Chronic Graft versus Host Disease (cGvHD) has been identified as the leading cause of late non-relapse mortality in Hemopoietic Stem Cell Transplant (HSCT) survivors. Up to now a standard satisfactory treatment for these patients does not exist. cGVHD is an immune-mediated disease, resulting from a complex interaction between donor and recipient adaptive immunity, but its exact pathogenesis is still incompletely defined. The purpose of this study is to determine safety and efficacy of Nilotinib in a population with steroid-refractory/or steroid-dependent cGvHD with a phase I study. In phase II the MTD will be used to define the efficacy of Nilotinib in a cGvHD steroid- refractory or steroid dependent population, with the same characteristics of the previously Imatinib-treated population.
Name: nilotinib
Description: Maximum tolerated dosage (MTD) will be defined in Phase I. First 3 patients (pts) will receive Nilotinib 200mg daily dose. If no dose limiting toxicities after at least 1month the next 3 pts will be treated with 300mg. If are>=2 dose limiting toxicities the Phase I will end and MTD will be defined as the next lower dosage. If they will observe 1dose limiting toxicities, they will treat other 3 pts (same dosage); if there isn't dose limiting toxicity, they will increase the dosage in the next cohort; but if they will observe another dose limiting toxicity (tot limiting toxicities 2/6 pts), the study will continue using the previous dose. MTD will be considered the maximum dosage used to treat 6 pts achieving at most 1 dose limiting toxicities, or the previous dosage if with this dosage they we will achieve 2 dose limiting toxicities. Doses will not be escalated beyond >600 or <200mg/die The MTD will be used for phase IIType: DrugNilotinib
Description: Primary is DLT - occurrence of any grade >3 toxicity after at least one month of treatment.
Measure: Dose Limiting Toxicity (DLT) Time: within 6 months since the start of treatmentDescription: Overall Response Rate (ORR)is defined as an Objective improvement at sixth month, and includes at least 1 of the following criteria: At least 50% reduction of body surface area involved; Reduction (at least 20%) of skin sclerosis, measured by Rodnan score Improvement>1 point in functional pulmonary tests, evaluated by LFS score; >50% steroid reduction (for at least 4 weeks)
Measure: Overall Response Rate (ORR) Time: 6 months after date of start of NilotinibDescription: Number of patients experiencing failure, from date of registration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months after the enrolment.
Measure: Time to treatment Failure (TTF) Time: participants will be followed for the duration of the 6 months of treatment, and for the follow-up for expected average of 12 monthsDescription: Number of patients alive from date of registration until the date of death from any cause, assessed up to 24 months after the enrolment
Measure: Overall Survival (OS) Time: participants will be followed for the duration of the 6 months of treatment, and for the follow-up for expected average of 12 monthsDescription: To assess how Nilotinib could interact with the putative pathogenetic pathways of the cGvHD: Presence and activity of auto-antibodies stimulating PDGF-R baseline and during treatment; Modifications of fibroblast (from skin biopsies from patients with skin involvement) characteristics (in terms of: ROS output, modification of both the PDGF-R and the TGFΒ downstream and collagen production)before and after treatment. Quantitative and qualitative modifications of the immune cell populations. Plasma levels of Nilotinib in order to find relationship between clinical improvement and plasma Nilotinib dosage.
Measure: BIOLOGICAL TASKS Time: Every 6 months starting from baseline (at enrolment), along the duration of the 6 months of treatment, and for the follow-up for expected average of 12 monthsSingle Group Assignment
There are 3 SNPs
It has to be noticed that in all the proliferation assays the concentration at which 50% of effect is inhibited of Nilotinib is lower than 50 nM, apart from the two BCR-ABL mutants (E255K and E255V) where the IC50 is 600 to 700 nM. --- E255K ---
It has to be noticed that in all the proliferation assays the concentration at which 50% of effect is inhibited of Nilotinib is lower than 50 nM, apart from the two BCR-ABL mutants (E255K and E255V) where the IC50 is 600 to 700 nM. --- E255K --- --- E255V ---
More interesting and more important (Table 2), Nilotinib is more active that Imatinib against a number of BCR-ABL mutants, with the exception of the T315I. --- T315I ---