Multicenter Single-arm Pilot Study Evaluating Efficacy of Nilotinib in CML Patients With Molecular Relapse After Glivec Discontinuation Within the Context of the STIM Trials (STIM and STIM2)

Chronic myeloid leukemia (CML) is a hematopoietic neoplasm characterized by the reciprocal translocation t(9;22). The resulting oncoprotein, bcr-abl is an essential trigger for growth and survival of leukemic cells. In the past decade, the bcr-abl tyrosine kinase inhibitor (TKI) imatinib (IM or Glivec©) has been the standard of care for patients with CML, inducing durable responses. However, requiring continuing IM indefinitely and the ability of IM to eradicate the CML clone was uncertain.

In a small proportion of patients, IM can induce complete molecular response (CMR) defined by the disappearance of the bcr-abl transcript in conventional quantitative RT-PCR. The question whether or not these patients are cured and can discontinue drug therapy has been assessed by Mahon and coll, in the STIM study. He demonstrates that IM can be safely discontinued in patient with a CMR of at least 2 year duration and all patients who relapsed after IM discontinuation mainly did it in the first 6 months and responded to reintroduction of imatinib.

Nilotinib is a rationally designed second generation tyrosine kinase inhibitor with improved target specificity over imatinib. Its efficacy and safety in the treatment of patients who are resistant or intolerant to imatinib as well as patients with newly diagnosed CML-CP led to the registration in second and first line treatment of CML-CP patients. Nilotinib produces even faster and deeper responses with more occurrence of CMR than does Imatinib. Consequently, one can assume that a more potent drug such nilotinib could induce deeper and sustained CMR allowing longer period off treatment than IM.

The objective of this pilot trial is to assess if Nilotinib can rescue STIM patients in molecular relapse after IM discontinuation and to provide an estimation about duration of CMR after nilotinib discontinuation in 2nd line therapy among patients experiencing 2 years of stable CMR with nilotinib.

Patients with CML included in STIM trials, stopped their treatment by imatinib because the signal was not detectable. In case of reappearance of this transcript Bcr-Abl, the patient relapses. The trial Nilo Post STIM is suggested to the patient to assess if Nilotinib can rescue STIM patients in molecular relapse after IM discontinuation and to provide an estimation about duration of CMR after nilotinib discontinuation in 2nd line therapy among patients experiencing 2 years of stable CMR with nilotinib.

The treatment/strategy for this study:

* Screening

  * Inclusion/exclusion criteria
  * CML history
  * Confirm molecular relapse after discontinuation of imatinib (quantitative RT-PCR on two consecutive assessments from peripheral blood samples)
* Treatment

  • Nilotinib 300mg BID for 2 years
  * Premature treatment discontinuation while on study: primary or secondary resistance progression to accelerated phase or blast crisis, AE (to be defined later).
  * In case of unsatisfactory response: transcript stability or increase on two consecutive PCR: nilotinib blood monitoring, and nilotinib dose escalation up to 400mg BID will be proposed
  * Discontinuation at 2 years for patients who resumed confirmed CMR
* Follow-up while on treatment with nilotinib:

  * Physical exam, basic laboratory parameters, monthly during the first 3 months then every 3 months.
  * Centralized quantitative RT-PCR for Bcr-Abl monthly for 6 months then every 3 months for 24 months
  * Follow AE management guidelines for nilotinib reduction/interruptions
* Follow-up after nilotinib discontinuation

  * Patients in confirmed molecular relapse

    * Physical exam, event collection, basic laboratory parameters (including glycemic and lipid profile) every 2 months during the first year then every 3 months
    * Hematology and centralized quantitative RT-PCR monthly the first year then every 3 months for 12 months
  * Patients without confirmed molecular relapse will take another treatment (dasatinib for example) and will stop their follow-up in the trial

Eligibility Criteria:
Inclusion Criteria:

* Male and female patients
* Patient participating to the STIM trials (including STIM, STIM2 et EURO-SKI) and with confirmed molecular relapse on two consecutive RQ PCR, after imatinib discontinuation
* Still in chronic phase
* Not yet treated for this relapse
* At least 18 years old (no upper age limit)
* SGOT and SGPT \< 2.5 UNL
* Serum creatinin \< 2 UNL
* No planned allogeneic stem cell transplantation
* Signed informed consent
* ECOG score 0 to 2

Exclusion Criteria:

* Pregnancy, lactation
* Prior or concurrent malignancy other than CML (exceptions to be mentioned)
* Serious uncontrolled cardiovascular disease
* Severe psychiatric/neurological disease (previous or ongoing)
* Ongoing treatment at risk for inducing "torsades de pointe"
* QTcF \> 450ms despite correction of predisposing factors (i.e electrolytes...)
* Congenital long QTcF
* No health insurance coverage