Clinical trial NCT02602314: Sustained Treatment-free Remission in BCR-ABL+ Chronic Myeloid Leukemia
Official title: Sustained Treatment-free Remission in BCR-ABL+ Chronic Myeloid Leukemia: a Prospective Study Comparing Nilotinib Versus Imatinib With Switch to Nilotinib in Absence of Optimal Response. SUSTRENIM Study - GIMEMA CLM1415
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Chronyc Myeloid Leukemia
Keywords: Chronic myeloid leukemia
Nilotinib
Imatinib
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor class: OTHER
First posted: 2015-11-11
Enrollment: 450
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.

Primary outcomes:
measure: Number of of patients with molecular response
timeFrame: At 24 months from study entry
measure: Number of patients who remain in sustained treatment free remission, without molecular relapse
timeFrame: After 12 months after entering the treatment-free-remission (TFR) phase
Secondary outcomes:
measure: Number of patients with molecular response
timeFrame: 4 years after study entry
measure: Number of patiens in progression-free survival
timeFrame: 5 years after study entry
measure: Number of patients with major molecular response
timeFrame: At 1, 2, 3 and 4 years from study entry
measure: Number of toxic events
timeFrame: At 5 years from study entry
measure: Number of patients who discontinue treatment
timeFrame: At 5 years from study entry
measure: Number of patients with quality of life differences between treatment arms over time
timeFrame: At baseline and at 3, 6, 12, 18, 24, 30, 36, 42, 48, and 60 months 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 Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. Lancisi G. Salesi
city: Ascoli Piceno
country: Italy
facility: Area Vasta N. 5 Ascoli Piceno - S. Benedetto Del Tronto, Presidio Ospedaliero Av5 Osp. Gen. Prov.Le "C.G.Mazzoni" - Uoc Ematologia
city: Asti
country: Italy
facility: Asl Di Asti, Ospedali Riuniti - Presidio Ospedaliero Cardinal G. Massaia - Sc Oncologia
city: Avellino
country: Italy
facility: Ao Di Rilievo Nazionale E Di Alta Specialità "San Giuseppe Moscati" - Avellino - Uoc Ematologia Con Unità Di Trapianto
city: Bari
country: Italy
facility: Aou Consorziale Policlinico - Bari - Uo Ematologia Con Trapianto
city: Bari
country: Italy
facility: UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro
city: Barletta
country: Italy
facility: Asl Della Provincia Di Barletta, Andria, Trani, Ospedale "Mons. Dimiccoli" - Barletta - Uo Ematologia
city: Bergamo
country: Italy
facility: Ematologia Torre 6 piano 4 - ASST Papa Giovanni XXIII
city: Bologna
country: Italy
facility: Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi
city: Brescia
country: Italy
facility: USD Trapianti di midollo per adulti - Cattedra di Ematologia - Università degli Studi di Brescia
city: Cagliari
country: Italy
facility: ASL N.8 -Ospedale A. Businco
city: Cagliari
country: Italy
facility: Cagliari CTMO - Ematologia - Ospedale "Binaghi"
city: Campobasso
country: Italy
facility: Gemelli Molise - Campobasso - Uosd Onco-Ematologia
city: Castelfranco Veneto
country: Italy
facility: U.O.C. Oncoematologia - Istituto Oncologico Veneto Irccs, Presidio Ospedaliero S. Giacomo Apostolo
city: Catania
country: Italy
facility: Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"
city: Catanzaro
country: Italy
facility: Ao Di Catanzaro "Pugliese-Ciaccio", Presidio Ospedaliero "Ciaccio - de Lellis" - Ematologia
city: Civitanova Marche
country: Italy
facility: U.O. di Medicina Interna - ASUR Marche 8 - Ospedale Civile
city: Cona
country: Italy
facility: Azienda Ospedaliero Universitaria Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia e Fisiopatologia dell'Emostasi
city: Cosenza
country: Italy
facility: Ao Di Cosenza, Presidio Ospedaliero Annunziata - Uoc Ematologia
city: Cuneo
country: Italy
facility: S.C. Ematologia ASO S. Croce e Carle
city: Firenze
country: Italy
facility: Unità di Ricerca e di Malattie del sangue - Ematologia San Luca Vecchio Pad. 16 - 1° Piano
city: Foggia
country: Italy
facility: Aou Ospedali Riuniti - Foggia - Uoc Ematologia
city: Genova
country: Italy
facility: Irccs Aou San Martino - Genova - Uo Ematologia E Trapianti
city: Genova
country: Italy
facility: IRCCS_AOU San Martino-IST.Clinica Ematologica
city: Latina
country: Italy
facility: Asl Latina, Presidio Ospedaliero Nord - Ospedale Santa Maria Goretti - Uoc Ematologia
city: Lecce
country: Italy
facility: ASL Le/1 P.O. Vito Fazzi - U.O. di Ematologia ed UTIE
city: Meldola
country: Italy
facility: I.R.S.T. Srl Irccs - Meldola - Sc Oncologia Medica
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: Mestre
country: Italy
facility: U.O. di Ematologia- Ospedale dell'Angelo - Mestre
city: Milano
country: Italy
facility: Fondazione Irccs "Istituto Nazionale Tumori" - Milano - Sc Ematologia
city: Milano
country: Italy
facility: Fondazione Irccs Ca' Granda, Ospedale Maggiore Policlinico - Milano - Ematologia - Padiglione Marcora
city: Modena
country: Italy
facility: UO Ematologia - AOU Policlinico di Modena
city: Napoli
country: Italy
facility: Asl Napoli 1 Centro, Presidio Ospedaliero Ascalesi - Ospedale S.Maria Di Loreto Nuovo
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: Novara
country: Italy
facility: S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro
city: Nuoro
country: Italy
facility: U.O. CTMO Ematologia - Osp. S. Francesco
city: Orbassano
country: Italy
facility: Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2
city: Padova
country: Italy
facility: Aou Di Padova - Uo Ematologia
city: Pagani
country: Italy
facility: Asl Salerno, Presidio Ospedaliero Tortora Pagani - Ematologia
city: Palermo
country: Italy
facility: Ospedali Riuniti "Villa Sofia-Cervello"
city: Palermo
country: Italy
facility: 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"
city: Parma
country: Italy
facility: Aou Di Parma - Sc Ematologia E Centro Trapianti Midollo Osseo
city: Pesaro
country: Italy
facility: Div. di Ematologia di Muraglia - CTMO Ospedale San Salvatore
city: Pescara
country: Italy
facility: Asl Pescara, Presidio Ospedaliero 'Spirito Santo' - Uoc Ematologia Clinica
city: Piacenza
country: Italy
facility: Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale G. da Saliceto
city: Potenza
country: Italy
facility: Az.Ospedaliera S.G.Moscati
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: Ausl Della Romagna, Ospedale "Infermi" - Rimini - Uo Ematologia
city: Roma
country: Italy
facility: Asl Roma 2, Ospedale S. Eugenio- Ospedale S.Eugenio - Uoc Ematologia
city: Roma
country: Italy
facility: Az. Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia
city: Roma
country: Italy
facility: Divisione Ematologia - Università Campus Bio-Medico
city: Roma
country: Italy
facility: Università Cattolica del Sacro Cuore - Policlinico A. Gemelli
city: Roma
country: Italy
facility: UOC Pronto Soccorso e Accettazione Ematologica - Dipartimento Biotecnologie Cellulari ed Ematologia - Università degli Studi di Roma "Sapienza"
city: Rome
country: Italy
facility: U.O.C. Ematologia - Ospedale S. Eugenio
city: Rossano
country: Italy
facility: Unità Operativa di Oncologia Giovanni Paolo II "Vito Fazzi"
city: Rovigo
country: Italy
facility: Aulss 5 Polesana, Presidio Ospedaliero Di Rovigo - Uosd Ematologia
city: Salerno
country: Italy
facility: Aou "San Giovanni Di Dio E Ruggi D'Aragona" - Salerno - Uoc Ematologia E Trapianti Di Cellule Staminali Emopoietiche
city: San Giovanni Rotondo
country: Italy
facility: Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza
city: Sassari
country: Italy
facility: Ematologia - Dipartimento di Medicina Clinica e Sperimentale
city: Sassuolo
country: Italy
facility: Ospedale Di Sassuolo Spa - Ematologia
city: Siena
country: Italy
facility: Aou Senese - Uoc Ematologia E Trapianti
city: Terni
country: Italy
facility: A.O. Santa Maria - Terni S.C Oncoematologia
city: Torino
country: Italy
facility: Aou Città Della Salute E Della Scienza, Ospedale S. Giovanni Battista Molinette - Torino - Sc Ematologia - Università Degli Studi Di Torino
city: Torino
country: Italy
facility: Aou Città Della Salute E Della Scienza, Ospedale S. Giovanni Battista Molinette - Torino - Sc Ematologia 2
city: Torino
country: Italy
facility: Ospedale Mauriziano Umberto I - Torino - Scdu Ematologia
city: Treviso
country: Italy
facility: Unità Operativa Di Ematologia - Presidio Ospedaliero Di Treviso - Azienda Ulss N.2 Marca Trevigiana
city: Udine
country: Italy
facility: Clinica Ematologica-Centro Trapianti e Terapie cellulari Azienda Ospedaliero-Universitaria, Udine
city: Verona
country: Italy
facility: Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi
city: Vicenza
country: Italy
facility: Aulss 8 Berica - Ospedale Di Vicenza - Uoc Ematologia
city: Vicenza
country: Italy
facility: ULSS N.6 Osp. S. Bortolo
city: Amersfoort
country: Netherlands
facility: Meander Mc - Paesi Bassi
city: Amsterdam
country: Netherlands
facility: Vumc - Paesi Bassi
city: Delft
country: Netherlands
facility: Reinier de Graaf Gasthuis
city: Dordrecht
country: Netherlands
facility: A. Schweitzer Zh, Dordwijk - Paesi Bassi
city: Heerlen
country: Netherlands
facility: Zuyderland Medical Center - Paesi Bassi
city: Hoofddorp
country: Netherlands
facility: Spaarne Ziekenhuis - Paesi Bassi
Study officials:
affiliation: Università Federico II of Naples
name: Fabrizio Pane
role: STUDY_CHAIR
References: