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

January 3, 2022 updated by: Gruppo Italiano Malattie EMatologiche dell'Adulto

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.

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

74

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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:

  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

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
Time Frame
Complete cytogenetic response (CCgR ) rate
Time Frame: At 1 year
At 1 year

Secondary Outcome Measures

Outcome Measure
Time Frame
The complete and the partial cytogenetic response rate
Time Frame: At 6 months
At 6 months
The major molecular response (MMR) rate
Time Frame: At 1 year
At 1 year
The kinetics of haematologic, cytogenetic and molecular response to AMN107
Time Frame: At 1 year
At 1 year
The development of bcr-abl mutation during the treatment with AMN107 (number and type)
Time Frame: At 1 year
At 1 year
The safety and tolerability of nilotinib treatment at the dose of 300 mg b.i.d
Time Frame: At 1 year
At 1 year
To describe any SAE
Time Frame: At 1 year
At 1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Gruppo Italiano Malattie EMatologiche dell'Adulto

Investigators

  • Principal Investigator: Michele BACCARANI, Azienda Ospedaliera Universitaria -Policlincio S. Orsola-Malpighi

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 23, 2007

Primary Completion (Actual)

April 30, 2018

Study Completion (Actual)

April 30, 2018

Study Registration Dates

First Submitted

May 31, 2007

First Submitted That Met QC Criteria

May 31, 2007

First Posted (Estimate)

June 1, 2007

Study Record Updates

Last Update Posted (Actual)

January 18, 2022

Last Update Submitted That Met QC Criteria

January 3, 2022

Last Verified

January 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CML0307

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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