Nilotinib in PH+, BCR-, ABL+ CML Patients (CML0811)

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Myeloid Leukemia
• Intervention / Treatment: Drug: Nilotinib

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 Type: Interventional
• Enrollment (Anticipated): 109
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Ancona, Italy
    • Azienda ospedaliera Nuovo Ospedale "Torrette"
  • Avellino, Italy
    • S.G. Moscati Hospital
  • Bologna, Italy, 40138
    • Azienda Ospedaliera Di Bologna Policlinico S. Orsola - Malpighi
  • Brescia, Italy, 25123
    • USD Trapianti di midollo per adulti - Cattedra di Ematologia - Università degli Studi di Brescia
  • Catania, Italy
    • Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"
  • Catanzaro, Italy
    • Azienda Ospedaliera Pugliese Ciaccio - Presidio Ospedaliero A.Pugliese - Unità Operativa di Ematologia
  • Ferrara, Italy
    • Sezione di Ematologia e Fisiopatologia delle Emostasi - Azienda Ospedaliera - Arcispedale S. Anna
  • Foggia, Italy
    • Struttura Complessa di Ematologia Ospedali Riuniti Foggia - Azienda Ospedaliero-Universitaria
  • Genova, Italy
    • Clinica Ematologica - DiMI - Università degli Studi di Genova
  • Genova, Italy
    • Divisione Ematologia 1 - Azienda Ospedaliera Universitaria "San Martino"
  • Mestre, Italy
    • U.O. di Ematologia- Ospedale dell'Angelo - Mestre
  • Milano, Italy
    • U.O. Ematologia e Trapianto di MIdollo - Ist.Scientifico Ospedale San Raffaele
  • Modena, Italy
    • Centro Oncologico Modenese - Dipartimento di Oncoematologia
  • Padova, Italy
    • Università degli Studi di Padova - Ematologia ed Immunologia Clinica
  • Palermo, Italy, 90146
    • Ospedale Cervello
  • Palermo, Italy
    • Azienda Ospedaliera Universitaria - Policlinico Paolo Giaccone
  • Pesaro, Italy
    • Div. di Ematologia di Muraglia -CTMO Ospedale San Salvatore
  • Piacenza, Italy
    • Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza
  • Ravenna, Italy
    • Dipartimento Oncologico - Ospedale S.Maria delle Croci
  • Reggio Calabria, Italy
    • Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"
  • Reggio Emilia, Italy
    • Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova
  • Rimini, Italy
    • Ospedale "Infermi"
  • Rionero in Vulture, Italy
    • IRCCS Centro di Riferimento Oncologico di Basilicata
  • Roma, 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
  • San Giovanni Rotondo, Italy
    • Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza
  • Siena, Italy
    • U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"
  • Taranto, Italy
    • U.O.C. di Ematolgia - A.O. " SS Annunziata" - P.O. S.G. Moscati
  • Torino, Italy
    • SCDO Ematologia 2 AOU S.Giovanni Battista
  • Treviso, Italy, 31100
    • Azienda USL 9 Treviso - U.O. di Ematologia
  • Udine, Italy
    • Clinica Ematologica - Policlinico Universitario
  • Verona, Italy
    • Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity	Number of toxic events	At three years from study entry
Compliance	Number of fully compliant patients and number of patients who do not comply with treatment	At 3 years from study entry
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)	From the date of the first nilotinib dose to death	At three years from study entry
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
Failure Free Survival (FFS)	From the date of the first nilotinib dose to failure* or progression or death	At three years from study entry
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
Patient-reported quality of life (QoL)		At baseline and then at 3, 6, 12, 18 and 24 months

Collaborators and Investigators

• Sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Investigators: Study Chair: Gianantonio Rosti, Dpt of Hematology and Oncology, "Seràgnoli", Sant'Orsola-Malpighi. University Hospital of Bologna

Publications and helpful links

General Publications

• 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.

Helpful Links

• GIMEMA Foundation website

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2012
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): April 27, 2018

Study Registration Dates

• First Submitted: February 9, 2012
• First Submitted That Met QC Criteria: February 16, 2012
• First Posted (Estimate): February 17, 2012

Study Record Updates

• Last Update Posted (Actual): August 6, 2018
• Last Update Submitted That Met QC Criteria: August 3, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Chronic Myeloid Leukemia,; Nilotinib,; Philadelphia positive,; BCR-ABL+; Early chronic phase
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Other Study ID Numbers: CML0811; 2011-002787-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No