Study Evaluating SKI-606 (Bosutinib) In Advanced Malignant Solid Tumors

• ClinicalTrials.gov Identifier: NCT00195260
• Recruitment Status: Completed
• First Posted: September 19, 2005
• Results First Posted: February 11, 2013
• Last Update Posted: February 11, 2013
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Study Description

Brief Summary:

To evaluate the safety and tolerability of oral SKI-606 (bosutinib) administered on a daily schedule to subjects with advanced malignant solid tumors and to define a maximum tolerated dose (MTD) in this subject population.

Condition or disease	Intervention/treatment	Phase
Neoplasms	Drug: bosutinib	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 151 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Dose-Escalation Study Of Oral SKI-606 In Subjects With Advanced Malignant Solid Tumors
• Study Start Date: October 2004
• Actual Primary Completion Date: November 2007
• Actual Study Completion Date: November 2007

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dose escalation; Dose finding study of monotherapy bosutinib in patients with advanced solid tumors.	Drug: bosutinib; Dose levels evaluated 50mg, 100mg, 200mg, 300mg, 400mg, 500mg and 600mg. 500mg was identified as MTD, however due to GI toxicities at that dose, 400mg was selected as the RP2D. Drug was administered as long as tolerable and disease under study did not worsen.
Experimental: Colorectal Cancer; Enroll 30 patients at RP2D to further evaluate safety and efficacy in subgroup population.	Drug: bosutinib; 400mg QD bosutinib, as long as tolerated and disease under study does not worsen.
Experimental: Pancreatic Cancer; Enroll 30 patients at RP2D to further evaluate safety and efficacy in subgroup population.	Drug: bosutinib; 400mg QD bosutinib, as long as tolerated and disease under study does not worsen.
Experimental: Non-Small Cell Lung Cancer (NSCLC); Enroll 30 patients at RP2D to further evaluate safety and efficacy in subgroup population.	Drug: bosutinib; 400mg QD bosutinib, as long as tolerated and disease under study does not worsen.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Dose-limiting Toxicities (DLT) in Part 1 [ Time Frame: Part 1 Baseline up to Day 28 ]
   DLT included any grade 3 or 4 clinically-evident non-hematologic toxicity, grade 4 neutropenia of greater than or equal to (>=) 7-day duration or with fever >= 38.5 degrees Celsius (febrile neutropenia); grade 4 thrombocytopenia >= 2-day duration or with bleeding requiring platelet transfusion, any clinically-significant grade >= 2 toxicity that requires >=14 days to resolve (to less than or equal to [=<] grade 1) which occurred in first 21 days of study and considered at least possibly related to bosutinib.
2. Number of Participants With Adverse Events (AEs) by Seriousness [ Time Frame: Baseline up to 30 days after last dose ]
   Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Participants with multiple occurrences of an AE within a category were counted once within the category.
3. Duration of Most Frequently Observed Adverse Events (AEs) [ Time Frame: Baseline up to 30 days after last dose ]
   The most frequently observed treatment-emergent AEs were gastrointestinal disorders which included diarrhea, nausea and vomiting. Duration of AE per event is calculated as AE stop date minus AE start date plus 1.
4. Number of Participants With Best Overall Response (BOR) in Part 1 [ Time Frame: Part 1 Baseline, last week (Day 15 to 23) of cycles 2, 4, 6, 8 and thereafter every 3 cycles up to 30 days after last dose ]
   BOR:investigator assessment by modified Response Evaluation Criteria in Solid Tumors (RECIST), recorded from treatment start until disease progression/recurrence. Complete Response:disappearance of all lesions. Partial Response (PR):>=30% decrease in sum of longest diameters (SLDs) of target lesions (TLs) taking as reference baseline SLD. Progressive disease (PD):>=20% increase in SLD of TLs taking as reference smallest SLD since treatment start, or appearance of >=1 new lesion. Stable disease: neither shrinkage for PR nor increase for PD taking as reference smallest SLD since treatment start.
5. Number of Participants With Best Overall Response (BOR) in Part 2 [ Time Frame: Part 2 Baseline, last week (Day 15 to 23) of cycles 2, 4, 6, 8 and thereafter every 3 cycles up to 30 days after last dose ]
   BOR: investigator assessment by modified RECIST, recorded from treatment start until disease progression/recurrence. Complete Response: disappearance of all lesions. PR: >=30% decrease in SLDs of TLs taking as reference baseline SLD. PD: >=20% increase in SLD of TLs taking as reference smallest SLD since treatment start, or appearance of >=1 new lesion. Stable disease: neither shrinkage for PR nor increase for PD taking as reference smallest SLD since treatment start.
6. Maximum Tolerated Dose (MTD) in Part 1 [ Time Frame: Part 1 Day 1 up to Day 28 ]
   MTD: highest dose level at which not more than 1 of 6 participants experienced DLT after 21 days of treatment (Cycle 1). DLT included any grade 3 or 4 clinically-evident non-hematologic toxicity, grade 4 neutropenia of >= 7-day duration or with fever >= 38.5 degrees Celsius (febrile neutropenia); grade 4 thrombocytopenia >= 2-day duration or with bleeding requiring platelet transfusion, any clinically-significant grade >= 2 toxicity that requires >=14 days to resolve (to =< grade 1) which occurred in first 21 days of study and considered at least possibly related to bosutinib.

Secondary Outcome Measures :

1. Maximum Tolerated Dose (MTD) for Prolonged Use [ Time Frame: Part 1 Day 1 up to Day 28 ]
   MTD for prolonged use was the highest dose level at which not more than 1 of 6 participants experienced DLT after 21 days of treatment (Cycle 1) and was selected as recommended dose in Phase 2, due to substantial number of Grade 2 gastrointestinal toxicities observed in the MTD lead-in cohort (500 mg).
2. Number of Participants With Change From Baseline in Laboratory Test Results [ Time Frame: Baseline up to end of treatment (Week 95) ]
   Criteria for potentially clinically significant (PCS) laboratory values: albumin <20, hemoglobin <80 gram/liter(g/L); alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase >5*upper limit of normal(ULN) milliunit/milliliter(mU/mL); bilirubin total, creatinine>3*ULN micromole/L; calcium <1.75 and >3.1,potassium <3 and >6, sodium <130, glucose <2.2,phosphorous <0.6 millimole/L; international normalized ratio >2*ULN, partial thromboplastin time, prothrombin time >2*ULN seconds; platelet count <50*10^9/L. Participants meeting at least 1 PCS criteria are reported.
3. Number of Participants With Change From Baseline in Electrocardiogram (ECG) and Chest X-ray [ Time Frame: Baseline up to end of treatment (Week 95) ]
   Number of participants with PCS ECG findings is reported on-therapy (OT) and at final visit (FV). Criteria for PCS ECG findings: heart rate (HR) =<45 beats/minute (bpm) and decrease (Dec) >15/>=120 bpm and decrease of >15 bpm; PR interval (Int) >=220 millisecond (msec), increase (Inc) >=20 msec, QRS Int >=120 msec, corrected QT (QTc) and QTc using fridericia formula(QTcF) Int >500 msec, increase >60 msec; no sinus rhythm; overall ECG abnormal. Participants with at least 1 measurement exceeding the criteria for PCS are reported.
4. Concomitant Medications Used for Management of Adverse Events (AEs) [ Time Frame: Day 1 up to end of treatment (Week 95) ]
   Number of participants taking any non-study medications which were administered from Day 1 up to end of treatment (Week 95) as a management of an AE was to be reported.
5. Change From Baseline in Karnofsky Performance Score [ Time Frame: Baseline up to end of treatment (Week 95) ]
   Karnofsky performance score is used to quantify participant's general well-being and activities of daily life and participants are classified based on their functional impairment. Karnofsky performance score is 11 level score which ranges between 0 (death) to 100 (complete healthy status). Higher score means higher ability to perform daily tasks.
6. Number of Participants With Change From Baseline in Physical Examination [ Time Frame: Baseline up to end of treatment (Week 95) ]
   Physical examinations included body weight, height and vital signs and only finding that exceeded the criterion for PCS was weight. Criteria for weight was: an increase or decrease of >=10% from baseline.
7. Number of Participants With Change From Baseline in Opthalmologic Examination [ Time Frame: Baseline up to end of treatment (Week 95) ]
   Ophthalmologic evaluation included visual acuity, funduscopic examination, and any clinically-significant abnormality.
8. Overall Survival (OS) in Part 2 [ Time Frame: Part 2 Baseline until death or 3, 6, 9 and 12 months after treatment discontinuation ]
   Time in weeks from the start of study treatment to date of death due to any cause. OS was calculated as (the death date minus the date of first dose of study medication plus 1) divided by 7. Death was determined from death case report forms (CRFs) or from follow-up contact data (where the participant current status was death).
9. Progression Free Survival (PFS) in Part 2 [ Time Frame: Part 2 Baseline until death or 3, 6, 9 and 12 months after treatment discontinuation ]
   Time in weeks from start of study treatment to first documentation of objective tumor progression or death due to any cause. PFS was calculated as (first event date minus the date of first dose of study medication plus 1) divided by 7. Tumor progression was determined from oncologic assessment data (where data meet the criteria for PD, or from death CRFs).
10. Maximum Observed Plasma Concentration (Cmax) [ Time Frame: 0 hour (pre-dose) on Day 1, 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 (0 hour [pre-dose] on Day 15) hours post-dose on Day 14 ]
11. Time to Reach Maximum Observed Plasma Concentration (Tmax) [ Time Frame: 0 hour (pre-dose) on Day 1, 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 (0 hour [pre-dose] on Day 15) hours post-dose on Day 14 ]
12. Plasma Decay Half-Life (t1/2) [ Time Frame: 0 hour (pre-dose) on Day 1, 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 (0 hour [pre-dose] on Day 15) hours post-dose on Day 14 ]
    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
13. Area Under the Concentration-Time Curve (AUC) [ Time Frame: 0 hour (pre-dose) on Day 1, 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 (0 hour [pre-dose] on Day 15) hours post-dose on Day 14 ]
    AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. Steady state concentration was achieved at Day 15.

Other Outcome Measures:

1. Gene Expression at Baseline [ Time Frame: Baseline ]
   Gene expression profile was evaluated by measuring transcript levels of messenger RNA (mRNA) in peripheral blood samples. Expression profiling of mRNA: done to measure the expressed genome of mRNA transcripts or done in a gene-specific targeted manner.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Advanced or recurrent solid malignancy confirmed histologically or cytologically for which no effective therapy is available.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1.
• Measurable disease as outlined by the modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
• Other inclusion applies.

Exclusion Criteria:

• Use of any systemic antitumor agents or any investigational agent within 28 days before the first dose of test article is administered.
• Prior exposure to SKI-606 or any other Src-kinase inhibitor, major surgery or radiotherapy within 14 days before the first dose of test article (recovery from previous surgery should be complete before day 1).
• Active central nervous system (CNS) metastases, as indicated by clinical symptoms, cerebral edema, requirement for corticosteroids and/or progressive growth (Treated CNS metastases must be stable for >= 2 weeks before day 1).
• Other exclusion applies.

Contacts and Locations

Locations

United States, Alabama

Pfizer Investigational Site

Birmington, Alabama, United States, 35233

United States, Arizona

Pfizer Investigational Site

Scottsdale, Arizona, United States, 85258

United States, California

Pfizer Investigational Site

Los Angeles, California, United States, 90033

United States, Florida

Pfizer Investigational Site

Tampa, Florida, United States, 33612

United States, Georgia

Pfizer Investigational Site

Atlanta, Georgia, United States, 30341

United States, Indiana

Pfizer Investigational Site

Indianpolis, Indiana, United States, 46202

United States, Maryland

Pfizer Investigational Site

Baltimore, Maryland, United States, 21287

United States, Michigan

Pfizer Investigational Site

Detroit, Michigan, United States, 48202

Pfizer Investigational Site

Lansing, Michigan, United States, 48910

United States, New York

Pfizer Investigational Site

New York, New York, United States, 10016

Pfizer Investigational Site

New York, New York, United States, 10032

United States, North Carolina

Pfizer Investigational Site

Charlotte, North Carolina, United States, 28203

Pfizer Investigational Site

Charlotte, North Carolina, United States, 28211

Pfizer Investigational Site

UNC Chapel Hill, North Carolina, United States, 27514

Pfizer Investigational Site

UNC Chapel Hill, North Carolina, United States, 27759

United States, Ohio

Pfizer Investigational Site

Cleveland, Ohio, United States, 44106-1736

United States, Texas

Pfizer Investigational Site

San Antonio, Texas, United States, 78258

Pfizer Investigational Site

Tyler, Texas, United States, 75702

United States, Washington

Pfizer Investigational Site

Seattle, Washington, United States, 98104

Sponsors and Collaborators

Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Hsyu PH, Mould DR, Abbas R, Amantea M. Population pharmacokinetic and pharmacodynamic analysis of bosutinib. Drug Metab Pharmacokinet. 2014;29(6):441-8. doi: 10.2133/dmpk.DMPK-13-RG-126. Epub 2014 Jun 10. Retraction in: Drug Metab Pharmacokinet. 2019 Apr;34(2):163.

Retraction in: Drug Metab Pharmacokinet. 2019 Apr;34(2):163

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00195260
• Other Study ID Numbers: 3160A1-100; B1871012
• First Posted: September 19, 2005
• Results First Posted: February 11, 2013
• Last Update Posted: February 11, 2013
• Last Verified: January 2013

Keywords provided by Pfizer:

Solid tumors