| CTRI Number |
CTRI/2017/09/009931 [Registered on: 27/09/2017] Trial Registered Prospectively |
| Last Modified On: |
27/08/2024 |
| Post Graduate Thesis |
No |
| Type of Trial |
Interventional |
|
Type of Study
|
Drug |
| Study Design |
Randomized, Parallel Group Trial |
|
Public Title of Study
|
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 of Study
|
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 |
| Trial Acronym |
|
|
Secondary IDs if Any
|
| Secondary ID |
Identifier |
| CINC424D2301-Protocol version 00 dated 14-Mar-2017 |
Protocol Number |
| NCT03112603 |
ClinicalTrials.gov |
|
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Modification(s)
|
| Name |
Murugananthan K |
| Designation |
Country Monitoring Head |
| Affiliation |
Novartis Healthcare Pvt Ltd |
| Address |
Novartis Healthcare Private Limited Trial Monitoring – GDO, GDD India Inspire- BKC, 7th floor, G Block, BKC Main Road Bandra Kurla Complex Bandra (East) Mumbai
Mumbai
MAHARASHTRA
400051
India |
| Phone |
02250243544 |
| Fax |
|
| Email |
murugananthan.k@novartis.com |
|
Details of Contact Person
Scientific Query
Modification(s)
|
| Name |
Murugananthan K |
| Designation |
Country Monitoring Head |
| Affiliation |
Novartis Healthcare Private Limited |
| Address |
Novartis Healthcare Private Limited Trial Monitoring – GDO, GDD India Inspire- BKC, 7th floor, G Block, BKC Main Road Bandra Kurla Complex Bandra (East) Mumbai
Mumbai
MAHARASHTRA
400051
India |
| Phone |
02250243544 |
| Fax |
|
| Email |
murugananthan.k@novartis.com |
|
Details of Contact Person
Public Query
Modification(s)
|
| Name |
Murugananthan K |
| Designation |
Country Monitoring Head |
| Affiliation |
Novartis Healthcare Private Limited |
| Address |
Novartis Healthcare Private Limited Trial Monitoring – GDO, GDD India Inspire- BKC, 7th floor, G Block, BKC Main Road Bandra Kurla Complex Bandra (East) Mumbai
Mumbai
MAHARASHTRA
400051
India |
| Phone |
02250243544 |
| Fax |
|
| Email |
manish.mistry@novartis.com |
|
Source of Monetary or Material Support
Modification(s)
|
| Novartis Pharma AG, Basel, Switzerland |
|
Primary Sponsor
Modification(s)
|
| Name |
Novartis Healthcare Pvt Ltd |
| Address |
Medical Dept, 7 floor, Inspire BKC G Block, BKC Main Road, Bandra Kurla Complex Bandra (East), Mumbai- 400051 |
| Type of Sponsor |
Pharmaceutical industry-Global |
|
|
Details of Secondary Sponsor
|
|
|
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 |
Sites of Study
Modification(s)
|
| No of Sites = 4 |
| Name of Principal
Investigator |
Name of Site |
Site Address |
Phone/Fax/Email |
| Dr Biju George |
Christian Medical College |
810, Ida Scudder Road,
Vellore-632004
Vellore
TAMIL NADU |
918056416705
biju@cmcvellore.ac.in |
| Dr Dinesh Bhurani |
Rajiv Gandhi Cancer Institute and Research Centre |
Department of Hemato-Oncology,
Rohini, Sector 5, New Delhi-110085
New Delhi
DELHI |
919971500861
bhurani@gmail.com |
| Dr Shashikant Apte |
Sahyadri Speciality Hospital |
Department of Haematology,
Sahyadri Speciality Hospital,
30C, Erandawane, Karve Road,
Pune-411004
Pune
MAHARASHTRA |
9822404983
shashikant.apte@gmail.com |
| Dr Navin Khattry |
Tata Memorial Centre- Advanced Centre for Treatment |
Tata Memorial Centre, Advance Centre For Treatment Research & Education in Cancer Kharghar, Navi Mumbai-410210, Maharashtra, India.
Mumbai
MAHARASHTRA |
09892501884
nkhattry@gmail.com |
|
Details of Ethics Committee
Modification(s)
|
| No of Ethics Committees= 4 |
| Name of Committee |
Approval Status |
| Institutional Ethics Committee, TATA Memorial Centre, Dr. Navin |
Approved |
| Institutional Review Board-CMC |
Approved |
| Institutional Review Board-RGCI |
Approved |
| Institutuional Ethics Committee-Sahyadri Hospital |
Approved |
|
|
Regulatory Clearance Status from DCGI
|
|
Health Condition / Problems Studied
Modification(s)
|
| Health Type |
Condition |
| Patients |
(1) ICD-10 Condition: D619||Aplastic anemia, unspecified, Steroid-refractory chronic graft-versus-host disease , |
|
|
Intervention / Comparator Agent
|
| Type |
Name |
Details |
| Comparator Agent |
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). |
| Intervention |
Ruxolitinib |
Ruxolitinib twice daily at the protocol defined starting dose |
|
|
Inclusion Criteria
|
| Age From |
12.00 Year(s) |
| Age To |
99.00 Year(s) |
| Gender |
Both |
| Details |
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
|
|
| ExclusionCriteria |
| Details |
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 (>
176.8μmol/L), renal dialysis requirement
16. Cholestatic disorders, or unresolved sinusoidal obstructive syndrome/veno-occlusive
disease of the liver (defined as persistent bilirubin abnormalities not attributable to
cGvHD and ongoing organ dysfunction).
17. Impairment of gastrointestinal (GI) function (unrelated to GvHD) or GI disease (unrelated
to GvHD) that may significantly alter the absorption of oral ruxolitinib (e.g., ulcerativediseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small
bowel resection)
18. Any corticosteroid therapy for indications other than cGvHD at doses more than 1 mg per kg per day methylprednisolone or equivalent within 7 days of Cycle 1 Day 1
19. Patient is receiving treatment with medications that interfere with coagulation or platelet function including, but not limited to, aspirin more than 10mg per day and related drugs, heparin, or warfarin sodium. Use of low molecular weight heparin is allowed
20. Known allergies, hypersensitivity, or intolerance to ruxolitinib or any of its excipients
21. Investigational treatment within 30 days prior to randomization, or within 5 half-lives of
the investigational product, whichever is longer
22. Pregnant or nursing (lactating) women
23. Female patients more than or equal to 12 and less than 18 years of age and of childbearing potential (e.g. are menstruating) who do not agree to abstinence or, if sexually active, do not agree to the use of highly effective contraception as defined below, throughout the study and for up to 90 days after stopping treatment.OR
Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 90 days after stopping study medication. Highly effective
contraception methods
In case of use of oral contraception women should have been stable on the same pill for a
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have
had 12 months of natural amenorrhea with an appropriate clinical
profile i.e. age appropriate, history of vasomotor symptoms or have had surgical
bilateral oophorectomy with or without hysterectomy, total hysterectomy, or tubal
ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
24. For male patients randomized to BAT or as per label Sexually active males, unless they
use a condom during intercourse while taking the drug during treatment, and for 90 days
after stopping treatment, and should not father a child in this period. A condom is required
to be used also by vasectomized men, as well as during intercourse with a male partner in
order to prevent delivery of the drug via semen.
25. Subjects who are not able to understand and to comply with study instructions and
requirements |
|
|
Method of Generating Random Sequence
|
Computer generated randomization |
|
Method of Concealment
|
Not Applicable |
|
Blinding/Masking
|
Open Label |
|
Primary Outcome
|
| Outcome |
TimePoints |
| 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 visit |
Cycle 7 Day 1 from baseline to Day 168 |
|
|
Secondary Outcome
|
| Outcome |
TimePoints |
| Rate of failure-free survival |
From baseline to end of study treatment up to 36 months |
| Change in the modified Lee cGvHD symptom scale score |
Cycle 7 Day 1 |
| Best overall response |
From baseline to crossover or end of treatment up to 36 months |
| ORR at end of Cycle 3 |
Cycle 4 Day 1 |
| Duration of response |
Time from first response until GvHD progression or death, up to approximately 36 months |
| Overall survival |
From the date of randomization to the date of death due to any cause up to approximately 36 months |
| Cumulative incidence of non-relapse mortality |
Months 1, 2, 6, 12, 18, and 24 |
| Percentage of participants with ≥ 50% reduction in daily corticosteroid dose at Cycle 7 Day 1 |
Cycle 7 Day 1 |
| Percentage of participants successfully tapered off all corticosteroids at Cycle 7 Day 1 |
Cycle 7 Day 1 |
| Cumulative incidence of malignancy relapse/recurrence |
At 3, 6, 12, 18, and 24 months |
| Changes in Functional Assessment of Cancer therapy Bone Marrow Transplantation |
From baseline to end of treatment, up to 36 months |
| Changes in EQ-5D |
From baseline to end of treatment, up to 36 months |
| Incidence and severity of adverse events |
From baseline to 30 to 35 days after end of treatment, up to approximately 36 months |
|
|
Target Sample Size
|
Total Sample Size="324"
Sample Size from India="25"
Final Enrollment numbers achieved (Total)= "327"
Final Enrollment numbers achieved (India)="6" |
|
Phase of Trial
|
Phase 3 |
|
Date of First Enrollment (India)
|
15/11/2017 |
| Date of Study Completion (India) |
27/11/2021 |
| Date of First Enrollment (Global) |
01/07/2017 |
| Date of Study Completion (Global) |
15/12/2022 |
|
Estimated Duration of Trial
|
Years="4"
Months="6"
Days="0" |
Recruitment Status of Trial (Global)
Modification(s)
|
Completed |
| Recruitment Status of Trial (India) |
Completed |
|
Publication Details
|
publication not yet provided |
|
Individual Participant Data (IPD) Sharing Statement
|
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
|
|
Brief Summary
|
This is 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 target sample size for India is 25 patients FPFV will be in November 2017
|