Sustained Treatment-free Remission in BCR-ABL+ Chronic Myeloid Leukemia
- Registration Number
- NCT02602314
- Brief Summary
The study will investigate in newly diagnosed CP-CML patients the efficacy of NIL frontline therapy vs IM followed by switch to NIL in the case of absence of optimal response as defined by the ELN criteria.
- Detailed Description
This is a prospective, interventional, randomized, two arms, phase IV study evaluating both the depth of the molecular response and the rate of treatment free remission rate in newly diagnosed CP-CML patients treated with NIL or IM followed by switch to NIL in absence of optimal response (defined according the ELN 2013 criteria) as per clinical practice.
The enrolled patients will be randomized 1:1 between NIL and IM. Patients will be stratified according to the Sokal risk score to high versus intermediate/low risk groups. Newly diagnosed patients will be treated according to the registered dose of NIL and IM for frontline chronic phase CML (300 mg BID and 400 mg OAD, respectively). The patients intolerant to IM and the patients without optimal response to IM at 3 months, at 6 months, at 12 months (except the patients with progression to accelerated or blastic phase) will be switched to NIL second line.
The absence of optimal response is defined by at least one of the following ELN criteria: a) Absence of Complete Hematologic Response at 3 months or thereafter; b) Absence of Partial Cytogenetic Response (\> 35% Ph+ metaphases) at 3 months; c) BCR-ABL transcript level \> 10% according to the IS at 3 months; d) Absence of Complete Cytogenetic Response (\> 1% Ph+ metaphases) at 6 months; e) BCR-ABL transcript level \> 1% according to the IS at 6 months; f) Absence of Major Molecular Response (MR3.0, transcript level \> 0.1% according to the IS) at 12 months.
Treatment choice for the patients with progression to advanced disease phase while on IM and for the patients intolerant to or resistant (including progressions to advanced phases) to NIL will be up to the principal investigator of the participating Center. However, information concerning the course and outcome of these patients will be collected and recorded for at least 5 years, and they could be enrolled in investigational studies promoted by GIMEMA or other sponsors.
After the induction of deep molecular remission phase of therapy, i.e. the first two years of the study, residual disease will be closely monitored (quarterly) by Q-PCR assays. All the patients who obtain a reduction greater than 4.0 logs of residual disease (MR4.0) within the first three years of treatment, and maintain this level of response in all the subsequent tests up to the end of the fourth years of therapy qualify for the discontinuation phase of the study. Therefore, all patients who are in MR4.0 after a four-year period of TKI treatment, that must include in its final part at least one years of maintained MR4.0, defined as 12-month period during which the MR4.0 never is lost in 4 consecutive MRD analyses at three-monthly intervals, will enter the treatment free remission (TFR) phase of the study. In case of loss of MR3.0, the last assumed TKI will be resumed at the same dose.
All patients, including those who do not match the criteria for discontinuation of TKI treatment, will continue the assigned treatment and will be followed for 5 years, starting from the date of enrolment.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 450
- Patients with a confirmed diagnosis of BCR/ABL+ CML in chronic phase
Documented chronic phase CML must meet all the following criteria:
< 15% blasts in peripheral blood < 30% blasts plus promyelocytes in peripheral blood < 20% basophils in the peripheral blood
-
100 x 109/L (≥ 100,000/mm3) platelets
- Age ≥18
- ECOG performance status of 0-2
- Evidence of typical BCR-ABL transcripts which are amenable to standardized RQ-PCR
- Adequate end organ function as defined by:
Total bilirubin < 1.5 x ULN (ULN = upper limit of normal in a local institution lab).
Does not apply to patients with isolated hyperbilirubinemia (e.g., Gilbert's disease) grade < 3 SGOT (AST) and SGPT (ALT) ≤ 3 x ULN Serum amylase and lipase ≤ 2 x ULN Alkaline phosphatase ≤ 2.5 x ULN Serum creatinine < 1.5 x ULN
- Having completed the QoL baseline evaluation (i.e., before randomization)
- Written informed consent prior to any study procedures.
- Expression of any atypical BCR-ABL transcripts, instead of the classical P210-encoding type with the e13a2 or the e14a2 junction at screening.
- Previous treatment with BCR-ABL inhibitors for a period longer than 1 month.
- Previous anticancer agents (hydroxyurea, anagrelide, interferon) for CML for a time longer than three months.
- Poorly controlled diabetes mellitus (defined as HbA1c >8%).
- Prior documented history of coronary heart disease, including myocardial infarction, coronary bypass, coronary stent, and symptomatic angina:
LVEF <45% or below the institutional lower limit of the normal range (whichever ishigher) Complete left bundle branch block Right bundle branch block plus left anterior or posterior hemiblock Use of a ventricular-paced pacemaker Congenital long QT syndrome or a known family history of long QT syndrome History of or presence of clinically significant ventricular or atrial tachyarrhythmias
-
Atrial fibrillation or flutter
-
Clinically significant resting bradycardia (< 50 beats per minute)
-
QTc > 450 msec on the average of three serial screening ECGs (using the QTcF formula). If QTcF > 450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and the patient re-tested History or clinical signs of myocardial infarction within 12 months of study entry History of unstable angina within 12 months of study entry Other clinically significant heart disease (e.g. congestive heart failure)
- Uncontrolled hypertension is not a heart disease.
- History of peripheral arterial occlusive disease.
- History of acute pancreatitis within 12 months of study entry, or a past medical history of chronic pancreatitis.
- Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers which cannot be either discontinued or switched to a different medication prior to starting study drug.
- Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and for which cannot be either safely discontinued or switched to a different medication prior to starting study drug.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Imatinib + Nilotinib Imatinib - Imatinib + Nilotinib Nilotinib - Nilotinib Nilotinib -
- Primary Outcome Measures
Name Time Method Number of of patients with molecular response At 24 months from study entry Number of patients who remain in sustained treatment free remission, without molecular relapse After 12 months after entering the treatment-free-remission (TFR) phase
- Secondary Outcome Measures
Name Time Method Number of patiens in progression-free survival 5 years after study entry Number of patients who discontinue treatment At 5 years from study entry Number of patients with major molecular response At 1, 2, 3 and 4 years from study entry Number of toxic events At 5 years from study entry Number of patients with quality of life differences between treatment arms over time At baseline and at 3, 6, 12, 18, 24, 30, 36, 42, 48, and 60 months from study entry. To assess the patient-reported quality of life (QoL) and adherence to therapy at baseline and at 6, 12, 18, 24, 27, 33, 36, 39, 42, 48, 51, 54 and 60 months in the following QoL scales: Fatigue, Physical Functioning and Global Health Status/QoL (outcome measure: EORTC QLQ-C30), Impact on Daily Life and Symptom Burden (outcome measure: EORTC CML-24), Burden of Illness (outcome measure: EORTC QLQ-ELD14).
Number of patients with molecular response 4 years after study entry
Trial Locations
- Locations (82)
S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo
🇮🇹Alessandria, Italy
UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro
🇮🇹Bari, Italy
Ausl Della Romagna, Ospedale "Infermi" - Rimini - Uo Ematologia
🇮🇹Rimini, Italy
Azienda Ospedaliero Universitaria Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia e Fisiopatologia dell'Emostasi
🇮🇹Cona, Italy
Irccs Aou San Martino - Genova - Uo Ematologia E Trapianti
🇮🇹Genova, Italy
ASL Le/1 P.O. Vito Fazzi - U.O. di Ematologia ed UTIE
🇮🇹Lecce, Italy
Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2
🇮🇹Orbassano, Italy
Aou Di Padova - Uo Ematologia
🇮🇹Padova, Italy
Ospedali Riuniti "Villa Sofia-Cervello"
🇮🇹Palermo, Italy
Area Vasta N. 5 Ascoli Piceno - S. Benedetto Del Tronto, Presidio Ospedaliero Av5 Osp. Gen. Prov.Le "C.G.Mazzoni" - Uoc Ematologia
🇮🇹Ascoli Piceno, Italy
Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. Lancisi G. Salesi
🇮🇹Ancona, Italy
Asl Di Asti, Ospedali Riuniti - Presidio Ospedaliero Cardinal G. Massaia - Sc Oncologia
🇮🇹Asti, Italy
Ao Di Rilievo Nazionale E Di Alta Specialità "San Giuseppe Moscati" - Avellino - Uoc Ematologia Con Unità Di Trapianto
🇮🇹Avellino, Italy
Aou Consorziale Policlinico - Bari - Uo Ematologia Con Trapianto
🇮🇹Bari, Italy
Asl Della Provincia Di Barletta, Andria, Trani, Ospedale "Mons. Dimiccoli" - Barletta - Uo Ematologia
🇮🇹Barletta, Italy
Ematologia Torre 6 piano 4 - ASST Papa Giovanni XXIII
🇮🇹Bergamo, Italy
Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi
🇮🇹Bologna, Italy
USD Trapianti di midollo per adulti - Cattedra di Ematologia - Università degli Studi di Brescia
🇮🇹Brescia, Italy
ASL N.8 -Ospedale A. Businco
🇮🇹Cagliari, Italy
Cagliari CTMO - Ematologia - Ospedale "Binaghi"
🇮🇹Cagliari, Italy
U.O.C. Oncoematologia - Istituto Oncologico Veneto Irccs, Presidio Ospedaliero S. Giacomo Apostolo
🇮🇹Castelfranco Veneto, Italy
Gemelli Molise - Campobasso - Uosd Onco-Ematologia
🇮🇹Campobasso, Italy
Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"
🇮🇹Catania, Italy
Ao Di Catanzaro "Pugliese-Ciaccio", Presidio Ospedaliero "Ciaccio - de Lellis" - Ematologia
🇮🇹Catanzaro, Italy
U.O. di Medicina Interna - ASUR Marche 8 - Ospedale Civile
🇮🇹Civitanova Marche, Italy
Ao Di Cosenza, Presidio Ospedaliero Annunziata - Uoc Ematologia
🇮🇹Cosenza, Italy
S.C. Ematologia ASO S. Croce e Carle
🇮🇹Cuneo, Italy
Aou Ospedali Riuniti - Foggia - Uoc Ematologia
🇮🇹Foggia, Italy
Unità di Ricerca e di Malattie del sangue - Ematologia San Luca Vecchio Pad. 16 - 1° Piano
🇮🇹Firenze, Italy
IRCCS_AOU San Martino-IST.Clinica Ematologica
🇮🇹Genova, Italy
Asl Latina, Presidio Ospedaliero Nord - Ospedale Santa Maria Goretti - Uoc Ematologia
🇮🇹Latina, Italy
I.R.S.T. Srl Irccs - Meldola - Sc Oncologia Medica
🇮🇹Meldola, 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. di Ematologia- Ospedale dell'Angelo - Mestre
🇮🇹Mestre, Italy
Asl Napoli 1 Centro, Presidio Ospedaliero Ascalesi - Ospedale S.Maria Di Loreto Nuovo
🇮🇹Napoli, Italy
Fondazione Irccs "Istituto Nazionale Tumori" - Milano - Sc Ematologia
🇮🇹Milano, Italy
Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia
🇮🇹Napoli, Italy
UO Ematologia - AOU Policlinico di Modena
🇮🇹Modena, Italy
Fondazione Irccs Ca' Granda, Ospedale Maggiore Policlinico - Milano - Ematologia - Padiglione Marcora
🇮🇹Milano, Italy
Azienda Ospedaliera di Rilievo Nazionale A. Cardarelli
🇮🇹Napoli, Italy
Ospedale San Gennaro - ASL Napoli 1
🇮🇹Napoli, Italy
Dipartimento Oncologico - Ospedale S.Maria delle Croci
🇮🇹Ravenna, Italy
Asl Salerno, Presidio Ospedaliero Tortora Pagani - Ematologia
🇮🇹Pagani, Italy
S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro
🇮🇹Novara, Italy
U.O. CTMO Ematologia - Osp. S. Francesco
🇮🇹Nuoro, Italy
Asl Pescara, Presidio Ospedaliero 'Spirito Santo' - Uoc Ematologia Clinica
🇮🇹Pescara, Italy
Aou Di Parma - Sc Ematologia E Centro Trapianti Midollo Osseo
🇮🇹Parma, Italy
U.O. di Ematologia con trapianto - Centro di Riferimento Regionale per le coagulopatie rare nel bambino e nell'adulto Dipart. Biomedico di Medicina Interna - A.U. Policlinico "Paolo Giaccone"
🇮🇹Palermo, Italy
Div. di Ematologia di Muraglia - CTMO Ospedale San Salvatore
🇮🇹Pesaro, Italy
Az.Ospedaliera S.G.Moscati
🇮🇹Potenza, Italy
Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale G. da Saliceto
🇮🇹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
Az. Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia
🇮🇹Roma, Italy
Asl Roma 2, Ospedale S. Eugenio- Ospedale S.Eugenio - Uoc Ematologia
🇮🇹Roma, Italy
Divisione Ematologia - Università Campus Bio-Medico
🇮🇹Roma, Italy
UOC Pronto Soccorso e Accettazione Ematologica - Dipartimento Biotecnologie Cellulari ed Ematologia - Università degli Studi di Roma "Sapienza"
🇮🇹Roma, Italy
Università Cattolica del Sacro Cuore - Policlinico A. Gemelli
🇮🇹Roma, Italy
U.O.C. Ematologia - Ospedale S. Eugenio
🇮🇹Rome, Italy
Unità Operativa di Oncologia Giovanni Paolo II "Vito Fazzi"
🇮🇹Rossano, Italy
Aou Senese - Uoc Ematologia E Trapianti
🇮🇹Siena, Italy
Aulss 5 Polesana, Presidio Ospedaliero Di Rovigo - Uosd Ematologia
🇮🇹Rovigo, Italy
Aou "San Giovanni Di Dio E Ruggi D'Aragona" - Salerno - Uoc Ematologia E Trapianti Di Cellule Staminali Emopoietiche
🇮🇹Salerno, Italy
Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza
🇮🇹San Giovanni Rotondo, Italy
Ospedale Di Sassuolo Spa - Ematologia
🇮🇹Sassuolo, Italy
Ematologia - Dipartimento di Medicina Clinica e Sperimentale
🇮🇹Sassari, Italy
A.O. Santa Maria - Terni S.C Oncoematologia
🇮🇹Terni, Italy
Aou Città Della Salute E Della Scienza, Ospedale S. Giovanni Battista Molinette - Torino - Sc Ematologia - Università Degli Studi Di Torino
🇮🇹Torino, Italy
Ospedale Mauriziano Umberto I - Torino - Scdu Ematologia
🇮🇹Torino, Italy
Unità Operativa Di Ematologia - Presidio Ospedaliero Di Treviso - Azienda Ulss N.2 Marca Trevigiana
🇮🇹Treviso, Italy
Aou Città Della Salute E Della Scienza, Ospedale S. Giovanni Battista Molinette - Torino - Sc Ematologia 2
🇮🇹Torino, Italy
Clinica Ematologica-Centro Trapianti e Terapie cellulari Azienda Ospedaliero-Universitaria, Udine
🇮🇹Udine, Italy
Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi
🇮🇹Verona, Italy
Aulss 8 Berica - Ospedale Di Vicenza - Uoc Ematologia
🇮🇹Vicenza, Italy
ULSS N.6 Osp. S. Bortolo
🇮🇹Vicenza, Italy
Vumc - Paesi Bassi
🇳🇱Amsterdam, Netherlands
Meander Mc - Paesi Bassi
🇳🇱Amersfoort, Netherlands
Reinier de Graaf Gasthuis
🇳🇱Delft, Netherlands
A. Schweitzer Zh, Dordwijk - Paesi Bassi
🇳🇱Dordrecht, Netherlands
Zuyderland Medical Center - Paesi Bassi
🇳🇱Heerlen, Netherlands
Spaarne Ziekenhuis - Paesi Bassi
🇳🇱Hoofddorp, Netherlands