CML1113: Front-line Treatment of BCR-ABL+ Chronic Myeloid Leukemia (CML) With Dasatinib

Sponsor

Gruppo Italiano Malattie EMatologiche dell'Adulto (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01761890

Collaborator

(none)

147

Enrollment

Locations

106.1

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Myeloid Leukemia	Behavioral: Dasatinib discontinuation

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.

Study Design

Study Type:

Observational

Actual Enrollment :

147 participants

Observational Model:

Case-Only

Time Perspective:

Prospective

Official Title:

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

Actual Study Start Date :

Jan 28, 2014

Actual Primary Completion Date :

Dec 2, 2018

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
CML patients	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.

Arm

Intervention/Treatment

CML patients

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.

Outcome Measures

Primary Outcome Measures

Number of dasatinib permanent discontinuing patients. [After 2 years from study entry.]
The cumulative rate of dasatinib permanent discontinuation by 2 years.

Secondary Outcome Measures

Number of dasatinib permanent discontinuing patients. [After 5 years from study entry.]
The cumulative rate of dasatinib permanent discontinuation by 5 years.
Number of confirmed MR4 and MR4.5. [After 2 years from study entry.]
The rate of confirmed MR4 and MR4.5 by 24 months.
Number of confirmed MR4 and MR4.5. [After 60 months from study entry.]
The rate of confirmed MR4 and MR4.5 by 60 months.
Number of stable MR4 and MR4.5 and characteristics. [After 60 months from study entry.]
The stability of MR4 and MR4.5.
Number of Complete Cytogenetic Responses (CCgR) [After one year from study entry.]
The rate of Complete Cytogenetic Response (CCgR) at 1 year.
Number of Major Molecular Response (MMR). [After one year from study entry.]
The rate of Major Molecular Response (MMR) at 1 year.
Number of days to response (CCgR, MMR, MR4, MR4.5). [After 4 years from study entry.]
The median time to response and the overall estimated probability of response (CCgR, MMR, MR4, MR4.5).
Number of overal surviving patients [After five years from study entry.]
Number of progression-free survival patients. [After five years from study entry.]
Number of failure-free survival patients. [After five years from study entry.]
Number of event-free survival patients. [After five years from study entry.]
Number of responses [After 7 years from study entry.]
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).
Number of responses according to BCR-ABL transcript levels. [After 3 and 6 months from study entry.]
Overall responses and long-term outcome according to BCR-ABL transcript levels and CgR at 3 months and at 6 months.
Number of patients with fasting glucose modifications. [After 24 months from study entry.]
Fasting glucose modifications (diabetic and normo-glycemic patients) and HbA1C modifications (diabetic patients only) during the first 24 months.
Number of patients with modifications of body mass index during treatment compared to baseline. [After 7 years from study entry.]
Modifications of body mass index during treatment compared to baseline.
Number of patients with modifications of serum lipids during treatment compared to baseline. [After 7 years from study entry.]
Modifications of serum lipids during treatment compared to baseline.
Patient reported quality of life. [At 3, 6, 9, 12, 18, 24 months from study entry.]
Number of adverse events. [At 3, 6, 9, 12, 18, 24 months from study entry.]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Centro Oncologico Basilicata	Rionero in Vulture	Potenza	Italy
2	S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo	Alessandria		Italy
3	Azienda Ospedaliera - Nuovo Ospedale "Torrette"	Ancona		Italy
4	U.O.C. Ematologia e Terapia Cellulare - Ospedale "C. e G. Mazzoni" di Ascoli Piceno	Ascoli Piceno		Italy
5	Az.Ospedaliera S.G.Moscati	Avellino		Italy
6	UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro	Bari		Italy
7	Azienda Ospedaliera Di Bologna Policlinico S. Orsola - Malpighi	Bologna		Italy	40138
8	U.O.C. di Onco-Ematologia - Centro di Ricerca e Formazione ad Alta tecnologia nelle Scienze Biomediche	Campobasso		Italy
9	US Dipartimentale - Centro per le malattie del sangue - Ospedale Civile - S.Giacomo	Castelfranco Veneto		Italy
10	Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"	Catania		Italy
11	Azienda Ospedaliero Universitaria Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia e Fisiopatologia dell'Emostasi	Ferrara		Italy
12	Azienda Ospedaliera di Firenze	Firenze		Italy	50011
13	Centro Aziendale di Ematologia ASL N. 6	Livorno		Italy
14	Azienda Ospedaliera Universitaria - Policlinico G. Martino Dipartimento di Medicina Interna - U.O. Messina	Messina		Italy
15	Divisione di Ematologia - Azienda Ospedaliera Ospedali Riuniti "Papardo Piemonte"	Messina		Italy
16	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico UOC Oncoematologia- Padiglione Marcora 2° piano	Milano		Italy
17	Ospedale San Gennaro - ASL Napoli 1	Napoli		Italy
18	zienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia	Napoli		Italy
19	Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2	Orbassano		Italy
20	La Maddalena Casa di Cura di Alta Specialità Dipartimento Oncologico di III Livello	Palermo		Italy
21	zienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia	Palermo		Italy
22	Cattedra di Ematologia CTMO Università degli Studi di Parma	Parma		Italy
23	U.O. Ematologia Clinica - Azienda USL di Pescara	Pescara		Italy
24	Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza	Piacenza		Italy
25	Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"	Reggio Calabria		Italy
26	Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova	Reggio Emilia		Italy
27	Az. Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia	Roma		Italy
28	Complesso Ospedaliero S. Giovanni Addolorata	Roma		Italy
29	Padiglione Cesalpino - I piano - Divisione di Ematologia - Ospedale S. Camillo	Roma		Italy
30	S.C. di Ematologia e Trapianti - I.F.O. Istituto Nazionale Tumori Regina Elena	Roma		Italy
31	U.O.C. Ematologia - Ospedale S.Eugenio	Roma		Italy
32	Università Cattolica del Sacro Cuore - Policlinico A. Gemelli	Roma		Italy
33	Rotondo Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo		Italy
34	U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"	Siena		Italy
35	Dipartimento di Oncologia ed Ematologia S.C. Ematologia 2 A.O. Città della Salute e della Scienza di Torino San Giovanni Battista	Torino		Italy
36	Clinica Ematologica - Policlinico Universitario	Udine		Italy
37	Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi	Verona		Italy