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.

Trial Health

On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Strong global presence with extensive site network

Enrollment

571

participants targeted

Target at P75+ for phase_2

Timeline

Completed

Started Jan 2006

Longer than P75 for phase_2

Geographic Reach

26 countries

106 active sites

Status

completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

9.6 years study duration

First Submitted

Initial submission to the registry

December 2, 2005

Completed

3 days until next milestone

First Posted

Study publicly available on registry

December 5, 2005

Completed

1 month until next milestone

Study Start

First participant enrolled

January 18, 2006

Completed

3.7 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

September 25, 2009

Completed

3.5 years until next milestone

Results Posted

Study results publicly available

March 12, 2013

Completed

2.4 years until next milestone

Study Completion

Last participant's last visit for all outcomes

August 6, 2015

Completed

Last Updated

July 27, 2017

Status Verified

June 1, 2017

Enrollment Period

3.7 years

First QC Date

December 2, 2005

Results QC Date

October 4, 2012

Last Update Submit

June 28, 2017

Conditions

Chronic Myeloid Leukemia

Keywords

Leukemiatyrosine kinase inhibitorphiladelphia chromosomeMyeloidPhiladelphia Positive

Outcome Measures

Primary Outcomes (16)

Number of Participants With Dose Limiting Toxicity (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).
Part 1 Baseline up to Day 28
Maximum Tolerated Dose (MTD)
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.
Part 1 Baseline up to Day 28
Maximum Observed Plasma Concentration (Cmax) - Part 1
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
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
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. NA = not estimable.
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
AUC(0-48)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-48).
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
AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. NA = not estimable.
0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Apparent Oral Clearance (CL/F) - Part 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.
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
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.
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
Maximum plasma concentration over 24 hours at steady state (ss), on Day 15.
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 to reach maximum observed plasma concentration over 24 hours at steady state (ss), on Day 15.
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
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.
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
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.
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
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.
0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
Accumulation Ratio (R)
R=accumulation ratio (AUCss on Day 15/AUC0-24 on Day 1)
0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 1 and Day 15
Percentage of Participants With MCyR at Week 24 in Chronic Phase Second-line Imatinib Resistant CML Population - Part 2
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.
Week 24

Secondary Outcomes (25)

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)
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) 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)
+20 more secondary outcomes

Study Arms (1)

SKI-606

EXPERIMENTAL

Drug: Bosutinib

Interventions

BosutinibDRUG

Part 1, starting dose 400 mg oral, daily dosing in the dose-escalation component. Part 2, 500 mg oral, continuous, daily dosing.

Also known as: SKI-606

SKI-606

Eligibility Criteria

Age18 Years+

Sexall

Healthy VolunteersNo

Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

Subjects with Philadelphia chromosome, and bcr-abl negative CML
Overt leptomeningeal leukemia
Subjects without evidence of leukemia in bone marrow (extramedullary disease only)

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Pfizerlead

Study Sites (111)

City of Hope National Medical Center

Duarte, California, 91010, United States

Location

HealthONE Presbyterian

Denver, Colorado, 80218, United States

Location

Rocky Mountain Cancer Centers

Denver, Colorado, 80218, United States

Location

Georgetown University Hospital

Washington D.C., District of Columbia, 20007, United States

Location

Emory Clinic

Atlanta, Georgia, 30322, United States

Location

Emory University Hospital

Atlanta, Georgia, 30322, United States

Location

Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Oncology Specialists, S.C.

Niles, Illinois, 60714, United States

Location

Indiana Blood and Marrow Transplantation

Indianapolis, Indiana, 46237, United States

Location

LSU Health Sciences Center

Shreveport, Louisiana, 71103, United States

Location

University Of Maryland Medical Center

Baltimore, Maryland, 21201, United States

Location

University Of Maryland

Baltimore, Maryland, 21201, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

Hudson Valley Hematology and Oncology Associates

Hawthorne, New York, 10532, United States

Location

Westchester Oncology Hematology Group, P.C.

Hawthorne, New York, 10532, United States

Location

Westchester Oncology Hematology, Group, P.C.

Hawthorne, New York, 10532, United States

Location

New York Presbyterian Hospital

New York, New York, 10021, United States

Location

New York Presbyterian Hospital

New York, New York, 10065, United States

Location

University of Rochester Cancer Center Pharmacy