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REACH2: Safety and Efficacy of Ruxolitinib Versus Best Available Therapy in Patients With Corticosteroid-refractory Acute Graft vs. Host Disease After Allogeneic Stem Cell Transplantation

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT02913261
Collaborator
(none)
310
Enrollment
103
Locations
2
Arms
49.4
Actual Duration (Months)
3
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To evaluate the safety and efficacy of ruxolitinib compared to Best Available Therapy in patients with corticosteroid-refractory acute graft vs. host disease after allogeneic stem cell transplantation

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
310 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 Versus Best Available Therapy in Patients With Corticosteroid-refractory Acute Graft vs. Host Disease After Allogeneic Stem Cell Transplantation
Actual Study Start Date :
Mar 10, 2017
Actual Primary Completion Date :
Jun 24, 2019
Actual Study Completion Date :
Apr 23, 2021

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Ruxolitinib

Ruxolitinib 10 mg Bis In Diem (BID)

Drug: Ruxolitinib
Tablet for oral use
Other Names:
  • INC424

    		•
    Active Comparator: Best Available Therapy (BAT)

    As selected by the investigator

    Drug: Best Available Therapy (BAT)
    Best Available Therapy

    Outcome Measures

    Primary Outcome Measures

    1. Overall Response Rate (ORR) [28 Days]

      ORR is defined as the proportion of patients with a best overall response defined as complete response or partial response

    Secondary Outcome Measures

    1. Durable Overall Response Rate [Day 56]

      Proportion of all patients in each arm who achieve a complete response (CR) or partial response (PR) at Day 28 (primary endpoint) AND maintain a CR or PR at Day 56.

    2. ORR [Day 14]

      Proportion of patients who achieved OR (CR+PR) at Day 14

    3. Duration of response (DOR) [Up to 24 months]

      DOR is the time from first response until acute Graft versus Host Disease (aGvHD) progression or the date of additional systemic therapies for aGvHD.

    4. Cumulative steroid dose [56 Days]

      Weekly cumulative steroid dose for each subject up to Day 56 or end of treatment

    5. Overall Survival (OS) [Up to 24 months]

      OS is defined as the time from the date of randomization to the date of death due to any cause.

    6. Event-free survival [Up to 24 months]

      Event-free survival, defined as the time from the date of randomization to the date of hematologic disease relapse/progression, graft failure, or death due to any cause.

    7. Failure-Free survival (FFS) [Up to 24 months]

      FFS is defined as the time from the date of randomization to date of hematologic disease relapse/progression, non-relapse mortality, or addition of new systemic aGvHD treatment.

    8. Non Relapse Mortality (NRM) [Up to 24 months]

      NRM is defined as the time from date of randomization to date of death not preceded by hematologic disease relapse/progression

    9. Malignancy Relapse/Progression (MR) [Up to 24 months]

      MR is defined as the time from date of randomization to hematologic malignancy relapse/progression. Calculated for patients with underlying hematologic malignant disease.

    10. Incidence of chronic Graft versus Host Disease (cGvHD) [Up to 24 months]

      cGvHD, defined as the diagnosis of any cGvHD including mild, moderate, severe

    11. Pharmacokinetic (PK) parameter: Plasma concentration at peak (CMax) after single dose and at steady state of ruxolitinib in corticosteroid refractory acute GvHD patients [168 Days]

      plasma concentration at peak (Cmax)Ruxolitinib after a single dose and at steady state

    12. Exposure-efficacy relationship of ruxolitinib in corticosteroid refractory aGvHD [168 Days]

      exposure-efficacy relationship of ruxolitinib in terms of concentration-effect and dose-effect (effect: overall response rate at Day 28 and durable response at Day 56; Overall survival at 6 months)

    13. Patient Reported Outcomes (PROs): Functional Assesment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) [Baseline, Up to 30 day follow-up visit]

      Change in Functional Assesment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) from baseline

    14. Patient Reported Outcomes (PROs): EuroQol-5D-5L change [Baseline, Up to 30 day follow-up visit]

      Change in EuroQol-5D-5D from baseline

    15. Pharmacokinetic (PK) parameter: Area Under the Curve (AUC) after single dose and at steady state of ruxolitinib in corticosteroid refractory acute GvHD patients [168 Days]

      AUC from time zero to the last measurable concentration sampling time and from time zero to infinity, and Accumulation ratio (Racc). Ruxolitinib after a single dose and at steady state. AUC at end of a dosing interval (AUC tau) at steady state.

    16. Pharmacokinetic (PK) parameter: total body clearance of ruxolitinib from the plasma after single dose and at steady state of ruxolitinib in corticosteroid refractory acute GvHD patients [168 Days]

      total body clearance of ruxolitinib from the plasma after a single dose and at steady state

    17. Pharmacokinetic (PK) parameter: apparent volume of distribution during terminal phase after single dose and at steady state of ruxolitinib in corticosteroid refractory acute GvHD patients [168 Days]

      apparent volume of distribution during terminal phase after a single dose and at steady state

    18. Best Overall Response (BOR) [up to day 28]

      Proportion of patients who achieved OR (CR+PR) at any time point up to and including Day 28 and before the start of additional systemic therapy for aGvHD.

    19. Pharmacokinetic (PK) parameter: Ctough [168 Days]

      Minimum concentration (Ctough) of ruxolitininb after a single dose and at steady state in corticosteroid refractory acute GVHD patients

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    12 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Have undergone Allogeneic Stem Cell Transplanttaion (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

    • Clinically diagnosed Grades II to IV acute GvHD as per standard criteria occurring after alloSCT requiring systemic immune suppressive therapy. Biopsy of involved organs with aGvHD is encouraged but not required for study screening.

    • Confirmed diagnosis of steroid refractory aGvHD defined as patients administered high-dose systemic corticosteroids (methylprednisolone 2 mg/kg/day [or equivalent prednisone dose 2.5 mg/kg/day]), given alone or combined with calcineurin inhibitors (CNI) and either:

    • Progressing based on organ assessment after at least 3 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD, OR

    • Failure to achieve at a minimum partial response based on organ assessment after 7 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD,OR

    • Patients who fail corticosteroid taper defined as fulfilling either one of the following criteria:

    • Requirement for an increase in the corticosteroid dose to methylprednisolone ≥2 mg/kg/day (or equivalent prednisone dose ≥2.5 mg/kg/day) , OR

    • Failure to taper the methylprednisolone dose to <0.5 mg/kg/day (or equivalent prednisone dose <0.6 mg/kg/day) for a minimum 7 days.

    Exclusion Criteria:

    • Has received more than one systemic treatment for steroid refractory aGvHD.

    • Presence of an active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.

    • Evidence of uncontrolled viral infection including Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Human Herpes Virus-6 (HHV-6), Hepatitis Virus (HBV), or Hepatitis C Virus (HCV) based on assessment by the treating physician.

    • Presence of relapsed primary malignancy, or who have been treated for relapse after the alloHSCT was performed, or who may require rapid immune suppression withdrawal as pre-emergent treatment of early malignancy relapse.

    Other protocol-defined inclusion/exclusion criteria may apply.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Novartis Investigative Site Westmead New South Wales Australia 2145
    2 Novartis Investigative Site Herston Queensland Australia 4029
    3 Novartis Investigative Site Parkville Victoria Australia 3002
    4 Novartis Investigative Site Murdoch Western Australia Australia 6150
    5 Novartis Investigative Site Graz Austria 8036
    6 Novartis Investigative Site Linz Austria A-4010
    7 Novartis Investigative Site Sofia Bulgaria 1756
    8 Novartis Investigative Site Calgary Alberta Canada T2N 4N2
    9 Novartis Investigative Site Vancouver British Columbia Canada V5Z 1M9
    10 Novartis Investigative Site Hamilton Ontario Canada L8V 5C2
    11 Novartis Investigative Site Ottawa Ontario Canada K1H 8L6
    12 Novartis Investigative Site Toronto Ontario Canada M5G 2M9
    13 Novartis Investigative Site Montreal Quebec Canada H1T 2M4
    14 Novartis Investigative Site Montreal Quebec Canada H4A 3J1
    15 Novartis Investigative Site Saskatoon Saskatchewan Canada S7N 4H4
    16 Novartis Investigative Site Praha 2 Czech Republic Czechia 128 20
    17 Novartis Investigative Site Copenhagen Denmark DK-2100
    18 Novartis Investigative Site Saint Priest en Jarez Loire France 42270
    19 Novartis Investigative Site Angers Cedex 1 France 49033
    20 Novartis Investigative Site Besancon cedex France 25030
    21 Novartis Investigative Site Grenoble France 38043
    22 Novartis Investigative Site Lille France 59000
    23 Novartis Investigative Site Lille France 59037
    24 Novartis Investigative Site Limoges cedex France 87042
    25 Novartis Investigative Site Nice cedex 3 France 06202
    26 Novartis Investigative Site Paris Cedex 10 France 75475
    27 Novartis Investigative Site Paris Cedex France 75019
    28 Novartis Investigative Site Paris France 75012
    29 Novartis Investigative Site Paris France 75013
    30 Novartis Investigative Site Pessac France 33604
    31 Novartis Investigative Site Pierre Benite Cedex France 69495
    32 Novartis Investigative Site Toulouse France 31059
    33 Novartis Investigative Site Vandoeuvre les Nancy cedex France 54511
    34 Novartis Investigative Site Mannheim Baden-Wuerttemberg Germany 68305
    35 Novartis Investigative Site Augsburg Germany 86179
    36 Novartis Investigative Site Berlin Germany 13125
    37 Novartis Investigative Site Berlin Germany 13353
    38 Novartis Investigative Site Dresden Germany 01307
    39 Novartis Investigative Site Duesseldorf Germany 40225
    40 Novartis Investigative Site Essen Germany 45147
    41 Novartis Investigative Site Freiburg Germany 79106
    42 Novartis Investigative Site Hamburg Germany 20246
    43 Novartis Investigative Site Hannover Germany 30625
    44 Novartis Investigative Site Jena Germany 07740
    45 Novartis Investigative Site Leipzig Germany 04103
    46 Novartis Investigative Site Mainz Germany 55131
    47 Novartis Investigative Site Muenster Germany 48149
    48 Novartis Investigative Site Tübingen Germany 72076
    49 Novartis Investigative Site Ulm Germany 89081
    50 Novartis Investigative Site Thessaloniki GR Greece 570 10
    51 Novartis Investigative Site Hong Kong Hong Kong
    52 Novartis Investigative Site Haifa Israel 3109601
    53 Novartis Investigative Site Jerusalem Israel 9112001
    54 Novartis Investigative Site Petach Tikva Israel 4910002
    55 Novartis Investigative Site Tel Aviv Israel 6423906
    56 Novartis Investigative Site Ancona AN Italy 60126
    57 Novartis Investigative Site Bergamo BG Italy 24127
    58 Novartis Investigative Site Bologna BO Italy 40138
    59 Novartis Investigative Site Brescia BS Italy 25123
    60 Novartis Investigative Site San Giovanni Rotondo FG Italy 71013
    61 Novartis Investigative Site Firenze FI Italy 50134
    62 Novartis Investigative Site Genova GE Italy 16147
    63 Novartis Investigative Site Milano MI Italy 20162
    64 Novartis Investigative Site Roma RM Italy 00168
    65 Novartis Investigative Site Torino TO Italy 10126
    66 Novartis Investigative Site Udine UD Italy 33100
    67 Novartis Investigative Site Nagoya Aichi Japan 453-8511
    68 Novartis Investigative Site Fukuoka city Fukuoka Japan 812-8582
    69 Novartis Investigative Site Sapporo city Hokkaido Japan 060 8648
    70 Novartis Investigative Site Kobe-city Hyogo Japan 650-0047
    71 Novartis Investigative Site Nishinomiya Hyogo Japan 663 8501
    72 Novartis Investigative Site Isehara Kanagawa Japan 259-1193
    73 Novartis Investigative Site Sendai city Miyagi Japan 980 8574
    74 Novartis Investigative Site Okayama-city Okayama Japan 700-8558
    75 Novartis Investigative Site Suita city Osaka Japan 565 0871
    76 Novartis Investigative Site Bunkyo ku Tokyo Japan 113-8677
    77 Novartis Investigative Site Chuo ku Tokyo Japan 104 0045
    78 Novartis Investigative Site Minato ku Tokyo Japan 105-8470
    79 Novartis Investigative Site Shinjuku-ku Tokyo Japan 160 8582
    80 Novartis Investigative Site Osaka Japan 545-8586
    81 Novartis Investigative Site Seoul Korea, Republic of 03080
    82 Novartis Investigative Site Seoul Korea, Republic of 06351
    83 Novartis Investigative Site Utrecht The Netherlands Netherlands 3508 GA
    84 Novartis Investigative Site Oslo Norway 0372
    85 Novartis Investigative Site Moscow Russian Federation 125167
    86 Novartis Investigative Site Riyadh Saudi Arabia 11211
    87 Novartis Investigative Site Sevilla Andalucia Spain 41013
    88 Novartis Investigative Site Oviedo Asturias Spain 33006
    89 Novartis Investigative Site Barcelona Catalunya Spain 08035
    90 Novartis Investigative Site Barcelona Catalunya Spain 08036
    91 Novartis Investigative Site Vigo Pontevedra Spain 36212
    92 Novartis Investigative Site Madrid Spain 28009
    93 Novartis Investigative Site Madrid Spain 28034
    94 Novartis Investigative Site Malaga Spain 29009
    95 Novartis Investigative Site Valencia Spain 46026
    96 Novartis Investigative Site Taichung Taiwan 40447
    97 Novartis Investigative Site Ankara Turkey 06100
    98 Novartis Investigative Site Ankara Turkey 06500
    99 Novartis Investigative Site Istanbul Turkey 41400
    100 Novartis Investigative Site Izmir Turkey
    101 Novartis Investigative Site London United Kingdom SE5 9RS
    102 Novartis Investigative Site London United Kingdom WC1E 6HX
    103 Novartis Investigative Site Manchester United Kingdom M13 9WL

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT02913261
    Other Study ID Numbers:
    • CINC424C2301
    First Posted:
    Sep 23, 2016
    Last Update Posted:
    Sep 2, 2021
    Last Verified:
    Sep 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Novartis Pharmaceuticals
    GvHD (Graft versus Host Disease)
    INC424
    ruxolitinib
    best available therapy (BAT)
    corticosteroid-refractory acute graft vs. host disease
    allogeneic stem cell transplantation
    steroid refractory acute graft vs. host disease
    Janus Kinase (JAK) inhibitor
    Additional relevant MeSH terms:
    Graft vs Host Disease

    Study Results

    No Results Posted as of Sep 2, 2021