A Study of Ruxolitinib versus a Best Available Therapy in Patients With Steroid resistant Chronic Graft versus Host Disease After Bone Marrow Transplantation

• Register: CTRI
• Last refreshed on: 24 November 2021
• Main ID: CTRI/2017/09/009931
• Date of registration: 27-09-2017
• Prospective Registration: Yes
• Primary sponsor: Novartis Healthcare Pvt Ltd
• Public title: A Study of Ruxolitinib versus a Best Available Therapy in Patients With Steroid resistant Chronic Graft versus Host Disease After Bone Marrow Transplantation
• Scientific 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 allogenic stem cell transplantation
• Date of first enrolment: 15-11-2017
• Target sample size: 324
• Recruitment status: Closed to Recruitment of Participants
• URL: http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=19129
• Study type: Interventional
• Study design: Randomized, Parallel Group Trial; Method of generating randomization sequence:Computer generated randomization Method of allocation concealment:Not Applicable Blinding and masking:Open Label
• Phase: Phase 3

Countries of recruitment

Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Czech Republic, Denmark, Egypt, Finland, France, Germany, Greece, Hong Kong, Hungary, India, Israel, Italy, Japan, Jordan, Lebanon, Mexico, Netherlands, Norway, Peru, Poland, Portugal, Republic of Korea, Romania, Russian Federation, Saudi Arabia, Singapore, Spain, Sweden, Switzerland, Taiwan, Turkey, United Kingdom, United States of America

Contacts

• Name: Murugananthan K
• Affiliation: Novartis Healthcare Private Limited

• Name: Murugananthan K
• Affiliation: Novartis Healthcare Private Limited

Key inclusion & exclusion criteria

Inclusion criteria: 1. Written informed consent according to local guidelines, signed by the patients and or by

the parents or legal guardian prior to any study related screening procedures are performed.

2. Male or female patients more than or equal to 12 years old at the time of informed consent

3. Able to swallow tablets

4. Have undergone alloSCT from any donor source matched unrelated donor, sibling, haploidentical

using bone marrow, peripheral blood stem cells, or cord blood. Recipients of

non-myeloablative, myeloablative, and reduced intensity conditioning are eligible

5. Evident myeloid and platelet engraftment:

Absolute neutrophil count (ANC) more than 1000 per mm3 and platelet count more than 25,000 per mm3

6.Patients with clinically diagnosed cGvHD staging of moderate to severe according to NIH

Consensus Criteria prior to Cycle 1 Day 1ï?· 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

7.Patients currently receiving systemic or topical corticosteroids for the treatment of cGvHD

for a duration of less than 6 months prior to Cycle 1 Day 1, and have a confirmed diagnosis of

corticosteroid refractory cGvHD defined per 2014 NIH consensus criteria irrespective of the concomitant use of a calcineurin inhibitor, as follows

a. A lack of response or disease progression after administration of minimum prednisone

1 mg per kg per day for at least 1 week

OR

b. Disease persistence without improvement despite continued treatment with

prednisone at less than 0.5 mg per kg per day or 1 mg per kg per every other day for at least 4 weeks

OR

c. Increase to prednisolone dose to less than 0.25 mg per kg per day after two unsuccessful attempts to taper the dose

8.Patient has Eastern Cooperative Oncology Group performance status of 0-2

9.Patient must accept to be treated with only one of the following BAT options on Cycle 1

Day 1 extracorporeal photopheresis, low-dose methotrexate, mycophenolate mofetil, mTOR inhibitors everolimus or sirolimus, infliximab, rituximab, pentostatin, imatinib


Exclusion criteria: 1. Patients who have received systemic treatment for cGvHD in addition to corticosteroids ±

CNI for cGvHD

2. Patients with overlap syndrome defined as presence of simultaneous features of both

chronic and acute GvHD, or patients that transition from aGvHD to cGvHD without

tapering off corticosteroids ± CNI and any systemic treatment

3. Patients who were treated with prior JAK inhibitors for aGvHD; except when the patient

achieved complete or partial response and has been off JAK inhibitor treatment for at least

8 weeks prior to Cycle 1 Day 1

4. Failed prior alloSCT within the past 6 months from Cycle 1 Day 1

5. Patients with relapsed primary malignancy, or who have been treated for relapse after the

alloSCT was performed

6. SR-cGvHD occurring after a non-scheduled donor lymphocyte infusion (DLI)

administered for pre-emptive treatment of malignancy recurrence. Patients who have

received a scheduled DLI as part of their transplant procedure and not for management of

malignancy relapse are eligible

7. History of progressive multifocal leuko-encephalopathy (PML)

8. Active uncontrolled bacterial, fungal, parasitic, or viral infection. Infections are

considered controlled if appropriate therapy has been instituted and, at the time of

screening, no signs of infection 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

9. Known human immunodeficiency virus (HIV) infection

10. Active tuberculosis infection that developed after alloSCT

11. Evidence of active viral disease including CMV, EBV, HHV-6, HBV, HCV, or BK virus.

Patients with pre-transplant positive serology results must have negative viral load results for

HBV and HCV within 28 days prior to randomization. Patients with unknown viral testing

results prior to transplant must have viral load results confirming no evidence of active viral

disease within 28 days prior to randomization.

12. Patients on mechanical ventilation or have a resting O2 saturation less than 90 percent by pulse

oximetry

13. History or current diagnosis of cardiac disease indicating significant risk of safety for

patients participating in the study such as uncontrolled or significant cardiac disease,

including any of the following:

ï?· recent myocardial infarction (within last 6 months from randomization)

ï?· New York Heart Association Class III or IV congestive heart failure

ï?· unstable angina (within last 6 months prior to randomization)

ï?· clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular

tachycardia, and clinically significant second or third degree AV block without a

pacemaker)

ï?· uncontrolled hypertension

14. Any concurrent severe and/or uncontrolled medical conditions which, in the opinion of the

investigator, could compromise participation in the study, pose a significant risk to the

subject, or interfere with study results

15. Presence of severely impaired renal function defined by serum creatinine > 2 mg/dL ( >

17

Age minimum:
Age maximum:
Gender:

Health Condition(s) or Problem(s) studied

Health Condition 1: D619- Aplastic anemia, unspecified Health Condition 2: null- Steroid-refractory chronic graft-versus-host disease

Intervention(s)

Intervention1: Ruxolitinib: Ruxolitinib twice daily at the protocol defined starting dose
Control Intervention1: Best Available Therapy: Extracorporeal photopheresis (ECP); Low-dose methotrexate (MTX); Mycophenolate mofetil (MMF); mechanistic Target of Rapamycin (mTOR) inhibitors (everolimus or sirolimus); Infliximab; Rituximab; Pentostatin; Imatinib: 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 above treatments currently used in this setting (no other types or combinations of BATs are permitted in this study).

Primary Outcome(s)

Efficacy of ruxolitinib versus investigators choice best available therapy in participants with moderate or severe SR cGvHD assessed by overall response rate at the Cycle 7 Day 1 visitTimepoint: Cycle 7 Day 1 from baseline to Day 168

Secondary Outcome(s)

Change in the modified Lee cGvHD symptom scale scoreTimepoint: Cycle 7 Day 1

ORR at end of Cycle 3Timepoint: Cycle 4 Day 1

Percentage of participants successfully tapered off all corticosteroids at Cycle 7 Day 1Timepoint: Cycle 7 Day 1

Changes in EQ-5DTimepoint: From baseline to end of treatment, up to 36 months

Incidence and severity of adverse eventsTimepoint: From baseline to 30 to 35 days after end of treatment, up to approximately 36 months

Changes in Functional Assessment of Cancer therapy Bone Marrow TransplantationTimepoint: From baseline to end of treatment, up to 36 months

Cumulative incidence of non-relapse mortalityTimepoint: Months 1, 2, 6, 12, 18, and 24

Overall survivalTimepoint: From the date of randomization to the date of death due to any cause up to approximately 36 months

Duration of responseTimepoint: Time from first response until GvHD progression or death, up to approximately 36 months

Percentage of participants with â?¥ 50% reduction in daily corticosteroid dose at Cycle 7 Day 1Timepoint: Cycle 7 Day 1

Best overall responseTimepoint: From baseline to crossover or end of treatment up to 36 months

Rate of failure-free survivalTimepoint: From baseline to end of study treatment up to 36 months

Cumulative incidence of malignancy relapse/recurrenceTimepoint: At 3, 6, 12, 18, and 24 months

Secondary ID(s)

NCT03112603

CINC424D2301-Protocol version 00 dated 14-Mar-2017

Source(s) of Monetary Support

Novartis Pharma AG, Basel, Switzerland

Ethics review

Status: Approved
Approval date: 17/08/2017
Contact:

Institutuional Ethics Committee-Sahyadri Hospital

Status: Approved
Approval date: 06/11/2017
Contact:

Institutional Review Board-RGCI

Status: Approved
Approval date: 14/12/2017
Contact:

Institutional Review Board-CMC

Status: Approved
Approval date: 07/12/2018
Contact:

Institutional Ethics Committee, TATA Memorial Centre, Dr. Navin