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Trial record 1 of 1 for:    NCT03112603
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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)

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ClinicalTrials.gov Identifier: NCT03112603
Recruitment Status : Active, not recruiting
First Posted : April 13, 2017
Last Update Posted : May 7, 2021
Sponsor:
Information provided by (Responsible Party):
Incyte Corporation

Tracking Information
First Submitted Date  ICMJE April 4, 2017
First Posted Date  ICMJE April 13, 2017
Last Update Posted Date May 7, 2021
Actual Study Start Date  ICMJE March 7, 2018
Actual Primary Completion Date May 8, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 7, 2017)
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 (from baseline to Day 168) ]
ORR defined as the percentage of participants in each arm demonstrating a complete response (CR) or partial response (PR) based on NIH Consensus Criteria 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 4, 2021)
  • Rate of failure-free survival (FFS) [ Time Frame: From baseline to end of study treatment, up to 36 months ]
    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).
  • Change in the modified Lee cGvHD symptom scale score [ Time Frame: Cycle 7 Day 1 (from baseline to Day 168) ]
    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.
  • Best overall response (BOR) [ Time Frame: From baseline to crossover or end of treatment up to 36 months ]
    Defined as percentage of participants who achieved an overall response (CR+PR) based on NIH consensus criteria at any time point (up to Cycle 7 Day 1 or the start of additional systemic therapy for cGvHD).
  • ORR at end of Cycle 3 [ Time Frame: Cycle 4 Day 1 (from baseline to Day 84) ]
    Percentage of participants who achieved an overall response (CR+PR) based on NIH consensus criteria at Cycle 4 Day 1.
  • Duration of response [ Time Frame: Time from first response until GvHD progression or death, up to approximately 36 months ]
    Assessed for responders only; response based on NIH consensus criteria.
  • 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.
  • Cumulative incidence of non-relapse mortality (NRM) [ Time Frame: Months 1, 2, 6, 12, 18, and 24 ]
    Defined as date of randomization to date of death not preceded by underlying disease relapse/recurrence.
  • Percentage of participants with ≥ 50% reduction in daily corticosteroid dose at Cycle 7 Day 1 [ Time Frame: Cycle 7 Day 1 (from baseline to Day 168) ]
    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.
  • Percentage of participants successfully tapered off all corticosteroids at Cycle 7 Day 1 [ Time Frame: Cycle 7 Day 1 (from baseline to Day 168) ]
    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.
  • Cumulative incidence of malignancy relapse/recurrence (MR) [ Time Frame: At 3, 6, 12, 18, and 24 months ]
    Defined as the time from date of randomization to hematologic malignancy relapse/recurrence. Calculated for participants with underlying hematologic malignant disease.
  • Changes in Functional Assessment of Cancer therapy - Bone Marrow Transplantation (FACT-BMT) [ Time Frame: From baseline to end of treatment, up to 36 months ]
    FACT-BMT will be administered to measure symptoms and quality of life for patients affected by cGvHD, and potential changes over time.
  • Changes in EQ-5D [ Time Frame: From baseline to end of treatment, up to 36 months ]
    EQ-5D will be administered to measure symptoms and quality of life for patients affected by cGvHD, and potential changes over time.
  • 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.
  • Pharmacokinetics Parameter : Cmax of ruxolitinib [ Time Frame: Cycle 1 Day 1 and Day 15 ]
    Maximum Observed Plasma Concentration of ruxolitinib
  • 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
  • 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
  • Pharmacokinetics Parameter : CL/F of ruxolitinib [ Time Frame: Cycle 1 Day 1 and Day 15 ]
    Oral dose clearance of ruxolitinib
  • Pharmacokinetics Parameter : Vz/F of ruxolitinib [ Time Frame: Cycle 1 Day 1 and Day 15 ]
    Apparent oral dose volume of distribution of ruxolitinib
  • Pharmacokinetics Parameter : Tmax of ruxolitinib [ Time Frame: Cycle 1 Day 1 and Day 15 ]
    Time to reach maximum plasma concentration of ruxolitinib
  • Pharmacokinetics Parameter : T1/2 of ruxolitinib [ Time Frame: Cycle 1 Day 1 and Day 15 ]
    Apparent terminal phase disposition half-life of ruxolitinib
  • Utilization of Medical Resources [ Time Frame: 36 months ]
    Defined as frequency and duration of hospitalizations, emergency room visits, outpatient office visits, general practitioner, specialist, and urgent care visits.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 7, 2017)
  • Rate of failure-free survival (FFS) [ Time Frame: From baseline to end of study treatment, up to 36 months ]
    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).
  • Change in the modified Lee cGvHD symptom scale score [ Time Frame: Cycle 7 Day 1 (from baseline to Day 168) ]
    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.
  • Best overall response (BOR) [ Time Frame: From baseline to crossover or end of treatment up to 36 months ]
    Defined as percentage of participants who achieved an overall response (CR+PR) based on NIH consensus criteria at any time point (up to Cycle 7 Day 1 or the start of additional systemic therapy for cGvHD).
  • ORR at end of Cycle 3 [ Time Frame: Cycle 4 Day 1 (from baseline to Day 84) ]
    Percentage of participants who achieved an overall response (CR+PR) based on NIH consensus criteria at Cycle 4 Day 1.
  • Duration of response [ Time Frame: Time from first response until GvHD progression or death, up to approximately 36 months ]
    Assessed for responders only; response based on NIH consensus criteria.
  • 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.
  • Cumulative incidence of non-relapse mortality (NRM) [ Time Frame: Months 1, 2, 6, 12, 18, and 24 ]
    Defined as date of randomization to date of death not preceded by underlying disease relapse/recurrence.
  • Percentage of participants with ≥ 50% reduction in daily corticosteroid dose at Cycle 7 Day 1 [ Time Frame: Cycle 7 Day 1 (from baseline to Day 168) ]
    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.
  • Percentage of participants successfully tapered off all corticosteroids at Cycle 7 Day 1 [ Time Frame: Cycle 7 Day 1 (from baseline to Day 168) ]
    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.
  • Cumulative incidence of malignancy relapse/recurrence (MR) [ Time Frame: At 3, 6, 12, 18, and 24 months ]
    Defined as the time from date of randomization to hematologic malignancy relapse/recurrence. Calculated for participants with underlying hematologic malignant disease.
  • Changes in Functional Assessment of Cancer therapy - Bone Marrow Transplantation (FACT-BMT) [ Time Frame: From baseline to end of treatment, up to 36 months ]
    FACT-BMT will be administered to measure symptoms and quality of life for patients affected by cGvHD, and potential changes over time.
  • Changes in EQ-5D [ Time Frame: From baseline to end of treatment, up to 36 months ]
    EQ-5D will be administered to measure symptoms and quality of life for patients affected by cGvHD, and potential changes over time.
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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)
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).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Graft-versus-host Disease (GVHD)
Intervention  ICMJE
  • Drug: Ruxolitinib
    Ruxolitinib twice daily at the protocol-defined starting dose.
    Other Name: Jakafi, INCB018424
  • 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.
Study Arms  ICMJE
  • Experimental: Ruxolitinib
    Ruxolitinib for the treatment period and extension period.
    Intervention: Drug: Ruxolitinib
  • Active Comparator: Best Available Therapy
    Best available therapy for the treatment period and extension period, with optional crossover to ruxolitinib after Cycle 6.
    Interventions:
    • 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
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 4, 2021)
330
Original Estimated Enrollment  ICMJE
 (submitted: April 7, 2017)
324
Estimated Study Completion Date  ICMJE May 14, 2022
Actual Primary Completion Date May 8, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE 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,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03112603
Other Study ID Numbers  ICMJE INCB 18424-365 (REACH3)
CINC424D2301 ( Other Identifier: Novartis Pharmaceuticals )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Incyte Corporation
Study Sponsor  ICMJE Incyte Corporation
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Fitzroy Dawkins, MD Incyte Corporation
PRS Account Incyte Corporation
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP