Nilotinib and Imatinib Mesylate in Treating Patients With Early Chronic Phase Chronic Myelogenous Leukemia

Leukemia Clinical Trial

— CML0408  

Official title:

Front-line Treatment of Philadelphia Positive (Ph Pos), BCRABL Positive, Chronic Myeloid Leukemia (CML) With Two Tyrosine Kinase Inhibitors (TKI) (Nilotinib and Imotinib) A Phase II Exploratory Multicentric Centre.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00769327
• Other study ID #: CML0408
• Secondary ID: GIMEMA-CML0408EU
• Status: Completed
• Phase: Phase 2
• Start date: February 9, 2009
• Est. completion date: October 10, 2014

Study information

• Verified date: January 2022
• Source: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Nilotinib and imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. PURPOSE: This phase II trial is studying how well giving nilotinib together with imatinib mesylate works in treating patients with early chronic phase chronic myelogenous leukemia.

Description:

OBJECTIVES: Primary - To assess the complete cytogenetic response rate at 12 months in patients with Philadelphia chromosome- and BCR-ABL-positive early chronic phase chronic myelogenous leukemia treated with nilotinib and imatinib mesylate. Secondary - To assess the complete cytogenetic response rate at 6 and 24 months in these patients. - To assess the major and complete molecular response rate at 6, 12, and 24 months in these patients. - To assess the frequency and the types of BCR-ABL kinase domain mutations at 24 months during and for 3 years after study treatment. - To assess the rate of failures and the time to failure at 12, 24, and 60 months in these patients. - To assess compliance, toxicity, and adverse events in these patients. - To understand the relationship between response, gene expression profile, biomarkers, and drug plasma concentrations in these patients. OUTLINE: This is a multicenter study. Patients receive oral nilotinib twice daily in months 1-3, 7-9, 13-15, and 19-21 and oral imatinib mesylate once daily in months 4-6, 10-12, 16-18, and 22-24. Treatment continues for 24 months in the absence of disease progression or unacceptable toxicity. Patients may be eligible to continue oral nilotinib and oral imatinib mesylate for up to another 36 months if it is in the interest of the patient. Blood samples and bone marrow biopsies are collected periodically for cytogenetic response by chromosome banding analysis and FISH analysis; real-time quantitative PCR mutational analysis and single nucleotide polymorphism analysis of BCR-ABL transcripts; and gene expression profiling and correlative biomarker studies. After completion of study therapy, patients are followed every 6 months for 3 years and then every 12 months for 5 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 129
• Est. completion date: October 10, 2014
• Est. primary completion date: October 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

DISEASE CHARACTERISTICS:

• Cytologically and cytogenetically confirmed chronic myelogenous leukemia meeting the

following criteria:

• Early chronic phase disease (< 6 months from diagnosis)
• Philadelphia chromosome-positive disease
• BCR-ABL-positive

PATIENT CHARACTERISTICS:

• WHO performance status 0-1
• ALT and AST = 2.5 times upper limit of normal (ULN) (5.0 times ULN if considered due to leukemia)
• Alkaline phosphatase = 2.5 times ULN (unless considered due to leukemia)
• Serum bilirubin = 1.5 times ULN
• Serum creatinine = 1.5 times ULN
• Serum amylase = 1.5 times ULN
• Serum lipase = 1.5 times ULN
• Normal serum levels of the following or correctable with supplements:
• Potassium
• Total calcium (corrected for serum albumin)
• Magnesium
• Phosphorus
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier method contraception during study and for up to 3 months following completion of study treatment
• No impaired cardiac function, including any of the following:
• LVEF < 45% by MUGA scan or echocardiogram
• Uncontrolled congestive heart failure
• Uncontrolled hypertension
• Uncontrolled angina pectoris
• Myocardial infarction within the past 12 months
• No significant electric heart abnormalities, including any of the following:
• History or active ventricular or atrial tachyarrhythmias
• Congenital long QT syndrome and/or QTc > 450 msec on screening ECG
• No history of acute (within one year) or chronic pancreatitis
• No impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
• No acute or chronic liver or renal disease considered unrelated to leukemia
• No known diagnosis of HIV infection
• No 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
• No other primary malignancy that is currently clinically significant or requires active intervention

PRIOR CONCURRENT THERAPY:

• More than 2 weeks since prior major surgery and recovered
• More than 30 days since prior imatinib mesylate, with a washout period of = 7 days
• More than 4 weeks since prior investigational drug
• No prior hematopoietic stem cell transplantation
• No concurrent therapeutic coumarin derivates (i.e., warfarin, acenocoumarol, phenprocoumon)
• No concurrent medications that would prolong the QT interval
• No concurrent chemotherapy, investigational agents, radiotherapy, or biologic therapy
• Prior treatment with hydroxyurea or anagrelide allowed

Related Conditions & MeSH terms

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

Intervention

Drug:
• imatinib mesylate

• nilotinib

Genetic:
• cytogenetic analysis

• fluorescence in situ hybridization

• microarray analysis

• mutation analysis

• polymerase chain reaction

• polymorphism analysis

Other:
• laboratory biomarker analysis

Locations

Country	Name	City	State
Italy	Ospedale Civile Alessandria	Alessandria
Italy	Dipartimento Area Medica P.O.	Ascoli Piceno
Italy	S.G. Moscati Hospital	Avellino
Italy	Unità Operativa Ematologia 1 - Università degli Studi di Bari	Bari
Italy	Ospedali Riuniti di Bergamo	Bergamo
Italy	Ist.Ematologia e Oncologia Medica L.e A. Seragnoli	Bologna
Italy	ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO	Cagliari
Italy	Ctc U.O Di Ematologia Con Trapianto Di Midollo Osseo - Catania	Catania
Italy	Unità di Oncoematologia Azienda Ospedaliera Garibaldi	Catania
Italy	Azienda Ospedaliera Pugliese Ciaccio - Presidio Ospedaliero A.Pugliese - Unità Operativa di Ematologia	Catanzaro
Italy	Sez.Ematologia e Dip. scienze Biomediche Arcispedale S. Anna	Ferrara
Italy	Azienda Ospedaliera di Firenze	Firenze
Italy	Struttura Complessa di Ematologia Ospedali Riuniti Foggia - Azienda Ospedaliero-Universitaria	Foggia
Italy	Clinica Ematologica - DiMI - Università degli Studi di Genova	Genova
Italy	Clinica Ematologica - Università degli Studi	Genova
Italy	A.O. Universitaria Policlinico Martina di Messina	Messina
Italy	Azienda ospedaliera Ospedali Riuniti "Papardo Piemonte"	Messina
Italy	Sez. di medicina Interna Oncologia ed Ematologia	Modena
Italy	Universtià degli Studi di Napoli "Federico II" - Facoltà di medicina e chirurgia	Napoli
Italy	S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro	Novara
Italy	Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga	Orbassano
Italy	Ospedali Riuniti "Villa Sofia-Cervello"	Palermo
Italy	U.O. Ematologia Clinica - Azienda USL di Pescara	Pescara
Italy	Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza	Piacenza
Italy	Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"	Reggio Calabria
Italy	Unità operativa complessa di Ematologia	Reggio Emilia
Italy	Centro Oncologico Basilicata	Rionero in Vulture	Potenza
Italy	A.O Umberto I	Roma
Italy	Complesso Ospedaliero S. Giovanni Addolorata	Roma
Italy	Ospedale S.Eugenio	Roma
Italy	Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo
Italy	U.O. Ematologia, Azienda Ospedaliera Universitaria Senese	Siena
Italy	Azienda ospedaliera S. Maria di Terni	Terni
Italy	SCDO Ematologia 2 AOU S.Giovanni Battista	Torino
Italy	Policlinico Universitario Udine	Udine
Italy	Policlinico G. B. Rossi - Borgo Roma	Verona
Italy	Ospedale San Bortolo	Vicenza

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 cytogenetic response rate		At 12 months from study entry
Secondary	Complete cytogenetic response		At at 6 and 24 months from study entry
Secondary	Major and complete molecular response rate		At at 6, 12 and 24 months from study entry
Secondary	Development of BCR-ABL kinase domain mutations (number, timing, and type)		At at 24 months during and for 3 years after study treatment
Secondary	Rate of failures and the time to failure		At 12, 24, and 60 months from study entry
Secondary	Safety and tolerability		At 24 months from study entry
Secondary	Frequency and type of adverse events (AE) and severe AE		At 24 months from study entry
Secondary	Relationship between response, the gene expression profile, the biomarkers of leukemic cells, and plasma concentrations of nilotinib and imatinib mesylate		At 24 months from study entry