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

Sponsor

Gruppo Italiano Malattie EMatologiche dell'Adulto (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02602314

Collaborator

(none)

450

Enrollment

Locations

Arms

86.7

Anticipated Duration (Months)

5.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

450 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 :

Nov 11, 2016

Anticipated Primary Completion Date :

Feb 1, 2023

Anticipated Study Completion Date :

Feb 1, 2024

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: Imatinib + Nilotinib

Drug: Imatinib

Drug: Nilotinib

Experimental: Nilotinib

Drug: Nilotinib

Outcome Measures

Primary Outcome Measures

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

Number of patients with molecular response [4 years after study entry]
Number of patiens in progression-free survival [5 years after 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 who discontinue treatment [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).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country
1	S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo	Alessandria	Italy
2	Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. Lancisi G. Salesi	Ancona	Italy
3	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
4	Asl Di Asti, Ospedali Riuniti - Presidio Ospedaliero Cardinal G. Massaia - Sc Oncologia	Asti	Italy
5	Ao Di Rilievo Nazionale E Di Alta Specialità "San Giuseppe Moscati" - Avellino - Uoc Ematologia Con Unità Di Trapianto	Avellino	Italy
6	Aou Consorziale Policlinico - Bari - Uo Ematologia Con Trapianto	Bari	Italy
7	UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro	Bari	Italy
8	Asl Della Provincia Di Barletta, Andria, Trani, Ospedale "Mons. Dimiccoli" - Barletta - Uo Ematologia	Barletta	Italy
9	Ematologia Torre 6 piano 4 - ASST Papa Giovanni XXIII	Bergamo	Italy
10	Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi	Bologna	Italy
11	USD Trapianti di midollo per adulti - Cattedra di Ematologia - Università degli Studi di Brescia	Brescia	Italy
12	ASL N.8 -Ospedale A. Businco	Cagliari	Italy
13	Cagliari CTMO - Ematologia - Ospedale "Binaghi"	Cagliari	Italy
14	Gemelli Molise - Campobasso - Uosd Onco-Ematologia	Campobasso	Italy
15	U.O.C. Oncoematologia - Istituto Oncologico Veneto Irccs, Presidio Ospedaliero S. Giacomo Apostolo	Castelfranco Veneto	Italy
16	Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"	Catania	Italy
17	Ao Di Catanzaro "Pugliese-Ciaccio", Presidio Ospedaliero "Ciaccio - de Lellis" - Ematologia	Catanzaro	Italy
18	U.O. di Medicina Interna - ASUR Marche 8 - Ospedale Civile	Civitanova Marche	Italy
19	Azienda Ospedaliero Universitaria Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia e Fisiopatologia dell'Emostasi	Cona	Italy
20	Ao Di Cosenza, Presidio Ospedaliero Annunziata - Uoc Ematologia	Cosenza	Italy
21	S.C. Ematologia ASO S. Croce e Carle	Cuneo	Italy
22	Unità di Ricerca e di Malattie del sangue - Ematologia San Luca Vecchio Pad. 16 - 1° Piano	Firenze	Italy
23	Aou Ospedali Riuniti - Foggia - Uoc Ematologia	Foggia	Italy
24	Irccs Aou San Martino - Genova - Uo Ematologia E Trapianti	Genova	Italy
25	IRCCS_AOU San Martino-IST.Clinica Ematologica	Genova	Italy
26	Asl Latina, Presidio Ospedaliero Nord - Ospedale Santa Maria Goretti - Uoc Ematologia	Latina	Italy
27	ASL Le/1 P.O. Vito Fazzi - U.O. di Ematologia ed UTIE	Lecce	Italy
28	I.R.S.T. Srl Irccs - Meldola - Sc Oncologia Medica	Meldola	Italy
29	Azienda Ospedaliera Universitaria - Policlinico G. Martino Dipartimento di Medicina Interna - U.O. Messina	Messina	Italy
30	Divisione di Ematologia - Azienda Ospedaliera Ospedali Riuniti "Papardo Piemonte"	Messina	Italy
31	U.O. di Ematologia- Ospedale dell'Angelo - Mestre	Mestre	Italy
32	Fondazione Irccs "Istituto Nazionale Tumori" - Milano - Sc Ematologia	Milano	Italy
33	Fondazione Irccs Ca' Granda, Ospedale Maggiore Policlinico - Milano - Ematologia - Padiglione Marcora	Milano	Italy
34	UO Ematologia - AOU Policlinico di Modena	Modena	Italy
35	Asl Napoli 1 Centro, Presidio Ospedaliero Ascalesi - Ospedale S.Maria Di Loreto Nuovo	Napoli	Italy
36	Azienda Ospedaliera di Rilievo Nazionale A. Cardarelli	Napoli	Italy
37	Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia	Napoli	Italy
38	Ospedale San Gennaro - ASL Napoli 1	Napoli	Italy
39	S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro	Novara	Italy
40	U.O. CTMO Ematologia - Osp. S. Francesco	Nuoro	Italy
41	Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2	Orbassano	Italy
42	Aou Di Padova - Uo Ematologia	Padova	Italy
43	Asl Salerno, Presidio Ospedaliero Tortora Pagani - Ematologia	Pagani	Italy
44	Ospedali Riuniti "Villa Sofia-Cervello"	Palermo	Italy
45	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
46	Aou Di Parma - Sc Ematologia E Centro Trapianti Midollo Osseo	Parma	Italy
47	Div. di Ematologia di Muraglia - CTMO Ospedale San Salvatore	Pesaro	Italy
48	Asl Pescara, Presidio Ospedaliero 'Spirito Santo' - Uoc Ematologia Clinica	Pescara	Italy
49	Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale G. da Saliceto	Piacenza	Italy
50	Az.Ospedaliera S.G.Moscati	Potenza	Italy
51	Dipartimento Oncologico - Ospedale S.Maria delle Croci	Ravenna	Italy
52	Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"	Reggio Calabria	Italy
53	Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova	Reggio Emilia	Italy
54	Ausl Della Romagna, Ospedale "Infermi" - Rimini - Uo Ematologia	Rimini	Italy
55	Asl Roma 2, Ospedale S. Eugenio- Ospedale S.Eugenio - Uoc Ematologia	Roma	Italy
56	Az. Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia	Roma	Italy
57	Divisione Ematologia - Università Campus Bio-Medico	Roma	Italy
58	Università Cattolica del Sacro Cuore - Policlinico A. Gemelli	Roma	Italy
59	UOC Pronto Soccorso e Accettazione Ematologica - Dipartimento Biotecnologie Cellulari ed Ematologia - Università degli Studi di Roma "Sapienza"	Roma	Italy
60	U.O.C. Ematologia - Ospedale S. Eugenio	Rome	Italy
61	Unità Operativa di Oncologia Giovanni Paolo II "Vito Fazzi"	Rossano	Italy
62	Aulss 5 Polesana, Presidio Ospedaliero Di Rovigo - Uosd Ematologia	Rovigo	Italy
63	Aou "San Giovanni Di Dio E Ruggi D'Aragona" - Salerno - Uoc Ematologia E Trapianti Di Cellule Staminali Emopoietiche	Salerno	Italy
64	Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo	Italy
65	Ematologia - Dipartimento di Medicina Clinica e Sperimentale	Sassari	Italy
66	Ospedale Di Sassuolo Spa - Ematologia	Sassuolo	Italy
67	Aou Senese - Uoc Ematologia E Trapianti	Siena	Italy
68	A.O. Santa Maria - Terni S.C Oncoematologia	Terni	Italy
69	Aou Città Della Salute E Della Scienza, Ospedale S. Giovanni Battista Molinette - Torino - Sc Ematologia - Università Degli Studi Di Torino	Torino	Italy
70	Aou Città Della Salute E Della Scienza, Ospedale S. Giovanni Battista Molinette - Torino - Sc Ematologia 2	Torino	Italy
71	Ospedale Mauriziano Umberto I - Torino - Scdu Ematologia	Torino	Italy
72	Unità Operativa Di Ematologia - Presidio Ospedaliero Di Treviso - Azienda Ulss N.2 Marca Trevigiana	Treviso	Italy
73	Clinica Ematologica-Centro Trapianti e Terapie cellulari Azienda Ospedaliero-Universitaria, Udine	Udine	Italy
74	Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi	Verona	Italy
75	Aulss 8 Berica - Ospedale Di Vicenza - Uoc Ematologia	Vicenza	Italy
76	ULSS N.6 Osp. S. Bortolo	Vicenza	Italy
77	Meander Mc - Paesi Bassi	Amersfoort	Netherlands
78	Vumc - Paesi Bassi	Amsterdam	Netherlands
79	Reinier de Graaf Gasthuis	Delft	Netherlands
80	A. Schweitzer Zh, Dordwijk - Paesi Bassi	Dordrecht	Netherlands
81	Zuyderland Medical Center - Paesi Bassi	Heerlen	Netherlands
82	Spaarne Ziekenhuis - Paesi Bassi	Hoofddorp	Netherlands