Sustained Treatment-free Remission in BCR-ABL+ Chronic Myeloid Leukemia

Chronyc Myeloid Leukemia Clinical Trial

— SUSTRENIM  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02602314
• Other study ID #: CML1415
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: November 11, 2016
• Est. completion date: February 2024

Study information

• Verified date: January 2022
• Source: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 450
• Est. completion date: February 2024
• Est. primary completion date: February 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Chronyc Myeloid Leukemia
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Intervention

Drug:
• Imatinib

• Nilotinib

Locations

Country	Name	City	State
Italy	S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo	Alessandria
Italy	Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. Lancisi G. Salesi	Ancona
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	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	UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro	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	Gemelli Molise - Campobasso - Uosd Onco-Ematologia	Campobasso
Italy	U.O.C. Oncoematologia - Istituto Oncologico Veneto Irccs, Presidio Ospedaliero S. Giacomo Apostolo	Castelfranco Veneto
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	Azienda Ospedaliero Universitaria Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia e Fisiopatologia dell'Emostasi	Cona
Italy	Ao Di Cosenza, Presidio Ospedaliero Annunziata - Uoc Ematologia	Cosenza
Italy	S.C. Ematologia ASO S. Croce e Carle	Cuneo
Italy	Unità di Ricerca e di Malattie del sangue - Ematologia San Luca Vecchio Pad. 16 - 1° Piano	Firenze
Italy	Aou Ospedali Riuniti - Foggia - Uoc Ematologia	Foggia
Italy	Irccs Aou San Martino - Genova - Uo Ematologia E Trapianti	Genova
Italy	IRCCS_AOU San Martino-IST.Clinica Ematologica	Genova
Italy	Asl Latina, Presidio Ospedaliero Nord - Ospedale Santa Maria Goretti - Uoc Ematologia	Latina
Italy	ASL Le/1 P.O. Vito Fazzi - U.O. di Ematologia ed UTIE	Lecce
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	Fondazione Irccs "Istituto Nazionale Tumori" - Milano - Sc Ematologia	Milano
Italy	Fondazione Irccs Ca' Granda, Ospedale Maggiore Policlinico - Milano - Ematologia - Padiglione Marcora	Milano
Italy	UO Ematologia - AOU Policlinico di Modena	Modena
Italy	Asl Napoli 1 Centro, Presidio Ospedaliero Ascalesi - Ospedale S.Maria Di Loreto Nuovo	Napoli
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	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	Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2	Orbassano
Italy	Aou Di Padova - Uo Ematologia	Padova
Italy	Asl Salerno, Presidio Ospedaliero Tortora Pagani - Ematologia	Pagani
Italy	Ospedali Riuniti "Villa Sofia-Cervello"	Palermo
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	Aou Di Parma - Sc Ematologia E Centro Trapianti Midollo Osseo	Parma
Italy	Div. di Ematologia di Muraglia - CTMO Ospedale San Salvatore	Pesaro
Italy	Asl Pescara, Presidio Ospedaliero 'Spirito Santo' - Uoc Ematologia Clinica	Pescara
Italy	Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale G. da Saliceto	Piacenza
Italy	Az.Ospedaliera S.G.Moscati	Potenza
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	Ausl Della Romagna, Ospedale "Infermi" - Rimini - Uo Ematologia	Rimini
Italy	Asl Roma 2, Ospedale S. Eugenio- Ospedale S.Eugenio - Uoc Ematologia	Roma
Italy	Az. Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia	Roma
Italy	Divisione Ematologia - Università Campus Bio-Medico	Roma
Italy	Università Cattolica del Sacro Cuore - Policlinico A. Gemelli	Roma
Italy	UOC Pronto Soccorso e Accettazione Ematologica - Dipartimento Biotecnologie Cellulari ed Ematologia - Università degli Studi di Roma "Sapienza"	Roma
Italy	U.O.C. Ematologia - Ospedale S. Eugenio	Rome
Italy	Unità Operativa di Oncologia Giovanni Paolo II "Vito Fazzi"	Rossano
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	Ematologia - Dipartimento di Medicina Clinica e Sperimentale	Sassari
Italy	Ospedale Di Sassuolo Spa - Ematologia	Sassuolo
Italy	Aou Senese - Uoc Ematologia E Trapianti	Siena
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	Aou Città Della Salute E Della Scienza, Ospedale S. Giovanni Battista Molinette - Torino - Sc Ematologia 2	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	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
Netherlands	Meander Mc - Paesi Bassi	Amersfoort
Netherlands	Vumc - Paesi Bassi	Amsterdam
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

Sponsors (1)

Lead Sponsor	Collaborator
Gruppo Italiano Malattie EMatologiche dell'Adulto

Countries where clinical trial is conducted

Italy,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of of patients with molecular response		At 24 months from study entry
Primary	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	Number of patients with molecular response		4 years after study entry
Secondary	Number of patiens in progression-free survival		5 years after study entry
Secondary	Number of patients with major molecular response		At 1, 2, 3 and 4 years from study entry
Secondary	Number of toxic events		At 5 years from study entry
Secondary	Number of patients who discontinue treatment		At 5 years from study entry
Secondary	Number of patients with quality of life differences between treatment arms over time	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).	At baseline and at 3, 6, 12, 18, 24, 30, 36, 42, 48, and 60 months from study entry.