Front-line Treatment of BCR-ABL+ Chronic Myeloid Leukemia (CML) With Dasatinib

Chronic Myeloid Leukemia Clinical Trial

— CML1113  

Official title:

Front-line Treatment of BCR-ABL+ Chronic Myeloid Leukemia (CML) With Dasatinib. An Observational Multicentric Study.

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01761890
• Other study ID #: CML1113
• Secondary ID: RSO ID 714
• Status: Active, not recruiting
• Start date: January 28, 2014
• Est. completion date: December 2022

Study information

• Verified date: August 2021
• Source: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 147
• Est. completion date: December 2022
• Est. primary completion date: December 2, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Chronic Myeloid Leukemia
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Intervention

Behavioral:
• Dasatinib discontinuation
Treatment decision is at the discretion of the investigator and must not be made on the basis of this observational study. Patients should have their treatment initiated in accordance with the summary of product characteristics.

Locations

Country	Name	City	State
Italy	S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo	Alessandria
Italy	Azienda Ospedaliera - Nuovo Ospedale "Torrette"	Ancona
Italy	U.O.C. Ematologia e Terapia Cellulare - Ospedale "C. e G. Mazzoni" di Ascoli Piceno	Ascoli Piceno
Italy	Az.Ospedaliera S.G.Moscati	Avellino
Italy	UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro	Bari
Italy	Azienda Ospedaliera Di Bologna Policlinico S. Orsola - Malpighi	Bologna
Italy	U.O.C. di Onco-Ematologia - Centro di Ricerca e Formazione ad Alta tecnologia nelle Scienze Biomediche	Campobasso
Italy	US Dipartimentale - Centro per le malattie del sangue - Ospedale Civile - S.Giacomo	Castelfranco Veneto
Italy	Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"	Catania
Italy	Azienda Ospedaliero Universitaria Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia e Fisiopatologia dell'Emostasi	Ferrara
Italy	Azienda Ospedaliera di Firenze	Firenze
Italy	Centro Aziendale di Ematologia ASL N. 6	Livorno
Italy	Azienda Ospedaliera Universitaria - Policlinico G. Martino Dipartimento di Medicina Interna - U.O. Messina	Messina
Italy	Divisione di Ematologia - Azienda Ospedaliera Ospedali Riuniti "Papardo Piemonte"	Messina
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico UOC Oncoematologia- Padiglione Marcora 2° piano	Milano
Italy	Ospedale San Gennaro - ASL Napoli 1	Napoli
Italy	zienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia	Napoli
Italy	Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2	Orbassano
Italy	La Maddalena Casa di Cura di Alta Specialità Dipartimento Oncologico di III Livello	Palermo
Italy	zienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia	Palermo
Italy	Cattedra di Ematologia CTMO Università degli Studi di Parma	Parma
Italy	U.O. Ematologia Clinica - Azienda USL di Pescara	Pescara
Italy	Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza	Piacenza
Italy	Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"	Reggio Calabria
Italy	Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova	Reggio Emilia
Italy	Centro Oncologico Basilicata	Rionero in Vulture	Potenza
Italy	Az. Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia	Roma
Italy	Complesso Ospedaliero S. Giovanni Addolorata	Roma
Italy	Padiglione Cesalpino - I piano - Divisione di Ematologia - Ospedale S. Camillo	Roma
Italy	S.C. di Ematologia e Trapianti - I.F.O. Istituto Nazionale Tumori Regina Elena	Roma
Italy	U.O.C. Ematologia - Ospedale S.Eugenio	Roma
Italy	Università Cattolica del Sacro Cuore - Policlinico A. Gemelli	Roma
Italy	Rotondo Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo
Italy	U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"	Siena
Italy	Dipartimento di Oncologia ed Ematologia S.C. Ematologia 2 A.O. Città della Salute e della Scienza di Torino San Giovanni Battista	Torino
Italy	Clinica Ematologica - Policlinico Universitario	Udine
Italy	Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi	Verona

Sponsors (1)

Lead Sponsor	Collaborator
Gruppo Italiano Malattie EMatologiche dell'Adulto

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of dasatinib permanent discontinuing patients.	The cumulative rate of dasatinib permanent discontinuation by 2 years.	After 2 years from study entry.
Secondary	Number of dasatinib permanent discontinuing patients.	The cumulative rate of dasatinib permanent discontinuation by 5 years.	After 5 years from study entry.
Secondary	Number of confirmed MR4 and MR4.5.	The rate of confirmed MR4 and MR4.5 by 24 months.	After 2 years from study entry.
Secondary	Number of confirmed MR4 and MR4.5.	The rate of confirmed MR4 and MR4.5 by 60 months.	After 60 months from study entry.
Secondary	Number of stable MR4 and MR4.5 and characteristics.	The stability of MR4 and MR4.5.	After 60 months from study entry.
Secondary	Number of Complete Cytogenetic Responses (CCgR)	The rate of Complete Cytogenetic Response (CCgR) at 1 year.	After one year from study entry.
Secondary	Number of Major Molecular Response (MMR).	The rate of Major Molecular Response (MMR) at 1 year.	After one year from study entry.
Secondary	Number of days to response (CCgR, MMR, MR4, MR4.5).	The median time to response and the overall estimated probability of response (CCgR, MMR, MR4, MR4.5).	After 4 years from study entry.
Secondary	Number of overal surviving patients		After five years from study entry.
Secondary	Number of progression-free survival patients.		After five years from study entry.
Secondary	Number of failure-free survival patients.		After five years from study entry.
Secondary	Number of event-free survival patients.		After five years from study entry.
Secondary	Number of responses	Overall responses and long-term outcome according to baseline prognostic factors (including: Sokal score34, Euro score35 and EUTOS score36; presence of additional chromosomal abnormalities in Ph+ cells; BCR-ABL transcript type; comorbidity score index).	After 7 years from study entry.
Secondary	Number of responses according to BCR-ABL transcript levels.	Overall responses and long-term outcome according to BCR-ABL transcript levels and CgR at 3 months and at 6 months.	After 3 and 6 months from study entry.
Secondary	Number of patients with fasting glucose modifications.	Fasting glucose modifications (diabetic and normo-glycemic patients) and HbA1C modifications (diabetic patients only) during the first 24 months.	After 24 months from study entry.
Secondary	Number of patients with modifications of body mass index during treatment compared to baseline.	Modifications of body mass index during treatment compared to baseline.	After 7 years from study entry.
Secondary	Number of patients with modifications of serum lipids during treatment compared to baseline.	Modifications of serum lipids during treatment compared to baseline.	After 7 years from study entry.
Secondary	Patient reported quality of life.		At 3, 6, 9, 12, 18, 24 months from study entry.
Secondary	Number of adverse events.		At 3, 6, 9, 12, 18, 24 months from study entry.

External Links

•   GIMEMA Foundation