Clinical trial NCT01699217: Front-line Nilotinib Treatment of BCR-ABL+ Chronic Myeloid Leukaemia in Chronic Phase
Official title: Front-line Nilotinib Treatment of BCR-ABL+ Chronic Myeloid Leukaemia in Chronic Phase. An Observational Multicentre Study of the GIMEMA CML WP.
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Chronic Phase Philadelphia Positive
BCR-ABL Positive
Chronic Myeloid Leukaemia
Keywords: Chronic Myeloid Leukaemia
Philadelphia positive
BCR-ABL positive
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor class: OTHER
First posted: 2012-10-03
Enrollment: 129
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: 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.

Brief summary: The GIMEMA CML Working Party promotes a multicentre, observational, prospective study of CML patients treated frontline with NIL. Patients will be followed for 5 years. This study will help the definition of guidelines for the treatment of CML patients in early CP.

Detailed description: The primary objective of the study is to describe the stability of molecular response with NIL as frontline therapy in newly diagnosed, unselected, CP CML patients, in an independent, investigator-initiated observational study. Imatinib mesylate (IM), 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)1,2. Nilotinib (NIL) is a second generation TKI, effective in IM-resistant and IM-intolerant patients, which demonstrated superior efficacy to IM in early CP BCR-ABL+ CML patients3. Currently, the most important target of the treatment of CML with TKIs is the major molecular response (MMR), defined as a ≥ 3 log reduction in BCR-ABL/ABL transcript level, marker of better long-term outcome. With imatinib therapy, achieving a MMR correlates with an improved probability of a durable cytogenetic remission30. Results from IRIS suggest that a MMR after 12 months of imatinib therapy may be a marker of stable response. Further on, the IRIS study showed that patients with a MMR after 12 months of therapy had a significantly better probability of disease-free survival compared with those in complete cytogenetic remission, but not in MMR31. Moreover, obtaining an undetectable BCR-ABL transcript level 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, 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. 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). Standardized molecular monitoring has become widely available in Europe through the efforts of EUTOS cooperation19 and now allows for the generation of comparable data on the residual disease using recalculation on the international scale despite these data being analyzed in many different laboratories. These advances in the standardization of molecular responses and the improvement of targeted therapy have allowed for comparable response assessment across Italian Centres and early treatment optimization of patients.

In summary, 1) monitoring of molecular response and of deep and sustained molecular response, provides a straightforward opportunity to assess patients' response and possible prognosis in the use of targeted therapy. 2) Most data on second generation TKIs are from company-sponsored studies generally implemented in selected referral centres. 3) The detailed description of the kinetic of the molecular response and, particularly, the rate of stable MR4, potentially related in turn with a subsequent treatment discontinuation, within the frame of a long-term post-marketing surveillance observational trial offered to all eligible patients followed at a nation-wide, independent multicentre group is the core distinctive feature of this observational trial.

Eligibility criteria: Inclusion Criteria:

* Age: \>=18 years;
* Patients with chronic phase Ph+ and/or BCR-ABL+ CML, newly diagnosed (less than 6 months);
* Prior treatment with Hydroxyurea or Anagrelide is allowed;
* Prior treatment with IM for less than 30 days is allowed;
* Signed written informed const according to ICH/EU/GCP and national local laws.

Exclusion Criteria:

* Patients who are pregnant (negative pregnancy test is requested within 2 days before nilotinib start) or breast feeding, or adults of reproductive potential not employing an effective method of birth control.
* Newly diagnosed Ph+ and/or BCR-ABL+ CML patients in advanced phases (accelerated or blastic phase).
* Prior treatment with nilotinib, dasatinib, or other tyrosine-kinase inhibitors.

Primary outcomes:
measure: The rate of confirmed MR4
timeFrame: At 24 months from study entry
Secondary outcomes:
measure: The rate of MMR
timeFrame: At 24, 36, 48, and 60 months from study entry.
measure: The rate of MR4
timeFrame: At 24, 36, 48, and 60 months from study entry.
measure: The rate of MR4.5
timeFrame: At 24, 36, 48, and 60 months from study entry.
measure: The rate of confirmed MR4
timeFrame: At 36, 48, and 60 months from study entry.
measure: The rate of stable MR4
timeFrame: At 24, 36, 48, and 60 months from study entry
measure: The rate of stable MR4.5
timeFrame: At 24, 36, 48, and 60 months from study entry
measure: The rate of confirmed loss of MMR (MR3)
timeFrame: At 60 months from study entry
measure: The rate of confirmed loss of MMR
timeFrame: At one year from study entry
measure: The rate of Complete Cytogenetic Response
timeFrame: At one year.
measure: The cumulative rate of permanent NIL discontinuation
timeFrame: At 5 years from study entry
Other outcomes:
Locations:
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: Dipartimento Area Medica - Presidio Ospedaliero "C. e G.Mazzoni"
city: Bari
country: Italy
facility: Ematologia con trapianto-Università degli Studi di Bari Aldo Moro
city: Bologna
country: Italy
facility: Policlinico Sant'Orsola Malpighi
city: Brescia
country: Italy
facility: USD Trapianti di midollo per adulti - Cattedra di Ematologia - Università degli Studi di Brescia
city: Brindisi
country: Italy
facility: Divisione di Ematologia Ospedale A. Perrino
city: Cagliari
country: Italy
facility: ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO
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: Cremona
country: Italy
facility: ezione di Ematologia C.T.M.O. Istituti Ospitalieri
city: Cuneo
country: Italy
facility: Ospedale Santa Croce Divisione di Ematologia Cuneo
city: Firenze
country: Italy
facility: Policlinico di Careggi, Università delgi studi di Firenze
city: Foggia
country: Italy
facility: Struttura Complessa di Ematologia Ospedali Riuniti Foggia - Azienda Ospedaliero-Universitaria
city: Genova
country: Italy
facility: Clinica Ematologica - DiMI - Università degli Studi di Genova
city: Genova
country: Italy
facility: IRCCS_AOU San Martino-IST-Ematologia 1-Monoblocco 11°piano- lato ponente
city: Ivrea
country: Italy
facility: SOC Ematologia e Centro Trasfusionale Ospedale di Ivrea - ASL TO4
city: Latina
country: Italy
facility: Divisione di Ematologia Ospedale "Santa Maria Goretti"
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: U.O. Ematologia e Trapianto di MIdollo - Ist.Scientifico Ospedale San Raffaele
city: Milano
country: Italy
facility: UO Centro Trapianti di Midollo - IRCCS Ospedale Maggiore Policlinico
city: Napoli
country: Italy
facility: Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli"
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia
city: Napoli
country: Italy
facility: Ospedale San Gennaro - ASL Napoli 1
city: Nuoro
country: Italy
facility: Sez. di Ematologia Clinica Ospedale San Francesco
city: Orbassano
country: Italy
facility: Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2 Prof. Giuseppe Saglio
city: Padova
country: Italy
facility: Università degli Studi di Padova - Ematologia ed Immunologia Clinica
city: Palermo
country: Italy
facility: Divisione di Ematologia con trapianto di midollo - A.U. Policlinico "Paolo Giaccone"
city: Palermo
country: Italy
facility: La Maddalena Casa di Cura di Alta Specialità Dipartimento Oncologico di III Livello
city: Palermo
country: Italy
facility: Ospedali Riuniti "Villa Sofia-Cervello"
city: Parma
country: Italy
facility: Cattedra di Ematologia CTMO Università degli Studi di Parma
city: Pesaro
country: Italy
facility: Div. di Ematologia di Muraglia - CTMO Ospedale San Salvatore
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: Pisa
country: Italy
facility: Università di Pisa - Azienda Ospedaliera Pisana - Dipartimento di Oncologia, dei Trapianti e delle nuove Tecnologie in Medicina - Divisione di Ematologia
city: Ravenna
country: Italy
facility: Dipartimento Oncologico - Ospedale S.Maria delle Croci
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: Rimini
country: Italy
facility: Ospedale "Infermi"
city: Rionero in Vulture
country: Italy
facility: U.O. di Ematologia - Centro Oncologico Basilicata
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: Pronto Soccorso e Accettazione Ematologica - Dipartimento Biotecnologie Cellulari ed Ematologia - Università degli Studi di Roma "Sapienza"
city: Roma
country: Italy
facility: Segreteria di Ematologia - 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: Ronciglione
country: Italy
facility: Azienda Sanitaria Locale Viterbo - Polo Ospedaliero Centrale - Ospedale Di Ronciglione - U.O. di Ematologia
city: San Giovanni Rotondo
country: Italy
facility: 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: Terni
country: Italy
facility: SS.C. di Oncoematologia - Dipartimento di Medicina Clinica e Sperimentale - Azienda Ospedaliera - S. Maria Di Terni
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: Trento
country: Italy
facility: Sezione di Ematologia - Med.II Div. Presidio Ospedaliero S. Chiara di Trento
city: Treviso
country: Italy
facility: Azienda U.L.S.S.9 - U.O. di Ematologia
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: Department of Hematology and Oncological Sciences, S.Orsola-Malpighi Hospital, University of Bologna
name: Gianantonio Rosti, Pr.
role: PRINCIPAL_INVESTIGATOR
References: