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

NCT ID: NCT02913261

Last Updated: 2023-02-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 310 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-03-10
• Study Completion Date: 2021-04-23

Brief Summary

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

Detailed Description

This randomized, phase III, open-label study investigated the efficacy and safety of ruxolitinib vs. BAT added to the patient's immunosuppressive regimen in adults and adolescents (≥ 12 years old) with grade II-IV Steroid-refractory Acute Graft vs. Host Disease (SR-aGvHD). During the screening period, patients were monitored for a diagnosis of SR-aGvHD, which was defined as patients who had high-dose systemic corticosteroids (methylprednisolone 2 mg/kg/day [or equivalent prednisone dose 2.5 mg/kg/day]), given alone or combined with CNI, who either:

1. Progressed 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

2. Failed to achieve at a minimum a 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

3. Failed 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.

Patients meeting eligibility criteria were randomized 1:1 to receive either ruxolitinib or BAT stratifying on aGvHD grade at the time of randomization (Grade II vs III vs IV).

Study treatment began on Day 1 (no later than 72 hours after randomization) followed by regular visits for assessments of efficacy and safety. Study treatment was administered until the patient met any of the criteria for discontinuation of study treatment or, in responders (i.e. patients achieving PR or CR) until the dosing schedule for ruxolitinib or BAT was completed.

All responders were to be tapered off during the treatment period by, first tapering from corticosteroids, followed by CNI and ruxolitinib. A slow tapering extending beyond 24 weeks was permitted for ruxolitinib at Investigator's discretion rather than an abrupt cessation, as the latter could result in an aGvHD flare.

During the Treatment Period, patients randomized to BAT could have crossed over to ruxolitinib between Day 28 and Week 24 if they:

• Failed to meet the primary endpoint response definition (CR or PR) at Day 28 OR
• Lost the response thereafter and met criteria for progression, mixed response, or no response, necessitating new additional systemic immunosuppressive treatment for aGvHD.

AND

• Did not have signs/symptoms of chronic Graft vs. Host Disease (cGvHD) (overlap syndrome, progressive, or de novo cGvHD)

Patients who crossed over to ruxolitinib were followed until completion of treatment with ruxolitinib and received the same treatment and tapering schedule as patients randomized to ruxolitinib treatment.

The End of Treatment (EOT) visit occurred when the patient completed the study treatment period or earlier if the patient met any of the criteria for discontinuation of study treatment.

Patient's treatment period was up to 6 months (Week 24). However, ruxolitinib taper could be delayed up to 2 years from randomization due to an aGvHD flare or other safety concerns.

Conditions

Corticosteroid Refractory Acute Graft vs Host Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Ruxolitinib

These patients were administered Ruxolitinib orally twice per day (b.i.d) at a dose of 10 mg bid, as two 5-mg tablets. Ruxolitinib was taken without regards to food.

Group Type: EXPERIMENTAL

Ruxolitinib (RUX)

Intervention Type: DRUG

Ruxolitinib was provided as 5 mg tablets for oral use.

Best Available Therapy (BAT)

These patients were administered BAT per the Investigator's best judgement based on a specific list of BAT.

Group Type: ACTIVE_COMPARATOR

Best Available Therapy (BAT)

Intervention Type: DRUG

BAT was based on the investigator's best judgment, taking into account the manufacturer's instructions, labeling, patient's medical condition, and institutional guidelines for any dose adjustment. The BAT in this study was identified by the investigator prior to patient randomization among the following treatments currently used in this setting: anti-thymocyte globulin (ATG), extracorporeal photopheresis (ECP), mesenchymal stromal cells (MSC), low-dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), etanercept, or infliximab. No other types or combinations of BAT were permitted.

Interventions

Ruxolitinib (RUX)

Ruxolitinib was provided as 5 mg tablets for oral use.

Intervention Type: DRUG

Best Available Therapy (BAT)

BAT was based on the investigator's best judgment, taking into account the manufacturer's instructions, labeling, patient's medical condition, and institutional guidelines for any dose adjustment. The BAT in this study was identified by the investigator prior to patient randomization among the following treatments currently used in this setting: anti-thymocyte globulin (ATG), extracorporeal photopheresis (ECP), mesenchymal stromal cells (MSC), low-dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), etanercept, or infliximab. No other types or combinations of BAT were permitted.

Intervention Type: DRUG

Other Intervention Names

INC424

Eligibility Criteria

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.

• Minimum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Westmead, New South Wales, Australia

Novartis Investigative Site

Herston, Queensland, Australia

Novartis Investigative Site

Parkville, Victoria, Australia

Novartis Investigative Site

Murdoch, Western Australia, Australia

Novartis Investigative Site

Graz, , Austria

Novartis Investigative Site

Linz, , Austria

Novartis Investigative Site

Sofia, , Bulgaria

Novartis Investigative Site

Calgary, Alberta, Canada

Novartis Investigative Site

Vancouver, British Columbia, Canada

Novartis Investigative Site

Hamilton, Ontario, Canada

Novartis Investigative Site

Ottawa, Ontario, Canada

Novartis Investigative Site

Toronto, Ontario, Canada

Novartis Investigative Site

Montreal, Quebec, Canada

Novartis Investigative Site

Montreal, Quebec, Canada

Novartis Investigative Site

Saskatoon, Saskatchewan, Canada

Novartis Investigative Site

Prague, Czech Republic, Czechia

Novartis Investigative Site

Copenhagen, , Denmark

Novartis Investigative Site

Saint Priest En Jarez, Pays de la Loire Region, France

Novartis Investigative Site

Angers, , France

Novartis Investigative Site

Besançon, , France

Novartis Investigative Site

Grenoble, , France

Novartis Investigative Site

Lille, , France

Novartis Investigative Site

Lille, , France

Novartis Investigative Site

Limoges, , France

Novartis Investigative Site

Nice, , France

Novartis Investigative Site

Paris, , France

Novartis Investigative Site

Paris, , France

Novartis Investigative Site

Paris, , France

Novartis Investigative Site

Paris, , France

Novartis Investigative Site

Pessac, , France

Novartis Investigative Site

Pierre-Bénite, , France

Novartis Investigative Site

Toulouse, , France

Novartis Investigative Site

Vandœuvre-lès-Nancy, , France

Novartis Investigative Site

Mannheim, Baden-Wurttemberg, Germany

Novartis Investigative Site

Augsburg, , Germany

Novartis Investigative Site

Berlin, , Germany

Novartis Investigative Site

Berlin, , Germany

Novartis Investigative Site

Dresden, , Germany

Novartis Investigative Site

Düsseldorf, , Germany

Novartis Investigative Site

Essen, , Germany

Novartis Investigative Site

Freiburg im Breisgau, , Germany

Novartis Investigative Site

Hamburg, , Germany

Novartis Investigative Site

Hanover, , Germany

Novartis Investigative Site

Jena, , Germany

Novartis Investigative Site

Leipzig, , Germany

Novartis Investigative Site

Mainz, , Germany

Novartis Investigative Site

Münster, , Germany

Novartis Investigative Site

Tübingen, , Germany

Novartis Investigative Site

Ulm, , Germany

Novartis Investigative Site

Thessaloniki, GR, Greece

Novartis Investigative Site

Hong Kong, , Hong Kong

Novartis Investigative Site

Haifa, , Israel

Novartis Investigative Site

Jerusalem, , Israel

Novartis Investigative Site

Petah Tikva, , Israel

Novartis Investigative Site

Tel Aviv, , Israel

Novartis Investigative Site

Ancona, AN, Italy

Novartis Investigative Site

Bergamo, BG, Italy

Novartis Investigative Site

Bologna, BO, Italy

Novartis Investigative Site

Brescia, BS, Italy

Novartis Investigative Site

San Giovanni Rotondo, FG, Italy

Novartis Investigative Site

Florence, FI, Italy

Novartis Investigative Site

Genova, GE, Italy

Novartis Investigative Site

Milan, MI, Italy

Novartis Investigative Site

Roma, RM, Italy

Novartis Investigative Site

Torino, TO, Italy

Novartis Investigative Site

Udine, UD, Italy

Novartis Investigative Site

Nagoya, Aichi-ken, Japan

Novartis Investigative Site

Fukuoka, Fukuoka, Japan

Novartis Investigative Site

Sapporo, Hokkaido, Japan

Novartis Investigative Site

Kobe, Hyōgo, Japan

Novartis Investigative Site

Nishinomiya, Hyōgo, Japan

Novartis Investigative Site

Isehara, Kanagawa, Japan

Novartis Investigative Site

Sendai, Miyagi, Japan

Novartis Investigative Site

Okayama, Okayama-ken, Japan

Novartis Investigative Site

Suita, Osaka, Japan

Novartis Investigative Site

Bunkyo Ku, Tokyo, Japan

Novartis Investigative Site

Chuo Ku, Tokyo, Japan

Novartis Investigative Site

Minato Ku, Tokyo, Japan

Novartis Investigative Site

Shinjuku-ku, Tokyo, Japan

Novartis Investigative Site

Osaka, , Japan

Novartis Investigative Site

Utrecht, The Netherlands, Netherlands

Novartis Investigative Site

Oslo, , Norway

Novartis Investigative Site

Moscow, , Russia

Novartis Investigative Site

Riyadh, , Saudi Arabia

Novartis Investigative Site

Seoul, , South Korea

Novartis Investigative Site

Seoul, , South Korea

Novartis Investigative Site

Seville, Andalusia, Spain

Novartis Investigative Site

Barcelona, Catalonia, Spain

Novartis Investigative Site

Barcelona, Catalonia, Spain

Novartis Investigative Site

Vigo, Pontevedra, Spain

Novartis Investigative Site

Oviedo, Principality of Asturias, Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Málaga, , Spain

Novartis Investigative Site

Valencia, , Spain

Novartis Investigative Site

Taichung, , Taiwan

Novartis Investigative Site

Ankara, , Turkey (Türkiye)

Novartis Investigative Site

Ankara, , Turkey (Türkiye)

Novartis Investigative Site

Istanbul, , Turkey (Türkiye)

Novartis Investigative Site

Izmir, , Turkey (Türkiye)

Novartis Investigative Site

London, , United Kingdom

Novartis Investigative Site

London, , United Kingdom

Novartis Investigative Site

Manchester, , United Kingdom

Countries

Australia; Austria; Bulgaria; Canada; Czechia; Denmark; France; Germany; Greece; Hong Kong; Israel; Italy; Japan; Netherlands; Norway; Russia; Saudi Arabia; South Korea; Spain; Taiwan; Turkey (Türkiye); United Kingdom

References

Mahmoudjafari Z, Kintsch E, Xue Z, Bhatt V, Galvin J, Locatelli F, Zeiser R. Impact of concomitant azoles on ruxolitinib treatment in patients with GVHD: post hoc analyses of REACH2 and REACH3. Blood Adv. 2025 Aug 26;9(16):4206-4216. doi: 10.1182/bloodadvances.2025016212.

Reference Type: DERIVED

PMID: 40472328 (View on PubMed)

Socie G, Niederwieser D, von Bubnoff N, Mohty M, Szer J, Or R, Garrett J, Prahallad A, Wilke C, Zeiser R. Prognostic value of blood biomarkers in steroid-refractory or steroid-dependent acute graft-versus-host disease: a REACH2 analysis. Blood. 2023 Jun 1;141(22):2771-2779. doi: 10.1182/blood.2022018579.

Reference Type: DERIVED

PMID: 36827620 (View on PubMed)

Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, Szer J, Wagner EM, Zuckerman T, Mahuzier B, Xu J, Wilke C, Gandhi KK, Socie G; REACH2 Trial Group. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med. 2020 May 7;382(19):1800-1810. doi: 10.1056/NEJMoa1917635. Epub 2020 Apr 22.

Reference Type: DERIVED

PMID: 32320566 (View on PubMed)

Jagasia M, Zeiser R, Arbushites M, Delaite P, Gadbaw B, Bubnoff NV. Ruxolitinib for the treatment of patients with steroid-refractory GVHD: an introduction to the REACH trials. Immunotherapy. 2018 Apr;10(5):391-402. doi: 10.2217/imt-2017-0156. Epub 2018 Jan 10.

Reference Type: DERIVED

PMID: 29316837 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2016-002584-33

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CINC424C2301

Identifier Type: -

Identifier Source: org_study_id