (GVHD) Clinical Trial

Official title:
A Phase III Randomized Open-label Multi-center Study of Ruxolitinib vs. Best Available Therapy in Patients With Corticosteroid-refractory Chronic Graft vs Host Disease After Allogeneic Stem Cell Transplantation (REACH3)

Clinical Trial Details — Status: Completed

Administrative data
NCT number NCT03112603
Other study ID # INCB 18424-365 (REACH3)
Secondary ID CINC424D2301
Status Completed
Phase Phase 3
First received
Last updated
Start date June 29, 2017
Est. completion date December 15, 2022

Study information
Verified date July 2023
Source Incyte Corporation
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

The purpose of this study is to assess the efficacy of ruxolitinib against best available therapy in participants with steroid-refractory chronic graft-versus-host disease (SR cGvHD).

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Study Design

Related Conditions & MeSH terms

Intervention

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Sponsors (1)
Lead Sponsor Collaborator
Incyte Corporation

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Bulgaria,  Canada,  Czechia,  Denmark,  France,  Germany,  Greece,  Hungary,  India,  Israel,  Italy,  Japan,  Jordan,  Korea, Republic of,  Netherlands,  Norway,  Poland,  Portugal,  Puerto Rico,  Romania,  Russian Federation,  Saudi Arabia,  Spain,  Sweden,  Switzerland,  Turkey,  United Kingdom, 

Outcome
Type Measure Description Time frame Safety issue
Primary Efficacy of Ruxolitinib Versus Investigator's Choice Best Available Therapy (BAT) in Participants With Moderate or Severe Steroid Refractory Chronic Graft Versus Host Disease (SR-cGvHD) Assessed by Overall Response Rate (ORR) at the Cycle 7 Day 1 Visit ORR was defined as the percentage of participants in each arm demonstrating a complete response (CR) or partial response (PR) based on chronic GvHD (cGvHD) disease assessments (National Institutes of Health Consensus Criteria) without the requirement of additional systemic therapies for an earlier progression, mixed response, or non-response. Scoring of response was relative to the organ score at the time of randomization. CR: complete resolution of all signs and symptoms of cGVHD in all evaluable organs without the initiation or addition of new systemic therapy. PR: improvement in at least one organ (e.g., improvement of 1 or more points on a 4- to 7-point scale, or an improvement of 2 or more points on a 10- to 12-point scale) without progression in other organs or sites, initiation, or addition of new systemic therapies. Cycle 7 Day 1 (each cycle was comprised of 4 weeks)
Secondary Rate of Participants With Clinically Relevant Improvement of the Modified Lee cGvHD Symptom Scale Score To assess improvement of symptoms based on the total symptom score (TSS); a responder was defined as having achieved a clinically relevant reduction from Baseline of the TSS. The scale consists of 30 items in 7 subscales (skin, eye, mouth, lung, nutrition, energy, and psychological). Participants reported their level of symptom "bother" over the previous month on a 5-point likert scale: not at all, slightly, moderately, quite a bit, or extremely. Subscale scores and the summary score range from 0 to 100, with a higher score indicating worse symptoms. Baseline; Cycle 7 Day 1 (each cycle was comprised of 4 weeks)
Secondary Rate of Failure-free Survival (FFS) Composite time to event endpoint incorporating the following FFS events: (i) relapse or recurrence of underlying disease or death due to underlying disease, (ii) nonrelapse mortality, or (iii) addition or initiation of another systemic therapy for cGvHD. Baseline to when the last participant reached Cycle 7 Day 1 (each cycle was comprised of 4 weeks)
Secondary Rate of FFS at Study Completion Composite time to event endpoint incorporating the following FFS events: (i) relapse or recurrence of underlying disease or death due to underlying disease, (ii) nonrelapse mortality, or (iii) addition or initiation of another systemic therapy for cGvHD. From Baseline to Last Participant Last Visit (LPLV) (approximately 5 years)
Secondary Best Overall Response (BOR) at Cycle 7 Day 1 BOR was defined as the percentage of participants who achieved an overall response (CR+PR) based on cGvHD disease assessments (National Institutes of Health Consensus Criteria) without the requirement of additional systemic therapies for an earlier progression, mixed response, or non-response at any time point (up to Cycle 7 Day 1 or the start of additional systemic therapy for cGvHD). Scoring of response was relative to the organ score at the time of randomization. CR: complete resolution of all signs and symptoms of cGVHD in all evaluable organs without the initiation or addition of new systemic therapy. PR: improvement in at least one organ (e.g., improvement of 1 or more points on a 4- to 7-point scale, or an improvement of 2 or more points on a 10- to 12-point scale) without progression in other organs or sites, initiation, or addition of new systemic therapies. This analysis was based on the primary cutoff date (May 2020). up to Cycle 7 Day 1 (each cycle was comprised of 4 weeks)
Secondary BOR During Cross-over Treatment With Ruxolitinib BOR was defined as the percentage of participants who achieved an overall response (CR+PR) based on cGvHD disease assessments (National Institutes of Health Consensus Criteria) without the requirement of additional systemic therapies for an earlier progression, mixed response, or non-response at any time point (up to Cycle 7 Day 1 or the start of additional systemic therapy for cGvHD). Scoring of response was relative to the organ score at the time of randomization. CR: complete resolution of all signs and symptoms of cGVHD in all evaluable organs without the initiation or addition of new systemic therapy. PR: improvement in at least one organ (e.g., improvement of 1 or more points on a 4- to 7-point scale, or an improvement of 2 or more points on a 10- to 12-point scale) without progression in other organs or sites, initiation, or addition of new systemic therapies. from Crossover Cycle 1 Day 1 to any time point up to and including Crossover Cycle 7 Day 1 (each cycle was comprised of 4 weeks)
Secondary ORR at the End of Cycle 3 ORR was defined as the percentage of participants in each arm demonstrating a CR or PR based on cGvHD disease assessments (National Institutes of Health Consensus Criteria) without the requirement of additional systemic therapies for an earlier progression, mixed response, or non-response. Scoring of response was relative to the organ score at the time of randomization. CR: complete resolution of all signs and symptoms of cGVHD in all evaluable organs without the initiation or addition of new systemic therapy. PR: improvement in at least one organ (e.g., improvement of 1 or more points on a 4- to 7-point scale, or an improvement of 2 or more points on a 10- to 12-point scale) without progression in other organs or sites, initiation, or addition of new systemic therapies. Cycle 4 Day 1 (each cycle was comprised of 4 weeks)
Secondary Duration of Response Through Study Completion DOR was defined as the time from first response until cGvHD progression, death, or the date of change/addition of systemic therapies for cGvHD and as assessed for responders only. Response was based on cGvHD disease assessments (National Institutes of Health consensus criteria). Duration of response was evaluated in participants who achieved a CR or PR at or before Cycle 7 Day 1. The analysis included a larger number of participants than the number of participants who achieved CR or PR at Cycle 7 Day 1 (82 ruxolitinib and 42 BAT) because the analysis took into account not only those participants who achieved CR or PR at Cycle 7 Day 1, but also participants who achieved CR or PR before Cycle 7 Day 1 but who may have lost their response at Cycle 7 Day 1. For this reason, the number of participants in this analysis does not align with the best overall response (BOR) at Cycle 7 Day 1. This analysis was based on the cutoff date upon study completion (December 2022). from first response to LPLV (approximately 5 years)
Secondary Overall Survival (OS) Overall survival was defined as the time from the date of randomization to the date of death due to any cause. from the date of randomization to the date of death due to any cause up to LPLV (approximately 5 years)
Secondary Cumulative Incidence of Non-relapse Mortality (NRM) Defined as the cumulative incidence rate from competing risk analysis for NRM from the date of randomization to the date of death not preceded by underlying disease relapse/recurrence. Months 3, 6, 12, 18, 24, 30, and 36
Secondary Percentage of Participants With a = 50% Reduction in Daily Corticosteroid Dose All corticosteroid dosages prescribed to the participant and all dose changes during the study were to be recorded for assessment of participants with a = 50% reduction in daily corticosteroid dose. from Day 15 up to Day 182
Secondary Percentage of Participants Successfully Tapered Off of All Corticosteroids All corticosteroid dosages prescribed to the participant and all dose changes during the study were to be recorded for assessment of participants who successfully tapered off of all corticosteroids. Participants who completely tapered off corticosteroids refer to those who permanently discontinued steroids as per the dose administration panel and who did not restart steroids in the same interval. Participants who were tapered off and continued follow-up were also counted as being tapered off with 0 dose in subsequent intervals until they discontinued from the main treatment period or restarted steroid treatment. up to Day 179
Secondary Cumulative Incidence of Malignancy Relapse/Recurrence (MR) Defined as the cumulative incidence rate from competing risk analysis of MR from the date of randomization to hematologic malignancy relapse/recurrence. Months 3, 6, 12, 18, 24, 30, and 36
Secondary Change From Baseline in Functional Assessment of Cancer Therapy - Bone Marrow Transplantation (FACT-BMT) Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The FACT-BMT is a 50-item self-report questionnaire that measures the effect of a therapy on domains including physical, functional, social/family, and emotional well-being, together with additional concerns relevant for bone marrow transplantation participants. The questions were based on a 5-point Likert scale, where 0 corresponds to "not at all" and 4 corresponds to "very much." The higher the final score, the better the quality of life. The FACT-BMT total score ranges from 0 to 148. Baseline; up to Cycle 39 Day 1 (each cycle was comprised of 4 weeks)
Secondary Change From Baseline in EQ-5D-5L The EQ-5D-5L is a descriptive classification consisting of five dimensions of health: mobility, self-care, usual activities, anxiety/depression, and pain/discomfort. The five-level version (no problems, slight problems, moderate problems, severe problems, and extreme problems) uses a 5-point Likert scale, with 1 being no problems and 5 being extreme problems. Baseline; up to Cycle 39 Day 1 (each cycle was comprised of 4 weeks)
Secondary Number of Participants With Any Treatment-emergent Adverse Event (TEAE) Adverse events were defined as the appearance of (or worsening of any pre-existing) undesirable signs, symptoms, or medical conditions that occurred after the participant's signed informed consent was obtained. Abnormal laboratory values or test results occurring after informed consent constituted adverse events only if they induced clinical signs or symptoms, were considered clinically significant, required therapy (e.g., hematologic abnormality that required transfusion or hematological stem cell support), or required changes in study medication(s). TEAEs were defined as those AEs that started or worsened during the on-treatment period (either randomized or cross-over period). from Baseline to LPLV (approximately 5 years)
Secondary Cmax of Ruxolitinib After Single (Cycle 1 Day 1) and Multiple (Cycle 1 Day 15) Doses Cmax was defined as the maximum observed plasma concentration of ruxolitinib. Early enrolling participants (approximately the first 8 adult and first 4 adolescent participants) randomized to ruxolitinib arm followed an "extensive PK" sampling schedule. Subsequent participants randomized to ruxolitinib, any randomized participants receiving ruxolitinib after Cycle 6, and any randomized participants receiving BAT that cross over to ruxolitinib followed the "sparse PK" sampling schedule. Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose
Secondary AUClast of Ruxolitinib After Single (Cycle 1 Day 1) and Multiple (Cycle 1 Day 15) Doses AUClast was defined as the area under the concentration-time curve up to the last measurable concentration of ruxolitinib. Early enrolling participants (approximately the first 8 adult and first 4 adolescent participants) randomized to ruxolitinib arm followed an "extensive PK" sampling schedule. Subsequent participants randomized to ruxolitinib, any randomized participants receiving ruxolitinib after Cycle 6, and any randomized participants receiving BAT that cross over to ruxolitinib followed the "sparse PK" sampling schedule. Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose
Secondary AUCinf of Ruxolitinib After Single (Cycle 1 Day 1) and Multiple (Cycle 1 Day 15) Doses AUCinf was defined as the area under the concentration-time curve from time 0 to infinity. Early enrolling participants (approximately the first 8 adult and first 4 adolescent participants) randomized to ruxolitinib arm followed an "extensive PK" sampling schedule. Subsequent participants randomized to ruxolitinib, any randomized participants receiving ruxolitinib after Cycle 6, and any randomized participants receiving BAT that cross over to ruxolitinib followed the "sparse PK" sampling schedule. Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose
Secondary CL/F of Ruxolitinib After Single (Cycle 1 Day 1) and Multiple (Cycle 1 Day 15) Doses CL/F was defined as the oral dose clearance of ruxolitinib. Early enrolling participants (approximately the first 8 adult and first 4 adolescent participants) randomized to ruxolitinib arm followed an "extensive PK" sampling schedule. Subsequent participants randomized to ruxolitinib, any randomized participants receiving ruxolitinib after Cycle 6, and any randomized participants receiving BAT that cross over to ruxolitinib followed the "sparse PK" sampling schedule. Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose
Secondary Vz/F of Ruxolitinib After Single (Cycle 1 Day 1) and Multiple (Cycle 1 Day 15) Doses Vz/F was defined as the apparent oral dose volume of distribution of ruxolitinib. Early enrolling participants (approximately the first 8 adult and first 4 adolescent participants) randomized to ruxolitinib arm followed an "extensive PK" sampling schedule. Subsequent participants randomized to ruxolitinib, any randomized participants receiving ruxolitinib after Cycle 6, and any randomized participants receiving BAT that cross over to ruxolitinib followed the "sparse PK" sampling schedule. Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose
Secondary Tmax of Ruxolitinib After Single (Cycle 1 Day 1) and Multiple (Cycle 1 Day 15) Doses tmax was defined as the time to reach the maximum plasma concentration of ruxolitinib. Early enrolling participants (approximately the first 8 adult and first 4 adolescent participants) randomized to ruxolitinib arm followed an "extensive PK" sampling schedule. Subsequent participants randomized to ruxolitinib, any randomized participants receiving ruxolitinib after Cycle 6, and any randomized participants receiving BAT that cross over to ruxolitinib followed the "sparse PK" sampling schedule. Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose
Secondary t1/2 of Ruxolitinib After Single (Cycle 1 Day 1) and Multiple (Cycle 1 Day 15) Doses t1/2 was defined as the apparent terminal phase disposition half-life of ruxolitinib. Early enrolling participants (approximately the first 8 adult and first 4 adolescent participants) randomized to ruxolitinib arm followed an "extensive PK" sampling schedule. Subsequent participants randomized to ruxolitinib, any randomized participants receiving ruxolitinib after Cycle 6, and any randomized participants receiving BAT that cross over to ruxolitinib followed the "sparse PK" sampling schedule. Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose
Secondary Utilization of Medical Resources The percentage of participants with at least one submission to healthcare encounter was assessed. from Baseline to LPLV (approximately 5 years)
See also
  Status Clinical Trial Phase
Completed NCT03139604 - GRAVITAS-301: A Study of Itacitinib or Placebo in Combination With Corticosteroids for Treatment of Acute Graft-Versus-Host Disease Phase 3
Completed NCT02953678 - A Study of Ruxolitinib in Combination With Corticosteroids for the Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease (REACH-1) Phase 2
Completed NCT02614612 - Study of Itacitinib in Combination With Corticosteroids for the Treatment of Acute GVHD Phase 1
Approved for marketing NCT05722912 - Expanded Access of Ruxolitinib Cream to Treat a Single Patient With cGVHD
Approved for marketing NCT03147742 - An Expanded Access Program of Ruxolitinib for the Treatment of Graft-Versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplant