- Number of Participants Who Died, Experienced Adverse Events (AEs), Serious AEs (SAEs), Drug Related AEs and Discontinued Due to AEs [ Time Frame: From start of study drug therapy up to 30 days after the last dose. ] [ Designated as safety issue: Yes ]
AEs: any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Participants who discontinued the study due to an AE were recorded. Drug-related AEs: events with a relationship to the study therapy of certain; probable; possible; not likely or unrelated.
- Number of Participants With Grade 3 or 4 Hematology Abnormalities [ Time Frame: From start of study drug therapy up to 30 days after the last dose. ] [ Designated as safety issue: Yes ]
Hematology abnormalities were graded per the National Cancer Institute (NCI) Common. Terminology Criteria (CTC) version 3.0 criteria (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening). Grade 3 and 4 criteria are as follows: Absolute Neutrophil Count (ANC): Grade 3: 0.5 - <1.0*10^9/L, Grade 4: <0.5*10^9/L; lymphocytes: Grade 3: 0.2 - <0.5*10^9/L, Grade 4: <0.2*10^9/L.
- Number of Participants With Grade 3-4 Serum Chemistry Abnormalities [ Time Frame: From start of study drug therapy up to 30 days after the last dose. ] [ Designated as safety issue: Yes ]
Abnormalities were graded according to the NCI CTC, version 3.0 (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening). Grade 3 and 4 criteria are as follows: phosphorous: Grade 3: 1.0-<2.0 mg/dL, Grade 4: <1.0 mg/dL; calcium: Grade 3: 6.0-<7.0 or >12.5-13.5 mg/dL, Grade 4: <0.6->13.5 mg/dL; magnesium: Grade 3: >3.0 - 8.0 mg/dL or >1.23 - 3.30 mmol/L, Grade 4: >8.0 mg/dL or >3.30 mmol/L; albumin: Grade 3: <2 g/dL or <20 g/L.
- Most Frequent Grade 3-4 Hematology Abnormalities Occurring in >=10% Participants: Low Lymphocyte Count [ Time Frame: From start of study drug therapy up to 30 days after the last dose. ] [ Designated as safety issue: Yes ]
Abnormalities were graded according to the NCI CTC, version 3.0 (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening). Most frequent hematology Grade 3 and 4 abnormalities occurring in >=10% participants were recorded. Grade 3 and 4 criteria are as follows: lymphocyte count: Grade 3: 0.2 - <0.5*10^9/L, Grade 4: <0.2*10^9/L.
- Most Frequent Serum Chemistry Laboratory Abnormalities Occurring in >=10% Participants: High Magnesium [ Time Frame: From start of study drug therapy up to 30 days after the last dose. ] [ Designated as safety issue: Yes ]
Abnormalities were graded according to the NCI-CTC, version 3.0 (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening). Most frequent (>=10%) serum laboratory abnormalities were recorded. The following definitions specify the NCI-CTC AE criteria for serum laboratory abnormalities in the data presented: magnesium: Grade 3: >3.0 - 8.0 mg/dL or >1.23 - 3.30 mmol/L, Grade 4: >8.0 mg/dL or >3.30 mmol/L.
- Number of Participants With Clinically Meaningful Physical Examination Measures [ Time Frame: From screening, Day 1 in each treatment course and at the end of study ] [ Designated as safety issue: Yes ]
Interim and final physical examinations were performed. The investigator used his/her clinical judgment to decide whether or not physical examination findings were clinically significant.
- Number of Participants With Clinically Meaningful Vital Signs [ Time Frame: From screening, Day 1 , 8, 15 and 22 in the 1st treatment course, Day 8 and 22 in the second and subsequent courses and at the end of study ] [ Designated as safety issue: Yes ]
Vital signs measurements (including blood pressure, body temperature and pulse rate) were recorded. The investigator used his/her clinical judgment to decide whether or not abnormalities in vital signs were clinically significant.
- Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings [ Time Frame: From screening Day -1, and at pre-dose, 1 and 4 hours (post-dose) on Days 1, 14 and 28 in first treatment course, at pre-dose, 1 and 4 hours (post-dose) during the second and fourth week in subsequent courses and at the end of study ] [ Designated as safety issue: Yes ]
Standard 12-lead ECG was used to record selected ECG parameters like RR interval (the time between the two R waves in ECG), PR interval (interval measured from the beginning of the P wave to the beginning of the QRS complex; QRS complex is the name for some of the deflections seen on a typical ECG)), QRS duration, QT interval (time between onset of ventricular depolarization and end of ventricular repolarization), QT interval corrected for heart rate using Bazett's (QTcB) and Fridericia's (QTcF) formulas.
- Number of Participants With Clinically Significant Change in QT Interval Corrected for Heart Rate (QTcF) [ Time Frame: Baseline, Day 1, Day 14 and Day 28 ] [ Designated as safety issue: Yes ]
QT interval corrected for heart rate (QTcF) was assessed using triplicate 12-lead serial ECGs.
- Maximum Plasma Concentration (Cmax) of Dasatinib [ Time Frame: Blood samples were collected at 0 hour (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 12 and 24 hours (post dose) on Days 1, 14 and 28 ] [ Designated as safety issue: No ]
Cmax was obtained from the plasma concentration versus time data after oral administration of dasatinib.
- Area Under the Plasma-concentration-time Curve [AUC (INF)] of Dasatinib on Day 1 [ Time Frame: Blood samples were collected at 0 hour (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 12 and 24 hours (post dose) on Day 1 ] [ Designated as safety issue: No ]
AUC(INF), area under the plasma concentration-time curve from zero to the last time of the last quantifiable concentration within the dosing interval was calculated for Day 1.
- AUC[TAU] of Dasatinib [ Time Frame: Blood samples were collected at 0 hour (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 12 and 24 hours (post dose) on Days 1, 14 and 28 ] [ Designated as safety issue: No ]
Area under the plasma concentration-time curve within the dosing interval was determined. AUC(TAU), from time 0 to the time of the last measurable concentration (24 hours) was calculated for Day 1, 14, 28 respectively.
- Time to Reach Maximum Observed Plasma Concentration of Dasatinib (Tmax) [ Time Frame: Blood samples were collected at 0 hour (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 12 and 24 hours (post dose) on Days 1, 14 and 28 ] [ Designated as safety issue: No ]
Tmax, time to reach maximum observed plasma concentration of dasatinib was obtained directly from the plasma concentration versus time data.
- Terminal Elimination Half-life (T-half) of Dasatinib [ Time Frame: Blood samples were collected at 0 hour (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 12 and 24 hours (post dose) on Days 1, 14 and 28 ] [ Designated as safety issue: No ]
T-half of dasatinib was calculated using plasma concentration versus time data.
- Accumulation Index (AI) of Dasatinib [ Time Frame: Blood samples were collected at 0 hour (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 12 and 24 hours (post dose) on Days 1, 14 and 28 ] [ Designated as safety issue: No ]
AI of Dasatinib was calculated as ratio of geometric mean of AUC(TAU) (area under the plasma concentration versus time curve from time 0 to the time of the last measurable concentration) on Day 14 or Day 28 on Day 1.
- Mean Apparent Oral Clearance (CLo) of Dasatinib [ Time Frame: Blood samples were collected at 0 hour (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 12 and 24 hours (post dose) on Days 14 and 28 ] [ Designated as safety issue: No ]
Apparent oral clearance was obtained from the plasma concentration versus time data.
- Mean Apparent Volume of Distribution (Vz/F) of Dasatinib [ Time Frame: Blood samples were collected at 0 hour (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 12 and 24 hours (post dose) on Days 14 and 28 ] [ Designated as safety issue: No ]
Apparent volume of distribution after oral dosing was obtained from plasma concentration versus time data.
- Cmax of Metabolite BMS-582691 [ Time Frame: Blood samples were collected at 0 hour (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 12 and 24 hours (post dose) on Days 1, 14 and 28 ] [ Designated as safety issue: No ]
Maximum plasma concentration was obtained from plasma concentration versus time data of metabolite (BMS-582691).
- AUC (0-t) of Metabolite BMS-582691 [ Time Frame: Blood samples were collected at 0 hour (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 12 and 24 hours (post dose) on Days 1, 14 and 28 ] [ Designated as safety issue: No ]
AUC (0-t) was calculated using plasma concentration values of metabolite at time 0 to the time of the last measurable concentration (t).
- Tmax of the Metabolite BMS-582691 [ Time Frame: Blood samples were collected at 0 hour (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 12 and 24 hours (post dose) on Days 1, 14 and 28 ] [ Designated as safety issue: No ]
Tmax of the metabolite was obtained using plasma concentration versus time data of metabolite BMS-582691.
- Mean Urine Concentration of Urinary N-telopeptide Type 1 Collagen (NTx) Biological Marker [ Time Frame: Urine samples were collected at baseline (Day -1) and 0 hour (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 12 and 24 hours (post dose) on Days 14 and 28. ] [ Designated as safety issue: No ]
Urine NTx is a measure of bone metabolism. A decrease in the marker relative to baseline indicates a decrease in bone metabolism. Mean urine concentration of NTx biological marker was determined using enzyme linked immuno-sorbent assay (ELISA).
- Mean Urine Concentration of Deoxypyridinoline (Dpyr) Biological Marker [ Time Frame: Urine samples were collected at baseline (Day -1) and 0 hour (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6 12 and 24 hours post dose on Days 14 and 28 ] [ Designated as safety issue: No ]
Urine levels of DPyr is a measure of bone resorption. A decrease in Dpyr relative to the baseline indicates decrease in bone metabolism. Mean urine concentration of Dpyr biological marker was determined using ELISA.
- Mean Serum Concentration of Tartrate-resistant Acid Phosphatase Isoform 5b (TRACP-5b) Biological Marker [ Time Frame: Serum samples were assessed at baseline (Day -1) and on Days 14 and 28 ] [ Designated as safety issue: No ]
TRACP-5b is a measure of bone metabolism. A decrease in TRACP-5b relative to the baseline indicates decrease in bone metabolism. Serum TRACP-5b was quantified with enzyme-linked-immunosorbent serologic assay (ELISA).
- Mean Serum Concentration of Bone Alkaline Phosphatase (BAP) Biological Marker [ Time Frame: Serum samples were assessed on baseline (Day -1), and pre-dose on Days 14, 28 ] [ Designated as safety issue: No ]
BAP is a measure of bone metabolism. A decrease in BAP relative to the baseline indicates decrease in bone metabolism. Serum BAP was quantified with ELISA.
- Number of Participants With Sarcoma (Src) and Phosphorylated Src (pSRc) Protein Expression in Peripheral Blood Mononuclear Cells (PBMC) [ Time Frame: Plasma samples were collected on baseline (Day -1), 0 hour (pre-dose), 1 and 4 hours (post-dose) on Days 1, 14 and 28 ] [ Designated as safety issue: No ]
Src and pSrc protein expression was planned to be evaluated in PBMC for establishing PK/PD relationship between Src/pSrc protein expression in PBMC and exposure of BMS-354825.
- Number of Participants With Complete Response (CR) or Partial Response (PR) [ Time Frame: Within 4 weeks of first study drug administration, thereafter recorded every 4 or 8 weeks. ] [ Designated as safety issue: No ]
Tumor response was defined as the number of participants whose best response was CR or PR as per Response Evaluation Criteria In Solid Tumors (RECIST) criteria. CR: disappearance of all target/non-target lesions; PR: >= 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.
Purpose
