NCT00261846

Study Evaluating SKI-606 (Bosutinib) In Philadelphia Chromosome Positive Leukemias

Completed Phase 2 Results posted Last updated 27 July 2017

What this trial tests

Phase 2 trial testing Bosutinib in Chronic Myeloid Leukemia in 571 participants. Completed in 6 August 2015.

Timeline

18 January 2006

Primary endpoint
25 September 2009

6 August 2015

Quick facts

Lead sponsor	Pfizer
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	571
Start date	18 January 2006
Primary completion	25 September 2009
Estimated completion	6 August 2015
Sites	111 locations across Hong Kong, Colombia, Finland, Italy, Taiwan, South Korea, Netherlands, Russia

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 Dose Limiting Toxicity (DLT) Primary · Part 1 Baseline up to Day 28

DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: any grade 3 or 4 clinically-relevant non-hematologic toxicity, any clinically-significant grade 2 non-hematologic toxicity that requires 14 days to resolve (to grade 1).

Group	Value	95% CI
Bosutinib 400 mg (Part 1)	0
Bosutinib 500 mg (Part 1)	0
Bosutinib 600 mg (Part 1)	1

Maximum Tolerated Dose (MTD) Primary · Part 1 Baseline up to Day 28

MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced DLT. DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: any grade 3 or 4 clinically-relevant non-hematologic toxicity, any clinically-significant grade 2 non-hematologic toxicity that requires 14 days to resolve (to grade 1). NA = not estimable.

Group	Value	95% CI
Bosutinib 400 mg (Part 1)	NA
Bosutinib 500 mg (Part 1)	NA
Bosutinib 600 mg (Part 1)	NA

Maximum Observed Plasma Concentration (Cmax) - Part 1 Primary · 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

Group	Value	95% CI
Bosutinib 400 mg (Part 1)	89.3	± 50.0
Bosutinib 500 mg (Part 1)	101.0	± 35.6
Bosutinib 600 mg (Part 1)	120.0	± 40.2

Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1 Primary · 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

Group	Value	95% CI
Bosutinib 400 mg (Part 1)	4.00	3.33 – 48.08
Bosutinib 500 mg (Part 1)	6.00	6.00 – 6.00
Bosutinib 600 mg (Part 1)	4.00	2.17 – 49.33

Plasma Decay Half-Life (t1/2) - Part 1 Primary · 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. NA = not estimable.

Group	Value	95% CI
Bosutinib 400 mg (Part 1)	22.91	± 3.39
Bosutinib 500 mg (Part 1)	22.46	± 1.73
Bosutinib 600 mg (Part 1)	22.24	± 5.03

Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC(0-48)] - Part 1 Primary · 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

AUC(0-48)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-48).

Group	Value	95% CI
Bosutinib 400 mg (Part 1)	1850	± 710
Bosutinib 500 mg (Part 1)	2060	± 483
Bosutinib 600 mg (Part 1)	2340	± 1140

Area Under the Concentration-Time Curve (AUC) - Part 1 Primary · 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. NA = not estimable.

Group	Value	95% CI
Bosutinib 400 mg (Part 1)	2530	± 1160
Bosutinib 500 mg (Part 1)	2760	± 687
Bosutinib 600 mg (Part 1)	2420	± 457

Apparent Oral Clearance (CL/F) - Part 1 Primary · 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. NA = not estimable.

Group	Value	95% CI
Bosutinib 400 mg (Part 1)	177	± 81.3
Bosutinib 500 mg (Part 1)	189	± 47.5
Bosutinib 600 mg (Part 1)	258	± 61.2

Apparent Volume of Distribution (Vz/F) - Part 1 Primary · 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.

Group	Value	95% CI
Bosutinib 400 mg (Part 1)	6050	± 3550
Bosutinib 500 mg (Part 1)	6080	± 1230
Bosutinib 600 mg (Part 1)	8540	± 3820

Maximum Observed Plasma Concentration at Steady State (Cmax,ss) - Part 1 Primary · 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15

Maximum plasma concentration over 24 hours at steady state (ss), on Day 15.

Group	Value	95% CI
Bosutinib 400 mg (Part 1)	146	± 20.0
Bosutinib 500 mg (Part 1)	200	± 11.9
Bosutinib 600 mg (Part 1)	208	± 73.3

Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) - Part 1 Primary · 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15

Time to reach maximum observed plasma concentration over 24 hours at steady state (ss), on Day 15.

Group	Value	95% CI
Bosutinib 400 mg (Part 1)	4.05	3.08 – 6.08
Bosutinib 500 mg (Part 1)	6.05	4.00 – 8.00
Bosutinib 600 mg (Part 1)	6.00	2.83 – 11.08

Plasma Decay Half-Life at Steady State (t1/2,ss) - Part 1 Primary · 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Plasma decay half-life over 24 hours at steady state (ss), on Day 15 was calculated.

Group	Value	95% CI
Bosutinib 400 mg (Part 1)	45.96	± 32.30
Bosutinib 500 mg (Part 1)	21.71	± 4.64
Bosutinib 600 mg (Part 1)	25.87	± 24.85

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events (AEs) and serious AEs were assessed from informed consent through and including 30 days after last administration of study treatment or at the End of Treatment Visit, whichever comes last.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Bosutinib 500 mg, CP2L-CML IM-R (Part 2)

Serious: 81/195 (42%)

Deaths: —

Bosutinib 500 mg, CP2L-CML IM-I (Part 2)

Serious: 34/89 (38%)

Deaths: —

Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)

Serious: 1/5 (20%)

Deaths: —

Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)

Serious: 15/38 (39%)

Deaths: —

Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)

Serious: 19/50 (38%)

Deaths: —

Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)

Serious: 5/26 (19%)

Deaths: —

AP-CML Total (Part 2)

Serious: 43/79 (54%)

Deaths: —

BP-CML Total (Part 2)

Serious: 37/64 (58%)

Deaths: —

Bosutinib 500 mg, Ph+ ALL (Part 2)

Serious: 17/24 (71%)

Deaths: —

Serious adverse events (327 terms)

Reaction	System	Bosutinib 500 mg, CP2L-CML…	Bosutinib 500 mg, CP2L-CML…	Bosutinib 500 mg, CP3L-CML…	Bosutinib 500 mg, CP3L-CML…	Bosutinib 500 mg, CP3L-CML…	Bosutinib 500 mg, CP3L-CML…	AP-CML Total (Part 2)	BP-CML Total (Part 2)	Bosutinib 500 mg, Ph+ ALL …
Pneumonia	Infections and infestations	—	—	—	—	—	—	—	—	—
Pleural effusion	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Disease progression	General disorders	—	—	—	—	—	—	—	—	—
Sepsis	Infections and infestations	—	—	—	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—	—	—	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—	—	—	—	—	—	—
Cardiac failure	Cardiac disorders	—	—	—	—	—	—	—	—	—
Cardiac failure congestive	Cardiac disorders	—	—	—	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Chest pain	General disorders	—	—	—	—	—	—	—	—	—
General physical health deterioration	General disorders	—	—	—	—	—	—	—	—	—
Asthenia	General disorders	—	—	—	—	—	—	—	—	—
Cholelithiasis	Hepatobiliary disorders	—	—	—	—	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—	—	—	—	—

Other adverse events (151 terms — click to expand)

Reaction	System	Bosutinib 500 mg, CP2L-CML…	Bosutinib 500 mg, CP2L-CML…	Bosutinib 500 mg, CP3L-CML…	Bosutinib 500 mg, CP3L-CML…	Bosutinib 500 mg, CP3L-CML…	Bosutinib 500 mg, CP3L-CML…	AP-CML Total (Part 2)	BP-CML Total (Part 2)	Bosutinib 500 mg, Ph+ ALL …
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—	—	—	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—	—
Weight decreased	Investigations	—	—	—	—	—	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—
Asthenia	General disorders	—	—	—	—	—	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—	—	—	—	—	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Influenza	Infections and infestations	—	—	—	—	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—	—	—	—	—
Leukopenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—	—	—	—	—
Blood creatinine increased	Investigations	—	—	—	—	—	—	—	—	—
Pleural effusion	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—	—
Abdominal distension	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—	—	—	—	—	—
Lipase increased	Investigations	—	—	—	—	—	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—	—	—	—	—	—
Pain	General disorders	—	—	—	—	—	—	—	—	—
Platelet count decreased	Investigations	—	—	—	—	—	—	—	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—

Most-reported serious reactions: Pneumonia, Pleural effusion, Rash, Anaemia, Nausea, Pyrexia, Dyspnoea, Febrile neutropenia.

Data from ClinicalTrials.gov NCT00261846 adverse events section.

Sponsor's own description

This is an open-label, continuous daily dosing, two-part safety and efficacy study of SKI-606 (bosutinib) in Philadelphia chromosome positive leukemias (Ph+). Part 1 is a dose-escalation study in chronic phase Chronic Myelogenous Leukemia (CML) subjects to establish the maximum tolerated dose (MTD) in this subject population. Part 2 has begun after the completion of Part 1 and after a dose has been established for the compound in chronic phase subjects. Part 2 is a study of the the efficacy of 500mg daily oral SKI-606 (bosutinib) in patients with all phases of Ph+ CML and Ph+ Acute Lymphocytic Leukemia (ALL). The protocol will test the hypotheses that oral daily dosing of bosutinib at 500 mg will attain (1) Major Cytogenetic Response (MCyR) in chronic phase CML patients and (2) Overall Hematological Response (OHR) in advanced leukemia patients. Each phase of the disease will be evaluated as a separate cohort.

Publications & conference data

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

1. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib.
   Cortes JE, Kantarjian HM, Brümmendorf TH, Kim DW, et al · · 2011 · cited 317× · PMID 21865346 · DOI 10.1182/blood-2011-05-355594
2. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure.
   Khoury HJ, Cortes JE, Kantarjian HM, Gambacorti-Passerini C, et al · · 2012 · cited 219× · PMID 22371878 · DOI 10.1182/blood-2011-11-390120
3. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors.
   Kantarjian HM, Cortes JE, Kim DW, Khoury HJ, et al · · 2014 · cited 109× · PMID 24345751 · DOI 10.1182/blood-2013-07-513937
4. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: Minimum 24-month follow-up.
   Gambacorti-Passerini C, Brümmendorf TH, Kim DW, Turkina AG, et al · · 2014 · cited 78× · PMID 24711212 · DOI 10.1002/ajh.23728
5. 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
6. Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with bosutinib.
   Cortes JE, Jean Khoury H, Kantarjian H, Brümmendorf TH, et al · · 2016 · cited 69× · PMID 26971533 · DOI 10.1002/ajh.24360
7. 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
8. Regulation of Src Family Kinases during Colorectal Cancer Development and Its Clinical Implications.
   Jin W. · · 2020 · cited 53× · PMID 32456226 · DOI 10.3390/cancers12051339