Front-line Nilotinib Treatment of BCR-ABL+ Chronic Myeloid Leukaemia in Chronic Phase

Chronic Myeloid Leukaemia Clinical Trial

— CML0912  

Official title:

Front-line Nilotinib Treatment of BCR-ABL+ Chronic Myeloid Leukaemia in Chronic Phase. An Observational Multicentre Study of the GIMEMA CML WP.

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01699217
• Other study ID #: CML0912
• Status: Active, not recruiting
• Start date: June 21, 2013
• Est. completion date: December 2022

Study information

• Verified date: January 2022
• 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 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 127
• Est. completion date: December 2022
• Est. primary completion date: December 16, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• BCR-ABL Positive
• Chronic Myeloid Leukaemia
• Chronic Phase Philadelphia Positive
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

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	Dipartimento Area Medica - Presidio Ospedaliero "C. e G.Mazzoni"	Ascoli Piceno
Italy	Ematologia con trapianto-Università degli Studi di Bari Aldo Moro	Bari
Italy	Policlinico Sant'Orsola Malpighi	Bologna
Italy	USD Trapianti di midollo per adulti - Cattedra di Ematologia - Università degli Studi di Brescia	Brescia
Italy	Divisione di Ematologia Ospedale A. Perrino	Brindisi
Italy	ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO	Cagliari
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	ezione di Ematologia C.T.M.O. Istituti Ospitalieri	Cremona
Italy	Ospedale Santa Croce Divisione di Ematologia Cuneo	Cuneo
Italy	Policlinico di Careggi, Università delgi studi di Firenze	Firenze
Italy	Struttura Complessa di Ematologia Ospedali Riuniti Foggia - Azienda Ospedaliero-Universitaria	Foggia
Italy	Clinica Ematologica - DiMI - Università degli Studi di Genova	Genova
Italy	IRCCS_AOU San Martino-IST-Ematologia 1-Monoblocco 11°piano- lato ponente	Genova
Italy	SOC Ematologia e Centro Trasfusionale Ospedale di Ivrea - ASL TO4	Ivrea
Italy	Divisione di Ematologia Ospedale "Santa Maria Goretti"	Latina
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	U.O. Ematologia e Trapianto di MIdollo - Ist.Scientifico Ospedale San Raffaele	Milano
Italy	UO Centro Trapianti di Midollo - IRCCS Ospedale Maggiore Policlinico	Milano
Italy	Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli"	Napoli
Italy	Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia	Napoli
Italy	Ospedale San Gennaro - ASL Napoli 1	Napoli
Italy	Sez. di Ematologia Clinica Ospedale San Francesco	Nuoro
Italy	Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2 Prof. Giuseppe Saglio	Orbassano
Italy	Università degli Studi di Padova - Ematologia ed Immunologia Clinica	Padova
Italy	Divisione di Ematologia con trapianto di midollo - A.U. Policlinico "Paolo Giaccone"	Palermo
Italy	La Maddalena Casa di Cura di Alta Specialità Dipartimento Oncologico di III Livello	Palermo
Italy	Ospedali Riuniti "Villa Sofia-Cervello"	Palermo
Italy	Cattedra di Ematologia CTMO Università degli Studi di Parma	Parma
Italy	Div. di Ematologia di Muraglia - CTMO Ospedale San Salvatore	Pesaro
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	Università di Pisa - Azienda Ospedaliera Pisana - Dipartimento di Oncologia, dei Trapianti e delle nuove Tecnologie in Medicina - Divisione di Ematologia	Pisa
Italy	Dipartimento Oncologico - Ospedale S.Maria delle Croci	Ravenna
Italy	Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"	Reggio Calabria
Italy	Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova	Reggio Emilia
Italy	Ospedale "Infermi"	Rimini
Italy	U.O. di Ematologia - Centro Oncologico Basilicata	Rionero in Vulture
Italy	Az. Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia	Roma
Italy	Complesso Ospedaliero S. Giovanni Addolorata	Roma
Italy	Pronto Soccorso e Accettazione Ematologica - Dipartimento Biotecnologie Cellulari ed Ematologia - Università degli Studi di Roma "Sapienza"	Roma
Italy	Segreteria di Ematologia - 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	Azienda Sanitaria Locale Viterbo - Polo Ospedaliero Centrale - Ospedale Di Ronciglione - U.O. di Ematologia	Ronciglione
Italy	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	SS.C. di Oncoematologia - Dipartimento di Medicina Clinica e Sperimentale - Azienda Ospedaliera - S. Maria Di Terni	Terni
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	Sezione di Ematologia - Med.II Div. Presidio Ospedaliero S. Chiara di Trento	Trento
Italy	Azienda U.L.S.S.9 - U.O. di Ematologia	Treviso
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	The rate of confirmed MR4		At 24 months from study entry
Secondary	The rate of MMR		At 24, 36, 48, and 60 months from study entry.
Secondary	The rate of MR4		At 24, 36, 48, and 60 months from study entry.
Secondary	The rate of MR4.5		At 24, 36, 48, and 60 months from study entry.
Secondary	The rate of confirmed MR4		At 36, 48, and 60 months from study entry.
Secondary	The rate of stable MR4	(at least three PCR results with MR4 within the last year [± 2 months] and no results > 0.01% during the same period).	At 24, 36, 48, and 60 months from study entry
Secondary	The rate of stable MR4.5	(at least three PCR results with MR4.5 within the last year [± 2 months] and no results > 0.0032% during the same period)	At 24, 36, 48, and 60 months from study entry
Secondary	The rate of confirmed loss of MMR (MR3)		At 60 months from study entry
Secondary	The rate of confirmed loss of MMR		At one year from study entry
Secondary	The rate of Complete Cytogenetic Response		At one year.
Secondary	The cumulative rate of permanent NIL discontinuation	(for failure [defined according to ELN recommendations 2009], intolerance, and death for any reason; not for patients in = MR4 entering clinical trials exploring nilotinib discontinuation)	At 5 years from study entry