Bosutinib in Elderly Chronic Myeloid Leukemia (BEST)

January 4, 2022 updated by: Gruppo Italiano Malattie EMatologiche dell'Adulto

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

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Active, not recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
65

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • 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
      • Alessandria, Italy
        • S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo
      • Ancona, Italy
        • Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. LANCISI - G. SALESI
      • Bari, Italy
        • UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro
      • Bologna, Italy
        • Fausto Castagnetti
      • Bologna, Italy
        • Istituto di Ematologia "Lorenzo e A. Seragnoli" - Policlinico S. Orsola - Malpighi
      • Cagliari, Italy
        • ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO
      • Catania, Italy
        • Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"
      • Cuneo, Italy
        • S.C. Ematologia ASO S. Croce e Carle
      • Ferrara, Italy
        • Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia
      • Firenze, Italy
        • Policlinico di Careggi
      • Foggia, Italy
        • Struttura Complessa di Ematologia Ospedali Riuniti Foggia
      • Genova, Italy
        • IRCCS_AOU San Martino-IST-Ematologia 1-Monoblocco 11°piano- lato ponente
      • Lecce, Italy
        • ASL Le/1 P.O. Vito Fazzi - U.O. di Ematologia ed UTIE
      • Meldola, Italy
        • Istituto Scientifico Romagnoli per lo Studio e la Cura dei Tumori- IRST
      • Messina, Italy
        • Policlinico G. Martino Dipartimento di Medicina Interna - U.O. Messina
      • 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
        • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico UOC Oncoematologia
      • Monza, Italy
        • Azienda Ospedaliera "S.Gerardo"
      • Napoli, Italy
        • Azienda Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia
      • Novara, Italy
        • S.C.D.U. Ematologia - Università del Piemonte Orientale Amedeo Avogadro
      • Orbassano, Italy
        • Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2
      • Padova, Italy
        • Università degli Studi di Padova - Ematologia ed Immunologia Clinica
      • Palermo, Italy
        • U.O. di Ematologia con trapianto - A.U. Policlinico "Paolo Giaccone"
      • Parma, Italy
        • Cattedra di Ematologia CTMO Università degli Studi di Parma
      • Pavia, Italy
        • S.C. Ematologia - Fondazione IRCCS Policlinico S. Matteo
      • Piacenza, Italy
        • Dipartimento di Oncologia ed Ematologia - AUSL Ospedale G. da Saliceto
      • Potenza, Italy
        • Ematologia - Ospedale San Carlo
      • Ravenna, Italy
        • Dipartimento Oncologico - Ospedale S.Maria delle Croci
      • Reggio Emilia, Italy
        • Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova
      • Rimini, Italy
        • Ospedale "Infermi"
      • Rionero in Vulture, Italy
        • U.O. di Ematologia - Centro Oncologico Basilicata
      • Roma, Italy
        • Complesso Ospedaliero S. Giovanni Addolorata
      • Roma, Italy
        • Università Cattolica del Sacro Cuore - Policlinico A. Gemelli
      • Roma, Italy
        • Divisione Ematologia - Università Campus Bio-Medico
      • Roma, Italy
        • Padiglione Cesalpino - I piano - Divisione di Ematologia - Ospedale S. Camillo
      • Roma, Italy
        • UOC Pronto Soccorso - Dipartimento Biotecnologie Cellulari Università di Roma "Sapienza"
      • San Giovanni Rotondo, Italy
        • Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza
      • Siena, Italy
        • U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"
      • Terni, Italy
        • A.O. Santa Maria - Terni S.C Oncoematologia
      • Torino, 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
      • Udine, Italy
        • Clinica Ematologica-Centro Trapianti e Terapie cellulari
      • Varese, Italy
        • Medicina Interna I - Ospedale di Circolo
      • Verona, Italy
        • A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - 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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

60 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

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)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Bosutinib treatment
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).

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
Number of patients who are in major molecular response (MMR)
Time Frame: One year treatment
One year treatment

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
Number of patients who obtain molecular response
Time Frame: At 6 and 12 months from treatment start
At 6 and 12 months from treatment start
Number of patients discontinuing treatment for failure, adverse events or other reasons
Time Frame: At 12 and 36 months
At 12 and 36 months
Number of Adverse Events (AEs)
Time Frame: At 36 months
At 36 months
Number of patients alive
Time Frame: At 36 months
At 36 months
Number of patients on treatment at 200, 300 and 400 mg or more daily
Time Frame: At 6, 12 and 36 months
At 6, 12 and 36 months
Number and type of BCR-ABL1 mutations
Time Frame: At 36 months
At 36 months
Patient reported quality of life
Time Frame: At 3, 6, and 12 months
At 3, 6, and 12 months

Collaborators and Investigators

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

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Gruppo Italiano Malattie EMatologiche dell'Adulto

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Chair: Fausto Castagnetti, Department of Hematology, S. Orsola-Malpighi University of Bologna

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.

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)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 17, 2016

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
April 30, 2020

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 1, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 15, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 20, 2016

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
June 23, 2016

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
January 5, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 4, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
January 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • CML1516
  • 2016-002216-40 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

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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