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Nilotinib

Tyrosine Kinase Inhibitors

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Tyrosine

Administered orally at the dose of 300 mg twice daily (total daily dose 600 mg daily) for 24 months (study core), and indefinitely if it is in the interest of the patient (the drug will be given free-of-charge after 24 months to all those patients achieving the CMR4 at 24 months and in absence of safety concerns). Nilotinib dose is increased to 400 mg BID in case of suboptimal response or failure (with the exception of patients who will fail for progression to ABP: in case of progression to ABP, the patient will not be treated with study drug and the choise of the treatment will be up to the physician).

Gianantonio Rosti

This study is an open-label, multicentric, phase IIIb study of NILOTINIB administered orally twice daily for 24 months and indefinitely if it is in the interest of the patient.

The primary objective of the trial is to evaluate the efficacy of nilotinib, 300 mg twice daily with dose increase to 400 mg twice daily in case of suboptimal response or failure (excluding patients who will fail for progression to ABP), in a population of patients with Ph-positive, BCR-ABL positive CML in early CP.

This study is an open-label, multicentric, phase IIIb study of NILOTINIB administered orally at the dose of 300 mg twice daily (total daily dose 600 mg daily) for 24 months (study core), and indefinitely if it is in the interest of the patient (the drug will be given free-of-charge after 24 months to all those patients achieving the CMR4 at 24 months and in absence of safety concerns). Nilotinib dose is increased to 400 mg BID in case of suboptimal response or failure (with the exception of patients who will fail for progression to ABP: in case of progression to ABP, the patient will not be treated with study drug and the choice of the treatment will be up to the physician).

Study duration is estimated in 6 years, 1 year of estimated enrollment, 2 years therapy duration. Thereafter, information on course and survival is due for other 3 years.

The main data analysis will be performed when all patients will complete 24 months of treatment (or discontinued earlier). Safety and tolerability profile will be assessed by collecting hematologic and non-hematologic adverse events, laboratory examinations and ECG data. The molecular response will be assessed using the GIMEMA standardized molecular laboratories (Labnet network).

Nilotinib in PH+, BCR-, ABL+ CML Patients

The Protein Tyrosine Kinase Inhibitor Nilotinib as First-line Treatment of Ph+, BCR-, ABL+ Chronic Myeloid Leukemia (CML) in Early Chronic Phase: a Phase IIIb, Multicenter Study to Assess the Complete Molecular Response

To assess the complete molecular response (CMR4) rate at 24 months of treatment. For the purpose of this protocol, CMR is defined as a negative results of quantitative RT-PCR for BCR-ABL transcripts in a peripheral blood sample of at least 10 ml with a minimum sensitivity of 1:10,000, that corresponds to at least a 4-log reduction (hence, CMR4)

Number of fully compliant patients and number of patients who do not comply with treatment

From the date of the first nilotinib dose to death

From the date of the first nilotinib dose to progression to AP or BP or death

From the date of the first nilotinib dose to failure\* or progression or death

From the date of the first nilotinib to any event. Including treatment discontinuation for adverse events, failure, progression to AP or BP, or death, whichever comes first.

Gruppo Italiano Malattie EMatologiche dell'Adulto

Antineoplastic Agents

Antisickling Agents

Fibrinolytic Agents

Platelet Aggregation Inhibitors

Hydroxyurea

Anagrelide

Michele BACCARANI

Treating Ph pos CML with Imatinib is very effective since the majority of the patients achieve a complete cytogenetic response and a major molecular response and are alive and progression-free after 5 years. However, the great majority of responding patients are not leukemia-free and may be at risk of progression, molecular, cytogenetic and clinical, at any time. In case of disease progression due to Imatinib failure, nilotinib has been found to be very effective, as expected from the preclinical profile of the drug, that is much more potent against BCR-ABL and inhibits nearly all the imatinib-resistant BCR-ABL mutants. For these reasons, nilotinib is going to be registered for the treatment of imatinib-resistant CMl patients. For the same reasons, nilotinib is expected to be more efficient than imatinib also front-line, based on the principle that we should aim at preventing the emergence of resistance better that at treating resistance once it has emerged. This expectation can be tested safely, because the "toxicity profile" of Nilotinib may be even more convenient than that of Imatinib, due to the lower frequency of edema and fluid retention.

Study Phase:

Phase II, Prospective, multicentric, non randomized, open label

Objectives:

The primary objective of the trial is to investigate the cytogenetic and molecular effects of the protein tyrosine kinase (PTK) inhibitor nilotinib in the treatment of early chronic phase Ph+ CML.

The secondary objectives are:

To investigate in early CP Ph+ CML patients treated with nilotinib the clinical and the hematologic effects, the effect on bcr/abl point mutations, the kinetic of the response, the toxicity, the compliance to treatment and the dose density.

Study design:

This study is an open-label, multicenter, exploratory, Phase II study of nilotinib administered orally twice daily for one year. For the patients who will benefit an extension to 4 years is planned.

Visit Schedule and Assessments:

A visit with blood counts and differential and serum chemistry is due baseline, every 15 days for 3 months, hence every 30 days.

An ECG is due baseline, after 15 and 30 days, hence at 60, 90, 150, 240 and 360 days.

An echocardiogram is due baseline and at end-of-study (360 days) or early withdrawal.

A bone marrow aspirate is due baseline (cytology, cytogenetics and quantitative molecular biology), after 3 and 6 months (cytology and cytogenetics) and after 12 months (cytology, cytogenetics, quantitative molecular biology and mutational analysis).

A peripheral blood sample is due baseline, at 30, 60, 90, 180, 270 and 360 days for quantitative molecular biology.

After the end of the study (i.e. after one year) clinical, cytogenetic and molecular data are due every 6 months.

Biologic Monitoring:

Bone marrow and peripheral blood cells will be collected before, during and at the end of the study, stored at the central lab in Bologna and used for molecular assays that are listed in details in the protocol, with the exclusion of any test allowing the identification of patients genotype. The samples are kept for a minimum of 10 years and can be destroyed upon patient request. A specific consent form to the sample storage will be submitted to the patients.

Nilotinib as First-line Treatment of Ph+ CML in Early Chronic Phase

The Protein Tyrosine Kinase Inhibitor Nilotinib as First-line Treatment of Ph+ Chronic Myeloid Leucemia (CML) in Early Chronic Phase: a Phase II Exploratory, Multicenter Study. GIMEMA Protocol CML 0307. EUDRACT 2007-000597-22.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Nilotinib in PH+, BCR-, ABL+ CML Patients	NCT01535391	Chronic Myeloid...	Nilotinib	18 Years -	Gruppo Italiano Malattie EMatologiche dell'Adulto
Nilotinib as First-line Treatment of Ph+ CML in Early Chronic Phase	NCT00481052	Chronic Myeloid...	Nilotinib	18 Years -	Gruppo Italiano Malattie EMatologiche dell'Adulto

Spots Global Cancer Trial Database for early chronic phase