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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)

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03112603
Recruitment Status : Completed
First Posted : April 13, 2017
Results First Posted : April 15, 2022
Last Update Posted : February 8, 2023
Sponsor:
Information provided by (Responsible Party):
Incyte Corporation

Study Description
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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).

Condition or disease Intervention/treatment Phase
Graft-versus-host Disease (GVHD) Drug: Ruxolitinib Drug: Extracorporeal photopheresis (ECP) Drug: Low-dose methotrexate (MTX) Drug: Mycophenolate mofetil (MMF) Drug: mechanistic Target of Rapamycin (mTOR) inhibitors (everolimus or sirolimus) Drug: Infliximab Drug: Rituximab Drug: Pentostatin Drug: Imatinib Drug: Ibrutinib Phase 3

Expanded Access : An investigational treatment associated with this study has been approved for sale to the public.   More info ...

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 330 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : June 29, 2017
Actual Primary Completion Date : May 8, 2020
Actual Study Completion Date : December 15, 2022

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Ruxolitinib
Ruxolitinib for the treatment period and extension period.
 Drug: Ruxolitinib
Ruxolitinib twice daily at the protocol-defined starting dose.
Other Name: Jakafi, INCB018424
Active Comparator: Best Available Therapy
Best available therapy for the treatment period and extension period, with optional crossover to ruxolitinib after Cycle 6.
 Drug: Extracorporeal photopheresis (ECP)
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).

Drug: Low-dose methotrexate (MTX)
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.

Drug: Mycophenolate mofetil (MMF)
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.

Drug: mechanistic Target of Rapamycin (mTOR) inhibitors (everolimus or sirolimus)
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.

Drug: Infliximab
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.

Drug: Rituximab
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.

Drug: Pentostatin
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.

Drug: Imatinib
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.

Drug: Ibrutinib
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.


Outcome Measures
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Primary Outcome Measures :
  1. Efficacy of Ruxolitinib Versus Investigator's Choice Best Available Therapy (BAT) in Participants With Moderate or Severe SR-cGvHD Assessed by Overall Response Rate (ORR) at the Cycle 7 Day 1 Visit [ Time Frame: Cycle 7 Day 1 ]
    ORR defined as the percentage of participants in each arm demonstrating a complete response (CR) or partial response (PR) based on Chronic GvHD Disease assessments (NIH Consensus Criteria, Lee 2015) without the requirement of additional systemic therapies for an earlier progression, mixed response or non-response. Scoring of response will be relative to the organ score at the time of randomization.


Secondary Outcome Measures :
  1. Rate of Participants With Clinically Relevant Improvement of the Modified Lee cGvHD Symptom Scale Score [ Time Frame: Cycle 7 Day 1 ]
    To assess improvement of symptoms based on the total symptom score (TSS); a responder is defined as having achieved a clinically relevant reduction from baseline of the TSS. Scale that consists of 30 items in 7 subscales (skin, eye, mouth, lung, nutrition, energy and psychological). Patients report 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.

  2. Rate of Failure-free Survival (FFS) [ Time Frame: Baseline to last patient reached Cycle 7 Day 1 ]
    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 chronic GvHD (cGvHD).

  3. Best Overall Response (BOR) [ Time Frame: up to Cycle 7 Day 1 ]
    Defined as percentage of participants who achieved an overall response (CR+PR) based on based on Chronic GvHD Disease assessments (NIH Consensus Criteria, Lee 2015) at any time point (up to Cycle 7 Day 1 or the start of additional systemic therapy for cGvHD.

  4. ORR at End of Cycle 3 [ Time Frame: Cycle 4 Day 1 ]
    ORR defined as the percentage of participants in each arm demonstrating a complete response (CR) or partial response (PR) based on Chronic GvHD Disease assessments (NIH Consensus Criteria, Lee 2015) without the requirement of additional systemic therapies for an earlier progression, mixed response or non-response. Scoring of response will be relative to the organ score at the time of randomization.

  5. Duration of Response [ Time Frame: First response to the last patient reached C7D1 ]
    Assessed for responders only; response based on Chronic GvHD Disease assessments (NIH consensus criteria Lee 2015).

  6. Overall Survival (OS) [ Time Frame: From the date of randomization to the date of death due to any cause up to approximately 36 months. ]
    Defined as the time from the date of randomization to the date of death due to any cause.

  7. Cumulative Incidence of Non-relapse Mortality (NRM) [ Time Frame: Months 3, 6, 12, 18, and 24 ]
    Defined as the cumulative incidence rate from competing risk analysis for NRM from date of randomization to date of death not preceded by underlying disease relapse/recurrence.

  8. Percentage of Participants With ≥ 50% Reduction in Daily Corticosteroid Dose at Cycle 7 Day 1 [ Time Frame: Cycle 7 Day 1 ]
    All corticosteroid dosages prescribed to the patient and all dose changes during the study will be recorded for assessment of participants with ≥ 50% reduction in daily corticosteroid dose.

  9. Percentage of Participants Successfully Tapered Off All Corticosteroids at Cycle 7 Day 1 [ Time Frame: Cycle 7 Day 1 ]
    All corticosteroid dosages prescribed to the patient and all dose changes during the study will be recorded for assessment of participants who successfully tapered off all corticosteroids.

  10. Cumulative Incidence of Malignancy Relapse/Recurrence (MR) [ Time Frame: At 3, 6, 12, 18, and 24 months ]
    Defined as the cumulative incidence rate from competing risk analysis of MR from date of randomization to hematologic malignancy relapse/recurrence. Calculated for participants with underlying hematologic malignant disease.

  11. Changes in Functional Assessment of Cancer Therapy - Bone Marrow Transplantation (FACT-BMT) [ Time Frame: Up to Cycle 24 Day 1 ]
    The mean change from baseline of the FACT-BMT questionnaire. FACTBMT 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 patients. The questions were based on 5-point Likert scale, where 0 corresponds to 'not at all' and 4 correspond to 'very much'. The higher the final score, the better the quality of life. The FACT-BMT total score range from 0 to 148.

  12. Changes in EQ-5D-5L [ Time Frame: Up to Cycle 24 Day 1 ]

    The EQ-5D-5L: a descriptive classification consisting of five dimensions of health:

    mobility, self-care, usual activities, anxiety/depression, and pain/discomfort (Brooks 1996). 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.


  13. Incidence and Severity of Adverse Events [ Time Frame: From baseline to 30-35 days after end of treatment, up to approximately 36 months ]
    Adverse events include occurrence of any second primary malignancies, infections, physical exam findings, changes in vital signs, routine serum chemistry, hematology results, and coagulation profile.

  14. Pharmacokinetics Parameter : Cmax of Ruxolitinib [ Time Frame: Cycle 1 Day 1 and Day 15 ]
    Maximum Observed Plasma Concentration of ruxolitinib

  15. Pharmacokinetics Parameter : AUC Last of Ruxolitinib [ Time Frame: Cycle 1 Day 1 and Day 15 ]
    Area Under the concentration- time curve up to the last measurable concentration of ruxolitinib

  16. Pharmacokinetics Parameter : AUCinf of Ruxolitinib [ Time Frame: Cycle 1 Day 1 and Day 15 ]
    Area Under the Concentration-time Curve From 0 to Infinity of ruxolitinib

  17. Pharmacokinetics Parameter : CL/F of Ruxolitinib [ Time Frame: Cycle 1 Day 1 and Day 15 ]
    Oral dose clearance of ruxolitinib

  18. Pharmacokinetics Parameter : Vz/F of Ruxolitinib [ Time Frame: Cycle 1 Day 1 and Day 15 ]
    Apparent oral dose volume of distribution of ruxolitinib

  19. Pharmacokinetics Parameter : Tmax of Ruxolitinib [ Time Frame: Cycle 1 Day 1 and Day 15 ]
    Time to reach maximum plasma concentration of ruxolitinib

  20. Pharmacokinetics Parameter : T1/2 of Ruxolitinib [ Time Frame: Cycle 1 Day 1 and Day 15 ]
    Apparent terminal phase disposition half-life of ruxolitinib

  21. Utilization of Medical Resources [ Time Frame: Baseline to last patient reached Cycle 7 Day 1 ]
    Percentage of subjects with at least one submission to healthcare encounter.


Eligibility Criteria
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Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 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
Contacts and Locations
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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 ClinicalTrials.gov identifier (NCT number): NCT03112603


Locations
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Sponsors and Collaborators
Incyte Corporation
Investigators
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Study Director: Rodica Morariu-Zamfir Incyte Corporation
  Study Documents (Full-Text)

Documents provided by Incyte Corporation:
Study Protocol  [PDF] October 7, 2021
Statistical Analysis Plan  [PDF] July 6, 2020

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

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Responsible Party: Incyte Corporation
ClinicalTrials.gov Identifier: NCT03112603    
Other Study ID Numbers: INCB 18424-365 (REACH3)
CINC424D2301 ( Other Identifier: Novartis Pharmaceuticals )
First Posted: April 13, 2017    Key Record Dates
Results First Posted: April 15, 2022
Last Update Posted: February 8, 2023
Last Verified: January 2023
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
Keywords provided by Incyte Corporation:
Graft-versus-host disease (GvHD)
Chronic GvHD (cGvHD)
steroid-refractory
ruxolitinib
Janus kinase inhibitor
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases
Mycophenolic Acid
Sirolimus
Infliximab
Rituximab
Methotrexate
Everolimus
Imatinib Mesylate
Pentostatin
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
 Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Nucleic Acid Synthesis Inhibitors
MTOR Inhibitors
Protein Kinase Inhibitors
Antibiotics, Antineoplastic
Antibiotics, Antitubercular