Clinical trial NCT01761890: Front-line Treatment of BCR-ABL+ Chronic Myeloid Leukemia (CML) With Dasatinib
Official title: Front-line Treatment of BCR-ABL+ Chronic Myeloid Leukemia (CML) With Dasatinib. An Observational Multicentric Study.
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Chronic Myeloid Leukemia
Keywords: Chronic Myeloid Leukemia
Early phase
CML
Dasatinib
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor class: OTHER
First posted: 2013-01-07
Enrollment: 147
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: This is a multicentre, observational, prospective study of newly diagnosed chronic phase CML patients treated frontline with Dasatinib 100 mg QD.

Brief summary: The GIMEMA CML Working Party promotes a multicentric, observational, non company sponsored, prospective study of Chronic Myeloid Leukemia (CML) patients treated frontline with dasatinib. Patients will be followed for 5 years. This study will help the definition of guidelines for the treatment of CML patients in early phases.

The primary objective of the study is to describe, in the clinical practice, the rate of events leading to permanent discontinuation after 2 years of treatment with dasatinib as frontline therapy in newly diagnosed CML patients.

Detailed description: The primary objective is to describe, in the clinical practice, the rate of events leading to permanent discontinuation after 2 years of treatment with dasatinib as frontline therapy in newly diagnosed CML patients. Imatinib mesylate, a protein tyrosine kinase inhibitor (TKI) targeting BCR-ABL, has become in the last decade the standard of care for Chronic Myeloid Leukaemia (CML) in chronic phase (CP)1-3. Dasatinib is a second generation TKI, effective in imatinib-resistant and imatinib-intolerant patients, which demonstrated superior efficacy to imatinib in early CP BCR-ABL+ CML patients 4,6,7. Most data on second generation TKIs are from company-sponsored studies, generally implemented in selected referral centres. The long-term outcome is still unknown. The high rate of study discontinuation observed within the phase 3 study may influence the mid-term and the long-term data interpretation6,7. A long-term post-marketing surveillance in large independent trial is extremely important to confirm the feasibility of a frontline treatment with the second generation TKI dasatinib and to evaluate the efficacy in a nationwide experience. Moreover, obtaining a deep molecular response is extremely relevant in order to consider TKIs discontinuation. This condition is known as "Complete Molecular Response" (CMR) and is further defined according to the sensitivity achieved (for the definition see the "Criteria of evaluation" section). As far as treatment discontinuation, two experiences have been published so far, aimed at evaluating the persistence of the CMR after imatinib discontinuation. The first was a pilot study32 where 12 patients were included. These 12 patients discontinued imatinib after at least 2 years of CMR (median duration of negativity, 32 months). Six patients displayed a molecular relapse with a detectable BCR-ABL transcript at 1, 2, 3, 4, and 5 months. Imatinib was then reintroduced and led to a novel molecular response. Six other patients (50%) still have an undetectable level of BCR-ABL transcript after a median follow-up of 18 months (range, 9-24 months). The results of this pilot trial have been confirmed and extended in a second trial, the STIM trial33: 100 patients were enrolled, median follow-up 17 months, 69 patients with at least 12 months follow-up: 42 (61%) of these 69 patients relapsed (40 before 6 months, one patient at month 7, and one at month 19). At 12 months, the probability of persistent CMR for these 69 patients was 41% (95% CI 29-52). All patients who relapsed responded to reintroduction of imatinib. An increase of the CMR rate could possibly translate in a higher proportion of patients candidate to stopping anti-CML treatment, with higher probability of remaining disease-free in the long term. Interestingly, dasatinib was able to induce higher 36-month cumulative MR4 and MR4.5 rates than imatinib7. The advantages of this possible future scenario could be: first, the possibility of treatment discontinuation at least in patients with chronic clinical adverse events; second, a potential reduction of the costs of TKI treatment (after the introduction of TKI, the costs of CML treatment is increasing year by year, with the increasing prevalence of CML patients).

In summary, 1) Most data on second generation TKIs are from company-sponsored studies; 2) The high rate of study discontinuation observed within the phase III study may influence the data interpretation; 3) A long-term post-marketing surveillance in large independent trial is extremely important to confirm the efficacy in a nationwide experience; 4) The persistence of CMR after TKI discontinuation have been described in selected patients with "deep" molecular response; 5) A stable CMR is a pre-requisite for treatment discontinuation; 6) A detailed description of the kinetic of the molecular response, potentially related to a subsequent treatment discontinuation, will be done.

Eligibility criteria: Inclusion Criteria:

* Cytogenetic and/or molecular confirmed diagnosis of Ph+ and/or BCR-ABL+ CML; Age 18 years;
* Early chronic phase, less than 6 months from diagnosis. Prior treatment with Hydroxyurea or Anagrelide is allowed;
* Signed written informed consent according to ICH/EU/GCP and national local laws prior to any study procedures.

Exclusion Criteria:

* Prior treatment with any protein tyrosin-kinase inhibitor (TKI) or interferon;
* Recommendations and precautions before allocating a new CML case to dasatinib are fully described in the prescribing information.

Primary outcomes:
measure: Number of dasatinib permanent discontinuing patients.
timeFrame: After 2 years from study entry.
Secondary outcomes:
measure: Number of dasatinib permanent discontinuing patients.
timeFrame: After 5 years from study entry.
measure: Number of confirmed MR4 and MR4.5.
timeFrame: After 2 years from study entry.
measure: Number of confirmed MR4 and MR4.5.
timeFrame: After 60 months from study entry.
measure: Number of stable MR4 and MR4.5 and characteristics.
timeFrame: After 60 months from study entry.
measure: Number of Complete Cytogenetic Responses (CCgR)
timeFrame: After one year from study entry.
measure: Number of Major Molecular Response (MMR).
timeFrame: After one year from study entry.
measure: Number of days to response (CCgR, MMR, MR4, MR4.5).
timeFrame: After 4 years from study entry.
measure: Number of overal surviving patients
timeFrame: After five years from study entry.
measure: Number of progression-free survival patients.
timeFrame: After five years from study entry.
measure: Number of failure-free survival patients.
timeFrame: After five years from study entry.
measure: Number of event-free survival patients.
timeFrame: After five years from study entry.
measure: Number of responses
timeFrame: After 7 years from study entry.
measure: Number of responses according to BCR-ABL transcript levels.
timeFrame: After 3 and 6 months from study entry.
measure: Number of patients with fasting glucose modifications.
timeFrame: After 24 months from study entry.
measure: Number of patients with modifications of body mass index during treatment compared to baseline.
timeFrame: After 7 years from study entry.
measure: Number of patients with modifications of serum lipids during treatment compared to baseline.
timeFrame: After 7 years from study entry.
measure: Patient reported quality of life.
timeFrame: At 3, 6, 9, 12, 18, 24 months from study entry.
measure: Number of adverse events.
timeFrame: At 3, 6, 9, 12, 18, 24 months from study entry.
Other outcomes:
Locations:
city: Rionero in Vulture
country: Italy
facility: Centro Oncologico Basilicata
state: Potenza
city: Alessandria
country: Italy
facility: S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo
city: Ancona
country: Italy
facility: Azienda Ospedaliera - Nuovo Ospedale "Torrette"
city: Ascoli Piceno
country: Italy
facility: U.O.C. Ematologia e Terapia Cellulare - Ospedale "C. e G. Mazzoni" di Ascoli Piceno
city: Avellino
country: Italy
facility: Az.Ospedaliera S.G.Moscati
city: Bari
country: Italy
facility: UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro
city: Bologna
country: Italy
facility: Azienda Ospedaliera Di Bologna Policlinico S. Orsola - Malpighi
city: Campobasso
country: Italy
facility: U.O.C. di Onco-Ematologia - Centro di Ricerca e Formazione ad Alta tecnologia nelle Scienze Biomediche
city: Castelfranco Veneto
country: Italy
facility: US Dipartimentale - Centro per le malattie del sangue - Ospedale Civile - S.Giacomo
city: Catania
country: Italy
facility: Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"
city: Ferrara
country: Italy
facility: Azienda Ospedaliero Universitaria Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia e Fisiopatologia dell'Emostasi
city: Firenze
country: Italy
facility: Azienda Ospedaliera di Firenze
city: Livorno
country: Italy
facility: Centro Aziendale di Ematologia ASL N. 6
city: Messina
country: Italy
facility: Azienda Ospedaliera Universitaria - Policlinico G. Martino Dipartimento di Medicina Interna - U.O. Messina
city: Messina
country: Italy
facility: Divisione di Ematologia - Azienda Ospedaliera Ospedali Riuniti "Papardo Piemonte"
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico UOC Oncoematologia- Padiglione Marcora 2° piano
city: Napoli
country: Italy
facility: Ospedale San Gennaro - ASL Napoli 1
city: Napoli
country: Italy
facility: zienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia
city: Orbassano
country: Italy
facility: Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2
city: Palermo
country: Italy
facility: La Maddalena Casa di Cura di Alta Specialità Dipartimento Oncologico di III Livello
city: Palermo
country: Italy
facility: zienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia
city: Parma
country: Italy
facility: Cattedra di Ematologia CTMO Università degli Studi di Parma
city: Pescara
country: Italy
facility: U.O. Ematologia Clinica - Azienda USL di Pescara
city: Piacenza
country: Italy
facility: Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza
city: Reggio Calabria
country: Italy
facility: Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"
city: Reggio Emilia
country: Italy
facility: Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova
city: Roma
country: Italy
facility: Az. Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia
city: Roma
country: Italy
facility: Complesso Ospedaliero S. Giovanni Addolorata
city: Roma
country: Italy
facility: Padiglione Cesalpino - I piano - Divisione di Ematologia - Ospedale S. Camillo
city: Roma
country: Italy
facility: S.C. di Ematologia e Trapianti - I.F.O. Istituto Nazionale Tumori Regina Elena
city: Roma
country: Italy
facility: U.O.C. Ematologia - Ospedale S.Eugenio
city: Roma
country: Italy
facility: Università Cattolica del Sacro Cuore - Policlinico A. Gemelli
city: San Giovanni Rotondo
country: Italy
facility: Rotondo Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza
city: Siena
country: Italy
facility: U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"
city: Torino
country: Italy
facility: Dipartimento di Oncologia ed Ematologia S.C. Ematologia 2 A.O. Città della Salute e della Scienza di Torino San Giovanni Battista
city: Udine
country: Italy
facility: Clinica Ematologica - Policlinico Universitario
city: Verona
country: Italy
facility: Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi
Study officials:
affiliation: Orsola Malpighi, Bologna
name: Michele Baccarani, Pr.
role: STUDY_CHAIR
References: