Bosutinib in Elderly Chronic Myeloid Leukemia

Chronic Myeloid Leukemia Clinical Trial

— BEST  

Official title:

Bosutinib Efficacy, Safety, Tolerability (BEST) Study in Elderly Chronic Myeloid Leukemia Patients Failing Front-line Treatment With Other Tyrosine Kinase Inhibitors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02810990
• Other study ID #: CML1516
• Secondary ID: 2016-002216-40
• Status: Completed
• Phase: Phase 2
• Start date: November 17, 2016
• Est. completion date: June 22, 2022

Study information

• Verified date: February 2023
• Source: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 65
• Est. completion date: June 22, 2022
• Est. primary completion date: April 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years and older

Eligibility

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• Bosutinib
Bosutinib is given orally accordingly with this scheme: A. 200 mg OD: starting dose ("wash-in" period) at week 1 and week 2 B. 300 mg OD: from week 3 to the end of week 16 At the end of week 12 evaluation of molecular response (BCR-ABL1 level by RT-Q-PCR). Bosutinib dose is then managed as follows : C1. if BCR-ABL1 =1% at week 12: 300 mg OD from week 17 to week 52 C2. if BCR-ABL1 > 1% at week 12: 400 mg OD from week 17 to week 52 All the responsive patients who are still on Bosutinib at the end of week 52, will continue Bosutinib at the same dose (300 mg OD or 400 mg OD) for the next two years ( if tolerated and in absence of safety concerns).

Locations

Country	Name	City	State
Italy	S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo	Alessandria
Italy	Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. LANCISI - G. SALESI	Ancona
Italy	UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro	Bari
Italy	Fausto Castagnetti	Bologna
Italy	Istituto di Ematologia "Lorenzo e A. Seragnoli" - Policlinico S. Orsola - Malpighi	Bologna
Italy	ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO	Cagliari
Italy	Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"	Catania
Italy	S.C. Ematologia ASO S. Croce e Carle	Cuneo
Italy	Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia	Ferrara
Italy	Policlinico di Careggi	Firenze
Italy	Struttura Complessa di Ematologia Ospedali Riuniti Foggia	Foggia
Italy	IRCCS_AOU San Martino-IST-Ematologia 1-Monoblocco 11°piano- lato ponente	Genova
Italy	ASL Le/1 P.O. Vito Fazzi - U.O. di Ematologia ed UTIE	Lecce
Italy	Istituto Scientifico Romagnoli per lo Studio e la Cura dei Tumori- IRST	Meldola
Italy	Policlinico G. Martino Dipartimento di Medicina Interna - U.O. Messina	Messina
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico UOC Oncoematologia	Milano
Italy	U.O. Ematologia e Trapianto di MIdollo - Ist.Scientifico Ospedale San Raffaele	Milano
Italy	Unità Trapianto di Midollo Ist. Nazionale Tumori	Milano
Italy	Azienda Ospedaliera "S.Gerardo"	Monza
Italy	Azienda Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia	Napoli
Italy	S.C.D.U. Ematologia - Università del Piemonte Orientale Amedeo Avogadro	Novara
Italy	Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2	Orbassano
Italy	Università degli Studi di Padova - Ematologia ed Immunologia Clinica	Padova
Italy	U.O. di Ematologia con trapianto - A.U. Policlinico "Paolo Giaccone"	Palermo
Italy	Cattedra di Ematologia CTMO Università degli Studi di Parma	Parma
Italy	S.C. Ematologia - Fondazione IRCCS Policlinico S. Matteo	Pavia
Italy	Dipartimento di Oncologia ed Ematologia - AUSL Ospedale G. da Saliceto	Piacenza
Italy	Ematologia - Ospedale San Carlo	Potenza
Italy	Dipartimento Oncologico - Ospedale S.Maria delle Croci	Ravenna
Italy	Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova	Reggio Emilia
Italy	Ospedale "Infermi"	Rimini
Italy	U.O. di Ematologia - Centro Oncologico Basilicata	Rionero in Vulture
Italy	Complesso Ospedaliero S. Giovanni Addolorata	Roma
Italy	Divisione Ematologia - Università Campus Bio-Medico	Roma
Italy	Padiglione Cesalpino - I piano - Divisione di Ematologia - Ospedale S. Camillo	Roma
Italy	Università Cattolica del Sacro Cuore - Policlinico A. Gemelli	Roma
Italy	UOC Pronto Soccorso - Dipartimento Biotecnologie Cellulari Università di Roma "Sapienza"	Roma
Italy	Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo
Italy	U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"	Siena
Italy	A.O. Santa Maria - Terni S.C Oncoematologia	Terni
Italy	Divisione di Ematologia - "Città della Salute e della Scienza di Torino"	Torino
Italy	S.C. Ematologia 2 A.O. Città della Salute e della Scienza di Torino San Giovanni Battista	Torino
Italy	Clinica Ematologica-Centro Trapianti e Terapie cellulari	Udine
Italy	Medicina Interna I - Ospedale di Circolo	Varese
Italy	A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi	Verona

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	Number of patients who are in major molecular response (MMR)		One year treatment
Secondary	Number of patients who obtain molecular response		At 6 and 12 months from treatment start
Secondary	Number of patients discontinuing treatment for failure, adverse events or other reasons		At 12 and 36 months
Secondary	Number of Adverse Events (AEs)		At 36 months
Secondary	Number of patients alive		At 36 months
Secondary	Number of patients on treatment at 200, 300 and 400 mg or more daily		At 6, 12 and 36 months
Secondary	Number and type of BCR-ABL1 mutations		At 36 months
Secondary	Patient reported quality of life		At 3, 6, and 12 months

External Links

•   GIMEMA Foundation website