Treatment Modification Based on Early Assessment of CML Patients

Modification of Imatinib to Other Tyrosine Kinase Inhibitors Dependent on 3-months Molecular Response of CML Patients

The investigators will check the feasibility of using early molecular response for making treatment decisions. Patients diagnosed with chronic myeloid leukemia will commence imatinib treatment. After 3 months of treatment their response will be assessed. If molecular response would be less the 10% (BCR-ABL1/ABL ISI >10%)imatinib therapy will be stopped and patients will start a different TKI (as nilotinib, dasatinib). The investigators will follow on lab and clinical outcomes.

Study Overview

• Status: Unknown
• Conditions: CML
• Intervention / Treatment: Other: Treatment modification based on molecular response at 3 months

Detailed Description

Objectives:

To establish a national protocol for the treatment of patients with CML. Patients will be stratified by molecular response, and treatment will be adjusted accordingly.

Secondary outcomes To compare clinical outcomes of patients at high risk (transcript level above 10%) to those at low risk (<10%) while using the early switch approach To evaluate the prognostic value of EUTOS, HASFORD, and SOKAL scores using the early switch strategy Patients Patients may be enrolled to the protocol prior to any TKI treatment or at any time point from commencement of imatinib (started at 400 mg daily) and prior to 3 months assessment, if all the necessary baseline data is available, and all other inclusion criteria are met (patients will be excluded if they received treatment with a tyrosine kinase inhibitor other than imatinib)

Inclusion criteria:

1. Adult patients within 6 months after the diagnosis of Philadelphia chromosome-positive CML in the chronic phase

   1. who were not previously treated (with the exception of hydroyurea) for CML or
   2. who were treated with imatinib for CML for up to 3 months, and prior to 3 months assessment (patients will be excluded if they received treatment with a tyrosine kinase inhibitor other than imatinib).
2. Age > 18 years Diagnosis of CML will be made by conventional cytogenetic (chromosome banding analysis) and/or interphase fluorescent in situ hybridization (FISH) analysis of bone marrow containing at least one Philadelphia chromosome-positive metaphase cell. If BCR-ABL1 fusion gene (Philadelphia chromosome) is not detected by conventional cytogenetic analysis, the diagnosis of CML can be confirmed based on FISH analysis or molecular analysis (demonstration of bcr-abl by polymerase chain reaction (PCR)).

Inclusion of patients with any organ dysfunction (cardiac, renal, respiratory, liver) can be done based on the decision of the treating physician.

Exclusion criteria:

Patients will be excluded if they received treatment with a tyrosine kinase inhibitor other than imatinib (i.e., nilotinib, dasatinib) before study entry. Patients may take hydroxyurea or anagrelide for up to 4 weeks prior to imatinib treatment.

Interventions Imatinib 400 mg once daily Response will be assessed after 3 months of therapy. A complete blood count to assess hematologic response and a bone marrow biopsy and/or aspirate, including cytogenetic analysis and molecular analysis for quantitative RT-PCR for BCR-ABL1/ABL will be performed.

Response assessment Assessment of response by molecular analysis of bcr-abl1 will be performed in certified and standardized laboratories (a list of certified laboratories will be distributed).

If a patients has achieved CHR and BCR-ABL1/ABL ISI <10% at 3 months then imatinib will be continued at the dose of 400 mg daily.

If a patient has achieved CHR and BCR-ABL1/ABL ISI >10% at 3 months then imatinib will be stopped and nilotinib 300 mg twice daily or dasatinib 100 mg once daily will be instituted. ECG will be done prior to any change of therapy.

Mutation analysis is recommended prior to the commencement of nilotinib or dasatinib.

Patients will continue to receive the study treatment until the disease will progress or unacceptable toxic effects will developed. In the event of disease progression or the occurrence of adverse event treatment can be stopped or changed under the discretion of the treating physician.

Outcomes Rate of CCyR at 12 months CCyR is defined as absence of Ph-positive metaphases, determined on the basis of G-banding in at least 20 cells in metaphase per bone marrow sample Overall survival Rate of major molecular response at 6, 12, 18, 24 months Cumulative rate of optimal response at 12, 18 months

PFS:

Time from commencement of imatinib till meeting ELN criteria for failure, progression to AP/BC, or death from any cause

EFS:

Time from commencement of imatinib till meeting ELN criteria for failure, progression to AP/BC, grade 3 to 4 adverse event, drug discontinuation (except of the change of imatinib at 3 months according to molecular response), or death from any cause

Safety:

Adverse events will be classified according to the CTCAE NCI US v.3.0 Severe AE

• Study Type: Interventional
• Enrollment (Anticipated): 300
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Liat vidal, MD MSc; Email: vidallit@yahoo.com
• Study Contact Backup: Name: Ofer Shpilberg, MD MPH; Phone Number: +972-3-9377906

Study Locations

• Israel
  • Petah tikva, Israel, 49100
    • Recruiting
    • Rabin Medical Center
    • Contact: Liat vid; Email: vidallit@yahoo.com
    • Contact: Ofer, Shpilberg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 1. Adult patients within 6 months after the diagnosis of Philadelphia chromosome-positive CML in the chronic phase

  1. who were not previously treated (with the exception of hydroyurea) for CML or

  2. who were treated with imatinib for CML for up to 3 months, and prior to 3 months assessment (patients will be excluded if they received treatment with a tyrosine kinase inhibitor other than imatinib).

     2. Age > 18 years Diagnosis of CML will be made by conventional cytogenetic (chromosome banding analysis) and/or interphase fluorescent in situ hybridization (FISH) analysis of bone marrow containing at least one Philadelphia chromosome-positive metaphase cell. If BCR-ABL1 fusion gene (Philadelphia chromosome) is not detected by conventional cytogenetic analysis, the diagnosis of CML can be confirmed based on FISH analysis or molecular analysis (demonstration of bcr-abl by polymerase chain reaction (PCR)).

     Inclusion of patients with any organ dysfunction (cardiac, renal, respiratory, liver) can be done based on the decision of the treating physician.

     Exclusion Criteria:

     Patients will be excluded if they received treatment with a tyrosine kinase inhibitor other than imatinib (i.e., nilotinib, dasatinib) before study entry. Patients may take hydroxyurea or anagrelide for up to 4 weeks prior to imatinib treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Modified by molecular response; Patients will be treated with imatinib upon diagnosis of CML. Molecular response will be assessed at 3 months of therapy. Based on molecular response imatinib will be continued or changed to another TKI	Other: Treatment modification based on molecular response at 3 months; Patients will be treated with imatinib upon diagnosis of CML. Molecular response will be assessed at 3 months of therapy. Based on molecular response imatinib will be continued or changed to another TKI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Rate of complete cytogenetic response	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival		12 months
Rate of major molecular response	Cumulative rate of optimal response at 12, 18 months	12, 24 months
PFS	Time from commencement of imatinib till meeting ELN criteria for failure, progression to AP/BC, or death from any cause	12 months
Severe Adverse events	Adverse events will be classified according to the CTCAE NCI US v.3.0	12 months

Collaborators and Investigators

• Sponsor: Rabin Medical Center
• Collaborators: Rambam Health Care Campus; Hadassah Medical Organization; HaEmek Medical Center, Israel; Wolfson Medical Center; Bnai Zion Medical Center

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (ANTICIPATED): January 1, 2019
• Study Completion (ANTICIPATED): January 1, 2020

Study Registration Dates

• First Submitted: January 6, 2013
• First Submitted That Met QC Criteria: January 7, 2013
• First Posted (ESTIMATE): January 8, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): January 8, 2013
• Last Update Submitted That Met QC Criteria: January 7, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Other Study ID Numbers: CML-IS001