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Efficacy and Safety of Nilotinib in Patients With a Chronic Disease of the Graft Against the Host (DoubleITK)

Primary Purpose

Graft Versus Host Disease

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Imatinib Mesylate and Nilotinib
Sponsored by
University Hospital, Lille
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Graft Versus Host Disease focused on measuring allogeneic stem cell transplantation, imatinib Mesylate, Nilotinib

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Induction phase (IM):

  • Patients aged ≥18 years to 75 years
  • Patients who underwent allo-SCT for a hematological disorder
  • Body weight ≥ 40 Kg.

  • Confirmed diagnosis of cGVHD resistant to at least one systemic immunosuppressive therapy. The diagnosis of cGHVD should be based on the NIH Working Group Consensus (www.asbmt.org/gvhd/index.htm). Grading of cGVHD will be based on clinical manifestations including:

    1. ocular, oral and mucosal symptoms;
    2. performance status;
    3. evaluation of pulmonary functions;
    4. cutaneous evaluation;
    5. evaluation of musculo-skeletal manifestations;
    6. evaluation of liver involvement;
  • Any source of hematopoietic stem cell is allowed
  • Both myeloablative and nonmyeloablative conditioning regimens are authorized.
  • Absence of contra-indications to the use of IM or Nilotinib
  • Patient having French health care coverage
  • Female patients of childbearing potential must have before initiation of study drug and agree to have efficient contraceptive precautions throughout the trial and for 3 months after the end of the trial.
  • Signed informed consent.

Salvage phase (Nilotinib) :

Patients enrolled in the first phase and who failed to IM:

  • Patients, who discontinue imatinib mesylate at 3 months for lack of response (no response = stable disease),
  • those who experience progression at any time,
  • those who relapse after an initial response at any time
  • or those who discontinue for toxicity at any time.

Exclusion Criteria:

  • Patient developing acute GVHD (whether early or "late onset" form)
  • First episode of cGVHD
  • Patient who received IM or Nilotinib treatment or any other TKI after transplant 3 months before the inclusion on the study
  • Patient treated by TKI for a GVHD
  • Contra-indication to IM or Nilotinib
  • Neutropenia < 0.5 G/L
  • Uncontrolled systemic infection which can be associated, according to the investigator, to an enhanced risk of patient's death during the first month of treatment
  • Severe neurological or psychiatric disorders
  • Pregnancy or lactation
  • Known uncontrolled arrhythmias or symptomatic heart disease or left ventricular ejection fraction < 40% (cardiac tests as clinically indicated)
  • Recurrence of cancer for which the transplant was done except for presence of minimal residual disease by PCR

  • Patients with secondary malignancy ≤ 2 years prior study-entry except:

    • Basal cell carcinoma of the skin
    • Squamous cell carcinoma of the skin
    • Carcinoma in situ of the cervix
    • Carcinoma in situ of the breast
    • Prostate cancer (Tumor, Node, Metastasis [TNM] stage T1a or T1b)
  • Patients in emergency situation
  • Patients kept in detention
  • Patients unable or unwilling to comply with the protocol requirements

Sites / Locations

  • CHU Sart Tilman
  • CHU d'Amiens
  • CHU d'Angers
  • CHU Besançon
  • CHU Bordeaux
  • Hopital Morvan
  • CHU Clémenceau
  • HIA de Percy
  • CHU de Clermont Ferrand
  • CHU Grenoble
  • Diseases of Blood Service HURIEZ hospital CHRU de LILLE
  • Centre hospitalier et régional de Lille
  • CHU de Lyon
  • Institut Paoli Calmettes
  • Hôpital Saint Eloi
  • CHU Hotel Dieu
  • CHU de Nice
  • Hopital NECKER
  • Hôpital pitié Salpetrière
  • Centre Henri Becquerel
  • CHU de STRASBOURG
  • CHU Purpan

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

open-label

Arm Description

Induction phase: Imatinib mesylate - starting with 100 mg/day with increase of 100 mg/day each other week up to maximum tolerable dose or 400 mg/day whichever occurred first. For the responders and in absence of toxicity, the treatment will be maintained up to one year. Salvage phase: Nilotinib - starting with 200 mg/day with increase of 200 mg/day each other week up to maximum tolerable dose or 800 mg/day whichever occurred first. In absence of toxicity, the treatment will be maintained up to one year.

Outcomes

Primary Outcome Measures

Response rate at 3 months (complete and partial remission) after salvage treatment with Nilotinib in patients with chronic GVHD who failed Imatinib Mesylate (IM)
Response rate at 3 months (complete and partial remission) after salvage treatment with Nilotinib in patients with chronic GVHD who failed Imatinib Mesylate (IM)

Secondary Outcome Measures

Best response to IM within 12 months and the duration of this response
Best response rate to Nilotinib within 12 months and the duration of this response
use of systemic secondary treatment due to intolerance to IM
measure intolerance by IM failure
use of systemic secondary treatment due to intolerance to Nilotinib
measure intolerance by Nilotinib failure

Full Information

First Posted
September 1, 2016
Last Updated
July 9, 2019
Sponsor
University Hospital, Lille
Collaborators
Novartis
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1. Study Identification

Unique Protocol Identification Number
NCT02891395
Brief Title
Efficacy and Safety of Nilotinib in Patients With a Chronic Disease of the Graft Against the Host
Acronym
DoubleITK
Official Title
Efficacy and Safety of Nilotinib in Patients With a Chronic Disease of the Graft Against the Host (Graft Versus Host, GVH) Did Not Respond to Imatinib Mesylate.
Study Type
Interventional

2. Study Status

Record Verification Date
July 2019
Overall Recruitment Status
Completed
Study Start Date
December 24, 2012 (Actual)
Primary Completion Date
July 26, 2017 (Actual)
Study Completion Date
July 26, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Lille
Collaborators
Novartis

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Open label non-randomized multicenter phase 2 trial with direct individual benefice
Detailed Description
Induction phase: Imatinib mesylate - starting with 100 mg/day with increase of 100 mg/day each other week up to maximum tolerable dose or 400 mg/day whichever occurred first. For the responders and in absence of toxicity, the treatment will be maintained up to one year. Patients, who discontinue imatinib mesylate at 3 months for lack of response (no response = stable disease), those who experience progression at any time, those who relapse after an initial response at any time or those who discontinue for toxicity at any time, will go to the salvage phase. Salvage phase: Nilotinib - starting with 200 mg/day with increase of 200 mg/day each other week up to maximum tolerable dose or 800 mg/day whichever occurred first. In absence of toxicity, the treatment will be maintained up to one year.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graft Versus Host Disease
Keywords
allogeneic stem cell transplantation, imatinib Mesylate, Nilotinib

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
65 (Actual)

8. Arms, Groups, and Interventions

Arm Title
open-label
Arm Type
Experimental
Arm Description
Induction phase: Imatinib mesylate - starting with 100 mg/day with increase of 100 mg/day each other week up to maximum tolerable dose or 400 mg/day whichever occurred first. For the responders and in absence of toxicity, the treatment will be maintained up to one year. Salvage phase: Nilotinib - starting with 200 mg/day with increase of 200 mg/day each other week up to maximum tolerable dose or 800 mg/day whichever occurred first. In absence of toxicity, the treatment will be maintained up to one year.
Intervention Type
Drug
Intervention Name(s)
Imatinib Mesylate and Nilotinib
Intervention Description
For patients under Imatinib Mesylate: the total length of follow up period for those patients will be for 52 weeks following IM treatment, with a follow up at weeks IM4, IM8, IM12, IM26, IM38 and IM52. For patients requiring a salvage phase: after the switch for nilotinib, the total length of follow up period for this phase will be for 52 weeks following nilotinib treatment, with a follow up at weeks nilo4, nilo8, nilo12, nilo26, nilo38 and nilo52.
Primary Outcome Measure Information:
Title
Response rate at 3 months (complete and partial remission) after salvage treatment with Nilotinib in patients with chronic GVHD who failed Imatinib Mesylate (IM)
Description
Response rate at 3 months (complete and partial remission) after salvage treatment with Nilotinib in patients with chronic GVHD who failed Imatinib Mesylate (IM)
Time Frame
Between Baseline and minimum 12 weeks of treatment
Secondary Outcome Measure Information:
Title
Best response to IM within 12 months and the duration of this response
Time Frame
From 12 to 52 weeks of Imatinib Mesylate treatment
Title
Best response rate to Nilotinib within 12 months and the duration of this response
Time Frame
From 12 to 52 weeks of Nilotinib treatment
Title
use of systemic secondary treatment due to intolerance to IM
Description
measure intolerance by IM failure
Time Frame
From baseline to 12 weeks of IM treatment
Title
use of systemic secondary treatment due to intolerance to Nilotinib
Description
measure intolerance by Nilotinib failure
Time Frame
From baseline to 12 weeks of Nilotinib treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Induction phase (IM): Patients aged ≥18 years to 75 years Patients who underwent allo-SCT for a hematological disorder Body weight ≥ 40 Kg. Confirmed diagnosis of cGVHD resistant to at least one systemic immunosuppressive therapy. The diagnosis of cGHVD should be based on the NIH Working Group Consensus (www.asbmt.org/gvhd/index.htm). Grading of cGVHD will be based on clinical manifestations including: ocular, oral and mucosal symptoms; performance status; evaluation of pulmonary functions; cutaneous evaluation; evaluation of musculo-skeletal manifestations; evaluation of liver involvement; Any source of hematopoietic stem cell is allowed Both myeloablative and nonmyeloablative conditioning regimens are authorized. Absence of contra-indications to the use of IM or Nilotinib Patient having French health care coverage Female patients of childbearing potential must have before initiation of study drug and agree to have efficient contraceptive precautions throughout the trial and for 3 months after the end of the trial. Signed informed consent. Salvage phase (Nilotinib) : Patients enrolled in the first phase and who failed to IM: Patients, who discontinue imatinib mesylate at 3 months for lack of response (no response = stable disease), those who experience progression at any time, those who relapse after an initial response at any time or those who discontinue for toxicity at any time. Exclusion Criteria: Patient developing acute GVHD (whether early or "late onset" form) First episode of cGVHD Patient who received IM or Nilotinib treatment or any other TKI after transplant 3 months before the inclusion on the study Patient treated by TKI for a GVHD Contra-indication to IM or Nilotinib Neutropenia < 0.5 G/L Uncontrolled systemic infection which can be associated, according to the investigator, to an enhanced risk of patient's death during the first month of treatment Severe neurological or psychiatric disorders Pregnancy or lactation Known uncontrolled arrhythmias or symptomatic heart disease or left ventricular ejection fraction < 40% (cardiac tests as clinically indicated) Recurrence of cancer for which the transplant was done except for presence of minimal residual disease by PCR Patients with secondary malignancy ≤ 2 years prior study-entry except: Basal cell carcinoma of the skin Squamous cell carcinoma of the skin Carcinoma in situ of the cervix Carcinoma in situ of the breast Prostate cancer (Tumor, Node, Metastasis [TNM] stage T1a or T1b) Patients in emergency situation Patients kept in detention Patients unable or unwilling to comply with the protocol requirements
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
YAKOUB-AGHA Ibrahim, MD
Organizational Affiliation
University Hospital, Lille
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHU Sart Tilman
City
Liège
Country
Belgium
Facility Name
CHU d'Amiens
City
Amiens
Country
France
Facility Name
CHU d'Angers
City
Angers
Country
France
Facility Name
CHU Besançon
City
Besancon
Country
France
Facility Name
CHU Bordeaux
City
Bordeaux
Country
France
Facility Name
Hopital Morvan
City
Brest
Country
France
Facility Name
CHU Clémenceau
City
Caen
Country
France
Facility Name
HIA de Percy
City
Clamart
Country
France
Facility Name
CHU de Clermont Ferrand
City
Clermont Ferrand
Country
France
Facility Name
CHU Grenoble
City
Grenoble
Country
France
Facility Name
Diseases of Blood Service HURIEZ hospital CHRU de LILLE
City
LIlle
ZIP/Postal Code
59037
Country
France
Facility Name
Centre hospitalier et régional de Lille
City
Lille
Country
France
Facility Name
CHU de Lyon
City
Lyon
Country
France
Facility Name
Institut Paoli Calmettes
City
Marseille
Country
France
Facility Name
Hôpital Saint Eloi
City
Montpellier
Country
France
Facility Name
CHU Hotel Dieu
City
Nantes
Country
France
Facility Name
CHU de Nice
City
Nice
Country
France
Facility Name
Hopital NECKER
City
Paris
Country
France
Facility Name
Hôpital pitié Salpetrière
City
Paris
Country
France
Facility Name
Centre Henri Becquerel
City
Rouen
Country
France
Facility Name
CHU de STRASBOURG
City
Strasbourg
Country
France
Facility Name
CHU Purpan
City
Toulouse
Country
France

12. IPD Sharing Statement

Learn more about this trial

Efficacy and Safety of Nilotinib in Patients With a Chronic Disease of the Graft Against the Host

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