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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) (Nilo Post-STIM)

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2014 by University Hospital, Bordeaux
Sponsor:
Information provided by (Responsible Party):
University Hospital, Bordeaux
ClinicalTrials.gov Identifier:
NCT01774630
First received: January 22, 2013
Last updated: November 12, 2014
Last verified: November 2014
  Purpose

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.


Condition Intervention Phase
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Drug: Nilotinib
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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)

Resource links provided by NLM:


Further study details as provided by University Hospital, Bordeaux:

Primary Outcome Measures:
  • Estimated survival rate of patients without molecular relapse 3 years after enrollment [ Time Frame: Evaluation by RTq-PCR monthly the first year of treatment with nilotinib then every 3 months until 24 months, date of discontinuation of Nilotinib for patients in sustained complete molecular response (CMR). After discontinuation of Nilotinib patie ] [ Designated as safety issue: Yes ]
    CMR is defined as >5 log reduction in Bcr-Abl and Abl levels and undetectable transcripts on quantitative RTq-PCR


Secondary Outcome Measures:
  • Rate and kinetics of CMR while on treatment with nilotinib [ Time Frame: at 6 and 12 months of treatment with nilotinib ] [ Designated as safety issue: Yes ]
    Same definition of CMR as above

  • Duration of CMR while on treatment with nilotinib [ Time Frame: Any time ] [ Designated as safety issue: Yes ]
    Defined as the time from the date of first documented CMR to the date of first confirmed molecular relapse defined as positivity of Bcr-Abl transcripts in quantitative RT-PCR with a ratio of bcr-abl to Abl ≥ 10-5, as confirmed by a second analysis point at two successive assessments

  • Event free survival (EFS) [ Time Frame: Any time ] [ Designated as safety issue: Yes ]
    Events include loss of major molecular response (MMR) , loss of complete cytogenetic response (CCyR) loss of complete hematologic response (CHR), progression to accelerated phase and blst crisis (AP-BC), death whatever the cause, adverse-event leading to premature discontinuation of nilotinib

  • Safety tolerability of nilotinib and compliance [ Time Frame: Any time ] [ Designated as safety issue: Yes ]
    Haematological and non-haematological adverse events (AE) graded will be according to the NCI CTC AE v4. Compliance will be estimated using the 4 items Morisky scale

  • Duration of CMR after nilotinib discontinuation [ Time Frame: Measured from the start of nilotinib discontinuation to the date of first confirmed molecular relapse as defined above ] [ Designated as safety issue: Yes ]
  • Event free survival (EFS) [ Time Frame: Overall and after nilotinib discontinuation ] [ Designated as safety issue: Yes ]
    Same events as for EFS described above

  • Predictive factors of maintained CMR after nilotinib discontinuation: sex, Sokal risk score at diagnosis, duration of previous treatment with imatinib, CMR duration before and after discontinuation of imatinib [ Time Frame: After discontinuation of nilotinib ] [ Designated as safety issue: Yes ]
    Parameters will be recorded before and after both sequences of treatment imatinib and nilotinib


Estimated Enrollment: 70
Study Start Date: April 2013
Estimated Study Completion Date: April 2018
Estimated Primary Completion Date: April 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Nilotinib
300 mg/twice a day
Drug: Nilotinib
300 mg/twice a day

Detailed Description:

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01774630

Contacts
Contact: François-Xavier MAHON, MD PhD + 33 5 57 65 65 11 Francois-xavier.mahon@umr5540.u-bordeaux2.fr

Locations
France
CHU Angers Not yet recruiting
Angers, France, 49033
Contact: Martine GARDEMBAS, MD         
Principal Investigator: Martine GARDEMBAS, MD         
Institut Bergonié Not yet recruiting
Bordeaux, France, 33076
Contact: Gabriel ETIENNE, Dr       G.Etienne@bordeaux.unicancer.fr   
Principal Investigator: Gabriel ETIENNE, Dr         
Sub-Investigator: Josy REIFFERS, Pr         
Sub-Investigator: François-Xavier MAHON, Pr         
Sub-Investigator: Anna SCHMITT, Dr         
Chu Estaing Not yet recruiting
Clermont- Ferrand, France, 63003
Contact: Marc BERGER, MD, PhD         
Principal Investigator: Marc BERGER, MD,PhD         
Centre Hospitalier de Versailles - Hôpital André Mignot - Service de Médecine B Not yet recruiting
Le Chesnay, France, 78157
Contact: Philippe ROUSSELOT, Pr       prousselot@ch-versailles.fr   
Principal Investigator: Philippe ROUSSELOT, Pr         
Hôpital Claude Huriez, Service des Maladies du Sang Not yet recruiting
Lille, France, 59037
Contact: Marie-Pierre NOEL, Dr       mp-noel@chru-lille.fr   
Principal Investigator: Marie-Pierre NOEL, Dr         
Sub-Investigator: Valérie COITEUX, Dr         
Sub-Investigator: Nathalie CAMBIER, Dr         
Institut Paoli Calmette, Service Hématologie 3 Not yet recruiting
Marseille, France, 13273
Contact: Aude CHARBONNIER, Dr       charbonniera@marseille.fnclcc.fr   
Principal Investigator: Aude CHARBONNIER, Dr         
Sub-Investigator: Norbert VEY, Dr         
Sub-Investigator: Thomas PREBET, Dr         
Sub-Investigator: Jerôme REY, Dr         
Sub-Investigator: Anne ETIENNE, Dr         
Sub-Investigator: Evelyne D'INCAN, Dr         
CHU Hôtel Dieu, Service d'Hémato-Cancérologie Not yet recruiting
Nantes, France, 44035
Contact: Viviane DUBRUILLE, Dr       viviane.dubruille@chu-nantes.fr   
Principal Investigator: Viviane DUBRUILLE, Dr         
Sub-Investigator: Béatrice MAHE, Dr         
Sub-Investigator: CLAVERT Aline, Dr         
Sub-Investigator: Nicolas BLIN, Dr         
CHU de Nice, Service Hématologie Clinique Not yet recruiting
Nice, France, 06202
Contact: Laurence LEGROS, Dr       legros.l@chu-nice.fr   
Principal Investigator: Laurence LEGROS, Dr         
Sub-Investigator: Jean-Michel KARSENTI, Dr         
Hôpital Saint Louis, Service des Maladies du Sang Not yet recruiting
Paris, France, 75475
Contact: Philippe ROUSSELOT, Pr       philippe.rousselot@chu-stlouis.fr   
Principal Investigator: Philippe ROUSSELOT, Pr         
Sub-Investigator: Delphine REA, Dr         
Hôpital Necker-Enfants Malades, Service d'Hématologie Not yet recruiting
Paris, France, 75743
Contact: Bruno VARET, Pr       bruno.varet@nck.aphp.fr   
Principal Investigator: Bruno VARET, Pr         
Sub-Investigator: Agnès BUZYN, Pr         
Sub-Investigator: Felipe SUAREZ, Dr         
Hôpital Haut Lévêque, Service Hématologie Recruiting
Pessac, France, 33604
Contact: François-Xavier MAHON, Pr       Francois-Xavier.Mahon@umr5540.u-bordeaux2.fr   
Principal Investigator: François-Xavier MAHON, Pr         
Sub-Investigator: Gérald MARIT, Pr         
Centre Hospitalier Lyon Sud, Service Hématologie Recruiting
Pierre Benite, France, 69495
Contact: Franck NICOLINI, Dr       franck.nicolini@chu-lyon.fr   
Principal Investigator: Franck NICOLINI, Dr         
Sub-Investigator: Mauricette MICHALLET, Pr         
Sub-Investigator: Xavier THOMAS, Dr         
Sub-Investigator: Fiorenza BARACCO, Dr         
Sub-Investigator: Hélène LABUSSIERE, Dr         
Sub-Investigator: Marie DETRAIT, Dr         
Sub-Investigator: Youcef CHELGHOUM, Dr         
Sub-Investigator: Sophie DUCASTELLE, Dr         
CHRU de Poitiers Not yet recruiting
Poitiers, France, 86021
Contact: François GUILHOT, Md, PhD         
Principal Investigator: François GUILHOT, Md, PhD         
CH d'Annecy Recruiting
Pringy, France, 74374
Contact: Pascale CONY-MAKHOUL, Dr       pconymakhoul@ch-annecy.fr   
Principal Investigator: Pascale CONY-MAKHOUL, Dr         
Sub-Investigator: Bernadette CORRONT, Dr         
Hôpital Pontchaillou Recruiting
Rennes, France, 35033
Contact: Martine ESCOFFRE-BARBE, Dr       martine.escoffre-barbe@chu-rennes.fr   
Principal Investigator: Martine ESCOFFRE-BARBE, Dr         
Sub-Investigator: Bernard Marc, Dr         
Sub-Investigator: Charles DAURIAC, Dr         
Sub-Investigator: Stanislas NIMUBONA, Dr         
Sub-Investigator: Xavier CAHU, Dr         
Sub-Investigator: Thierry LAMY DE LA CHAPELLE, Dr         
Sub-Investigator: Roch HOUOT, Dr         
Sub-Investigator: Sophie DE GUIBERT, Dr         
CHU de Toulouse, Service d'Hématologie Recruiting
Toulouse, France, 31059
Contact: Françoise RIGAL-HUGUET, Dr       huguet.f@chu-toulouse.fr   
Sub-Investigator: Lucie OBERIC, Dr         
Sub-Investigator: Guy LAURENT, Pr         
Sub-Investigator: Christian RECHER, Pr         
Sub-Investigator: Anne HUYNH, Dr         
Sub-Investigator: Loïc YSEBAERT, Dr         
Principal Investigator: Françoise RIGAL-HUGUET, Dr         
CHU de Tours Not yet recruiting
Tours, France, 37044
Contact: Emmanuel GYAN, MD         
Principal Investigator: Emmanuel GYAN, MD         
CH Valence Recruiting
Valence, France, 26953
Contact: Jixing LIU, MD         
Principal Investigator: Jixing LIU, MD         
CHU Brabois, Service de Médecine A Not yet recruiting
Vandoeuvre Les Nancy, France, 54500
Contact: Agnès-Paule GUERCI, Dr       a.guerci@chu-nancy.fr   
Principal Investigator: Angès-Paule GUERCI, Dr         
Sponsors and Collaborators
University Hospital, Bordeaux
Investigators
Study Chair: Viviane DUBRUILLE Nantes University Hospital
Study Chair: Gabriel ETIENNE University Hospital Bordeaux, France
Study Chair: Franck NICOLINI University Hospital Lyon
Study Chair: Delphine REA APHP, St Louis Hospital
  More Information

No publications provided

Responsible Party: University Hospital, Bordeaux
ClinicalTrials.gov Identifier: NCT01774630     History of Changes
Other Study ID Numbers: CHUBX 2012/18
Study First Received: January 22, 2013
Last Updated: November 12, 2014
Health Authority: France: Ministry of Health
France: Agence Nationale de Sécurité du Médicament et des produits de santé

Keywords provided by University Hospital, Bordeaux:
Treatment, relapse, complete molecular response

Additional relevant MeSH terms:
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid
Bone Marrow Diseases
Hematologic Diseases
Leukemia
Myeloproliferative Disorders
Neoplasms
Neoplasms by Histologic Type

ClinicalTrials.gov processed this record on November 25, 2014