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

Open label non-randomized multicenter phase 2 trial with direct individual benefice

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.

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:

  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