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Bosutinib

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Dose finding study of monotherapy bosutinib in patients with advanced solid tumors.

Enroll 30 patients at RP2D to further evaluate safety and efficacy in subgroup population.

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.

bosutinib

400mg QD bosutinib, as long as tolerated and disease under study does not worsen.

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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.

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

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

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

Ophthalmologic evaluation included visual acuity, funduscopic examination, and any clinically-significant abnormality.

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).

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).

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

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.

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The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

Bosutinib 50 milligram (mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.

Bosutinib 50 mg

Bosutinib 100 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.

Bosutinib 100 mg

Bosutinib 200 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.

Bosutinib 200 mg

Bosutinib 300 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.

Bosutinib 300 mg

Bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.

Bosutinib 400 mg

Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.

Bosutinib 500 mg

Bosutinib 600 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.

Bosutinib 600 mg

MTD lead-in

Participants with colorectal cancer, pancreatic cancer, NSCLC received RP2D of bosutinib (400 mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.

RP2D 400 mg

Participants received bosutinib capsule orally once daily continuously in 21-day cycles in dose escalation schemes of 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, MTD-lead in (500 mg) until disease progression, unacceptable toxicity, or consent withdrawal.

Part 1 Total

Age Continuous

Sex: Female, Male

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MTD-lead in

Safety population included all participants enrolled in a dose escalation cohort who had taken at least 1 dose of study medication.

Number of Participants With Dose-limiting Toxicities (DLT) in Part 1

Serious adverse events (SAEs)

Safety population included all participants who had taken at least 1 dose of study medication.

Number of Participants With Adverse Events (AEs) by Seriousness

Diarrhea

Nausea

Vomiting

Duration of Most Frequently Observed Adverse Events (AEs)

Complete response

Partial response

Stable disease

Progressive disease

Indeterminate

Not done

Efficacy evaluable population: participants who received at least 1 cycle (15 doses) of study medication, had no eligibility violations, did not use prohibited anti-cancer treatment, had baseline disease assessment, at least 1 disease assessment post-baseline/had experienced clinical progression/death before first post-baseline disease assessment.

Number of Participants With Best Overall Response (BOR) in Part 1

Participants with colorectal cancer received bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.

Colorectal Cancer

Participants with pancreatic cancer received bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.

Pancreatic Cancer

Participants with NSCLC received bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.

Non-small Cell Lung Cancer (NSCLC)

Number of Participants With Best Overall Response (BOR) in Part 2

All participants who received bosutinib capsule (50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, MTD-lead in) orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.

All Participant

Maximum Tolerated Dose (MTD) in Part 1

Maximum Tolerated Dose (MTD) for Prolonged Use

Albumin (<20 g/L)

Alkaline phosphatase (>5*ULN)

Bilirubin total (>3*ULN)

Calcium (<1.75 mmol/L)

Calcium (>3.1 mmol/L)

Creatinine (>3*ULN)

Glucose (<2.2 mmol/L)

Phosphorus (<0.6 mmol/L)

Potassium (<3 mmol/L)

Potassium (>6 mmol/L)

Aspartate aminotransferase (> 5*ULN))

Alanine aminotransferase (> 5*ULN)

Sodium (<130 mmol/L)

International normalized ratio (>2*ULN)

Prothrombin time (>2*ULN)

Partial thromboplastin time (>2*ULN)

Hemoglobin (<80 g/L)

Platelets (<50*10^9/L)

Safety population included all participants who had taken at least 1 dose of study medication. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable (at least 1 on-therapy laboratory assessment) for this measure for each group respectively.

Number of Participants With Change From Baseline in Laboratory Test Results

OT: HR (<=45/Dec >15bpm) (n=4,4,6,7,7,7,10,6,93)

OT: HR (>=120/Inc >15bpm) (n=4,4,6,7,7,7,10,6,93)

OT:PR Int(>=220/Inc>20msec)(n=4,4,6,7,7,7,10,6,93)

OT: QRS Int (>=120 msec) (n=4,4,6,7,7,7,10,6,93)

OT: QTc Int (Inc >60 msec) (n=4,4,6,7,7,7,10,6,93)

OT: QTc Int (>500 msec) (n=4,4,6,7,7,7,10,6,93)

OT: QTcF Int (Inc >60 msec) (n=0,0,0,0,0,0,1,3,89)

OT: QTcF Int (>500 msec) (n=0,0,0,0,0,0,1,3,89)

OT: No sinus rhythm (n=4,4,6,7,7,7,10,6,93)

OT: Overall ECG abnormal (n=4,4,6,7,7,7,10,6,93)

FV: HR (>=120/Inc >15bpm) (n=1,2,2,4,3,4,3,1,42)

FV:PR Int(>=220/Inc >20msec)(n=1,2,3,4,3,4,3,1,42)

FV: QRS Int (>=120 msec) (n=1,2,2,4,3,4,3,1,42)

FV: QTc Int (>500 msec) (n=1,2,3,4,3,4,3,1,42)

FV: No sinus rhythm (n=1,2,2,4,3,4,3,1,42)

FV: Overall ECG abnormal (n=1,2,3,4,3,4,3,1,42)

Chest X-ray (n=0,0,0,0,0,0,0,0,0)

Safety population included all participants who had taken at least 1 dose of study medication. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable (at least 1 on-therapy assessment) for this measure and 'n' represents participants evaluable under each category for each group respectively.

Number of Participants With Change From Baseline in Electrocardiogram (ECG) and Chest X-ray

Data for this pre-specified outcome measure was not statistically summarized for analysis, but collected and reported in individual participant listings as planned.

Concomitant Medications Used for Management of Adverse Events (AEs)

Data for this pre-specified outcome was collected but not statistically summarized for analysis as there were no clinically significant changes observed.

Change From Baseline in Karnofsky Performance Score

Weight (decrease >=10%)

Weight (increase >=10%)

Safety population included all participants who had taken at least 1 dose of study medication. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable (at least 1 on-therapy assessment) for this measure for each group respectively.

Number of Participants With Change From Baseline in Physical Examination

Number of Participants With Change From Baseline in Opthalmologic Examination

Overall Survival (OS) in Part 2

Progression Free Survival (PFS) in Part 2

Day 1 (n = 4, 4, 6, 7, 54, 13, 10)

Day 15 (n = 3, 4, 5, 5, 69, 10, 2)

Bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal in both Part 1 and Part 2 participants.

Bosutinib 400 mg (Part 1 + Part 2)

Analysis population included all participants who had taken at least 1 dose of study medication. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure and 'n' signifies those participants evaluable for specific time points.

Maximum Observed Plasma Concentration (Cmax)

Analysis population included all participants who had taken at least one dose of study medication. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure and 'n' signifies those participants evaluable for specific time points.

Time to Reach Maximum Observed Plasma Concentration (Tmax)

Day 1 (n = 3, 4, 6, 7, 47, 13, 10)

Day 15 (n = 3, 4, 5, 4, 53, 9, 2)

Plasma Decay Half-Life (t1/2)

Day 15 (n = 3, 4, 5, 4, 58, 9, 2)

Area Under the Concentration-Time Curve (AUC)

Data was not analyzed as the analysis was cancelled due to lack of samples provided from sites.

Spots Global Cancer Trial Database for Study Evaluating SKI-606 (Bosutinib) In Advanced Malignant Solid Tumors

Trial Identification

Conditions

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Study Description

Keywords

Eligibility

Locations

Contact Details

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