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) (NiloPost-STIM)

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.

Study Overview

• Status: Completed
• Conditions: Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Intervention / Treatment: Drug: Nilotinib

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

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Angers, France, 49033
    • CHU Angers
  • Bordeaux, France, 33076
    • Institut Bergonie
  • Le Chesnay, France, 78157
    • Centre Hospitalier de Versailles - Hôpital André Mignot - Service de Médecine B
  • Nice, France, 06202
    • CHU de Nice, Service Hématologie Clinique
  • Pessac, France, 33604
    • Hôpital Haut Lévêque, Service Hématologie
  • Pierre Benite, France, 69495
    • Centre Hospitalier Lyon Sud, Service Hématologie
  • Pringy, France, 74374
    • CH d'Annecy
  • Rennes, France, 35033
    • Hopital Pontchaillou
  • Toulouse, France, 31059
    • CHU de Toulouse, Service d'Hématologie
  • Valence, France, 26953
    • Ch Valence

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nilotinib; 300 mg/twice a day	Drug: Nilotinib; 300 mg/twice a day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimated survival rate of patients without molecular relapse 3 years after enrollment	CMR is defined as >5 log reduction in Bcr-Abl and Abl levels and undetectable transcripts on quantitative RTq-PCR	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate and kinetics of CMR while on treatment with nilotinib	Same definition of CMR as above	at 6 and 12 months of treatment with nilotinib
Duration of CMR while on treatment with nilotinib	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	Any time
Event free survival (EFS)	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	Any time
Safety tolerability of nilotinib and compliance	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	Any time
Duration of CMR after nilotinib discontinuation		Measured from the start of nilotinib discontinuation to the date of first confirmed molecular relapse as defined above
Event free survival (EFS)	Same events as for EFS described above	Overall and after nilotinib discontinuation
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	Parameters will be recorded before and after both sequences of treatment imatinib and nilotinib	After discontinuation of nilotinib

Collaborators and Investigators

• Sponsor: University Hospital, Bordeaux
• Investigators: Study Chair: Viviane DUBRUILLE, Nantes University Hospital; Study Chair: Gabriel ETIENNE, University Hospital Bordeaux, France; Study Chair: Franck NICOLINI, Hospices Civils de LYON; Study Chair: Delphine REA, APHP, St Louis Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 10, 2013
• Primary Completion (Actual): December 21, 2020
• Study Completion (Actual): December 21, 2020

Study Registration Dates

• First Submitted: January 22, 2013
• First Submitted That Met QC Criteria: January 22, 2013
• First Posted (Estimate): January 24, 2013

Study Record Updates

• Last Update Posted (Actual): August 18, 2022
• Last Update Submitted That Met QC Criteria: August 17, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Treatment, relapse, complete molecular response
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Recurrence; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Other Study ID Numbers: CHUBX 2012/18

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO