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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01810718
Recruitment Status : Completed
First Posted : March 13, 2013
Last Update Posted : July 6, 2016
Information provided by (Responsible Party):
Gruppo Italiano Trapianto di Midollo Osseo

Brief 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.

Condition or disease Intervention/treatment Phase
Chronic Graft Versus Host Disease Drug: nilotinib Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 22 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Prospective, Phase I/II, Non-randomized, Open Label, Multicenter Study to Determine Safety and Efficacy of Nilotinib in a Population With Steroid-refractory/or Steroid-dependent cGVHD.
Study Start Date : November 2011
Actual Primary Completion Date : February 2015
Actual Study Completion Date : March 2016

Arm Intervention/treatment
Experimental: Nilotinib

3 patients (pts) will receive Nilotinib 200 mg daily dose. If no dose-limiting toxicity, the next 3 pts will be treated with next dose of Nilotinib 300 mg daily dose.

Doses will not be escalated beyond 600 or below 200 mg/die. The dose estimated as the MTD in phase I will be used for phase II.

Drug: nilotinib
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 II
Other Names:
  • tasigna
  • AMN107

Primary Outcome Measures :
  1. Dose Limiting Toxicity (DLT) [ Time Frame: within 6 months since the start of treatment ]
    Primary is DLT - occurrence of any grade >3 toxicity after at least one month of treatment.

  2. Overall Response Rate (ORR) [ Time Frame: 6 months after date of start of Nilotinib ]

    Overall Response Rate (ORR)is defined as an Objective improvement at sixth month, and includes at least 1 of the following criteria:

    1. At least 50% reduction of body surface area involved;
    2. Reduction (at least 20%) of skin sclerosis, measured by Rodnan score
    3. Improvement>1 point in functional pulmonary tests, evaluated by LFS score;
    4. >50% steroid reduction (for at least 4 weeks)

Secondary Outcome Measures :
  1. Time to treatment Failure (TTF) [ Time Frame: participants will be followed for the duration of the 6 months of treatment, and for the follow-up for expected average of 12 months ]
    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.

  2. Overall Survival (OS) [ Time Frame: participants will be followed for the duration of the 6 months of treatment, and for the follow-up for expected average of 12 months ]
    Number of patients alive from date of registration until the date of death from any cause, assessed up to 24 months after the enrolment

Other Outcome Measures:
  1. BIOLOGICAL TASKS [ Time Frame: 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 months ]

    To assess how Nilotinib could interact with the putative pathogenetic pathways of the cGvHD:

    1. Presence and activity of auto-antibodies stimulating PDGF-R baseline and during treatment;
    2. 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.
    3. Quantitative and qualitative modifications of the immune cell populations.
    4. Plasma levels of Nilotinib in order to find relationship between clinical improvement and plasma Nilotinib dosage.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 64 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01810718

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Chaim Sheba Medical Center
Tel Hashomer, Israel
Clinica di Ematologia - Ospedali Riuniti di Ancona
Ancona, Italy
S.C. Ematologia - Azienda Ospedaliera S. Croce e Carle
Cuneo, Italy
Trapianti Midollo Osseo - Div. di Ematologia 2 - Ospedale S. Martino
Genova, Italy
Ospedale Panico
Lecce, Italy
Divisione di Ematologia - Istituto Nazionale dei Tumori
Milano, Italy
Ospedale Niguarda Ca' Grande
Milano, Italy
U.O. Ematologia I - Centro Trapianti di Midollo - Ospedale Maggiore - Policlinico Mangiagalli e Regina Elena
Milano, Italy
Ospedale San Carlo
Potenza, Italy
Centro Unico Regionale Trapianti di Midollo Osseo - Ospedale Bianchi-Melacino-Morelli
Reggio Calabria, Italy
Ematologia e Centro Trapianti Midollo Osseo - Ospedale IRCCS Casa Sollievo della Sofferenza
S. Giovanni Rotondo (FG), Italy
Clinica Ematologica - AOU Santa Maria Della Misericordia
Udine, Italy
Sponsors and Collaborators
Gruppo Italiano Trapianto di Midollo Osseo
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Principal Investigator: Attilio Olivieri, MD Azienda Ospedaliero Universitaria OORR Umberto I - Marche
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Responsible Party: Gruppo Italiano Trapianto di Midollo Osseo Identifier: NCT01810718    
Other Study ID Numbers: GITMO Protocol Nilotinib-cGVHD
First Posted: March 13, 2013    Key Record Dates
Last Update Posted: July 6, 2016
Last Verified: September 2015
Keywords provided by Gruppo Italiano Trapianto di Midollo Osseo:
steroid therapy
cGVHD steroid refractory
intolerant to steroid therapy
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases