A Study of Ruxolitinib versus a Best Available Therapy in Patients With Steroid resistant Chronic Graft versus Host Disease After Bone Marrow Transplantation
Phase 3
Completed
- Conditions
- Aplastic anemia, unspecified, Steroid-refractory chronic graft-versus-host disease ,
- Registration Number
- CTRI/2017/09/009931
- Lead Sponsor
- Novartis Healthcare Pvt Ltd
- 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
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- All
- Target Recruitment
- 324
Inclusion Criteria
- 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.
- 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
- 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.
- 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).
- 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.
- 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.
- Subjects who are not able to understand and to comply with study instructions and requirements.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method 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 Measures
Name Time Method ORR at end of Cycle 3 Cycle 4 Day 1 Percentage of participants with ≥ 50% reduction in daily corticosteroid dose at Cycle 7 Day 1 Cycle 7 Day 1 Cumulative incidence of malignancy relapse/recurrence At 3, 6, 12, 18, and 24 months Rate of failure-free survival From baseline to end of study treatment up to 36 months Best overall response From baseline to crossover or end of treatment up to 36 months Percentage of participants successfully tapered off all corticosteroids at Cycle 7 Day 1 Cycle 7 Day 1 Change in the modified Lee cGvHD symptom scale score Cycle 7 Day 1 Overall survival From the date of randomization to the date of death due to any cause up to approximately 36 months Changes in EQ-5D From baseline to end of treatment, up to 36 months Duration of response Time from first response until GvHD progression or death, up to approximately 36 months Cumulative incidence of non-relapse mortality Months 1, 2, 6, 12, 18, and 24 Changes in Functional Assessment of Cancer therapy Bone Marrow Transplantation 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
Trial Locations
- Locations (4)
Christian Medical College
🇮🇳Vellore, TAMIL NADU, India
Rajiv Gandhi Cancer Institute and Research Centre
🇮🇳Delhi, DELHI, India
Sahyadri Speciality Hospital
🇮🇳Pune, MAHARASHTRA, India
Tata Memorial Centre- Advanced Centre for Treatment
🇮🇳Mumbai, MAHARASHTRA, India
Christian Medical College🇮🇳Vellore, TAMIL NADU, IndiaDr Biju GeorgePrincipal investigator918056416705biju@cmcvellore.ac.in