Safety and Efficacy Study of Bosutinib in Patients With Philadelphia Chromosome Positive Chronic Myeloid Leukemia Previously Treated with one or two more Tyrosine Kinase Inhibitors

• Register: EUCTR
• Last refreshed on: 23 November 2020
• Main ID: EUCTR2013-003250-25-SE
• Date of registration: 21/05/2014
• Prospective Registration: Yes
• Primary sponsor: Pfizer Inc, 235 East 42nd Street, New York, NY 10017
• Public title: Safety and Efficacy Study of Bosutinib in Patients With Philadelphia Chromosome Positive Chronic Myeloid Leukemia Previously Treated with one or two more Tyrosine Kinase Inhibitors
• Scientific title: A Phase 4 Safety and Efficacy Study of Bosutinib (Bosulif®) in Patients with Philadelphia Chromosome Positive Chronic Myeloid Leukemia Previously Treated with One or More Tyrosine Kinase Inhibitors
• Date of first enrolment: 24/06/2014
• Target sample size: 165
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-003250-25
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: yes; Other trial design description: Post Marketing Study for Safety and Efficacy; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Austria, Belgium, Finland, France, Germany, Italy, Netherlands, Norway, Spain, Sweden, United States

Contacts

• Name: Clinical Trials.gov Call Centre
• Affiliation: Pfizer Inc

• Name: Clinical Trials.gov Call Centre
• Affiliation: Pfizer Inc

Key inclusion & exclusion criteria

Inclusion criteria:
1. Cytogenetic or PCR-based diagnosis of Ph+ CML or BCR-ABL1+ if Ph- (from initial diagnosis). NOTE: Ph-CML patients will not count towards the 150 patients for primary and secondary analyses, which include Ph+ CML patients only.
NOTE: All patients must have screening bone marrow (BM) cytogenetic analysis with conventional G banding performed within 30 days prior to study entry (unless CML disease status is proven to be MMR by quantitative reverse transcription polymerase chain reaction [qRT-PCR]). Examination of at least 20 metaphases is required.
2. Prior treatment with 1 or more TKIs for CML.
3. Any CML phase, as long as the patient is resistant to, intolerant of, or otherwise not appropriate for treatment with imatinib, dasatinib and/or nilotinib.
4. ECOG Performance Status of 0 or 1 for CP patients, or 0, 1, 2, or 3 for 4th line CP (and beyond) and AP/ BP patients.
5. Adequate bone marrow function:
For 2nd and 3rd line CP CML patients:
• Absolute neutrophil count >1000/mm3 (>1 x109/L).
• Platelets =75,000/mm3 (=75 x109/L) absent any platelet transfusions during the preceding 14 days.
For 4th line CP and AP/BP CML patients:
• Absolute neutrophil count >500/mm3 (>0.5 x109/L).
• Platelets =50,000/mm3 (=50 x109/L) absent any platelet transfusions during the preceding 14 days.
6. Adequate hepatic and renal function:
• AST/ALT =2.5 x the upper limit of normal ULN or ALT/AST =5 x ULN if attributable to liver involvement of leukemia.
• Total bilirubin =1.5 x ULN (unless the bilirubin is principally unconjugated and there is a strong suspicion of subclinical hemolysis (e.g. chronic hemolysis without clinical symptoms), or the patient has documented Gilbert's Disease);
• Alkaline phosphatase =2.5 x ULN.
• Creatinine =1.5 x ULN or estimated creatinine clearance (CrCL) =60 mL/min as calculated using the standard method for the institution.
7. Able to take daily oral tablets.
8. Age =18 years.
9. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative/legal guardian) has been informed of all pertinent aspects of the study.
10. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
11. Male and female patients of childbearing potential must agree to use two highly effective methods of contraception throughout the study and for at least 28 days after the last dose of assigned treatment. A patient is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 132
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 33

Exclusion criteria:
1. Participation in other studies involving investigational drug(s) (Phase 1-4) within 14 days or 3 half-lives (whichever is longer) prior to the first dose of bosutinib.
2. Prior bosutinib or ponatinib exposure.
3. Prior hydroxyurea or anagrelide exposure within 72 hours of the baseline CML disease assessment.
4. Known T315I or V299L mutation in BCR-ABL1.
5. Clinically active leptomeningeal leukemia. Patients must be free of central nervous system (CNS) involvement for a minimum of 2 months.
6. Hypersensitivity to the active substance or to any of the following excipients:
Microcrystalline cellulose (E460), Croscarmellose sodium (E468), Poloxamer 188, Povidone (E1201), Magnesium stearate (E470b), Polyvinyl alcohol, Titanium dioxide (E171), Macrogol 3350, Talc (E553b), Iron oxide red (E172).
7. Pregnant or breastfeeding females.
8. Males and females of childbearing potential who are unwilling or unable to use two highly effective methods of contraception as outlined in this protocol for the duration of the study and for at least 28 days after last dose of investigational product.
9. Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior) or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
10. Patients who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or patients who are Pfizer employees directly involved in the conduct of the trial.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Philadelphia Chromosome Positive Chronic Myeloid Leukaemia
MedDRA version: 21.1 Level: PT Classification code 10009013 Term: Chronic myeloid leukaemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Trade Name: Bosulif
Pharmaceutical Form: Tablet
INN or Proposed INN: Bosutinib
Other descriptive name: BOSUTINIB MONOHYDRATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Trade Name: Bosulif
Pharmaceutical Form: Tablet
INN or Proposed INN: Bosutinib
Other descriptive name: BOSUTINIB MONOHYDRATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: 1 year (52 weeks)

Main Objective: Primary Objectives
•To estimate the 1-year (Week 52) probability of cumulative confirmed Major Cytogenetic Response (MCyR) in CP Ph+ CML patients with 1 or 2 prior lines of TKI therapy.
•To estimate the 1-year (Week 52) probability of cumulative confirmed MCyR in CP Ph+ CML patients with 3 or more prior lines of TKI therapy.
•To estimate the 1-year (Week 52) probability of cumulative confirmed Overall Hematological Response (OHR) in AP and BP Ph+ CML patients with any prior TKI therapy.

Primary end point(s): •Cumulative confirmed MCyR defined as Complete Cytogenetic Response (CCyR) or Partial Cytogenetic Response (PCyR) by 1 year (52 weeks) in 2nd and 3rd line CP patients.
•Cumulative confirmed MCyR by 1 year (52 weeks) in 4th and later-line CP patients.
•Cumulative confirmed OHR defined as Complete Hematological Response (CHR) or Return to CP (RCP) by 1 year (52 weeks) in AP and BP patients.

Secondary Objective: •To estimate the probability of cumulative MCyR in each disease phase (CP, AP and BP) for Ph+ CML patients.
•To estimate the probability of cumulative confirmed OHR in each disease phase (AP and BP) for Ph+ CML patients by number of lines of prior therapy.
•To characterize the distributions of best response (molecular, cytogenetic, or hematologic) in the CP, AP, and BP Ph+ CML patient populations.
•To estimate the probability of MCyR at 3, 6, 12, 18, and 24 months in the CP, AP, and BP Ph+ CML patient populations.
•To estimate the probability of confirmed OHR at 3, 6, 9, 12, 18, and 24 months in the AP and BP Ph+ CML patient populations.
•To estimate the probability of cumulative confirmed Complete Hematological Response (CHR) in the CP, AP and BP Ph+ CML patient populations.
•To estimate the probability of cumulative major molecular response (MMR) in the CP, AP and BP Ph+ CML patient populations.
•To estimate the duration of Complete Cytogenetic Response (CCyR).

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Various timepoints mainly 3, 6, 12, 18 and 24 months. See Table 1, schedule of activities in protocol.

Secondary end point(s): • Cumulative MCyR in CP, AP and BP patients.
• Cumulative confirmed OHR in AP and BP patients by line of therapy.
• Cumulative best response in CP, AP, and BP patients.
• MCyR at 3, 6, 12, 18, and 24 months in CP, AP, and BP patients.
• Confirmed OHR at 3, 6, 9, 12, 18, and 24 months in CP, AP and BP patients.
• Cumulative confirmed CHR.
• Cumulative MMR in CP, AP, and BP patients.
• Duration of CCyR.
• Duration of MMR.
• Assessment of adverse events will include type, incidence, severity (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v. 4.0), timing, seriousness, and relatedness; and laboratory abnormalities.

Secondary ID(s)

B1871039

Source(s) of Monetary Support

Pfizer Inc, 235 East 42nd Street, New York, NY 10017

Ethics review

Status: Approved
Approval date: 24/06/2014
Contact: