E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
corticosteroid refractory chronic Graft vs Host Disease |
|
E.1.1.1 | Medical condition in easily understood language |
chronic Graft vs Host Disease |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10072158 |
E.1.2 | Term | Chronic graft versus host disease in intestine |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10072159 |
E.1.2 | Term | Chronic graft versus host disease in skin |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066261 |
E.1.2 | Term | Chronic graft versus host disease |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10072160 |
E.1.2 | Term | Chronic graft versus host disease in liver |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
|
E.2.2 | Secondary objectives of the trial |
Key Secondary:
To compare the rate of failure free survival (FFS) and the change in the modified Lee 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 |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 < 12 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 equivalent), 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 equivalent) OR
● Increase to prednisolone dose to >0.25 mg/kg/day after two unsuccessful attempts
to taper the dose (or equivalent)
● 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, ibrutinib |
|
E.4 | Principal exclusion criteria |
● Patients who have received two or more systemic treatments (BAT) for cGvHD in addition to
corticosteroids ± CNI for cGvHD
● 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 |
|
E.5 End points |
E.5.1 | 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. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | 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 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
medical resource utilization |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Best Available Therapy (BAT) |
|
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 102 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Austria |
Belgium |
Bulgaria |
Canada |
China |
Czechia |
Denmark |
France |
Germany |
Greece |
Hungary |
India |
Israel |
Italy |
Japan |
Jordan |
Korea, Republic of |
Netherlands |
Norway |
Poland |
Portugal |
Romania |
Russian Federation |
Saudi Arabia |
Spain |
Sweden |
Switzerland |
Turkey |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of study is defined as the earliest occurrence of one of the following:
All patients have completed 39 cycles OR
discontinued from the study OR
died |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |