Nilotinib in PH+, BCR-, ABL+ CML Patients

Chronic Myeloid Leukemia Clinical Trial

— CML0811  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01535391
• Other study ID #: CML0811
• Secondary ID: 2011-002787-25
• Status: Completed
• Phase: Phase 3
• Start date: January 2012
• Est. completion date: April 27, 2018

Study information

• Verified date: August 2018
• Source: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 109
• Est. completion date: April 27, 2018
• Est. primary completion date: November 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• 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 choise of the treatment will be up to the physician).

Locations

Country	Name	City	State
Italy	Azienda Ospedaliera Nuovo Ospedale "Torrette"	Ancona
Italy	S.G. Moscati Hospital	Avellino
Italy	Azienda Ospedaliera Di Bologna Policlinico S. Orsola - Malpighi	Bologna
Italy	USD Trapianti di midollo per adulti - Cattedra di Ematologia - Università degli Studi di Brescia	Brescia
Italy	Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"	Catania
Italy	Azienda Ospedaliera Pugliese Ciaccio - Presidio Ospedaliero A.Pugliese - Unità Operativa di Ematologia	Catanzaro
Italy	Sezione di Ematologia e Fisiopatologia delle Emostasi - Azienda Ospedaliera - Arcispedale S. Anna	Ferrara
Italy	Struttura Complessa di Ematologia Ospedali Riuniti Foggia - Azienda Ospedaliero-Universitaria	Foggia
Italy	Clinica Ematologica - DiMI - Università degli Studi di Genova	Genova
Italy	Divisione Ematologia 1 - Azienda Ospedaliera Universitaria "San Martino"	Genova
Italy	U.O. di Ematologia- Ospedale dell'Angelo - Mestre	Mestre
Italy	U.O. Ematologia e Trapianto di MIdollo - Ist.Scientifico Ospedale San Raffaele	Milano
Italy	Centro Oncologico Modenese - Dipartimento di Oncoematologia	Modena
Italy	Università degli Studi di Padova - Ematologia ed Immunologia Clinica	Padova
Italy	Azienda Ospedaliera Universitaria - Policlinico Paolo Giaccone	Palermo
Italy	Ospedale Cervello	Palermo
Italy	Div. di Ematologia di Muraglia -CTMO Ospedale San Salvatore	Pesaro
Italy	Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza	Piacenza
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	Ospedale "Infermi"	Rimini
Italy	IRCCS Centro di riferimento Oncologico di Basilicata	Rionero in Vulture
Italy	Complesso Ospedaliero S. Giovanni Addolorata	Roma
Italy	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	Roma
Italy	Università degli Studi Policlinico di Tor Vergata	Roma
Italy	Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo
Italy	U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"	Siena
Italy	U.O.C. di Ematolgia - A.O. " SS Annunziata" - P.O. S.G. Moscati	Taranto
Italy	SCDO Ematologia 2 AOU S.Giovanni Battista	Torino
Italy	Azienda USL 9 Treviso - U.O. di Ematologia	Treviso
Italy	Clinica Ematologica - Policlinico Universitario	Udine
Italy	Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi	Verona

Sponsors (1)

Lead Sponsor	Collaborator
Gruppo Italiano Malattie EMatologiche dell'Adulto

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Complete molecular response	To assess the complete molecular response (CMR4) rate at 24 months of treatment. For the purpose of this protocol, CMR is defined as a negative results of quantitative RT-PCR for BCR-ABL transcripts in a peripheral blood sample of at least 10 ml with a minimum sensitivity of 1:10,000, that corresponds to at least a 4-log reduction (hence, CMR4)	At 24 months of treatment
Secondary	Toxicity	Number of toxic events	At three years from study entry
Secondary	Compliance	Number of fully compliant patients and number of patients who do not comply with treatment	At 3 years from study entry
Secondary	The complete cytogenetic response (CCgR) rate		At 3, 6, 12, 18 and 24 months from study entry
Secondary	The rate and the degree of molecular response		At 3, 6, 12, 18 and 24 months from study entry
Secondary	The time to CCgR, the time to MMR and the time to CMR		baseline
Secondary	Overall Survival (OS)	From the date of the first nilotinib dose to death	At three years from study entry
Secondary	Progression Free Survival (PFS)	From the date of the first nilotinib dose to progression to AP or BP or death	At three years from study entry
Secondary	Failure Free Survival (FFS)	From the date of the first nilotinib dose to failure* or progression or death	At three years from study entry
Secondary	Event Free Survival (EFS)	From the date of the first nilotinib to any event. Including treatment discontinuation for adverse events, failure, progression to AP or BP, or death, whichever comes first.	At three years from study entry
Secondary	Patient-reported quality of life (QoL)		At baseline and then at 3, 6, 12, 18 and 24 months

External Links

•   GIMEMA Foundation website