A Prospective Randomized Phase II Study Evaluating the Monitoring of Imatinib Mesylate Plasmatic Through Level in Patients Newly Diagnosed With CP-CML (OPTIMIMATINIB)

A Prospective Randomized Phase II Study Evaluating the Monitoring of Imatinib Mesylate (Glivec®) Plasmatic Through Level in Patients Newly Diagnosed With Chronic Phase Chronic Myelogenous Leukaemia (CP-CML).

Imatinib mesylate (Gleevec/Glivec, IM) is currently the gold standard or CML-CP front line therapy. The recommended dose of IM is 400 mg/day. The rates of complete cytogenetic responses at 3, 6 and 12 months are 27%, 50% and 69% respectively. The optimal IM daily dose is not yet determined and randomized studies addressing this question are on-going. First results from the TOPS trial (EHA 2008 congress) suggest a more rapid kinetic of response for patients treated with imatinib high dose. Recent studies revealed that initial Imatinib plasmatic dosage is predictive for achieving complete cytogenetic responses (CCR) and that a dosage of 1000 ng/ml is associated with a higher proportion of major molecular responses (MMR) (Picard et al., Blood 2007, Larson et al. Blood 2007).

Results from the study of Larson et al. indicate that around 40% of the patients had a trough plasmatic level below 1000 ng/ml after day 28 of imatinib 400 mg/d. The major molecular response rate at 12 months for the patients with the lower plasmatic through level is 25.4% compared to 40.1% for the patients with a plasmatic dosage over 800 to 1000 ng/ml.

Investigators propose to adapt the imatinib daily dose in case of imatinib through plasmatic level at day 28 below 1000 ng/ml. Patients with a trough plasmatic dosage ≤ 1000 ng/ml will be randomized between a prospective adaptation strategy of the imatinib daily dose (cohort 1) versus observation only (cohort 2). The patients with adequate imatinib dosage (> 1000 ng/ml) will be followed up according the ELN recommendation (cohort 3). Imatinib trough plasmatic level will then be rechecked every month thereafter for patients in cohort 1 and cohort 2 and every three months in cohort 3. The first endpoint of the study will be the rate of major molecular response at 12 months in cohort 1. Our hypothesis is to improve the 12 months MMR rate with the optimized strategy (cohort 1) from 25% of MMR at 12 months to 40% of MMR at 12 months.

Study Overview

• Status: Completed
• Conditions: Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Intervention / Treatment: Other: active comparator; Drug: Posology dose modification

• Study Type: Interventional
• Enrollment (Actual): 139
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Angers, France
    • CHU Angers
  • Annecy, France
    • CH d'Annecy
  • Argenteuil, France
    • CH Argenteuil
  • Bordeaux, France
    • Institut Bergonié
  • Bordeaux, France
    • CHU Bordeaux
  • Boulogne, France
    • Ch Boulogne
  • Caen, France
    • CHU Caen
  • Dieppe, France
    • CH de Dieppe
  • Dunkerque, France
    • Ch Dunkerque
  • Le Chesnay, France
    • CH Versailles
  • Lille, France
    • CHU Lille
  • Lyon, France
    • CHU Lyon
  • Meaux, France
    • CH Meaux
  • Metz, France
    • Hôpital Bon Secours
  • Nice, France
    • CHU Nice
  • Orléans La Source, France
    • Hôpital La Source
  • Paris, France
    • Hôpital Necker
  • Rennes, France
    • CHU Rennes
  • Toulouse, France
    • Hopital Purpan

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:

1. Male or female patient ≥ 18 years
2. Philadelphia chromosome positive newly diagnosed chronic myelogenous leukaemia (≤ 4 months) in first chronic phase.
3. Not previously treated with tyrosine kinase inhibitors other than imatinib
4. Prior treatment with imatinib during less than 13 weeks
5. Signed written inform consent
6. Women of childbearing potential (WOCBP) must be using an adequate method of contraception

Exclusion Criteria:

1. Patients with BCR-ABL positive, Philadelphia negative CML
2. Patient previously treated with TKI other than imatinib
3. Pregnancy
4. Active malignancy
5. Concurrent severe diseases which exclude the administration of therapy

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control Arm; cohort 3: Imatinib through dosage ≥ 1000 ng/ml
Active Comparator: Active comparator; Cohort 2 : Imatinib standard dose Imatinib through dosage < 1000 ng/ml	Other: active comparator; Other Names: Cohort 2 : Imatinib standard dose
Experimental: Experimental arm; Cohort 1 : dose adjustment based on trough plasmatic level value Imatinib through dosage < 1000 ng/ml	Drug: Posology dose modification; Other Names: Cohort 1 : dose adjustment based on trough plasmatic

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The major molecular response rate at 12 months in cohort 1.	12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival	5 years
Event free survival	5 years
Progression free survival	5 years
Complete cytogenetic response at 6 and 12 months	12 months
Major molecular response rate at 12 months in cohort 2 and cohort 3.	12 months
Major molecular response at 3, 6, and 9 months	9 months
Complete molecular response 6 and 12 months	12 months
Relationship between plasmatic dosage and efficacy	12 months
Relationship between plasmatic dosage and tolerance	12 months

Collaborators and Investigators

• Sponsor: Versailles Hospital

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): March 1, 2015
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: September 7, 2016
• First Submitted That Met QC Criteria: September 7, 2016
• First Posted (Estimate): September 12, 2016

Study Record Updates

• Last Update Posted (Actual): November 24, 2017
• Last Update Submitted That Met QC Criteria: November 21, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Imatinib Mesylate
• Other Study ID Numbers: 09/38_ Optim Imatinib

Plan for Individual participant data (IPD)

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