CML0811: Nilotinib in PH+, BCR-, ABL+ CML Patients

Sponsor

Gruppo Italiano Malattie EMatologiche dell'Adulto (Other)

Overall Status

Completed

CT.gov ID

NCT01535391

Collaborator

(none)

109

Enrollment

Locations

75.8

Actual Duration (Months)

3.2

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Myeloid Leukemia	Drug: Nilotinib	Phase 3

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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

109 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jan 1, 2012

Actual Primary Completion Date :

Nov 1, 2014

Actual Study Completion Date :

Apr 27, 2018

Outcome Measures

Primary Outcome Measures

Complete molecular response [At 24 months of treatment]
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)

Secondary Outcome Measures

Toxicity [At three years from study entry]
Number of toxic events
Compliance [At 3 years from study entry]
Number of fully compliant patients and number of patients who do not comply with treatment
The complete cytogenetic response (CCgR) rate [At 3, 6, 12, 18 and 24 months from study entry]
The rate and the degree of molecular response [At 3, 6, 12, 18 and 24 months from study entry]
The time to CCgR, the time to MMR and the time to CMR [baseline]
Overall Survival (OS) [At three years from study entry]
From the date of the first nilotinib dose to death
Progression Free Survival (PFS) [At three years from study entry]
From the date of the first nilotinib dose to progression to AP or BP or death
Failure Free Survival (FFS) [At three years from study entry]
From the date of the first nilotinib dose to failure* or progression or death
Event Free Survival (EFS) [At three years from study entry]
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.
Patient-reported quality of life (QoL) [At baseline and then at 3, 6, 12, 18 and 24 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Azienda Ospedaliera Nuovo Ospedale "Torrette"	Ancona	Italy
2	S.G. Moscati Hospital	Avellino	Italy
3	Azienda Ospedaliera Di Bologna Policlinico S. Orsola - Malpighi	Bologna	Italy	40138
4	USD Trapianti di midollo per adulti - Cattedra di Ematologia - Università degli Studi di Brescia	Brescia	Italy	25123
5	Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"	Catania	Italy
6	Azienda Ospedaliera Pugliese Ciaccio - Presidio Ospedaliero A.Pugliese - Unità Operativa di Ematologia	Catanzaro	Italy
7	Sezione di Ematologia e Fisiopatologia delle Emostasi - Azienda Ospedaliera - Arcispedale S. Anna	Ferrara	Italy
8	Struttura Complessa di Ematologia Ospedali Riuniti Foggia - Azienda Ospedaliero-Universitaria	Foggia	Italy
9	Clinica Ematologica - DiMI - Università degli Studi di Genova	Genova	Italy
10	Divisione Ematologia 1 - Azienda Ospedaliera Universitaria "San Martino"	Genova	Italy
11	U.O. di Ematologia- Ospedale dell'Angelo - Mestre	Mestre	Italy
12	U.O. Ematologia e Trapianto di MIdollo - Ist.Scientifico Ospedale San Raffaele	Milano	Italy
13	Centro Oncologico Modenese - Dipartimento di Oncoematologia	Modena	Italy
14	Università degli Studi di Padova - Ematologia ed Immunologia Clinica	Padova	Italy
15	Ospedale Cervello	Palermo	Italy	90146
16	Azienda Ospedaliera Universitaria - Policlinico Paolo Giaccone	Palermo	Italy
17	Div. di Ematologia di Muraglia -CTMO Ospedale San Salvatore	Pesaro	Italy
18	Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza	Piacenza	Italy
19	Dipartimento Oncologico - Ospedale S.Maria delle Croci	Ravenna	Italy
20	Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"	Reggio Calabria	Italy
21	Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova	Reggio Emilia	Italy
22	Ospedale "Infermi"	Rimini	Italy
23	IRCCS Centro di riferimento Oncologico di Basilicata	Rionero in Vulture	Italy
24	Complesso Ospedaliero S. Giovanni Addolorata	Roma	Italy
25	Pronto Soccorso e Accettazione Ematologica - Dipartimento Biotecnologie Cellulari ed Ematologia - Università degli Studi di Roma "Sapienza"	Roma	Italy
26	U.O.C. Ematologia Ospedale S. Eugenio	Roma	Italy
27	Università degli Studi Policlinico di Tor Vergata	Roma	Italy
28	Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo	Italy
29	U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"	Siena	Italy
30	U.O.C. di Ematolgia - A.O. " SS Annunziata" - P.O. S.G. Moscati	Taranto	Italy
31	SCDO Ematologia 2 AOU S.Giovanni Battista	Torino	Italy
32	Azienda USL 9 Treviso - U.O. di Ematologia	Treviso	Italy	31100
33	Clinica Ematologica - Policlinico Universitario	Udine	Italy
34	Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi	Verona	Italy