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

NCT01810718 | Completed Phase 1 DMC

• 1 other identifier: GITMO Protocol Nilotinib-cGVHD
• Study Type: interventional
• Target: 22
• Locations: 2 countries
• Sites: 12

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.

Conditions

Chronic Graft Versus Host Disease

Keywords

cGVHD; steroid therapy; Nilotinib; cGVHD steroid refractory; intolerant to steroid therapy; Tasigna; MTD

Outcome Measures

Primary Outcomes (2)

• Dose Limiting Toxicity (DLT)

  Primary is DLT - occurrence of any grade \>3 toxicity after at least one month of treatment.

  within 6 months since the start of treatment

• Overall Response Rate (ORR)

  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)

  6 months after date of start of Nilotinib

Secondary Outcomes (2)

• Time to treatment Failure (TTF)

  participants will be followed for the duration of the 6 months of treatment, and for the follow-up for expected average of 12 months

• Overall Survival (OS)

  participants will be followed for the duration of the 6 months of treatment, and for the follow-up for expected average of 12 months

Other Outcomes (1)

• BIOLOGICAL TASKS

  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

Study Arms (1)

Nilotinib

EXPERIMENTAL

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

Interventions

nilotinib DRUG

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

Also known as: tasigna, AMN107

Nilotinib

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Gruppo Italiano Trapianto di Midollo Osseo: lead

Study Sites (12)

Chaim Sheba Medical Center

Tel Litwinsky, Israel

Location

Ematologia e Centro Trapianti Midollo Osseo - Ospedale IRCCS Casa Sollievo della Sofferenza

San Giovanni Rotondo, Foggia, 71013, Italy

Location

Clinica di Ematologia - Ospedali Riuniti di Ancona

Ancona, Italy

Location

S.C. Ematologia - Azienda Ospedaliera S. Croce e Carle

Cuneo, Italy

Location

Trapianti Midollo Osseo - Div. di Ematologia 2 - Ospedale S. Martino

Genova, Italy

Location

Ospedale Panico

Lecce, Italy

Location

Divisione di Ematologia - Istituto Nazionale dei Tumori

Milan, Italy

Location

Ospedale Niguarda Ca' Grande

Milan, Italy

Location

U.O. Ematologia I - Centro Trapianti di Midollo - Ospedale Maggiore - Policlinico Mangiagalli e Regina Elena

Milan, Italy

Location

Ospedale San Carlo

Potenza, Italy

Location

Centro Unico Regionale Trapianti di Midollo Osseo - Ospedale Bianchi-Melacino-Morelli

Reggio Calabria, Italy

Location

Clinica Ematologica - AOU Santa Maria Della Misericordia

Udine, Italy

Location

MeSH Terms

Conditions

Bronchiolitis Obliterans Syndrome

Interventions

nilotinib

Condition Hierarchy (Ancestors)

Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases

Study Officials

• Attilio Olivieri, MD

  Azienda Ospedaliero Universitaria OORR Umberto I - Marche

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 6, 2013
• First Posted: March 13, 2013
• Study Start: November 1, 2011
• Primary Completion: February 1, 2015
• Study Completion: March 1, 2016
• Last Updated: March 10, 2023

Record last verified: 2023-03

Locations

IT (11); IL (1)