Clinical trial NCT01535391: Nilotinib in PH+, BCR-, ABL+ CML Patients
Official title: The Protein Tyrosine Kinase Inhibitor Nilotinib as First-line Treatment of Ph+, BCR-, ABL+ Chronic Myeloid Leukemia (CML) in Early Chronic Phase: a Phase IIIb, Multicenter Study to Assess the Complete Molecular Response
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Myeloid Leukemia
Keywords: Chronic Myeloid Leukemia,
Nilotinib,
Philadelphia positive,
BCR-ABL+
Early chronic phase
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor class: OTHER
First posted: 2012-02-17
Enrollment: 109
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study is an open-label, multicentric, phase IIIb study of NILOTINIB administered orally twice daily for 24 months and indefinitely if it is in the interest of the patient.

The primary objective of the trial is to evaluate the efficacy of nilotinib, 300 mg twice daily with dose increase to 400 mg twice daily in case of suboptimal response or failure (excluding patients who will fail for progression to ABP), in a population of patients with Ph-positive, BCR-ABL positive CML in early CP.

Detailed description: This study is an open-label, multicentric, phase IIIb study of NILOTINIB administered orally at the dose of 300 mg twice daily (total daily dose 600 mg daily) for 24 months (study core), and indefinitely if it is in the interest of the patient (the drug will be given free-of-charge after 24 months to all those patients achieving the CMR4 at 24 months and in absence of safety concerns). Nilotinib dose is increased to 400 mg BID in case of suboptimal response or failure (with the exception of patients who will fail for progression to ABP: in case of progression to ABP, the patient will not be treated with study drug and the choice of the treatment will be up to the physician).

Study duration is estimated in 6 years, 1 year of estimated enrollment, 2 years therapy duration. Thereafter, information on course and survival is due for other 3 years.

The main data analysis will be performed when all patients will complete 24 months of treatment (or discontinued earlier). Safety and tolerability profile will be assessed by collecting hematologic and non-hematologic adverse events, laboratory examinations and ECG data. The molecular response will be assessed using the GIMEMA standardized molecular laboratories (Labnet network).

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18
* Male or female patients with diagnosis of Ph+ and/or BCR-ABL+ CML
* Early chronic phase (within 6 months from diagnosis)
* Pretreatment with Hydroxyurea or Anagrelide for a duration of up to 3 months and/or pretreatment with Imatinib for up to 30 days are permitted
* Normal serum levels of potassium, magnesium, phosphorus, total calcium corrected for serum albumin or phosphorus, or correctable to within normal limits with supplements prior to the first dose of study medication
* Written informed consent prior to any study procedures being performed
* AST and ALT ≤ 2.5 x ULN or ≤ 5.0 x ULN if considered due to leukaemia
* Alkaline phosphatase ≤ 2.5 x ULN unless considered due to leukaemia
* Total direct bilirubin ≤ 1.5 x ULN, except know Mb. Gilbert
* Serum creatinine ≤ 1.5 x ULN

Exclusion Criteria:

* Known impaired cardiac function, including any of the following:
* LVEF \< 45%
* Complete left bundle branch block
* Right bundle branch block plus left anterior hemiblock, bifascicular block
* Use of a ventricular-paced pacemaker
* Congenital long QT syndrome
* History of or presence of clinically significant ventricular or atrial tachyarrhythmias
* Clinically significant resting bradycardia (\<50 beats per minute)
* QTc\>450 msec on screening ECG. If QTc \> 450 msec and electrolytes are not within normal ranges before Nilotinib dosing, electrolytes should be corrected and then the patient rescreened for QTc criterion.
* Myocardial infarction within 12 months prior to starting study drugs
* Other clinical significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension)
* Serum lipase and amylase \> 1.5 x ULN (upper limit of normal) or history of acute (i.e., within 1 year of starting study medication) or chronic pancreatitis
* Other concurrent uncontrolled medical conditions (e.g., uncontrolled diabetes, active or uncontrolled infections, acute or chronic liver and renal disease) that could cause unacceptable safety risks or compromise compliance with the protocol
* Impaired gastrointestinal function or disease that may alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting and diarrhea, malabsorption syndrome, small bowel resection or gastric by-pass surgery)
* Concomitant medications with potential QT prolongation (see link for complete list: http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm)
* Concomitant medications known to interact with CYP450 isoenzymes (CYP3A4, CYP2C9,andCYP2C8:link for complete list: http://medicine.iupui.edu/flockhart/table.html..
* Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
* Patients who are pregnant or breast feeding, or women of reproductive potential not employing an effective method of birth control. (Women of childbearing potential must have a negative serum pregnancy test within 48 hours prior to administration of nilotinib).
* Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention.
* Patients unwilling or unable to comply with the protocol

Primary outcomes:
measure: Complete molecular response
timeFrame: At 24 months of treatment
Secondary outcomes:
measure: Toxicity
timeFrame: At three years from study entry
measure: Compliance
timeFrame: At 3 years from study entry
measure: The complete cytogenetic response (CCgR) rate
timeFrame: At 3, 6, 12, 18 and 24 months from study entry
measure: The rate and the degree of molecular response
timeFrame: At 3, 6, 12, 18 and 24 months from study entry
measure: The time to CCgR, the time to MMR and the time to CMR
timeFrame: baseline
measure: Overall Survival (OS)
timeFrame: At three years from study entry
measure: Progression Free Survival (PFS)
timeFrame: At three years from study entry
measure: Failure Free Survival (FFS)
timeFrame: At three years from study entry
measure: Event Free Survival (EFS)
timeFrame: At three years from study entry
measure: Patient-reported quality of life (QoL)
timeFrame: At baseline and then at 3, 6, 12, 18 and 24 months
Other outcomes:
Locations:
city: Ancona
country: Italy
facility: Azienda Ospedaliera Nuovo Ospedale "Torrette"
city: Avellino
country: Italy
facility: S.G. Moscati Hospital
city: Bologna
country: Italy
facility: Azienda Ospedaliera 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: Catania
country: Italy
facility: Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"
city: Catanzaro
country: Italy
facility: Azienda Ospedaliera Pugliese Ciaccio - Presidio Ospedaliero A.Pugliese - Unità Operativa di Ematologia
city: Ferrara
country: Italy
facility: Sezione di Ematologia e Fisiopatologia delle Emostasi - Azienda Ospedaliera - Arcispedale S. Anna
city: Foggia
country: Italy
facility: Struttura Complessa di Ematologia Ospedali Riuniti Foggia - Azienda Ospedaliero-Universitaria
city: Genova
country: Italy
facility: Clinica Ematologica - DiMI - Università degli Studi di Genova
city: Genova
country: Italy
facility: Divisione Ematologia 1 - Azienda Ospedaliera Universitaria "San Martino"
city: Mestre
country: Italy
facility: U.O. di Ematologia- Ospedale dell'Angelo - Mestre
city: Milano
country: Italy
facility: U.O. Ematologia e Trapianto di MIdollo - Ist.Scientifico Ospedale San Raffaele
city: Modena
country: Italy
facility: Centro Oncologico Modenese - Dipartimento di Oncoematologia
city: Padova
country: Italy
facility: Università degli Studi di Padova - Ematologia ed Immunologia Clinica
city: Palermo
country: Italy
facility: Ospedale Cervello
city: Palermo
country: Italy
facility: Azienda Ospedaliera Universitaria - Policlinico Paolo Giaccone
city: Pesaro
country: Italy
facility: Div. di Ematologia di Muraglia -CTMO Ospedale San Salvatore
city: Piacenza
country: Italy
facility: Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza
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: Ospedale "Infermi"
city: Rionero in Vulture
country: Italy
facility: IRCCS Centro di riferimento Oncologico di Basilicata
city: Roma
country: Italy
facility: Complesso Ospedaliero S. Giovanni Addolorata
city: Roma
country: Italy
facility: Pronto Soccorso e Accettazione Ematologica - Dipartimento Biotecnologie Cellulari ed Ematologia - Università degli Studi di Roma "Sapienza"
city: Roma
country: Italy
facility: U.O.C. Ematologia Ospedale S. Eugenio
city: Roma
country: Italy
facility: Università degli Studi Policlinico di Tor Vergata
city: San Giovanni Rotondo
country: Italy
facility: Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza
city: Siena
country: Italy
facility: U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"
city: Taranto
country: Italy
facility: U.O.C. di Ematolgia - A.O. " SS Annunziata" - P.O. S.G. Moscati
city: Torino
country: Italy
facility: SCDO Ematologia 2 AOU S.Giovanni Battista
city: Treviso
country: Italy
facility: Azienda USL 9 Treviso - U.O. di Ematologia
city: Udine
country: Italy
facility: Clinica Ematologica - Policlinico Universitario
city: Verona
country: Italy
facility: Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi
Study officials:
affiliation: Dpt of Hematology and Oncology, "Seràgnoli", Sant'Orsola-Malpighi. University Hospital of Bologna
name: Gianantonio Rosti
role: STUDY_CHAIR
References:
citation: Castagnetti F, Breccia M, Gugliotta G, Martino B, D'Adda M, Stagno F, Carella AM, Avanzini P, Tiribelli M, Trabacchi E, Visani G, Gobbi M, Salvucci M, Levato L, Binotto G, Capalbo SF, Bochicchio MT, Soverini S, Cavo M, Martinelli G, Alimena G, Pane F, Saglio G, Rosti G, Baccarani M; GIMEMA CML Working Party. Nilotinib 300 mg twice daily: an academic single-arm study of newly diagnosed chronic phase chronic myeloid leukemia patients. Haematologica. 2016 Oct;101(10):1200-1207. doi: 10.3324/haematol.2016.144949. Epub 2016 Jul 28.