NCT01903733

Bosutinib Treatment Extension Study Only For Subjects With Chronic Myeloid Leukemia (CML) Who Have Previously Participated In Bosutinib Studies B1871006 Or B1871008

Completed NA Results posted Last updated 19 July 2022

What this trial tests

NA trial testing bosutinib in Chronic Myeloid Leukemia in 281 participants. Completed in 5 June 2020.

Timeline

28 August 2013

Primary endpoint
5 June 2020

5 June 2020

Quick facts

Lead sponsor	Pfizer
Phase	NA
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Enrollment	281
Start date	28 August 2013
Primary completion	5 June 2020
Estimated completion	5 June 2020
Sites	91 locations across Hong Kong, Colombia, Finland, Italy, Japan, Poland, South Korea, Netherlands

Drugs / interventions tested

• bosutinib (bosutinib) — full drug profile →

Conditions studied

• Chronic Myeloid Leukemia — all drugs for Chronic Myeloid Leukemia →

Sponsor

Pfizer — full company profile →

Who can join

18 and older, any sex, with Chronic Myeloid Leukemia. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 3.0) Primary · From first dose of drug up to 30 days after last dose (up to approximately 14 years)

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was any untoward medical occurrence at any dose that: resulted in death, was life threatening (immediate risk of death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions), resulted in congenital anomaly/birth defect. Treatment-emergent adverse events were defined as any event increasing in sever

Treatment-Emergent AEs

Group	Value	95% CI
Bosutinib, CP1L	241
Bosutinib, CP2L	283
Bosutinib, CP3L/CP4L	119
Bosutinib, ADV	165
Bosutinib, Total	808

Treatment-emergent SAEs

Group	Value	95% CI
Bosutinib, CP1L	102
Bosutinib, CP2L	124
Bosutinib, CP3L/CP4L	44
Bosutinib, ADV	98
Bosutinib, Total	368

Number of Participants With Grade 3 or 4 Treatment-Emergent Adverse Events (AEs) Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 3.0) Primary · From first dose of drug up to 30 days after last dose (up to approximately 14 years)

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AEs were assessed according to severity grading based on NCI CTCAE version 3.0. Grade 1 =mild; Grade 2 =moderate; Grade 3 =severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4 =life-threatening or disabling, urgent intervention indicated; Grade 5 =death. Treatment-emergent adverse events were defined as any event increasing in severity from baseline or any new event started

Group	Value	95% CI
Bosutinib, CP1L	191
Bosutinib, CP2L	223
Bosutinib, CP3L/CP4L	84
Bosutinib, ADV	144
Bosutinib, Total	642

Number of Participants With Treatment-Emergent Treatment Related Adverse Events (AEs) Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 3.0) Primary · From first dose of drug up to 30 days after last dose (up to approximately 14 years)

An AE was any untoward medical occurrence in a participant who received study drug. Treatment-emergent adverse events were defined as any event increasing in severity from baseline or any new event started during bosutinib therapy or within 30 days of the last dose of study drug. Related TEAEs were those AEs who were related to the study treatment as judged by the investigator.

Group	Value	95% CI
Bosutinib, CP1L	235
Bosutinib, CP2L	282
Bosutinib, CP3L/CP4L	119
Bosutinib, ADV	161
Bosutinib, Total	797

Number of Participants With Laboratory Test Abnormalities Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 4.03) Primary · From first dose of drug up to 30 days after last dose (up to approximately 14 years)

Laboratory parameters included Chemistry: high alkaline phosphatase; high alanine aminotransferase; high aspartate aminotransferase; high blood bilirubin; high creatinine. Hematology: absolute neutrophils count decreased; anemia; platelet count decreased; white blood cells (WBC) decreased. Abnormalities in laboratory tests were graded per NCI CTCAE version 4.03 as Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling.

Grade 1

Group	Value	95% CI
Bosutinib, CP1L	45
Bosutinib, CP2L	59
Bosutinib, CP3L/CP4L	28
Bosutinib, ADV	18
Bosutinib, Total	150

Grade 2

Group	Value	95% CI
Bosutinib, CP1L	86
Bosutinib, CP2L	80
Bosutinib, CP3L/CP4L	39
Bosutinib, ADV	24
Bosutinib, Total	229

Grade 3

Group	Value	95% CI
Bosutinib, CP1L	84
Bosutinib, CP2L	102
Bosutinib, CP3L/CP4L	27
Bosutinib, ADV	41
Bosutinib, Total	254

Grade 4

Group	Value	95% CI
Bosutinib, CP1L	33
Bosutinib, CP2L	42
Bosutinib, CP3L/CP4L	23
Bosutinib, ADV	82
Bosutinib, Total	180

Number of Participants With Adverse Events as Reason for Treatment Discontinuation Primary · From first dose of drug up to 30 days after last dose (up to approximately 14 years)

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.

Group	Value	95% CI
Bosutinib, CP1L	84
Bosutinib, CP2L	79
Bosutinib, CP3L/CP4L	37
Bosutinib, ADV	32
Bosutinib, Total	232

Number of Participants With Diarrhea After Switch From Bosutinib Clinical Formulation to Bosutinib Commercial Formulation Primary · Last 6 months on clinical formulation and first 6 months on commercial formulation

The incidence of diarrhea was collected and analyzed before and after the switch from the clinical formulation of bosutinib to the commercial formulation of bosutinib.

Clinical formulation (last 6 months)

Group	Value	95% CI
Bosutinib, CP1L	25
Bosutinib, CP2L	22
Bosutinib, CP3L/CP4L	3
Bosutinib, ADV	5
Bosutinib, Total	55

Commercial formulation (first 6 months)

Group	Value	95% CI
Bosutinib, CP1L	34
Bosutinib, CP2L	27
Bosutinib, CP3L/CP4L	4
Bosutinib, ADV	5
Bosutinib, Total	70

Number of Participants With Breakpoint Cluster Region Abelson Protooncogene (BCR-ABL) Mutations Present at Time of Bosutinib Treatment Discontinuation Primary · Post-baseline on Day 1 (maximum up to 14 years)

BCR-ABL is a gene resulting from the 9:22 chromosomal translocation (Philadelphia chromosome). In this outcome measure, the number of participants who had emergent mutation or new BCR-ABL mutations (participants who had a post-baseline mutation which was not present at baseline) were reported.

Group	Value	95% CI
Bosutinib, CP1L	7
Bosutinib, CP2L	28
Bosutinib, CP3L/CP4L	13
Bosutinib, ADV	14

Overall Survival (OS) Rate at Year 10 Primary · Year 10

OS was defined as the time from randomization (B1871008) and time from first dose (B1871006) to the occurrence of death due to any cause or censoring. Kaplan-Meier analysis was used for determination of OS. Percentage of participants who were alive were estimated in this outcome measure.

Group	Value	95% CI
Bosutinib, CP1L	88.2	83.3 – 93.2
Bosutinib, CP2L	71.5	64.4 – 78.7
Bosutinib, CP3L/CP4L	60.4	47.2 – 73.7
Bosutinib, ADV	34.2	25.0 – 43.4

Plasma Steady-State Trough Concentrations (Ctrough) of Bosutinib Primary · One pre-dose sample was collected at the first scheduled visit (after approval and implementation of protocol amendment 1) following at least 2 weeks of uninterrupted dosing at the same dose level

Ctrough refers to plasma concentration of bosutinib observed just before treatment administration.

Group	Value	95% CI
Bosutinib 200 mg	62.2	± 31.3
Bosutinib 300 mg	62.0	± 65.9
Bosutinib 400 mg	82.2	± 53.2
Bosutinib 500 mg	93.3	± 45.2
Bosutinib 600 mg	99.4	± 78.2

Kaplan-Meier Estimate of Probability of Maintaining Major Cytogenetic Response (MCyR) at Year 10: B1871006 Participants Primary · Year 10

Cytogenetic response (CyR) is based on prevalence of Ph+ cells. Duration for MCyR: time from first response to confirmed loss, progression of disease, or on-treatment death due to any cause, or censoring analyzed for responders only. Confirmed loss was defined as 2 consecutive non-responses at least 28 days apart. MCyR was categorized as either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). Response was achieved when there was 0% (CCyR) or 1-35% (PCyR) Ph+ cells analyzed from conventional cytogenetics based on the analysis of 20 to 100 metaphases or \<1% (CCyR) or

Group	Value	95% CI
Bosutinib, CP2L	65.3	56.6 – 74.0
Bosutinib, CP3L/CP4L	55.3	36.3 – 74.4
Bosutinib, ADV	30.6	16.4 – 44.7

Kaplan-Meier Estimate of Probability of Maintaining Complete Cytogenetic Response (CCyR) at Year 10: B1871006 Participants Primary · Year 10

Duration for CCyR was defined as time from first response to confirmed loss, progression of disease, or on-treatment death due to any cause, or censoring analyzed for responders only. Confirmed loss was defined as 2 consecutive assessments with \>0 Ph+ metaphases or \>=1% positive cells from FISH at least 28 days apart or progression or death. CCyR was achieved when there was 0% Ph+ cells analysed from conventional cytogenetics with 20 to 100 metaphases or \<1% Ph+ cells analysed from FISH with at least 200 nuclei. CCyR may be imputed on a specific date if MMR or better is achieved and denoted

Group	Value	95% CI
Bosutinib, CP2L	63.4	54.0 – 72.8
Bosutinib, CP3L/CP4L	40.8	22.0 – 59.6
Bosutinib, ADV	29.6	14.6 – 44.7

Kaplan-Meier Estimate of Probability of Maintaining Complete Hematologic Response (CHR) at Year 10: B1871006 Participants Primary · Year 10

Duration for CHR was defined as time from first response to confirmed loss, progression of disease, or on-treatment death due to any cause, or censoring analyzed for responders only. Confirmed loss was defined as 2 consecutive non-responses at least 14 days apart. Complete hematologic response was considered when participants met all of the following criteria: White blood cells equal to or less than (\<=) institutional upper limit of normal (ULN), no blasts or promyelocytes in blood, \<20% basophils in blood, no extramedullary involvement (including hepatomegaly or splenomegaly), myelocytes an

Group	Value	95% CI
Bosutinib, CP2L	44.1	35.2 – 52.9
Bosutinib, CP3L/CP4L	45.1	29.3 – 60.9
Bosutinib, ADV	NA	NA – NA

Adverse events — posted to ClinicalTrials.gov

Time frame: From first dose of study drug and up to 30 days after last dose (up to approximately 14 years). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Bosutinib, CP1L

Serious: 102/248 (41%)

Deaths: 23/248

Bosutinib, CP2L

Serious: 124/284 (44%)

Deaths: 55/284

Bosutinib, CP3L/CP4L

Serious: 44/119 (37%)

Deaths: 30/119

Bosutinib, ADV

Serious: 98/167 (59%)

Deaths: 98/167

Bosutinib, Total

Serious: 368/818 (45%)

Deaths: 206/818

Serious adverse events (423 terms)

Reaction	System	Bosutinib, CP1L	Bosutinib, CP2L	Bosutinib, CP3L/CP4L	Bosutinib, ADV	Bosutinib, Total
Pneumonia	Infections and infestations	—	—	—	—	—
Pleural effusion	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—
Pericardial effusion	Cardiac disorders	—	—	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—
Disease progression	General disorders	—	—	—	—	—
Sepsis	Infections and infestations	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—	—
Cardiac failure congestive	Cardiac disorders	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—
Coronary artery disease	Cardiac disorders	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—
Chest pain	General disorders	—	—	—	—	—
Cellulitis	Infections and infestations	—	—	—	—	—
Dehydration	Metabolism and nutrition disorders	—	—	—	—	—

Other adverse events (53 terms — click to expand)

Reaction	System	Bosutinib, CP1L	Bosutinib, CP2L	Bosutinib, CP3L/CP4L	Bosutinib, ADV	Bosutinib, Total
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Asthenia	General disorders	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Lipase increased	Investigations	—	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—
Leukopenia	Blood and lymphatic system disorders	—	—	—	—	—
Pleural effusion	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Blood creatinine increased	Investigations	—	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—	—	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—	—	—
Influenza	Infections and infestations	—	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—	—
Weight decreased	Investigations	—	—	—	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Amylase increased	Investigations	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—
Hypophosphataemia	Metabolism and nutrition disorders	—	—	—	—	—

Most-reported serious reactions: Pneumonia, Pleural effusion, Pyrexia, Diarrhoea, Thrombocytopenia, Dyspnoea, Anaemia, Pericardial effusion.

Data from ClinicalTrials.gov NCT01903733 adverse events section.

Sponsor's own description

The objective of the study is to provide long term access to bosutinib treatment and assess long term safety, tolerability and duration of clinical benefit, without any formal hypothesis testing; therefore, there is no formal primary endpoint.

Publications & conference data

5 peer-reviewed publications reference this trial (live from Europe PMC):

1. Long-term bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib.
   Cortes JE, Khoury HJ, Kantarjian HM, Lipton JH, et al · · 2016 · cited 73× · PMID 27531525 · DOI 10.1002/ajh.24536
2. Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors.
   Gambacorti-Passerini C, Kantarjian HM, Kim DW, Khoury HJ, et al · · 2015 · cited 56× · PMID 26040495 · DOI 10.1002/ajh.24034
3. Safety profile of bosutinib in Japanese versus non-Japanese patients with chronic myeloid leukemia: a pooled analysis.
   Takahashi N, Cortes JE, Sakaida E, Ishizawa K, et al · · 2022 · cited 6× · PMID 35235189 · DOI 10.1007/s12185-022-03314-y
4. XV Congress of the Italian Society of Experimental Hematology Rimini, Italy, October 18-20, 2018
   · 2018 · cited 1×
5. PB1966: THE EFFECT OF BODY MASS INDEX ON THE SAFETY OF BOSUTINIB IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA: A POST HOC POOLED DATA ANALYSIS
   Isfort S, Gambacorti-Passerini C, Brümmendorf T, Smith B, et al · · 2023