Clinical trial NCT02810990: Bosutinib in Elderly Chronic Myeloid Leukemia
Official title: Bosutinib Efficacy, Safety, Tolerability (BEST) Study in Elderly Chronic Myeloid Leukemia Patients Failing Front-line Treatment With Other Tyrosine Kinase Inhibitors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Myeloid Leukemia
Keywords: bosutinib
chronic myeloid leukemia
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor class: OTHER
First posted: 2016-06-23
Enrollment: 65
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The objective of the present study is to evaluate a new drug called bosutinib as it is believed that this agent may be able to predict an excellent prognosis in patients that did not obtain any benefit with other drugs before. Still, this needs to be proved and we hope this study is able to do so.

Detailed description: Bosutinib is a potent tyrosine kinase inhibitor (TKI) active at nM concentration on BCR-ABL1 and most BCR-ABL1 mutations. Bosutinib has been approved by the FDA and the EMA for the treatment of patients with Ph+/BCR-ABL1+ chronic myeloid leukemia who fail treatment with other TKIs, first or second line. The goal of second-line treatment of CML is to achieve a response that would predict for a survival equal to, or very close to, the survival of non leukemic people, that is to say to achieve a complete cytogenetic response (CCyR) or a major molecular response (MMR). To achieve that goal, it is necessary to find and keep the right balance between activity, safety, and tolerability. There are no studies comparing TKIs in second-line. From phase 2, single-arm, studies, the reported efficacy of Bosutinib is similar to the reported efficacy of dasatinib and nilotinib. The median age of newly diagnosed CML patients is about 56 years, and at least 40% of all newly diagnosed patients are more than 60 years old. Particularly for these patients, the choice of the TKI must take into account the safety and the tolerability profile of the TKIs. The use of dasatinib and nilotinib is burdened by pleural and pulmonary complications, by infections, and by cardiovascular, thrombotic and metabolic (diabetes mellitus, dyslipidemia) complications. These complications are more frequent and more clinically relevant in the elderly. The safety and tolerability of Bosutinib has been reported in first- as well as in second- and third-line. The standard dose (500 mg once daily) is tolerated and safe, but at that dose several adverse events (AEs) limit the tolerability, require dose reduction or interruption, and affect patient quality of life, including diarrhea, nausea, vomiting, skin rash. Also an increase of AST, ALT and lipase are of concern and a cause of treatment discontinuation. On the contrary, an increased frequency of infections and of pleuro-pulmonary, cardiovascular, thrombotic, and metabolic AEs has not been reported. The reported hematologic toxicity of Bosutinib is at least as low as, or even lower than, that reported for the other TKIs, in spite of the fact that Bosutinib is a dual, BCR-ABL1 and src inhibitor. Until today, all studies of TKIs in CML have tested a fixed initial dose, providing for dose adjustment in case of toxicity (dose decrease) or in case of unsatisfactory response (dose increase). No study so far was designed to test the adaptation of the dose to the response, taking advantage of the fact that the efficacy of TKI treatment can be assessed rapidly and precisely by measuring the BCR-ABL1 transcripts level with real-time PCR (RT-PCR) in peripheral blood cells. An RT-PCR monthly for the first few months provides the best assessment of the response to treatment. We predict that a more flexible strategy of treatment (adapting the dose to the response) will result into a more convenient balance between activity and toxicity, hence into a better outcome. Based on these premises, it is proposed to test the activity, the safety, and the tolerability of Bosutinib, second-line, beginning with a low dose and adjusting subsequent doses based on molecular response, and on AEs, in a population of elderly patients. In almost all prior studies of TKIs in second- or third-line, the primary efficacy was assessed using cytogenetic response, both major and complete, at different time points. To make the results of this study comparable to the results of prior studies, the cytogenetic response will be evaluated as specified in section 5, but since the response to therapy and the evaluation of the efficacy of therapy are more and more based on molecular response, dose adaptation and efficacy evaluation will be based primarily on molecular response.

Eligibility criteria: Inclusion Criteria:

1. Molecular confirmed diagnosis of BCR-ABL1+ CML
2. Chronic phase CML (ELN 2013 criteria)
3. 60 years of age or older
4. Prior first-line treatment with any other TKIs
5. Intolerance to prior treatment, based on investigator and patient assessment or failure of prior treatment according to any one of the ELN 2013 criteria, as listed below

   * Non complete hematologic response (CHR) at 3 months
   * No cytogenetic response (Ph+ \> 95%) at 6 months
   * Less than Partial Cytogenetic Response (PCyR) (Ph+ \>35%) at 6 months
   * BCR-ABL1 \> 10% at 6 months
   * Non complete CyR (CCyR) (Ph+ \> 0) at 12 months
   * BCR-ABL1 \> 1% at 12 months
   * Loss of CHR at any time
   * Loss of CCyR at any time
   * Confirmed loss of major molecular response (MMR) (BCR-ABL1 \> 0.1%) in two consecutive tests, of which one \> 1%, at any time
6. An effective form of contraception from enrolment through 30 days after the end of treatment
7. Signed written informed consent according to ICH/EU/GCP and national and local laws prior to any study procedures
8. Willingness and ability to comply with scheduled visits and study procedures.

Exclusion Criteria:

1. Accelerated or blastic phase CML (according to ELN 2013 criteria)
2. Patients with the T315I or the V299L mutation
3. Patients previously treated with 2 TKIs or more
4. Compelled to take medications that are known to be associated with Torsades de Pointes and/or with significant QTc prolongation
5. Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the drug
6. HBV markers positivity
7. Lack of informed consent

Primary outcomes:
measure: Number of patients who are in major molecular response (MMR)
timeFrame: One year treatment
Secondary outcomes:
measure: Number of patients who obtain molecular response
timeFrame: At 6 and 12 months from treatment start
measure: Number of patients discontinuing treatment for failure, adverse events or other reasons
timeFrame: At 12 and 36 months
measure: Number of Adverse Events (AEs)
timeFrame: At 36 months
measure: Number of patients alive
timeFrame: At 36 months
measure: Number of patients on treatment at 200, 300 and 400 mg or more daily
timeFrame: At 6, 12 and 36 months
measure: Number and type of BCR-ABL1 mutations
timeFrame: At 36 months
measure: Patient reported quality of life
timeFrame: At 3, 6, and 12 months
Other outcomes:
Locations:
city: Alessandria
country: Italy
facility: S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo
city: Ancona
country: Italy
facility: Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. LANCISI - G. SALESI
city: Bari
country: Italy
facility: UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro
city: Bologna
country: Italy
facility: Fausto Castagnetti
city: Bologna
country: Italy
facility: Istituto di Ematologia "Lorenzo e A. Seragnoli" - Policlinico S. Orsola - Malpighi
city: Cagliari
country: Italy
facility: ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO
city: Catania
country: Italy
facility: Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"
city: Cuneo
country: Italy
facility: S.C. Ematologia ASO S. Croce e Carle
city: Ferrara
country: Italy
facility: Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia
city: Firenze
country: Italy
facility: Policlinico di Careggi
city: Foggia
country: Italy
facility: Struttura Complessa di Ematologia Ospedali Riuniti Foggia
city: Genova
country: Italy
facility: IRCCS_AOU San Martino-IST-Ematologia 1-Monoblocco 11°piano- lato ponente
city: Lecce
country: Italy
facility: ASL Le/1 P.O. Vito Fazzi - U.O. di Ematologia ed UTIE
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnoli per lo Studio e la Cura dei Tumori- IRST
city: Messina
country: Italy
facility: Policlinico G. Martino Dipartimento di Medicina Interna - U.O. Messina
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico UOC Oncoematologia
city: Milano
country: Italy
facility: U.O. Ematologia e Trapianto di MIdollo - Ist.Scientifico Ospedale San Raffaele
city: Milano
country: Italy
facility: Unità Trapianto di Midollo Ist. Nazionale Tumori
city: Monza
country: Italy
facility: Azienda Ospedaliera "S.Gerardo"
city: Napoli
country: Italy
facility: Azienda Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia
city: Novara
country: Italy
facility: S.C.D.U. Ematologia - Università del Piemonte Orientale Amedeo Avogadro
city: Orbassano
country: Italy
facility: Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2
city: Padova
country: Italy
facility: Università degli Studi di Padova - Ematologia ed Immunologia Clinica
city: Palermo
country: Italy
facility: U.O. di Ematologia con trapianto - A.U. Policlinico "Paolo Giaccone"
city: Parma
country: Italy
facility: Cattedra di Ematologia CTMO Università degli Studi di Parma
city: Pavia
country: Italy
facility: S.C. Ematologia - Fondazione IRCCS Policlinico S. Matteo
city: Piacenza
country: Italy
facility: Dipartimento di Oncologia ed Ematologia - AUSL Ospedale G. da Saliceto
city: Potenza
country: Italy
facility: Ematologia - Ospedale San Carlo
city: Ravenna
country: Italy
facility: Dipartimento Oncologico - Ospedale S.Maria delle Croci
city: Reggio Emilia
country: Italy
facility: Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova
city: Rimini
country: Italy
facility: Ospedale "Infermi"
city: Rionero in Vulture
country: Italy
facility: U.O. di Ematologia - Centro Oncologico Basilicata
city: Roma
country: Italy
facility: Complesso Ospedaliero S. Giovanni Addolorata
city: Roma
country: Italy
facility: Divisione Ematologia - Università Campus Bio-Medico
city: Roma
country: Italy
facility: Padiglione Cesalpino - I piano - Divisione di Ematologia - Ospedale S. Camillo
city: Roma
country: Italy
facility: Università Cattolica del Sacro Cuore - Policlinico A. Gemelli
city: Roma
country: Italy
facility: UOC Pronto Soccorso - Dipartimento Biotecnologie Cellulari Università di Roma "Sapienza"
city: San Giovanni Rotondo
country: Italy
facility: Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza
city: Siena
country: Italy
facility: U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"
city: Terni
country: Italy
facility: A.O. Santa Maria - Terni S.C Oncoematologia
city: Torino
country: Italy
facility: Divisione di Ematologia - "Città della Salute e della Scienza di Torino"
city: Torino
country: Italy
facility: S.C. Ematologia 2 A.O. Città della Salute e della Scienza di Torino San Giovanni Battista
city: Udine
country: Italy
facility: Clinica Ematologica-Centro Trapianti e Terapie cellulari
city: Varese
country: Italy
facility: Medicina Interna I - Ospedale di Circolo
city: Verona
country: Italy
facility: A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi
Study officials:
affiliation: Department of Hematology, S. Orsola-Malpighi University of Bologna
name: Fausto Castagnetti
role: STUDY_CHAIR
References: