Phase I/II for Safety and Efficacy of Nilotinib in a Population Steroid-refractory/or Steroid-dependent cGVHD

• Status: Completed
• Trial end date: 2016-03-01
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Gruppo Italiano Trapianto di Midollo Osseo

Criteria

Inclusion Criteria:

• Written informed consent

• Male

• not pregnant female

• patients >=18 and <65 years old

• Weight >40 Kg

• Fertile female must use both anti-conception devices and oral contraceptives

• Diagnosis of cGVHD steroid refractory (no response after Prednisone ≥1mg/kg along 6-8 weeks) or steroid-dependent cGVHD (need of > 0.4 mg/Kg/die of Prednisone continuously)

• Patient intolerant to steroid therapy

• Patients with extensive cGVHD including one of the following features:

• skin sclerosis in more than 50% body surface area; active disease with significant progression in the last 6 months or

• skin sclerosis in less than 50% BSA, but presence of visceral involvement or

• Lung cGVHD involvement, documented by Histology (when possible) and/or High Resolution computed tomography scan plus significant alterations of Respiratory tests: forced vital capacity or diffusion capacity deterioration in the last 12 months; Forced expiratory volume in one second <75% predicted ratio within 1 year; evidence of air-trapping or small-airway thickening or bronchiectasis on High-resolution computed tomography or pathologic confirmation of constrictive bronchiolitis; no evidence of active infection in the respiratory tract, documented with investigations directed by clinical symptoms, including radiologic studies or microbiologic cultures. A quantitative lung involvement by cGVHD should be made by using the modified Lung Functional Score* (LFS).

• Visceral sclerosis clinically relevant with digestive involvement also without skin involvement; biopsy at physician discretion.

• In all patient with skin involvement the cGVHD should by documented by Histology

• Patients with visceral involvement clinically and technically documented, but without skin sclerosis will be included if the clinical diagnosis of cGVHD is conformed to NIH criteria

• LFS calculated according to NIH consensus project on criteria for clinical trials in cGVHD

• Failure of at least two immunosuppressive lines, including the steroids

• Lab criteria:

• Alanine aminotransferase and aspartate aminotransferase <2.5 x Upper Limit of Normal or >5.0 x Upper Limit of Normal if considered due to the disease Alkaline phosphatase <2.5 x Upper Limit of Normal

• Serum bilirubin <1.5 x Upper Limit of Normal

• Serum creatinine <1.5 x Upper Limit of Normal

• Serum amylase <1.5 x Upper Limit of Normal and serum lipase <1.5 x Upper Limit of Normal

• Normal serum level of potassium, total calcium corrected for serum albumin; magnesium and phosphorus

• Absolute neutrophil count≥1000/mmc

• Platelets ≥50,000 mmc

Exclusion Criteria:

• Patients with stable disease, well controlled by the current treatment

• Patients who do not need high-dose steroids (daily dose of prednisone <0.4 mg/kg/day) and/or other immunosuppressive agents

• Pregnancy, fertile female without intention to use contraceptives or breast feeding

• Previous treatment with Imatinib or Rituximab in the last six months

• Severe liver or renal impairment: serum creatinine >2,5 mg/dl; serum bilirubin>2,5 mg/dl (without evidence of hepatic cGVHD)

• Other uncontrolled malignancies including the persistence of the underlying malignancy before the Allogeneic Transplantation.

• Any other investigational agents administered within last four weeks

• History of myocardial infarction within the last 12 months

• Uncontrolled angina pectoris

• Cardiac insufficiency (>grade II, New York Heart Association classification)

• Arrhythmia

• Long QT syndrome and/or corrected QT interval >450 msec on screening ECG

• History of acute or chronic pancreatitis

• Use of therapeutic coumarin derivates

• Other concurrent severe and/or uncontrolled medical conditions that could cause unacceptable safety risks or compromise compliance with the protocol

• Use of all strong CYP3A4 inhibitors is excluded.