Clinical trial NCT02913261: Safety and Efficacy of Ruxolitinib Versus Best Available Therapy in Patients With Corticosteroid-refractory Acute Graft vs. Host Disease After Allogeneic Stem Cell Transplantation
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Corticosteroid Refractory Acute Graft vs Host Disease
Keywords: 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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-09-23
Enrollment: 310
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Overall Response Rate (ORR) at Day 28
timeFrame: Day 28
Secondary outcomes:
measure: Durable Overall Response Rate (DORR) (Key Secondary Endpoint) at Day 56
timeFrame: Day 56
measure: Overall Response Rate (ORR) at Day 14
timeFrame: Day 14
measure: Duration of Response (DOR)
timeFrame: Up to 24 months
measure: Cumulative Steroid Dosing Until Day 56
timeFrame: up to Day 56
measure: Kaplan Meier Estimates of Probability of Overall Survival (OS) by Time Interval
timeFrame: 1, 2, 6, 12, 18 & 24 months
measure: Kaplan Meier Estimates of Probability of Event-free Survival (EFS) by Time Interval
timeFrame: 1, 2, 6, 12, 18 & 24 months
measure: Cumulative Incidence Rate of Failure-Free Survival (FFS)
timeFrame: 1, 2, 6, 12, 18, & 24 Months
measure: Cumulative Probability of Non Relapse Mortality (NRM)
timeFrame: 1, 2, 6, 12, 18 & 24 months
measure: Cumulative Probability of Malignancy Relapse/Progression (MR)
timeFrame: 1, 2, 6, 12 , 18 & 24 months
measure: Cumulative Probability of Chronic Graft Versus Host Disease (cGvHD)
timeFrame: 1, 2, 6, 12, 18 & 24 months
measure: Exposure-efficacy Relationship of Ruxolitinib in Corticosteroid Refractory aGvHD: PK-Overall Response Rate
timeFrame: Day 28
measure: Exposure-efficacy Relationship of Ruxolitinib in Corticosteroid Refractory aGvHD: PK- Durable Overall Response Rate (DORR)
timeFrame: Day 56
measure: Exposure-efficacy Relationship of Ruxolitinib in Corticosteroid Refractory aGvHD: PK-Overall Survival
timeFrame: up to 24 months
measure: Best Overall Response Rate (BOR)
timeFrame: up to Day 28
measure: Patient Reported Outcomes (PROs): Change From Baseline in Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) Total Score
timeFrame: Baseline, Week 24
measure: Patient Reported Outcomes (PROs): Change From Baseline in EuroQol-5D-5L UK Score
timeFrame: Baseline, Week 24
measure: Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC) (AUCinf, AUClast, AUCtau) of Ruxolitinib
timeFrame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose
measure: Pharmacokinetic (PK) Parameter: Plasma Concentration at Peak (Cmax) of Ruxolitinib
timeFrame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose
measure: Pharmacokinetic (PK) Parameter: CL/F of Ruxolitinib
timeFrame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose
measure: Pharmacokinetic (PK) Parameter: VzF of Ruxolitinib
timeFrame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose
measure: Pharmacokinetic (PK) Parameter: Lambda_z of Ruxolitinib
timeFrame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose
measure: Pharmacokinetic (PK) Parameter: T1/2 of Ruxolitinib
timeFrame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose
measure: Pharmacokinetic (PK) Parameter: Tmax of Ruxolitinib
timeFrame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose
measure: Pharmacokinetic (PK) Parameter: Racc of Ruxolitinib
timeFrame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose
measure: Pharmacokinetic (PK) Parameter: Ctrough of Ruxolitinib
timeFrame: pre-dose
Other outcomes:
Locations:
city: Westmead
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Herston
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Parkville
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Murdoch
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Graz
country: Austria
facility: Novartis Investigative Site
city: Linz
country: Austria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
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city: Calgary
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Hamilton
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Ottawa
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Saskatoon
country: Canada
facility: Novartis Investigative Site
state: Saskatchewan
city: Praha 2
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Copenhagen
country: Denmark
facility: Novartis Investigative Site
city: Saint Priest en Jarez
country: France
facility: Novartis Investigative Site
state: Loire
city: Angers Cedex 1
country: France
facility: Novartis Investigative Site
city: Besancon cedex
country: France
facility: Novartis Investigative Site
city: Grenoble
country: France
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Limoges cedex
country: France
facility: Novartis Investigative Site
city: Nice Cedex
country: France
facility: Novartis Investigative Site
city: Paris Cedex 10
country: France
facility: Novartis Investigative Site
city: Paris Cedex
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Pessac
country: France
facility: Novartis Investigative Site
city: Pierre Benite Cedex
country: France
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Vandoeuvre les Nancy cedex
country: France
facility: Novartis Investigative Site
city: Mannheim
country: Germany
facility: Novartis Investigative Site
state: Baden-Wuerttemberg
city: Augsburg
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Duesseldorf
country: Germany
facility: Novartis Investigative Site
city: Essen
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city: Freiburg
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city: Hamburg
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city: Hannover
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city: Jena
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city: Leipzig
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city: Mainz
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city: Muenster
country: Germany
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city: Tübingen
country: Germany
facility: Novartis Investigative Site
city: Ulm
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city: Thessaloniki
country: Greece
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state: GR
city: Hong Kong
country: Hong Kong
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city: Haifa
country: Israel
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city: Jerusalem
country: Israel
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city: Petach Tikva
country: Israel
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city: Tel Aviv
country: Israel
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city: Ancona
country: Italy
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state: AN
city: Bergamo
country: Italy
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city: Bologna
country: Italy
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state: BO
city: Brescia
country: Italy
facility: Novartis Investigative Site
state: BS
city: San Giovanni Rotondo
country: Italy
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state: FG
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Genova
country: Italy
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state: GE
city: Milano
country: Italy
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state: MI
city: Roma
country: Italy
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state: RM
city: Torino
country: Italy
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state: TO
city: Udine
country: Italy
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state: UD
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Fukuoka city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Sapporo city
country: Japan
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state: Hokkaido
city: Kobe-city
country: Japan
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state: Hyogo
city: Nishinomiya
country: Japan
facility: Novartis Investigative Site
state: Hyogo
city: Isehara
country: Japan
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state: Kanagawa
city: Sendai city
country: Japan
facility: Novartis Investigative Site
state: Miyagi
city: Okayama-city
country: Japan
facility: Novartis Investigative Site
state: Okayama
city: Suita city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Bunkyo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Chuo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Minato ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Shinjuku-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Utrecht
country: Netherlands
facility: Novartis Investigative Site
state: The Netherlands
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Riyadh
country: Saudi Arabia
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Oviedo
country: Spain
facility: Novartis Investigative Site
state: Asturias
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Vigo
country: Spain
facility: Novartis Investigative Site
state: Pontevedra
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Malaga
country: Spain
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.