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

Study Overview
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Brief Summary
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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.

Official Title
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Phase I Dose-Escalation Study Of Oral SKI-606 In Subjects With Advanced Malignant Solid Tumors

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: bosutinib
* Drug: bosutinib
* Drug: bosutinib
* Drug: bosutinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation<br>Dose finding study of monotherapy bosutinib in patients with advanced solid tumors. | Drug: bosutinib<br>* 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.<br>|
| Experimental: Colorectal Cancer<br>Enroll 30 patients at RP2D to further evaluate safety and efficacy in subgroup population. | Drug: bosutinib<br>* 400mg QD bosutinib, as long as tolerated and disease under study does not worsen.<br>|
| Experimental: Pancreatic Cancer<br>Enroll 30 patients at RP2D to further evaluate safety and efficacy in subgroup population. | Drug: bosutinib<br>* 400mg QD bosutinib, as long as tolerated and disease under study does not worsen.<br>|
| Experimental: Non-Small Cell Lung Cancer (NSCLC)<br>Enroll 30 patients at RP2D to further evaluate safety and efficacy in subgroup population. | Drug: bosutinib<br>* 400mg QD bosutinib, as long as tolerated and disease under study does not worsen.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicities (DLT) in Part 1 | 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. | Part 1 Baseline up to Day 28 | 
| Number of Participants With Adverse Events (AEs) by Seriousness | 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. | Baseline up to 30 days after last dose | 
| Duration of Most Frequently Observed Adverse Events (AEs) | 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. | Baseline up to 30 days after last dose | 
| Number of Participants With Best Overall Response (BOR) in Part 1 | 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. | 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 | 
| Number of Participants With Best Overall Response (BOR) in Part 2 | 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. | 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 | 
| Maximum Tolerated Dose (MTD) in Part 1 | 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. | Part 1 Day 1 up to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) for Prolonged Use | 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). | Part 1 Day 1 up to Day 28 | 
| Number of Participants With Change From Baseline in Laboratory Test Results | 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. | Baseline up to end of treatment (Week 95) | 
| Number of Participants With Change From Baseline in Electrocardiogram (ECG) and Chest X-ray | 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. | Baseline up to end of treatment (Week 95) | 
| Concomitant Medications Used for Management of Adverse Events (AEs) | 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. | Day 1 up to end of treatment (Week 95) | 
| Change From Baseline in Karnofsky Performance Score | 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. | Baseline up to end of treatment (Week 95) | 
| Number of Participants With Change From Baseline in Physical Examination | 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. | Baseline up to end of treatment (Week 95) | 
| Number of Participants With Change From Baseline in Opthalmologic Examination | Ophthalmologic evaluation included visual acuity, funduscopic examination, and any clinically-significant abnormality. | Baseline up to end of treatment (Week 95) | 
| Overall Survival (OS) in Part 2 | 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). | Part 2 Baseline until death or 3, 6, 9 and 12 months after treatment discontinuation | 
| Progression Free Survival (PFS) in Part 2 | 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). | Part 2 Baseline until death or 3, 6, 9 and 12 months after treatment discontinuation | 
| Maximum Observed Plasma Concentration (Cmax) |  | 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 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) |  | 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 (t1/2) | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | 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 | 
| Area Under the Concentration-Time Curve (AUC) | 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. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid tumors