Nilotinib as First-line Treatment of Ph+ CML in Early Chronic Phase (CML0307)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Gruppo Italiano Malattie EMatologiche dell'Adulto
ClinicalTrials.gov Identifier:
NCT00481052
First received: May 31, 2007
Last updated: May 13, 2014
Last verified: May 2014
  Purpose

Treating Ph pos CML with Imatinib is very effective since the majority of the patients achieve a complete cytogenetic response and a major molecular response and are alive and progression-free after 5 years. However, the great majority of responding patients are not leukemia-free and may be at risk of progression, molecular, cytogenetic and clinical, at any time. In case of disease progression due to Imatinib failure, nilotinib has been found to be very effective, as expected from the preclinical profile of the drug, that is much more potent against BCR-ABL and inhibits nearly all the imatinib-resistant BCR-ABL mutants. For these reasons, nilotinib is going to be registered for the treatment of imatinib-resistant CMl patients. For the same reasons, nilotinib is expected to be more efficient than imatinib also front-line, based on the principle that we should aim at preventing the emergence of resistance better that at treating resistance once it has emerged. This expectation can be tested safely, because the "toxicity profile" of Nilotinib may be even more convenient than that of Imatinib, due to the lower frequency of edema and fluid retention.


Condition Intervention Phase
Chronic Myeloid Leukemia
Drug: Nilotinib
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: The Protein Tyrosine Kinase Inhibitor Nilotinib as First-line Treatment of Ph+ Chronic Myeloid Leucemia (CML) in Early Chronic Phase: a Phase II Exploratory, Multicenter Study. GIMEMA Protocol CML 0307. EUDRACT 2007-000597-22.

Resource links provided by NLM:


Further study details as provided by Gruppo Italiano Malattie EMatologiche dell'Adulto:

Primary Outcome Measures:
  • Complete cytogenetic response (CCgR ) rate [ Time Frame: At 1 year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • The complete and the partial cytogenetic response rate [ Time Frame: At 6 months ] [ Designated as safety issue: No ]
  • The major molecular response (MMR) rate [ Time Frame: At 1 year ] [ Designated as safety issue: No ]
  • The kinetics of haematologic, cytogenetic and molecular response to AMN107 [ Time Frame: At 1 year ] [ Designated as safety issue: No ]
  • The development of bcr-abl mutation during the treatment with AMN107 (number and type) [ Time Frame: At 1 year ] [ Designated as safety issue: No ]
  • The safety and tolerability of nilotinib treatment at the dose of 300 mg b.i.d [ Time Frame: At 1 year ] [ Designated as safety issue: Yes ]
  • To describe any SAE [ Time Frame: At 1 year ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 70
Study Start Date: June 2007
Estimated Study Completion Date: November 2018
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Detailed Description:

Study Phase:

Phase II, Prospective, multicentric, non randomized, open label

Objectives:

The primary objective of the trial is to investigate the cytogenetic and molecular effects of the protein tyrosine kinase (PTK) inhibitor nilotinib in the treatment of early chronic phase Ph+ CML.

The secondary objectives are:

To investigate in early CP Ph+ CML patients treated with nilotinib the clinical and the hematologic effects, the effect on bcr/abl point mutations, the kinetic of the response, the toxicity, the compliance to treatment and the dose density.

Study design:

This study is an open-label, multicenter, exploratory, Phase II study of nilotinib administered orally twice daily for one year. For the patients who will benefit an extension to 4 years is planned.

Visit Schedule and Assessments:

A visit with blood counts and differential and serum chemistry is due baseline, every 15 days for 3 months, hence every 30 days.

An ECG is due baseline, after 15 and 30 days, hence at 60, 90, 150, 240 and 360 days.

An echocardiogram is due baseline and at end-of-study (360 days) or early withdrawal.

A bone marrow aspirate is due baseline (cytology, cytogenetics and quantitative molecular biology), after 3 and 6 months (cytology and cytogenetics) and after 12 months (cytology, cytogenetics, quantitative molecular biology and mutational analysis).

A peripheral blood sample is due baseline, at 30, 60, 90, 180, 270 and 360 days for quantitative molecular biology.

After the end of the study (i.e. after one year) clinical, cytogenetic and molecular data are due every 6 months.

Biologic Monitoring:

Bone marrow and peripheral blood cells will be collected before, during and at the end of the study, stored at the central lab in Bologna and used for molecular assays that are listed in details in the protocol, with the exclusion of any test allowing the identification of patients genotype. The samples are kept for a minimum of 10 years and can be destroyed upon patient request. A specific consent form to the sample storage will be submitted to the patients.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with a cytologic and cytogenetic confirmed diagnosis of Ph+ CML.
  • Age ≥ 18 years old
  • Early CP (within 6 months from diagnosis)
  • No prior treatment with any antileukemic drugs with the exception of Hydroxyurea (HU) and Anagrelide.
  • WHO performance status of ≤ 2
  • Normal serum level of potassium, total calcium corrected for serum albumin, magnesium and phosphorus, or correctable with supplements
  • ALT and AST ≤ 2.5 x ULN or ≤ 5.0 x ULN if considered due to leukaemia.
  • Alkaline phosphatase ≤ 2.5 x ULN unless considered due to leukemia.
  • Serum bilirubin ≤ 1.5 x ULN
  • Serum creatinine ≤ 1.5 x ULN
  • Serum amylase ≤ 1.5 x ULN and serum lipase ≤ 1.5 x ULN.
  • Written informed consent prior to any study procedures being performed.

Exclusion criteria:

  • Impaired cardiac function, including LVEF < 45% as determined by MUGA scan or echocardiogram, uncontrolled congestive heart failure, uncontrolled hypertension
  • History of myocardial infarction within three months, or uncontrolled angina pectoris.
  • Significant electric heart abnormalities, including history or presence of significant ventricular or atrial tachyarrhythmias, congenital long QT syndrome and/or QTc > 450 msec on screening ECG (using the QTcF formula).
  • Patients with ventricular pacemakers and clinically significant bradycardias.
  • Patients with heart blocks.
  • History of acute or chronic pancreatitis.
  • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of nilotinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
  • Use of therapeutic coumarin derivates (i.e. warfarin, acenocoumarol, phenprocoumon).
  • Acute or chronic liver or renal disease considered unrelated to leukaemia
  • Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol
  • Patients who are currently receiving treatment with any of the medications listed in Appendix E and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. The medications listed in Appendix E have the potential to prolong QT, with the exception of HU and Anagrelide.
  • Patients who have received any antileukemic agents and treatments, including HSCT, with the exception of HU and Anagrelide.
  • Patients who have received any investigational drug ≤ 4 weeks.
  • 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 adults of reproductive potential not employing an effective method of birth control. (Women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of nilotinib). Post menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug.
  • Treatment with any hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF) 1 week prior to starting study drug.
  • Patients who have received immunotherapy 1 week prior to starting study drug or who have not recovered from side effects of such therapy.
  • Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory).
  • 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00481052

Locations
Italy
Dipartimento Area Medica P.O.
Ascoli Piceno, Italy, 63100
Unità Operativa Ematologica - Università degli Studi di Bari
Bari, Italy, 70124
Ospedali Riuniti
Bergamo, Italy, 24100
stituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi
Bologna, Italy
Azienda Spedali Civili
Brescia, Italy, 25100
Sezione di Ematologia e Trapianti Spedali Civili
Brescia, Italy, 21125
ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO
Cagliari, Italy
Ospedale Ferrarotto
Catania, Italy, 95124
Azienda Ospedaliera Pugliese Ciaccio
Catanzaro, Italy, 88100
Sezione di Ematologia e Fisiopatologia delle Emostasi - Azienda Ospedaliera - Arcispedale S. Anna
Ferrara, Italy
Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia
Napoli, Italy
Ospedale S. Luigi Gonzaga
Orbassano, Italy, 10043
La Maddalena Casa di Cura di Alta Specialità Dipartimento Oncologico di III Livello
Palermo, Italy
Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza
Piacenza, Italy
Ospedale S.Maria delle Croci
Ravenna, Italy, 48100
Calabria Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"
Reggio Calabria, Italy
Università degli Studi "Sapienza" - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia
Roma, Italy
Complesso Ospedaliero S. Giovanni Addolorata
Roma, Italy, 00184
Università La Cattolica del Sacro Cuore
Roma, Italy, 00168
U.O. Ematologia, Azienda Ospedaliera Universitaria Senese
Siena, Italy, 53100
Policlinico Universitario - Clinica Ematologia
Udine, Italy, 33100
Policlinico G.B. Rossi
Verona, Italy, 37134
Sponsors and Collaborators
Gruppo Italiano Malattie EMatologiche dell'Adulto
Investigators
Principal Investigator: Michele BACCARANI Azienda Ospedaliera Universitaria -Policlincio S. Orsola-Malpighi
  More Information

Additional Information:
Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Gruppo Italiano Malattie EMatologiche dell'Adulto
ClinicalTrials.gov Identifier: NCT00481052     History of Changes
Other Study ID Numbers: CML0307
Study First Received: May 31, 2007
Last Updated: May 13, 2014
Health Authority: Italy: The Italian Medicines Agency

Keywords provided by Gruppo Italiano Malattie EMatologiche dell'Adulto:
Adult
CML
Philadelphia positive
Nilotinib
early chronic phase
untreated or treated only with Hydroxyurea or Anagrelide
Chronic Myeloid Leukemia

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases

ClinicalTrials.gov processed this record on July 24, 2014