Overview

This trial is active, not recruiting.

Condition chronic myeloid leukemia
Treatment bosutinib
Phase phase 1/phase 2
Target BCR-ABL
Sponsor Pfizer
Start date January 2006
End date September 2009
Trial size 571 participants
Trial identifier NCT00261846, 2005-004230-40, 3160A4-200, B1871006, B1871006, 3160A4-200-WW

Summary

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Endpoint classification safety/efficacy study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
bosutinib SKI-606
Part 1, starting dose 400 mg oral, daily dosing in the dose-escalation component. Part 2, 500 mg oral, continuous, daily dosing.

Primary Outcomes

Measure
Number of Participants With Dose Limiting Toxicity (DLT)
time frame: Part 1 Baseline up to Day 28
Maximum Tolerated Dose (MTD)
time frame: Part 1 Baseline up to Day 28
Maximum Observed Plasma Concentration (Cmax) - Part 1
time frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1
time frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Plasma Decay Half-Life (t1/2) - Part 1
time frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) - Part 1
time frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Area Under the Concentration-Time Curve (AUC) - Part 1
time frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Apparent Oral Clearance (CL/F) - Part 1
time frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Apparent Volume of Distribution (Vz/F) - Part 1
time frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Maximum Observed Plasma Concentration at Steady State (Cmax,ss) - Part 1
time frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) - Part 1
time frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
Plasma Decay Half-Life at Steady State (t1/2,ss) - Part 1
time frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
Area Under the Concentration-Time Curve at Steady State (AUCss) - Part 1
time frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
Apparent Oral Clearance at Steady State (CL/F,ss) - Part 1
time frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
Accumulation Ratio (R)
time frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 1 and Day 15
Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line Imatinib Resistant CML Population - Part 2
time frame: Week 24
Population Pharmacokinetics - Part 2
time frame: 0 (pre-dose), 2, 4, 6 hours on Day 1, Day 21, 20-23 hours post-dose on Day 21, 0 (pre-dose) hours on Day 84, 168, 252

Secondary Outcomes

Measure
Percentage of Participants With Major Cytogenetic Response (MCyR) - Part 1
time frame: Baseline, thereafter assessed every 12 weeks up to 2 years then every 24 weeks up to Year 5
Phosphorylation Inhibition of Breakpoint Cluster Region-Abelson Kinase (Bcr-Abl) - Part 1
time frame: Baseline, Week 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks up to Year 5
Phosphorylated Cancer-Testis 10 (CT10) Regulator of Kinase Like (p-CrkL) Protein Level in Blood at Baseline - Part 1
time frame: 0 (pre-dose) on Day 1 (Baseline)
Percent Change From Baseline in Phosphorylated Cancer-testis 10 (CT10) Regulator of Kinase Like (p-CrkL) Protein Level in Blood at Day 1, 8 and 15 - Part 1
time frame: 6 hours post-dose on Day 1, 0 (pre-dose), 6 hours post-dose on Day 8, 15
Percentage of Participants With Major Cytogenetic Response (MCyR) in Chronic Phase Second-line Imatinib Intolerant CML and Chronic Phase Third-line CML Population - Part 2
time frame: Week 24 for second line, Baseline through Week 24 for third line
Percentage of Participants With Major Cytogenetic Response (MCyR) in Chronic Phase Second-line CML and Chronic Phase Third-line CML - Part 2
time frame: Baseline, Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks up to Year 5
Duration of Major Cytogenetic Response (MCyR) in Chronic Phase Second-line CML and Chronic Phase Third-line CML - Part 2
time frame: Baseline, Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks up to Year 5
Time to Achieve Major Cytogenetic Response (MCyR) in Chronic Phase Second-line CML and Chronic Phase Third-line CML - Part 2
time frame: Baseline, Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks up to Year 5
Duration of Complete Hematologic Response (CHR) - Part 2
time frame: Baseline, Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks up to Year 5
Time to Achieve Complete Hematologic Response (CHR) - Part 2
time frame: Baseline, Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks up to Year 5
Progression Free Survival (PFS) Rate - Part 2
time frame: Baseline up to Year 1, Year 2
Overall Survival (OS) Rate - Part 2
time frame: Baseline up to Year 2
Percentage of Participants With Complete Hematologic Response (CHR) in Advanced Leukemia Population - Part 2
time frame: Baseline, Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks up to Year 5
Percentage of Participants With Overall Hematologic Response (OHR) by Week 48 in Advanced Leukemia Population - Part 2
time frame: Week 48
Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
time frame: Baseline up to follow up visit (30 days after last dose of study treatment)
Duration of Potentially Clinically Important (PCI) Adverse Events (AEs)
time frame: Baseline up to follow up visit (30 days after last dose of study treatment)
Number of Participants With Change From Baseline in Laboratory Tests Results
time frame: Week 1, 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks up to Year 5
Number of Participants With Change From Baseline in Electrocardiogram (ECG) Findings
time frame: Baseline, 0 (pre-dose), 2, 4, 6 hours on Day 1, 0 (pre-dose), 2, 4, 6, 20-23 hours on Day 21, and end of treatment visit
Number of Participants With Change From Baseline in Findings of Chest X-ray
time frame: Baseline, Week 8, and end of treatment
Number of Participants Who Received Concomitant Medications for Management of Adverse Events (AEs)
time frame: Baseline up to end of treatment (Year 5)
Number of Participants With Change From Baseline in Eastern Co-operative Oncology Group Performance Status (ECOG-PS)
time frame: Baseline, Week 1, 2, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks up to Year 5
Number of Participants With Change From Baseline in Physical Examinations and Vital Signs
time frame: Baseline up to end of treatment (Year 5)

Eligibility Criteria

Male or female participants at least 18 years old.

Inclusion Criteria: - Ph+ CML or Ph+ ALL who are primarily refractory to full-dose imatinib (600 mg), have disease progression/relapse while on full-dose imatinib, or are intolerant of any dose of imatinib. - At least 3 months post stem cell transplantation - Able to take daily oral capsules/tablets reliably Exclusion Criteria: - Subjects with Philadelphia chromosome, and bcr-abl negative CML - Overt leptomeningeal leukemia - Subjects without evidence of leukemia in bone marrow (extramedullary disease only)

Additional Information

Official title A Phase 1/2 Study Of Bosutinib (Ski-606) In Philadelphia Chromosome Positive Leukemias
Trial information was received from ClinicalTrials.gov and was last updated in April 2015.
Information provided to ClinicalTrials.gov by Pfizer.