Clinical trial NCT00769327: Nilotinib and Imatinib Mesylate in Treating Patients With Early Chronic Phase Chronic Myelogenous Leukemia
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia
Keywords: chronic myelogenous leukemia, BCR-ABL1 positive
chronic phase chronic myelogenous leukemia
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor class: OTHER
First posted: 2008-10-09
Enrollment: 129
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Complete cytogenetic response rate
timeFrame: At 12 months from study entry
Secondary outcomes:
measure: Complete cytogenetic response
timeFrame: At at 6 and 24 months from study entry
measure: Major and complete molecular response rate
timeFrame: At at 6, 12 and 24 months from study entry
measure: Development of BCR-ABL kinase domain mutations (number, timing, and type)
timeFrame: At at 24 months during and for 3 years after study treatment
measure: Rate of failures and the time to failure
timeFrame: At 12, 24, and 60 months from study entry
measure: Safety and tolerability
timeFrame: At 24 months from study entry
measure: Frequency and type of adverse events (AE) and severe AE
timeFrame: At 24 months from study entry
measure: Relationship between response, the gene expression profile, the biomarkers of leukemic cells, and plasma concentrations of nilotinib and imatinib mesylate
timeFrame: At 24 months from study entry
Other outcomes:
Locations:
city: Rionero in Vulture
country: Italy
facility: Centro Oncologico Basilicata
state: Potenza
city: Alessandria
country: Italy
facility: Ospedale Civile Alessandria
city: Ascoli Piceno
country: Italy
facility: Dipartimento Area Medica P.O.
city: Avellino
country: Italy
facility: S.G. Moscati Hospital
city: Bari
country: Italy
facility: Unità Operativa Ematologia 1 - Università degli Studi di Bari
city: Bergamo
country: Italy
facility: Ospedali Riuniti di Bergamo
city: Bologna
country: Italy
facility: Ist.Ematologia e Oncologia Medica L.e A. Seragnoli
city: Cagliari
country: Italy
facility: ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO
city: Catania
country: Italy
facility: Ctc U.O Di Ematologia Con Trapianto Di Midollo Osseo - Catania
city: Catania
country: Italy
facility: Unità di Oncoematologia Azienda Ospedaliera Garibaldi
city: Catanzaro
country: Italy
facility: Azienda Ospedaliera Pugliese Ciaccio - Presidio Ospedaliero A.Pugliese - Unità Operativa di Ematologia
city: Ferrara
country: Italy
facility: Sez.Ematologia e Dip. scienze Biomediche Arcispedale S. Anna
city: Firenze
country: Italy
facility: Azienda Ospedaliera di Firenze
city: Foggia
country: Italy
facility: Struttura Complessa di Ematologia Ospedali Riuniti Foggia - Azienda Ospedaliero-Universitaria
city: Genova
country: Italy
facility: Clinica Ematologica - DiMI - Università degli Studi di Genova
city: Genova
country: Italy
facility: Clinica Ematologica - Università degli Studi
city: Messina
country: Italy
facility: A.O. Universitaria Policlinico Martina di Messina
city: Messina
country: Italy
facility: Azienda ospedaliera Ospedali Riuniti "Papardo Piemonte"
city: Modena
country: Italy
facility: Sez. di medicina Interna Oncologia ed Ematologia
city: Napoli
country: Italy
facility: Universtià degli Studi di Napoli "Federico II" - Facoltà di medicina e chirurgia
city: Novara
country: Italy
facility: S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro
city: Orbassano
country: Italy
facility: Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga
city: Palermo
country: Italy
facility: Ospedali Riuniti "Villa Sofia-Cervello"
city: Pescara
country: Italy
facility: U.O. Ematologia Clinica - Azienda USL di Pescara
city: Piacenza
country: Italy
facility: Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza
city: Reggio Calabria
country: Italy
facility: Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"
city: Reggio Emilia
country: Italy
facility: Unità operativa complessa di Ematologia
city: Roma
country: Italy
facility: A.O Umberto I
city: Roma
country: Italy
facility: Complesso Ospedaliero S. Giovanni Addolorata
city: Roma
country: Italy
facility: Ospedale S.Eugenio
city: San Giovanni Rotondo
country: Italy
facility: Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza
city: Siena
country: Italy
facility: U.O. Ematologia, Azienda Ospedaliera Universitaria Senese
city: Terni
country: Italy
facility: Azienda ospedaliera S. Maria di Terni
city: Torino
country: Italy
facility: SCDO Ematologia 2 AOU S.Giovanni Battista
city: Udine
country: Italy
facility: Policlinico Universitario Udine
city: Verona
country: Italy
facility: Policlinico G. B. Rossi - Borgo Roma
city: Vicenza
country: Italy
facility: Ospedale San Bortolo
Study officials:
affiliation: Gruppo Italiano Malattie EMatologiche dell'Adulto
name: Michele Baccarani, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Castagnetti F, Gugliotta G, Baccarani M, Breccia M, Specchia G, Levato L, Abruzzese E, Rossi G, Iurlo A, Martino B, Pregno P, Stagno F, Cuneo A, Bonifacio M, Gobbi M, Russo D, Gozzini A, Tiribelli M, de Vivo A, Alimena G, Cavo M, Martinelli G, Pane F, Saglio G, Rosti G; GIMEMA CML Working Party. Differences among young adults, adults and elderly chronic myeloid leukemia patients. Ann Oncol. 2015 Jan;26(1):185-192. doi: 10.1093/annonc/mdu490. Epub 2014 Oct 30.