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

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ClinicalTrials.gov Identifier: NCT02602314
Recruitment Status : Recruiting
First Posted : November 11, 2015
Last Update Posted : October 17, 2017
Sponsor:
Information provided by (Responsible Party):
Gruppo Italiano Malattie EMatologiche dell'Adulto

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.

Condition or disease Intervention/treatment Phase
Chronyc Myeloid Leukemia Drug: Imatinib Drug: Nilotinib Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 600 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : November 11, 2016
Estimated Primary Completion Date : February 2023
Estimated Study Completion Date : February 2024


Arm Intervention/treatment
Experimental: Imatinib + Nilotinib Drug: Imatinib
Drug: Nilotinib
Experimental: Nilotinib Drug: Nilotinib



Primary Outcome Measures :
  1. Number of of patients with molecular response [ Time Frame: At 24 months from study entry ]
  2. Number of patients who remain in sustained treatment free remission, without molecular relapse [ Time Frame: After 12 months after entering the treatment-free-remission (TFR) phase ]

Secondary Outcome Measures :
  1. Number of patients with molecular response [ Time Frame: 4 years after study entry ]
  2. Number of patiens in progression-free survival [ Time Frame: 5 years after study entry ]
  3. Number of patients with major molecular response [ Time Frame: At 1, 2, 3 and 4 years from study entry ]
  4. Number of toxic events [ Time Frame: At 5 years from study entry ]
  5. Number of patients who discontinue treatment [ Time Frame: At 5 years from study entry ]
  6. Number of patients with quality of life differences between treatment arms over time [ Time Frame: 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).



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02602314


Contacts
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Contact: Paola Fazi p.fazi@gimema.it
Contact: Enrico Crea e.crea@gimema.it

Locations
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Italy
S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo Recruiting
Alessandria, Italy
Contact: Massimo Pini         
Principal Investigator: Massimo Pini         
Sub-Investigator: Federico Monaco         
Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. Lancisi G. Salesi Recruiting
Ancona, Italy
Contact: Serena Rupoli         
Principal Investigator: Serena Rupoli         
Sub-Investigator: Anna Rita Scortecchini         
Az.Ospedaliera S.G.Moscati Not yet recruiting
Avellino, Italy
Contact: Fausto Palmieri         
Principal Investigator: Fausto Palmieri         
Sub-Investigator: Raffaele Palmieri         
UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro Not yet recruiting
Bari, Italy
Contact: Giorgina Specchia         
Principal Investigator: Giorgina Specchia         
Sub-Investigator: Antonella Russo         
Ematologia Torre 6 piano 4 - ASST Papa Giovanni XXIII Recruiting
Bergamo, Italy
Contact: Alessandro Rambaldi         
Principal Investigator: Alessandro Rambaldi         
Sub-Investigator: Giulia Quaresmini         
Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi Recruiting
Bologna, Italy
Contact: Gianantonio Rosti         
Principal Investigator: Gianantonio Rosti         
Sub-Investigator: Gabriele Gugliotta         
USD Trapianti di midollo per adulti - Cattedra di Ematologia - Università degli Studi di Brescia Not yet recruiting
Brescia, Italy
Contact: Domenico Russo         
Principal Investigator: Domenico Russo         
Sub-Investigator: Michele Malagola         
ASL N.8 -Ospedale A. Businco Recruiting
Cagliari, Italy
Contact: Emilio Usala         
Principal Investigator: Emilio Usala         
Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto" Not yet recruiting
Catania, Italy
Contact: Francesco Di Raimondo         
Principal Investigator: Francesco Di Raimondo         
Sub-Investigator: Fabio Stagno         
U.O. di Medicina Interna - ASUR Marche 8 - Ospedale Civile Not yet recruiting
Civitanova Marche, Italy
Contact: Riccardo Centurione         
Principal Investigator: Riccardo Centurione         
Sub-Investigator: Jacopo Olivieri         
Azienda Ospedaliero Universitaria Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia e Fisiopatologia dell'Emostasi Not yet recruiting
Cona, Italy
Contact: Francesco Cavazzini         
Principal Investigator: Francesco Cavazzini         
Sub-Investigator: Enrico Lista         
S.C. Ematologia ASO S. Croce e Carle Recruiting
Cuneo, Italy
Contact: Davide Rapezzi         
Principal Investigator: Davide Rapezzi         
Sub-Investigator: Roberto Sorasio         
Unità di Ricerca e di Malattie del sangue - Ematologia San Luca Vecchio Pad. 16 - 1° Piano Not yet recruiting
Firenze, Italy
Contact: Antonella Gozzini         
Principal Investigator: Antonella Gozzini         
Sub-Investigator: Barbara Scappini         
IRCCS_AOU San Martino-IST.Clinica Ematologica Recruiting
Genova, Italy
Contact: Marco Gobbi         
Principal Investigator: Marco Gobbi         
Sub-Investigator: Micaela Bergamaschi         
ASL Le/1 P.O. Vito Fazzi - U.O. di Ematologia ed UTIE Recruiting
Lecce, Italy
Contact: Nicola Di Renzo         
Principal Investigator: Nicola Di Renzo         
Sub-Investigator: Giovanni Reddiconto         
Azienda Ospedaliera Universitaria - Policlinico G. Martino Dipartimento di Medicina Interna - U.O. Messina Recruiting
Messina, Italy
Contact: Caterina Musolino         
Principal Investigator: Caterina Musolino         
Sub-Investigator: Sabina Russo         
Divisione di Ematologia - Azienda Ospedaliera Ospedali Riuniti "Papardo Piemonte" Recruiting
Messina, Italy
U.O. di Ematologia- Ospedale dell'Angelo - Mestre Recruiting
Mestre, Italy
Contact: Renato Bassan         
Principal Investigator: Renato Bassan         
Sub-Investigator: Rosaria Sancetta         
UO Ematologia - AOU Policlinico di Modena Recruiting
Modena, Italy
Contact: Roberto Marasca         
Principal Investigator: Roberto Marasca         
Sub-Investigator: Giovanna Leonardi         
Azienda Ospedaliera di Rilievo Nazionale A. Cardarelli Recruiting
Napoli, Italy
Contact: Mario Annunziata         
Principal Investigator: Mario Annunziata         
Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia Recruiting
Napoli, Italy
Contact: Fabrizio Pane         
Ospedale San Gennaro - ASL Napoli 1 Not yet recruiting
Napoli, Italy
Contact: Lucia Mastrullo         
Principal Investigator: Lucia Mastrullo         
Sub-Investigator: Maria Rosaria Esposito         
S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro Not yet recruiting
Novara, Italy
Contact: Monia Lunghi         
Principal Investigator: Monia Lunghi         
U.O. CTMO Ematologia - Osp. S. Francesco Recruiting
Nuoro, Italy
Contact: Alessandro Murgia         
Principal Investigator: Alessandro Murgia         
Sub-Investigator: Maria Monne         
Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2 Not yet recruiting
Orbassano, Italy
Contact: Giovanna Rege         
Principal Investigator: Giovanna Rege         
Sub-Investigator: Carmen Fava         
Ospedali Riuniti "Villa Sofia-Cervello" Recruiting
Palermo, Italy
Contact: Francesco Fabbiano         
Principal Investigator: Francesco Fabbiano         
Sub-Investigator: Alessandra Malato         
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" Not yet recruiting
Palermo, Italy
Contact: Sergio Siragusa         
Principal Investigator: Sergio Siragusa         
Div. di Ematologia di Muraglia - CTMO Ospedale San Salvatore Recruiting
Pesaro, Italy
Contact: Giuseppe Visani         
Principal Investigator: Giuseppe Visani         
Sub-Investigator: Sara Barulli         
Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale G. da Saliceto Recruiting
Piacenza, Italy
Contact: Daniele Vallisa         
Principal Investigator: Daniele Vallisa         
Sub-Investigator: Elena Trabacchi         
Az.Ospedaliera S.G.Moscati Not yet recruiting
Potenza, Italy
Contact: Michele Pizzuti         
Principal Investigator: Michele Pizzuti         
Sub-Investigator: Angela Matturro         
Dipartimento Oncologico - Ospedale S.Maria delle Croci Not yet recruiting
Ravenna, Italy
Contact: Maria Salvucci         
Principal Investigator: Maria Salvucci         
Sub-Investigator: Roberto Zanchini         
Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli" Not yet recruiting
Reggio Calabria, Italy
Contact: Bruno Martino         
Principal Investigator: Bruno Martino         
Sub-Investigator: Caterina Alati         
Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova Recruiting
Reggio Emilia, Italy
Contact: Paolo Avanzini         
Principal Investigator: Paolo Avanzini         
Sub-Investigator: Isabella Capodanno         
Az. Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia Recruiting
Roma, Italy
Contact: Agostino Tafuri         
Principal Investigator: Agostino Tafuri         
Sub-Investigator: Enrico Montefusco         
Divisione Ematologia - Università Campus Bio-Medico Not yet recruiting
Roma, Italy
Contact: Marianna De Muro         
Principal Investigator: Marianna De Muro         
Università Cattolica del Sacro Cuore - Policlinico A. Gemelli Recruiting
Roma, Italy
Contact: Simona Sica         
Principal Investigator: Simona Sica         
Sub-Investigator: Federica Sorà         
UOC Pronto Soccorso e Accettazione Ematologica - Dipartimento Biotecnologie Cellulari ed Ematologia - Università degli Studi di Roma "Sapienza" Not yet recruiting
Roma, Italy
Contact: Massimo Breccia         
Principal Investigator: Massimo Breccia         
Sub-Investigator: Giuliana Alimena         
U.O.C. Ematologia - Ospedale S. Eugenio Recruiting
Rome, Italy
Contact: Elisabetta Abruzzese         
Principal Investigator: Elisabetta Abruzzese         
Unità Operativa di Oncologia Giovanni Paolo II "Vito Fazzi" Recruiting
Rossano, Italy
Contact: Francesco Iuliano         
Principal Investigator: Francesco Iuliano         
Sub-Investigator: Maria Aquila Santoro         
Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza Recruiting
San Giovanni Rotondo, Italy
Contact: Nicola Cascavilla         
Principal Investigator: Nicola Cascavilla         
Sub-Investigator: Nicola Sgherza         
Ematologia - Dipartimento di Medicina Clinica e Sperimentale Not yet recruiting
Sassari, Italy
Contact: Claudio Fozza         
Principal Investigator: Claudio Fozza         
Sub-Investigator: Francesco Longu         
A.O. Santa Maria - Terni S.C Oncoematologia Recruiting
Terni, Italy
Contact: Anna Marina Liberati         
Principal Investigator: Anna Marina Liberati         
Principal Investigator: Debora Luzi         
Clinica Ematologica-Centro Trapianti e Terapie cellulari Azienda Ospedaliero-Universitaria, Udine Not yet recruiting
Udine, Italy
Contact: Mauro Tiribelli         
Principal Investigator: Mauro Tiribelli         
Sub-Investigator: Federico De Marchi         
Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi Not yet recruiting
Verona, Italy
Contact: Massimiliano Bonifacio         
Principal Investigator: Massimiliano Bonifacio         
Sub-Investigator: Luigi Scaffidi         
ULSS N.6 Osp. S. Bortolo Not yet recruiting
Vicenza, Italy
Contact: Eros Di Bona         
Principal Investigator: Eros Di Bona         
Sponsors and Collaborators
Gruppo Italiano Malattie EMatologiche dell'Adulto
Investigators
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Study Chair: Fabrizio Pane Università Federico II of Naples

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Responsible Party: Gruppo Italiano Malattie EMatologiche dell'Adulto
ClinicalTrials.gov Identifier: NCT02602314     History of Changes
Other Study ID Numbers: CML1415
First Posted: November 11, 2015    Key Record Dates
Last Update Posted: October 17, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Gruppo Italiano Malattie EMatologiche dell'Adulto:
Chronic myeloid leukemia
Nilotinib
Imatinib
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Imatinib Mesylate
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action