Study of efficacy and safety of ruxolitinib vs. best available therapy (BAT) in patients with corticosteroid refractory chronic graft versus host disease after bone marrow transplantation

• Register: EUCTR
• Last refreshed on: 19 March 2018
• Main ID: EUCTR2016-004432-38-FR
• Date of registration: 27/07/2017
• Prospective Registration: No
• Primary sponsor: Novartis Pharma AG
• Public title: Study of efficacy and safety of ruxolitinib vs. best available therapy (BAT) in patients with corticosteroid refractory 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 versus host disease after allogenic stem cell transplantation - REACH 3
• Date of first enrolment: 24/07/2017
• Target sample size: 324
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-004432-38
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: yes; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: yes; Other specify the comparator: Best Available Therapy (BAT); Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Belgium, Bulgaria, Canada, China, Czech Republic, Denmark, France, Germany, Greece, Hungary, India, Israel, Italy, Japan, Jordan, Korea, Republic of, Netherlands, Norway, Portugal, Russian Federation, Saudi Arabia, Spain, Sweden, Switzerland, Turkey, United Kingdom, United States

Contacts

• Name: Information&Communication Medicales
• Affiliation: Novartis Pharma S.A.S.

• Name: Information&Communication Medicales
• Affiliation: Novartis Pharma S.A.S.

Key inclusion & exclusion criteria

Inclusion criteria:
? Male or female patients =12 years old at the time of signing the ICF
? Have undergone 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/mm3 and platelet count > 25,000/ mm3
? Patients with clinically diagnosed moderate to severe cGvHD according to NIH
Consensus Criteria (Jagasia 2015) 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
? Patients currently receiving systemic or topical corticosteroids for the treatment of
cGvHD for a duration of < 6 months prior to Cycle 1 Day 1 (if applicable), and have a
confirmed diagnosis of steroid refractory cGvHD defined per 2014 NIH consensus
criteria (Martin 2015) irrespective of the concomitant use of a calcineurin inhibitor, 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 two unsuccessful attempts
to taper the dose
? Patient 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
Are the trial subjects under 18? yes
Number of subjects for this age range: 30
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 132
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 162

Exclusion criteria:
? Patients who have received systemic treatment for cGvHD in addition to
corticosteroids ± CNI for cGvHD
? 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
? 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
? Failed prior alloSCT within the past 6 months from Cycle 1 Day 1
? Patients with relapsed primary malignancy, or who have been treated for relapse
after the alloSCT was performed
? 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
? 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


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

corticosteroid refractory chronic Graft vs Host Disease
MedDRA version: 20.1 Level: PT Classification code 10072158 Term: Chronic graft versus host disease in intestine System Organ Class: 10021428 - Immune system disorders
MedDRA version: 20.1 Level: PT Classification code 10072159 Term: Chronic graft versus host disease in skin System Organ Class: 10021428 - Immune system disorders
MedDRA version: 20.1 Level: PT Classification code 10066261 Term: Chronic graft versus host disease System Organ Class: 10021428 - Immune system disorders
MedDRA version: 20.1 Level: PT Classification code 10072160 Term: Chronic graft versus host disease in liver System Organ Class: 10021428 - Immune system disorders

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Trade Name: Jakavi
Product Name: ruxolitinib
Product Code: INC424
Pharmaceutical Form: Tablet
INN or Proposed INN: ruxolitinib
CAS Number: 1092939-17-7
Current Sponsor code: INC424
Other descriptive name: RUXOLITINIB PHOSPHATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Primary Outcome(s)

Secondary Objective: Key Secondary:
To compare the rate of failure free survival (FFS) and the change in the modified Lee cGvHD Symptom Scale score between treatment groups

Other secondary:
? Best overall response (BOR)
? Estimate ORR at the end of Cycle 3
? Duration of response
? Overall survival
? Non-relapse mortality (NRM)
? Proportion of patients with =50% reduction in the daily steroid dose at Cycle 7 Day 1
? Proportion of patients who successfully tapered off all steroids at Cycle 7 Day 1
? Cumulative incidence of Malignancy Relapse/Recurrence (MR)
? Change in FACT-BMT and EQ-5D
? To assess pharmacokinetics of ruxolitinib
? Safety and tolerability of ruxolitinib and BAT
? Medical resource utilization

Timepoint(s) of evaluation of this end point: Cycle 7 Day 1

Main Objective: To compare the efficacy of ruxolitinib versus Investigator’s choice Best Available Therapy (BAT) in patients with moderate or severe SR-cGvHD assessed by Overall Response Rate (ORR) at the Cycle 7 Day 1 visit.

Primary end point(s): overall response rate (ORR) on Cycle 7 Day 1 after
randomization, defined as the proportion of patients in
each arm demonstrating a complete response (CR) or
partial response (PR) 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 randomization.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: for all:
Cycle 7 Day 1

Secondary end point(s): Key secondary:
Composite time to event endpoint incorporating the following FFS events:
i) relapse or recurrence of underlying disease or death due to underlying disease,
ii) non-relapse mortality, or
iii) addition or initiation of another systemic therapy for cGvHD

Rate of patients with clinically relevant improvement of
the modified Lee symptoms score at Cycle 7 Day 1.

FFS will be used as the first key secondary endpoint for all regions except the US (ROW). The modified Lee symptom score will be used as the first key secondary
endpoint for the US

Other secondary:
- Proportion of patients who achieved OR (CR+PR) at any time point (up Cycle 7 day 1 or the start of additional systemic therapy for cGvHD)
- To estimate ORR at end of Cycle 3 Proportion of patients who achieved OR (CR+PR) at Cycle 4 Day 1.
- Duration of Response Duration of response (DOR) is assessed for responders only
- Overall survival, defined as the time from the date of randomization to the date of death due to any cause
- Non-relapse mortality (NRM), defined as the time from date of randomization to date of death not preceded by underlying disease relapse/recurrence
- Malignancy Relapse/Recurrence (MR) is defined as the time from date of randomization to hematologic malignancy relapse/recurrence
- Change in FACT-BMT from baseline to each visit where measured.
- Change in EQ-5D from baseline to each visit where measured
- Pharmacokinetic parameters of ruxolitinib after a single dose and at steady state. Cmax, AUClast, and AUCinf. Other PK parameters are CL/F, Vz/F, Tmax and T1/2
- Safety and tolerability including myelosuppression, infections, and bleeding will be assessed by monitoring the frequency, duration, and severity of Adverse Events including occurrence of any second primary malignancies, infections, by performing physical exams, and evaluating changes in vital signs from baseline, routine serum chemistry, hematology results and coagulation profile
- Resources including duration and frequency of hospitalization, emergency room visits, additional outpatient office visits to general practitioner, specialist, and urgent care visits

Secondary ID(s)

2016-004432-38-DE

CINC424D2301

Source(s) of Monetary Support

Novartis Pharma AG