A Phase 1/2 Study Of Bosutinib (Ski-606) In Philadelphia Chromosome Positive Leukemias
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Pfizer
- Enrollment
- 571
- Locations
- 110
- Primary Endpoint
- Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) - Part 1
Study Overview
Brief 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.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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)
Arms & Interventions
SKI-606
Intervention: Bosutinib (Drug)
Outcomes
Primary Outcomes
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
Time to reach maximum observed plasma concentration over 24 hours at steady state (ss), on Day 15.
Number of Participants With Dose Limiting Toxicity (DLT)
Time Frame: 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).
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
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. NA = not estimable.
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
AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. NA = not estimable.
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
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.
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
AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AUC over 24 hours at steady state (ss), on Day 15 was calculated.
Maximum Tolerated Dose (MTD)
Time Frame: 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.
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
Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC(0-48)] - Part 1
Time Frame: 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).
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
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.
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
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.
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
Maximum plasma concentration over 24 hours at steady state (ss), 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
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. Apparent oral clearence over 24 hours at steady state (ss), on Day 15 was calculated.
Accumulation Ratio (R)
Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 1 and Day 15
R=accumulation ratio (AUCss on Day 15/AUC0-24 on Day 1)
Percentage of Participants With MCyR at Week 24 in Chronic Phase Second-line Imatinib Resistant CML Population - Part 2
Time Frame: Week 24
CyR is based on the prevalence of Ph+ cells. Major cytogenetic response was categorized as either CCyR or partial CyR (PCyR). CCyR was achieved when there was 0 percent (%) Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or less than (\<) 1% positive cells from at least 200 cells analyzed from fluorescent in situ hybridization (FISH). PCyR was achieved when 1 to 35% Ph+ cells were present.
Secondary Outcomes
- Percent Change From Baseline in Phosphorylation Inhibition of Crk Like Protein (CrkL) at Day 1, 8 and 15 - Part 1(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) - Part 1(Weeks 12, 24, 36, 48 and the end of active treatment phase of Part 1 (Week 52))
- Phosphorylation Inhibition of Breakpoint Cluster Region-Abelson Kinase (Bcr-Abl) - Part 1(Baseline, Weeks 4, 8, 12, 24, 36, 48 and the end of the active treatment phase of Part 1 (Week 52))
- Phosphorylation Inhibition of Crk Like (CrkL) Protein at Baseline - Part 1(0 (pre-dose) on Day 1 (Baseline))
- Percentage of Participants With Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Chronic Phase Third-line CML Population - Part 2(Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L) or Year 5 (CP2L))
- Kaplan-Meier Estimate of Retaining an Attained/Maintained Major Cytogenetic Response (MCyR) at Year 5 in Chronic Phase Second-line CML - Part 2(From first MCyR to loss of MCyR or censoring, assessed every 12 weeks up to 2 years and then every 24 weeks thereafter up to Year 5)
- Time to Achieve Major Cytogenetic Response (MCyR) in Chronic Phase Second-line CML for Responders Only - Part 2(Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 5)
- Kaplan-Meier Estimate of Maintaining Complete Hematologic Response (CHR) at Year 4 (CP3L and ADV) or Year 5 (CP2L) - Part 2(From date of first confirmed CHR to loss of CHR or censoring, assessed at 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 thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L))
- Time to Achieve Complete Hematologic Response (CHR) for Responders Only - Part 2(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 thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L))
- Duration of Complete Hematologic Response (CHR) - Part 2(From date of first confirmed CHR to loss of CHR or censoring, assessed at 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 thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L))
- Cumulative Incidence of Progression/Death - Part 2(Years 1, 2, 3, 4, and 5 (CP2L only))
- Progression Free Survival (PFS) - Part 2(Years 1, 2, 3, 4, and 5 (CP2L only))
- Overall Survival (OS) - Part 2(Years 1, 2, 3, 4, and 5 (CP2L only))
- Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)(Baseline up to follow up visit (30 days after last dose of study treatment))
- Number of Participants With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS)(Baseline, Week 1, 2, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter)
- Percentage of Participants With Change From Baseline in Physical Examinations and Vital Signs and Number of Participants With PCI Values(Post-therapy)
- Kaplan-Meier Estimate of Overall Survival (OS) - Part 2(Years 1, 2, 3, 4, and 5 (CP2L only))
- Percentage of Participants With Confirmed Complete Hematologic Response (CHR) - Part 2(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 thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L))
- Percentage of Participants With Overall Hematologic Response (OHR) by Week 48 in Advanced Leukemia Population - Part 2(Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 1 year)
- Duration of Potentially Clinically Important (PCI) Adverse Events (AEs)(Baseline up to follow-up visit (30 days after last dose of study treatment))
- Percentage of Participants With Change From Baseline in Laboratory Tests Results(Week 1, 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter)
- Percentage of Participants With On-treatment PCI Change From Baseline in Electrocardiogram (ECG) Findings(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(Baseline, Week 8, and end of treatment)
- Number of Participants Who Received Concomitant Medications for Management of Adverse Events (AEs)(Baseline and Weeks 1, 2, 3, 4, 8, 12, then every 12 weeks thereafter until end of treatment, for a mean duration of 28 months)
- Percentage of Participants With Change From Baseline in Physical Examinations and Vital Signs(Screening, Baseline, and end of treatment)