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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)

Primary Purpose

Graft-versus-host Disease (GVHD)

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Ruxolitinib

Extracorporeal photopheresis (ECP)

Low-dose methotrexate (MTX)

Mycophenolate mofetil (MMF)

mechanistic Target of Rapamycin (mTOR) inhibitors (everolimus or sirolimus)

Infliximab

Rituximab

Pentostatin

Imatinib

Ibrutinib

About this trial

This is an interventional treatment trial for Graft-versus-host Disease (GVHD) focused on measuring Graft-versus-host disease (GvHD), Chronic GvHD (cGvHD), steroid-refractory, ruxolitinib, Janus kinase inhibitor

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Have undergone allogeneic stem cell transplantation (alloSCT) from any donor source (matched unrelated donor, sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or cord blood. Recipients of non-myeloablative, myeloablative, and reduced intensity conditioning are eligible
Evident myeloid and platelet engraftment: Absolute neutrophil count (ANC) > 1000/mm^3 and platelet count > 25,000/ mm^3
Participants with clinically diagnosed moderate to severe cGvHD according to NIH Consensus Criteria prior to randomization:
- Moderate cGvHD: At least one organ (not lung) with a score of 2, 3 or more organs involved with a score of 1 in each organ, or lung score of 1
- Severe cGvHD: at least 1 organ with a score of 3, or lung score of 2 or 3
Participants currently receiving systemic or topical corticosteroids for the treatment of cGvHD for a duration of < 12 months prior to Cycle 1 Day 1 (if applicable), and have a confirmed diagnosis of steroid-refractory cGvHD defined per 2014 NIH consensus criteria irrespective of the concomitant use of a calcineurin inhibitor (CNI), as follows:
- A lack of response or disease progression after administration of minimum prednisone 1 mg/kg/day for at least 1 week, OR
- Disease persistence without improvement despite continued treatment with prednisone at > 0.5 mg/kg/day or 1 mg/kg/every other day for at least 4 weeks, OR
- Increase to prednisolone dose to > 0.25 mg/kg/day after 2 unsuccessful attempts to taper the dose
Participant must accept to be treated with only one of the following BAT options on Cycle 1 Day 1 (additions and changes are allowed during the course of the study, but only with BAT from the following BAT options): extracorporeal photopheresis (ECP), low-dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), infliximab, rituximab, pentostatin, imatinib, ibrutinib

Exclusion Criteria:

Participants who have received 2 or more systemic treatment for cGvHD in addition to corticosteroids ± CNI for cGvHD
Patients that transition from active aGvHD to cGvHD without tapering off corticosteroids ± CNI and any systemic treatment
* Patients receiving up to 30 mg by mouth once a day of hydrocortisone (i.e., physiologic replacement dose) of corticosteroids are allowed.
Participants who were treated with prior JAK inhibitors for aGvHD; except when the participant achieved complete or partial response and has been off JAK inhibitor treatment for at least 8 weeks prior to Cycle 1 Day 1
Failed prior alloSCT within the past 6 months from Cycle 1 Day 1
Participants with relapsed primary malignancy, or who have been treated for relapse after the alloSCT was performed
Steroid refractory cGvHD occurring after a non-scheduled donor lymphocyte infusion (DLI) administered for preemptive treatment of malignancy recurrence. Participants who have received a scheduled DLI as part of their transplant procedure and not for management of malignancy relapse are eligible
Any corticosteroid therapy for indications other than cGvHD at doses > 1 mg/kg/day methylprednisolone or equivalent within 7 days of Cycle 1 Day 1

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Ruxolitinib

Best Available Therapy

Arm Description

Ruxolitinib for the treatment period and extension period.

Best available therapy for the treatment period and extension period, with optional crossover to ruxolitinib after Cycle 6.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

Rate of FFS at Study Completion

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).

BOR During Cross-over Treatment With Ruxolitinib

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.

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).

Overall Survival (OS)

Overall survival was defined as the time from the date of randomization to the date of death due to any cause.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

Utilization of Medical Resources

The percentage of participants with at least one submission to healthcare encounter was assessed.

Full Information

NCT ID

NCT03112603

First Posted

April 4, 2017

Last Updated

July 17, 2023

Sponsor

Incyte Corporation

1. Study Identification

Unique Protocol Identification Number

NCT03112603

Brief Title

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)

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)

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Completed

Study Start Date

June 29, 2017 (Actual)

Primary Completion Date

May 8, 2020 (Actual)

Study Completion Date

December 15, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Incyte Corporation

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief 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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Graft-versus-host Disease (GVHD)

Keywords

Graft-versus-host disease (GvHD), Chronic GvHD (cGvHD), steroid-refractory, ruxolitinib, Janus kinase inhibitor

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

330 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ruxolitinib

Arm Type

Experimental

Arm Description

Ruxolitinib for the treatment period and extension period.

Arm Title

Best Available Therapy

Arm Type

Active Comparator

Arm Description

Best available therapy for the treatment period and extension period, with optional crossover to ruxolitinib after Cycle 6.

Intervention Type

Drug

Intervention Name(s)

Ruxolitinib

Other Intervention Name(s)

Jakafi, INCB018424

Intervention Description

Ruxolitinib twice daily at the protocol-defined starting dose.

Intervention Type

Drug

Intervention Name(s)

Extracorporeal photopheresis (ECP)

Intervention Description

Best available therapy (BAT) will be selected by the investigator for each participant. BAT may not include experimental agents (ie, those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements. The BAT in this study will be among the following treatments currently used in this setting (no other types or combinations of BATs are permitted in this study).

Intervention Type

Drug

Intervention Name(s)

Low-dose methotrexate (MTX)

Intervention Description

Patients will receive BAT based on the Investigator's opinion, taking into account the manufacturer's instructions, labeling, subject's medical condition, and institutional guidelines for any dose adjustment.

Intervention Type

Drug

Intervention Name(s)

Mycophenolate mofetil (MMF)

Intervention Description

Intervention Type

Drug

Intervention Name(s)

mechanistic Target of Rapamycin (mTOR) inhibitors (everolimus or sirolimus)

Intervention Description

Intervention Type

Drug

Intervention Name(s)

Infliximab

Intervention Description

Intervention Type

Drug

Intervention Name(s)

Rituximab

Intervention Description

Intervention Type

Drug

Intervention Name(s)

Pentostatin

Intervention Description

Intervention Type

Drug

Intervention Name(s)

Imatinib

Intervention Description

Intervention Type

Drug

Intervention Name(s)

Ibrutinib

Intervention Description

Primary Outcome Measure Information:

Title

Description

Time Frame

Cycle 7 Day 1 (each cycle was comprised of 4 weeks)

Secondary Outcome Measure Information:

Title

Rate of Participants With Clinically Relevant Improvement of the Modified Lee cGvHD Symptom Scale Score

Description

Time Frame

Baseline; Cycle 7 Day 1 (each cycle was comprised of 4 weeks)

Title

Rate of Failure-free Survival (FFS)

Description

Time Frame

Baseline to when the last participant reached Cycle 7 Day 1 (each cycle was comprised of 4 weeks)

Title

Rate of FFS at Study Completion

Description

Time Frame

From Baseline to Last Participant Last Visit (LPLV) (approximately 5 years)

Title

Best Overall Response (BOR) at Cycle 7 Day 1

Description

Time Frame

up to Cycle 7 Day 1 (each cycle was comprised of 4 weeks)

Title

BOR During Cross-over Treatment With Ruxolitinib

Description

Time Frame

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)

Title

ORR at the End of Cycle 3

Description

Time Frame

Cycle 4 Day 1 (each cycle was comprised of 4 weeks)

Title

Duration of Response Through Study Completion

Description

Time Frame

from first response to LPLV (approximately 5 years)

Title

Overall Survival (OS)

Description

Overall survival was defined as the time from the date of randomization to the date of death due to any cause.

Time Frame

from the date of randomization to the date of death due to any cause up to LPLV (approximately 5 years)

Title

Cumulative Incidence of Non-relapse Mortality (NRM)

Description

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.

Time Frame

Months 3, 6, 12, 18, 24, 30, and 36

Title

Percentage of Participants With a ≥ 50% Reduction in Daily Corticosteroid Dose

Description

Time Frame

from Day 15 up to Day 182

Title

Percentage of Participants Successfully Tapered Off of All Corticosteroids

Description

Time Frame

up to Day 179

Title

Cumulative Incidence of Malignancy Relapse/Recurrence (MR)

Description

Defined as the cumulative incidence rate from competing risk analysis of MR from the date of randomization to hematologic malignancy relapse/recurrence.

Time Frame

Months 3, 6, 12, 18, 24, 30, and 36

Title

Change From Baseline in Functional Assessment of Cancer Therapy - Bone Marrow Transplantation (FACT-BMT)

Description

Time Frame

Baseline; up to Cycle 39 Day 1 (each cycle was comprised of 4 weeks)

Title

Change From Baseline in EQ-5D-5L

Description

Time Frame

Baseline; up to Cycle 39 Day 1 (each cycle was comprised of 4 weeks)

Title

Number of Participants With Any Treatment-emergent Adverse Event (TEAE)

Description

Time Frame

from Baseline to LPLV (approximately 5 years)

Title

Cmax of Ruxolitinib After Single (Cycle 1 Day 1) and Multiple (Cycle 1 Day 15) Doses

Description

Time Frame