Tumors
Conditions
Keywords
Solid tumors (including relapsed disease) that are refractory to standard therapies or for which no effective standard therapy exists
Brief summary
The primary objective of this study is to determine the maximum tolerated dose (MTD) or the maximum administered dose (MAD) of Dasatinib (BMS-354825) in patients in Japan.
Interventions
DRUGDasatinib
tablets, Oral, 100 mg, once daily for 4 weeks
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Performance status (general conditions) specified by the Eastern Cooperative Oncology Group: 0-2 * Histologic or cytologic diagnosis of a solid tumor which has progressed on or following standard therapies (including relapsed disease) or for which no standard therapy exists. * men and women, ages 20 and over * women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 3 months after the study in such a manner that the risk of pregnancy is minimized * Adequate hepatic function
Exclusion criteria
* Participants who are eligible and willing to undergo transplantation at pre- study. * Women who are pregnant or breastfeeding with known brain metastasis or symptoms of brain metastasis * Uncontrolled or significant bleeding disorder unrelated to a primary tumor * Dementia or mental illness that would prohibit understanding or giving informed consent. * Severe allergy to drugs required for appropriate supportive care of patients in this study. * History of gastrointestinal surgery or of any digestive disorder which has the potential to inhibit absorption of the study drug. * Pleural effusion \> Grade 1 * Patient with dysphagia * Does not agree to blood/blood products transfusion(s) * Donated blood over 200 mL within 4 weeks prior to the start of study therapy * Medication that known to have a risk of causing Torsade de pointes * Participants who are compulsorily detained for legal reasons or treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) and Maximum Acceptable Dose (MAD) of Dasatinib as Determined by Number of Participants With Dose-Limiting Toxicities (DLTs) Related to Dasatinib Treatment | From start of the treatment i.e.Day 1 to end of Cycle 1 i.e. Day 30 (4 weeks) | MAD: highest dose level at which \>=1 DLTs were reported, MTD: dose one step lower than MAD. DLT: any of the following considered related to dasatinib during course 1:Grade 3(dose reduction by 1 dose level)/Grade 4:recurring nausea, vomiting or diarrhea; any other Grade \>=3 non-hematologic toxicity except alopecia or fatigue;any grade toxicity requiring two dose reductions or participant's discontinuation; Grade 4 neutropenia \<500 cells/mm\^3 for \>=5 consecutive days or febrile neutropenia; Grade 4 thrombocytopenia \<25,000 cells/mm\^3 or Grade 3 bleeding requiring platelet transfusion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Died, Experienced Adverse Events (AEs), Serious AEs (SAEs), Drug Related AEs and Discontinued Due to AEs | From start of study drug therapy up to 30 days after the last dose. | 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 | From start of study drug therapy up to 30 days after the last dose. | 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 | From start of study drug therapy up to 30 days after the last dose. | 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 | From start of study drug therapy up to 30 days after the last dose. | 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. |
| Area Under the Plasma-concentration-time Curve [AUC (INF)] of Dasatinib on Day 1 | 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 | 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. |
| Most Frequent Serum Chemistry Laboratory Abnormalities Occurring in >=10% Participants: High Magnesium | From start of study drug therapy up to 30 days after the last dose. | 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 | From screening, Day 1 in each treatment course and at the end of study | 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 | 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 | 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 | 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 | 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) | Baseline, Day 1, Day 14 and Day 28 | QT interval corrected for heart rate (QTcF) was assessed using triplicate 12-lead serial ECGs. |
| AUC[TAU] of Dasatinib | 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 | 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) | 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 | Tmax, time to reach maximum observed plasma concentration of dasatinib was obtained directly from the plasma concentration versus time data. |
| Maximum Plasma Concentration (Cmax) of Dasatinib | 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 | Cmax was obtained from the plasma concentration versus time data after oral administration of dasatinib. |
| Accumulation Index (AI) of Dasatinib | 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 | 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 | 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 | Apparent oral clearance was obtained from the plasma concentration versus time data. |
| Mean Apparent Volume of Distribution (Vz/F) of Dasatinib | 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 | Apparent volume of distribution after oral dosing was obtained from plasma concentration versus time data. |
| Cmax of Metabolite BMS-582691 | 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 | Maximum plasma concentration was obtained from plasma concentration versus time data of metabolite (BMS-582691). |
| AUC (0-t) of Metabolite BMS-582691 | 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 | 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 | 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 | 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 | 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. | 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 | 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 | 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 | Serum samples were assessed at baseline (Day -1) and on Days 14 and 28 | 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 | Serum samples were assessed on baseline (Day -1), and pre-dose on Days 14, 28 | 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) | Plasma samples were collected on baseline (Day -1), 0 hour (pre-dose), 1 and 4 hours (post-dose) on Days 1, 14 and 28 | 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) | Within 4 weeks of first study drug administration, thereafter recorded every 4 or 8 weeks. | 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. |
| Terminal Elimination Half-life (T-half) of Dasatinib | 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 | T-half of dasatinib was calculated using plasma concentration versus time data. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dasatinib 100 mg Participants were administered an oral dose of 100 mg dasatinib tablet once daily for a period of 4 weeks. Initially, 3 participants were treated at one dose level. If no dose limiting toxicity (DLT) was observed, the dose was escalated to next higher level. If a DLT was observed among 1 of 3 treated participants in the first course at a dose level, 3 participants were additionally enrolled and treated at the same dose level. If no further DLT was observed during the first course in these additional participants, the dose was escalated to next higher dose level. Dose was not escalated above 200 mg daily. | 9 |
| Dasatinib 150 mg Participants were administered an oral dose of 150 mg dasatinib tablet once daily for a period of 4 weeks. Initially, 3 participants were treated at one dose level. If no DLT was observed, the dose was escalated to next higher level. If a DLT was observed among 1 of 3 treated participants in the first course at a dose level, 3 participants were additionally enrolled and treated at the same dose level. If no further DLT was observed during the first course in these additional participants, the dose was escalated to next higher dose level. Dose was not escalated above 200 mg daily. | 3 |
| Dasatinib 200 mg Participants were administered an oral dose of 200 mg dasatinib tablet once daily for a period of 4 weeks. Initially, 3 participants were treated at one dose level. If no DLT was observed, the dose was escalated to next higher level. If a DLT was observed among 1 of 3 treated participants in the first course at a dose level, 3 participants were additionally enrolled and treated at the same dose level. Dose was not escalated above 200 mg daily. | 4 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Disease progression | 5 | 2 | 2 |
| Overall Study | Participant's request to discontinuation | 1 | 0 | 1 |
| Overall Study | Study drug toxicity | 3 | 1 | 1 |
Baseline characteristics
| Characteristic | Dasatinib 100 mg | Dasatinib 150 mg | Dasatinib 200 mg | Total |
|---|---|---|---|---|
| Age Continuous | 58.0 years | 55.0 years | 47.5 years | 54.0 years |
| Age, Customized < 65 years | 7 participants | 3 participants | 4 participants | 14 participants |
| Age, Customized >=65 years | 2 participants | 0 participants | 0 participants | 2 participants |
| Eastern Cooperative Oncology group (ECOG) Performance Status (PS) 0 = Fully active | 7 Units on a scale | 1 Units on a scale | 2 Units on a scale | 10 Units on a scale |
| Eastern Cooperative Oncology group (ECOG) Performance Status (PS) 1 = Ambulatory and able to work | 2 Units on a scale | 2 Units on a scale | 2 Units on a scale | 6 Units on a scale |
| Eastern Cooperative Oncology group (ECOG) Performance Status (PS) 2 = Ambulatory but unable to work | 0 Units on a scale | 0 Units on a scale | 0 Units on a scale | 0 Units on a scale |
| Eastern Cooperative Oncology group (ECOG) Performance Status (PS) 3 = Capable of only limited self care | 0 Units on a scale | 0 Units on a scale | 0 Units on a scale | 0 Units on a scale |
| Eastern Cooperative Oncology group (ECOG) Performance Status (PS) 4 = Completely disabled | 0 Units on a scale | 0 Units on a scale | 0 Units on a scale | 0 Units on a scale |
| Sex: Female, Male Female | 7 Participants | 1 Participants | 3 Participants | 11 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 9 | 3 / 3 | 4 / 4 |
| serious Total, serious adverse events | 1 / 9 | 1 / 3 | 1 / 4 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) and Maximum Acceptable Dose (MAD) of Dasatinib as Determined by Number of Participants With Dose-Limiting Toxicities (DLTs) Related to Dasatinib Treatment
MAD: highest dose level at which \>=1 DLTs were reported, MTD: dose one step lower than MAD. DLT: any of the following considered related to dasatinib during course 1:Grade 3(dose reduction by 1 dose level)/Grade 4:recurring nausea, vomiting or diarrhea; any other Grade \>=3 non-hematologic toxicity except alopecia or fatigue;any grade toxicity requiring two dose reductions or participant's discontinuation; Grade 4 neutropenia \<500 cells/mm\^3 for \>=5 consecutive days or febrile neutropenia; Grade 4 thrombocytopenia \<25,000 cells/mm\^3 or Grade 3 bleeding requiring platelet transfusion.
Time frame: From start of the treatment i.e.Day 1 to end of Cycle 1 i.e. Day 30 (4 weeks)
Population: All treated participants who received at least one dose of the study drug and were evaluable for DLT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasatinib 100 mg | Maximum Tolerated Dose (MTD) and Maximum Acceptable Dose (MAD) of Dasatinib as Determined by Number of Participants With Dose-Limiting Toxicities (DLTs) Related to Dasatinib Treatment | 1 participants |
| Dasatinib 150 mg | Maximum Tolerated Dose (MTD) and Maximum Acceptable Dose (MAD) of Dasatinib as Determined by Number of Participants With Dose-Limiting Toxicities (DLTs) Related to Dasatinib Treatment | 0 participants |
| Dasatinib 200 mg | Maximum Tolerated Dose (MTD) and Maximum Acceptable Dose (MAD) of Dasatinib as Determined by Number of Participants With Dose-Limiting Toxicities (DLTs) Related to Dasatinib Treatment | 1 participants |
Secondary
Accumulation Index (AI) of Dasatinib
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.
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
Population: All treated participants with adequate PK profiles (PK population). The 'n' signifies those participants who received study drug and were evaluated for this measure (each group respectively).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Dasatinib 100 mg | Accumulation Index (AI) of Dasatinib | Day 14 (n = 5, 4, 2) | 0.81 ratio |
| Dasatinib 100 mg | Accumulation Index (AI) of Dasatinib | Day 28 (n= 3, 2, 2) | 1.12 ratio |
| Dasatinib 150 mg | Accumulation Index (AI) of Dasatinib | Day 14 (n = 5, 4, 2) | 1.78 ratio |
| Dasatinib 150 mg | Accumulation Index (AI) of Dasatinib | Day 28 (n= 3, 2, 2) | 0.48 ratio |
| Dasatinib 200 mg | Accumulation Index (AI) of Dasatinib | Day 14 (n = 5, 4, 2) | 2.30 ratio |
| Dasatinib 200 mg | Accumulation Index (AI) of Dasatinib | Day 28 (n= 3, 2, 2) | 1.72 ratio |
Secondary
Area Under the Plasma-concentration-time Curve [AUC (INF)] of Dasatinib on Day 1
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.
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
Population: All treated participants with adequate PK profiles (PK population).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Dasatinib 100 mg | Area Under the Plasma-concentration-time Curve [AUC (INF)] of Dasatinib on Day 1 | 537.98 ng*hours/ml |
| Dasatinib 150 mg | Area Under the Plasma-concentration-time Curve [AUC (INF)] of Dasatinib on Day 1 | 544.36 ng*hours/ml |
| Dasatinib 200 mg | Area Under the Plasma-concentration-time Curve [AUC (INF)] of Dasatinib on Day 1 | 595.62 ng*hours/ml |
Secondary
AUC (0-t) of Metabolite BMS-582691
AUC (0-t) was calculated using plasma concentration values of metabolite at time 0 to the time of the last measurable concentration (t).
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
Population: All treated participants with adequate PK profiles (PK population). The 'n' signifies those participants who received study drug and were evaluated for this measure (each group respectively).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Dasatinib 100 mg | AUC (0-t) of Metabolite BMS-582691 | Day 28 (n= 3, 1, 2) | 27.20 ng*hr/mL |
| Dasatinib 100 mg | AUC (0-t) of Metabolite BMS-582691 | Day 14 (n = 5, 4, 2) | 15.24 ng*hr/mL |
| Dasatinib 100 mg | AUC (0-t) of Metabolite BMS-582691 | Day 1 (n = 8, 3, 3) | 21.24 ng*hr/mL |
| Dasatinib 150 mg | AUC (0-t) of Metabolite BMS-582691 | Day 28 (n= 3, 1, 2) | 13.03 ng*hr/mL |
| Dasatinib 150 mg | AUC (0-t) of Metabolite BMS-582691 | Day 1 (n = 8, 3, 3) | 5.99 ng*hr/mL |
| Dasatinib 150 mg | AUC (0-t) of Metabolite BMS-582691 | Day 14 (n = 5, 4, 2) | 26.05 ng*hr/mL |
| Dasatinib 200 mg | AUC (0-t) of Metabolite BMS-582691 | Day 28 (n= 3, 1, 2) | 4.67 ng*hr/mL |
| Dasatinib 200 mg | AUC (0-t) of Metabolite BMS-582691 | Day 14 (n = 5, 4, 2) | 37.65 ng*hr/mL |
| Dasatinib 200 mg | AUC (0-t) of Metabolite BMS-582691 | Day 1 (n = 8, 3, 3) | 36.96 ng*hr/mL |
Secondary
AUC[TAU] of Dasatinib
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 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
Population: All treated participants with adequate PK profiles (PK population). The 'n' signifies those participants who received study drug and were evaluated for this measure (each group respectively).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Dasatinib 100 mg | AUC[TAU] of Dasatinib | Day 14 (n = 5, 4, 2) | 499.69 ng*hours/ml |
| Dasatinib 100 mg | AUC[TAU] of Dasatinib | Day 1 (n = 9, 3, 4) | 524.55 ng*hours/ml |
| Dasatinib 100 mg | AUC[TAU] of Dasatinib | Day 28 (n= 3, 2, 2) | 738.76 ng*hours/ml |
| Dasatinib 150 mg | AUC[TAU] of Dasatinib | Day 14 (n = 5, 4, 2) | 694.90 ng*hours/ml |
| Dasatinib 150 mg | AUC[TAU] of Dasatinib | Day 1 (n = 9, 3, 4) | 530.81 ng*hours/ml |
| Dasatinib 150 mg | AUC[TAU] of Dasatinib | Day 28 (n= 3, 2, 2) | 273.10 ng*hours/ml |
| Dasatinib 200 mg | AUC[TAU] of Dasatinib | Day 1 (n = 9, 3, 4) | 528.65 ng*hours/ml |
| Dasatinib 200 mg | AUC[TAU] of Dasatinib | Day 28 (n= 3, 2, 2) | 534.33 ng*hours/ml |
| Dasatinib 200 mg | AUC[TAU] of Dasatinib | Day 14 (n = 5, 4, 2) | 716.27 ng*hours/ml |
Secondary
Cmax of Metabolite BMS-582691
Maximum plasma concentration was obtained from plasma concentration versus time data 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
Population: All treated participants with adequate PK profiles (PK population). The 'n' signifies those participants who received study drug and were evaluated for this measure (each group respectively).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Dasatinib 100 mg | Cmax of Metabolite BMS-582691 | Day 14 (n = 5, 4, 2) | 4.63 ng/ml |
| Dasatinib 100 mg | Cmax of Metabolite BMS-582691 | Day 1 (n = 8, 3, 3) | 5.18 ng/ml |
| Dasatinib 100 mg | Cmax of Metabolite BMS-582691 | Day 28 (n= 3, 1, 2) | 6.68 ng/ml |
| Dasatinib 150 mg | Cmax of Metabolite BMS-582691 | Day 14 (n = 5, 4, 2) | 4.61 ng/ml |
| Dasatinib 150 mg | Cmax of Metabolite BMS-582691 | Day 1 (n = 8, 3, 3) | 2.89 ng/ml |
| Dasatinib 150 mg | Cmax of Metabolite BMS-582691 | Day 28 (n= 3, 1, 2) | 4.66 ng/ml |
| Dasatinib 200 mg | Cmax of Metabolite BMS-582691 | Day 1 (n = 8, 3, 3) | 7.90 ng/ml |
| Dasatinib 200 mg | Cmax of Metabolite BMS-582691 | Day 28 (n= 3, 1, 2) | 3.04 ng/ml |
| Dasatinib 200 mg | Cmax of Metabolite BMS-582691 | Day 14 (n = 5, 4, 2) | 5.99 ng/ml |
Secondary
Maximum Plasma Concentration (Cmax) of Dasatinib
Cmax was obtained from the plasma concentration versus time data after oral administration 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
Population: All treated participants with adequate pharmacokinetic (PK)profiles (PK population). The 'n' signifies those participants who received study drug and were evaluated for this measure (each group respectively).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Dasatinib 100 mg | Maximum Plasma Concentration (Cmax) of Dasatinib | Day 14 (n = 5, 4, 2) | 137.03 nanograms (ng)/ml |
| Dasatinib 100 mg | Maximum Plasma Concentration (Cmax) of Dasatinib | Day 1 (n = 9, 3, 4) | 139.83 nanograms (ng)/ml |
| Dasatinib 100 mg | Maximum Plasma Concentration (Cmax) of Dasatinib | Day 28 (n= 3, 2, 2) | 253.77 nanograms (ng)/ml |
| Dasatinib 150 mg | Maximum Plasma Concentration (Cmax) of Dasatinib | Day 14 (n = 5, 4, 2) | 166.43 nanograms (ng)/ml |
| Dasatinib 150 mg | Maximum Plasma Concentration (Cmax) of Dasatinib | Day 1 (n = 9, 3, 4) | 127.1 nanograms (ng)/ml |
| Dasatinib 150 mg | Maximum Plasma Concentration (Cmax) of Dasatinib | Day 28 (n= 3, 2, 2) | 103.32 nanograms (ng)/ml |
| Dasatinib 200 mg | Maximum Plasma Concentration (Cmax) of Dasatinib | Day 1 (n = 9, 3, 4) | 124.48 nanograms (ng)/ml |
| Dasatinib 200 mg | Maximum Plasma Concentration (Cmax) of Dasatinib | Day 28 (n= 3, 2, 2) | 80.92 nanograms (ng)/ml |
| Dasatinib 200 mg | Maximum Plasma Concentration (Cmax) of Dasatinib | Day 14 (n = 5, 4, 2) | 102.61 nanograms (ng)/ml |
Secondary
Mean Apparent Oral Clearance (CLo) of Dasatinib
Apparent oral clearance was obtained from the plasma concentration versus time data.
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
Population: All treated participants with adequate PK profiles (PK population). The 'n' signifies those participants who received study drug and were evaluated for this measure (each group respectively).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dasatinib 100 mg | Mean Apparent Oral Clearance (CLo) of Dasatinib | Day 14 (n = 5, 4, 2) | 200.12 L/hour | Full Range 134.3 |
| Dasatinib 100 mg | Mean Apparent Oral Clearance (CLo) of Dasatinib | Day 28 (n= 3, 2, 2) | 135.36 L/hour | Full Range 53.3 |
| Dasatinib 150 mg | Mean Apparent Oral Clearance (CLo) of Dasatinib | Day 14 (n = 5, 4, 2) | 215.86 L/hour | Full Range 204.7 |
| Dasatinib 150 mg | Mean Apparent Oral Clearance (CLo) of Dasatinib | Day 28 (n= 3, 2, 2) | 549.26 L/hour | Full Range 489.6 |
| Dasatinib 200 mg | Mean Apparent Oral Clearance (CLo) of Dasatinib | Day 14 (n = 5, 4, 2) | 279.22 L/hour | Full Range 537.4 |
| Dasatinib 200 mg | Mean Apparent Oral Clearance (CLo) of Dasatinib | Day 28 (n= 3, 2, 2) | 374.30 L/hour | Full Range 231.3 |
Secondary
Mean Apparent Volume of Distribution (Vz/F) of Dasatinib
Apparent volume of distribution after oral dosing was obtained from plasma concentration versus time data.
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
Population: All treated participants with adequate PK profiles (PK population). The 'n' signifies those participants who received study drug and were evaluated for this measure (each group respectively).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dasatinib 100 mg | Mean Apparent Volume of Distribution (Vz/F) of Dasatinib | Day 14 (n = 5, 4, 2) | 1156.57 L | Full Range 2010 |
| Dasatinib 100 mg | Mean Apparent Volume of Distribution (Vz/F) of Dasatinib | Day 28 (n= 3, 2, 2) | 566.93 L | Full Range 286 |
| Dasatinib 150 mg | Mean Apparent Volume of Distribution (Vz/F) of Dasatinib | Day 14 (n = 5, 4, 2) | 1285.05 L | Full Range 1967 |
| Dasatinib 150 mg | Mean Apparent Volume of Distribution (Vz/F) of Dasatinib | Day 28 (n= 3, 2, 2) | 3443.56 L | Full Range 5920 |
| Dasatinib 200 mg | Mean Apparent Volume of Distribution (Vz/F) of Dasatinib | Day 14 (n = 5, 4, 2) | 2903.18 L | Full Range 12216 |
| Dasatinib 200 mg | Mean Apparent Volume of Distribution (Vz/F) of Dasatinib | Day 28 (n= 3, 2, 2) | 3362.08 L | Full Range 6081 |
Secondary
Mean Serum Concentration of Bone Alkaline Phosphatase (BAP) Biological Marker
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.
Time frame: Serum samples were assessed on baseline (Day -1), and pre-dose on Days 14, 28
Population: All treated participants with adequate PD profiles (PD population). The 'n' signifies those participants who received study drug and were evaluated for this measure (each group respectively).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dasatinib 100 mg | Mean Serum Concentration of Bone Alkaline Phosphatase (BAP) Biological Marker | Day -1 (n = 16) | 29.11 U/L | Standard Deviation 11.21 |
| Dasatinib 100 mg | Mean Serum Concentration of Bone Alkaline Phosphatase (BAP) Biological Marker | Day 14 (n= 13) | 32.34 U/L | Standard Deviation 11.92 |
| Dasatinib 100 mg | Mean Serum Concentration of Bone Alkaline Phosphatase (BAP) Biological Marker | Day 28 (n= 7) | 28.20 U/L | Standard Deviation 6.21 |
Secondary
Mean Serum Concentration of Tartrate-resistant Acid Phosphatase Isoform 5b (TRACP-5b) Biological Marker
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).
Time frame: Serum samples were assessed at baseline (Day -1) and on Days 14 and 28
Population: All treated participants with adequate PD profiles (PD population). The 'n' signifies those participants who received study drug and were evaluated for this measure (each group respectively).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dasatinib 100 mg | Mean Serum Concentration of Tartrate-resistant Acid Phosphatase Isoform 5b (TRACP-5b) Biological Marker | Day -1 (n = 16) | 5.13 U/L | Standard Deviation 1.89 |
| Dasatinib 100 mg | Mean Serum Concentration of Tartrate-resistant Acid Phosphatase Isoform 5b (TRACP-5b) Biological Marker | Day 14 (n= 12) | 4.13 U/L | Standard Deviation 1.25 |
| Dasatinib 100 mg | Mean Serum Concentration of Tartrate-resistant Acid Phosphatase Isoform 5b (TRACP-5b) Biological Marker | Day 28 (n= 7) | 3.40 U/L | Standard Deviation 0.61 |
Secondary
Mean Urine Concentration of Deoxypyridinoline (Dpyr) Biological Marker
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.
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
Population: All treated participants with adequate PD profiles (PD population). The 'n' signifies those participants who received study drug and were evaluated for this measure (each group respectively).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dasatinib 100 mg | Mean Urine Concentration of Deoxypyridinoline (Dpyr) Biological Marker | Day 14 (n= 6, 3, 4) | 27.08 nanomol (nmol)/mL | Standard Deviation 32.15 |
| Dasatinib 100 mg | Mean Urine Concentration of Deoxypyridinoline (Dpyr) Biological Marker | Day -1 (n = 9, 3, 4) | 37.79 nanomol (nmol)/mL | Standard Deviation 50.04 |
| Dasatinib 100 mg | Mean Urine Concentration of Deoxypyridinoline (Dpyr) Biological Marker | Day 28 (n= 3, 2, 2) | 15.77 nanomol (nmol)/mL | Standard Deviation 17.34 |
| Dasatinib 150 mg | Mean Urine Concentration of Deoxypyridinoline (Dpyr) Biological Marker | Day 14 (n= 6, 3, 4) | 25.37 nanomol (nmol)/mL | Standard Deviation 25.22 |
| Dasatinib 150 mg | Mean Urine Concentration of Deoxypyridinoline (Dpyr) Biological Marker | Day -1 (n = 9, 3, 4) | 50.37 nanomol (nmol)/mL | Standard Deviation 54.05 |
| Dasatinib 150 mg | Mean Urine Concentration of Deoxypyridinoline (Dpyr) Biological Marker | Day 28 (n= 3, 2, 2) | 40.55 nanomol (nmol)/mL | Standard Deviation 37.97 |
| Dasatinib 200 mg | Mean Urine Concentration of Deoxypyridinoline (Dpyr) Biological Marker | Day -1 (n = 9, 3, 4) | 116.85 nanomol (nmol)/mL | Standard Deviation 134.73 |
| Dasatinib 200 mg | Mean Urine Concentration of Deoxypyridinoline (Dpyr) Biological Marker | Day 28 (n= 3, 2, 2) | 14.80 nanomol (nmol)/mL | Standard Deviation 14.14 |
| Dasatinib 200 mg | Mean Urine Concentration of Deoxypyridinoline (Dpyr) Biological Marker | Day 14 (n= 6, 3, 4) | 46.73 nanomol (nmol)/mL | Standard Deviation 47.24 |
Secondary
Mean Urine Concentration of Urinary N-telopeptide Type 1 Collagen (NTx) Biological Marker
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).
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.
Population: All treated participants with adequate pharmacodynamic (PD) profiles (PD population). The 'n' signifies those participants who received study drug and were evaluated for this measure (each group respectively).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dasatinib 100 mg | Mean Urine Concentration of Urinary N-telopeptide Type 1 Collagen (NTx) Biological Marker | Day 14 (n= 6, 3, 4) | 51.55 nmol*bone collagen equivalent (BCE)/mmol | Standard Deviation 59.74 |
| Dasatinib 100 mg | Mean Urine Concentration of Urinary N-telopeptide Type 1 Collagen (NTx) Biological Marker | Day -1 ( n= 9, 3, 4) | 51.71 nmol*bone collagen equivalent (BCE)/mmol | Standard Deviation 39.75 |
| Dasatinib 100 mg | Mean Urine Concentration of Urinary N-telopeptide Type 1 Collagen (NTx) Biological Marker | Day 28 (n= 3, 2, 2) | 25.33 nmol*bone collagen equivalent (BCE)/mmol | Standard Deviation 4.26 |
| Dasatinib 150 mg | Mean Urine Concentration of Urinary N-telopeptide Type 1 Collagen (NTx) Biological Marker | Day 14 (n= 6, 3, 4) | 36.47 nmol*bone collagen equivalent (BCE)/mmol | Standard Deviation 26 |
| Dasatinib 150 mg | Mean Urine Concentration of Urinary N-telopeptide Type 1 Collagen (NTx) Biological Marker | Day -1 ( n= 9, 3, 4) | 62.57 nmol*bone collagen equivalent (BCE)/mmol | Standard Deviation 15.78 |
| Dasatinib 150 mg | Mean Urine Concentration of Urinary N-telopeptide Type 1 Collagen (NTx) Biological Marker | Day 28 (n= 3, 2, 2) | 40.10 nmol*bone collagen equivalent (BCE)/mmol | Standard Deviation 16.4 |
| Dasatinib 200 mg | Mean Urine Concentration of Urinary N-telopeptide Type 1 Collagen (NTx) Biological Marker | Day -1 ( n= 9, 3, 4) | 103.90 nmol*bone collagen equivalent (BCE)/mmol | Standard Deviation 57.37 |
| Dasatinib 200 mg | Mean Urine Concentration of Urinary N-telopeptide Type 1 Collagen (NTx) Biological Marker | Day 28 (n= 3, 2, 2) | 36.15 nmol*bone collagen equivalent (BCE)/mmol | Standard Deviation 36.84 |
| Dasatinib 200 mg | Mean Urine Concentration of Urinary N-telopeptide Type 1 Collagen (NTx) Biological Marker | Day 14 (n= 6, 3, 4) | 51.33 nmol*bone collagen equivalent (BCE)/mmol | Standard Deviation 30.08 |
Secondary
Most Frequent Grade 3-4 Hematology Abnormalities Occurring in >=10% Participants: Low Lymphocyte Count
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.
Time frame: From start of study drug therapy up to 30 days after the last dose.
Population: All treated participants who received at least one dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasatinib 100 mg | Most Frequent Grade 3-4 Hematology Abnormalities Occurring in >=10% Participants: Low Lymphocyte Count | 0 participants |
| Dasatinib 150 mg | Most Frequent Grade 3-4 Hematology Abnormalities Occurring in >=10% Participants: Low Lymphocyte Count | 1 participants |
| Dasatinib 200 mg | Most Frequent Grade 3-4 Hematology Abnormalities Occurring in >=10% Participants: Low Lymphocyte Count | 2 participants |
Secondary
Most Frequent Serum Chemistry Laboratory Abnormalities Occurring in >=10% Participants: High Magnesium
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.
Time frame: From start of study drug therapy up to 30 days after the last dose.
Population: All participants who received at least one dose of the study drug (safety population).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasatinib 100 mg | Most Frequent Serum Chemistry Laboratory Abnormalities Occurring in >=10% Participants: High Magnesium | 1 participants |
| Dasatinib 150 mg | Most Frequent Serum Chemistry Laboratory Abnormalities Occurring in >=10% Participants: High Magnesium | 0 participants |
| Dasatinib 200 mg | Most Frequent Serum Chemistry Laboratory Abnormalities Occurring in >=10% Participants: High Magnesium | 1 participants |
Secondary
Number of Participants Who Died, Experienced Adverse Events (AEs), Serious AEs (SAEs), Drug Related AEs and Discontinued Due to AEs
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.
Time frame: From start of study drug therapy up to 30 days after the last dose.
Population: All participants who received at least one dose of the study drug (safety population).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 100 mg | Number of Participants Who Died, Experienced Adverse Events (AEs), Serious AEs (SAEs), Drug Related AEs and Discontinued Due to AEs | Drug-related AEs | 9 participants |
| Dasatinib 100 mg | Number of Participants Who Died, Experienced Adverse Events (AEs), Serious AEs (SAEs), Drug Related AEs and Discontinued Due to AEs | SAEs | 1 participants |
| Dasatinib 100 mg | Number of Participants Who Died, Experienced Adverse Events (AEs), Serious AEs (SAEs), Drug Related AEs and Discontinued Due to AEs | Deaths | 0 participants |
| Dasatinib 100 mg | Number of Participants Who Died, Experienced Adverse Events (AEs), Serious AEs (SAEs), Drug Related AEs and Discontinued Due to AEs | AEs | 9 participants |
| Dasatinib 100 mg | Number of Participants Who Died, Experienced Adverse Events (AEs), Serious AEs (SAEs), Drug Related AEs and Discontinued Due to AEs | All AEs Leading to Discontinuation | 3 participants |
| Dasatinib 150 mg | Number of Participants Who Died, Experienced Adverse Events (AEs), Serious AEs (SAEs), Drug Related AEs and Discontinued Due to AEs | SAEs | 1 participants |
| Dasatinib 150 mg | Number of Participants Who Died, Experienced Adverse Events (AEs), Serious AEs (SAEs), Drug Related AEs and Discontinued Due to AEs | Deaths | 0 participants |
| Dasatinib 150 mg | Number of Participants Who Died, Experienced Adverse Events (AEs), Serious AEs (SAEs), Drug Related AEs and Discontinued Due to AEs | AEs | 3 participants |
| Dasatinib 150 mg | Number of Participants Who Died, Experienced Adverse Events (AEs), Serious AEs (SAEs), Drug Related AEs and Discontinued Due to AEs | Drug-related AEs | 3 participants |
| Dasatinib 150 mg | Number of Participants Who Died, Experienced Adverse Events (AEs), Serious AEs (SAEs), Drug Related AEs and Discontinued Due to AEs | All AEs Leading to Discontinuation | 1 participants |
| Dasatinib 200 mg | Number of Participants Who Died, Experienced Adverse Events (AEs), Serious AEs (SAEs), Drug Related AEs and Discontinued Due to AEs | All AEs Leading to Discontinuation | 1 participants |
| Dasatinib 200 mg | Number of Participants Who Died, Experienced Adverse Events (AEs), Serious AEs (SAEs), Drug Related AEs and Discontinued Due to AEs | Drug-related AEs | 4 participants |
| Dasatinib 200 mg | Number of Participants Who Died, Experienced Adverse Events (AEs), Serious AEs (SAEs), Drug Related AEs and Discontinued Due to AEs | Deaths | 0 participants |
| Dasatinib 200 mg | Number of Participants Who Died, Experienced Adverse Events (AEs), Serious AEs (SAEs), Drug Related AEs and Discontinued Due to AEs | SAEs | 1 participants |
| Dasatinib 200 mg | Number of Participants Who Died, Experienced Adverse Events (AEs), Serious AEs (SAEs), Drug Related AEs and Discontinued Due to AEs | AEs | 4 participants |
Secondary
Number of Participants With Clinically Meaningful Physical Examination Measures
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.
Time frame: From screening, Day 1 in each treatment course and at the end of study
Population: All participants who received at least one dose of the study drug (safety population). Analysis for significant physical examination findings was not done.
Secondary
Number of Participants With Clinically Meaningful Vital Signs
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.
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
Population: All participants who received at least one dose of the study drug (safety population).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasatinib 100 mg | Number of Participants With Clinically Meaningful Vital Signs | 0 participants |
| Dasatinib 150 mg | Number of Participants With Clinically Meaningful Vital Signs | 0 participants |
| Dasatinib 200 mg | Number of Participants With Clinically Meaningful Vital Signs | 0 participants |
Secondary
Number of Participants With Clinically Significant Change in QT Interval Corrected for Heart Rate (QTcF)
QT interval corrected for heart rate (QTcF) was assessed using triplicate 12-lead serial ECGs.
Time frame: Baseline, Day 1, Day 14 and Day 28
Population: All participants who received at least one dose of the study drug (safety population).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasatinib 100 mg | Number of Participants With Clinically Significant Change in QT Interval Corrected for Heart Rate (QTcF) | 0 participants |
| Dasatinib 150 mg | Number of Participants With Clinically Significant Change in QT Interval Corrected for Heart Rate (QTcF) | 0 participants |
| Dasatinib 200 mg | Number of Participants With Clinically Significant Change in QT Interval Corrected for Heart Rate (QTcF) | 0 participants |
Secondary
Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings
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.
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
Population: All participants who received at least one dose of the study drug (safety population).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasatinib 100 mg | Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings | 0 participants |
| Dasatinib 150 mg | Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings | 0 participants |
| Dasatinib 200 mg | Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings | 0 participants |
Secondary
Number of Participants With Complete Response (CR) or Partial Response (PR)
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.
Time frame: Within 4 weeks of first study drug administration, thereafter recorded every 4 or 8 weeks.
Population: All treated participants with measurable disease at baseline and received at least one dose of the study drug (efficacy population).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 100 mg | Number of Participants With Complete Response (CR) or Partial Response (PR) | CR | 0 participants |
| Dasatinib 100 mg | Number of Participants With Complete Response (CR) or Partial Response (PR) | PR | 0 participants |
| Dasatinib 150 mg | Number of Participants With Complete Response (CR) or Partial Response (PR) | CR | 0 participants |
| Dasatinib 150 mg | Number of Participants With Complete Response (CR) or Partial Response (PR) | PR | 0 participants |
| Dasatinib 200 mg | Number of Participants With Complete Response (CR) or Partial Response (PR) | CR | 0 participants |
| Dasatinib 200 mg | Number of Participants With Complete Response (CR) or Partial Response (PR) | PR | 0 participants |
Secondary
Number of Participants With Grade 3-4 Serum Chemistry Abnormalities
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.
Time frame: From start of study drug therapy up to 30 days after the last dose.
Population: All participants who received at least one dose of the study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 100 mg | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low phosphorus | 0 participants |
| Dasatinib 100 mg | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low calcium | 0 participants |
| Dasatinib 100 mg | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | High magnesium | 1 participants |
| Dasatinib 100 mg | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low albumin | 0 participants |
| Dasatinib 150 mg | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low albumin | 0 participants |
| Dasatinib 150 mg | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low phosphorus | 0 participants |
| Dasatinib 150 mg | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | High magnesium | 0 participants |
| Dasatinib 150 mg | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low calcium | 0 participants |
| Dasatinib 200 mg | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low albumin | 1 participants |
| Dasatinib 200 mg | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low calcium | 1 participants |
| Dasatinib 200 mg | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | High magnesium | 1 participants |
| Dasatinib 200 mg | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low phosphorus | 1 participants |
Secondary
Number of Participants With Grade 3 or 4 Hematology Abnormalities
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.
Time frame: From start of study drug therapy up to 30 days after the last dose.
Population: All participants who received at least one dose of the study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 100 mg | Number of Participants With Grade 3 or 4 Hematology Abnormalities | Low neutrophils count | 1 participants |
| Dasatinib 100 mg | Number of Participants With Grade 3 or 4 Hematology Abnormalities | Low lymphocyte count | 0 participants |
| Dasatinib 150 mg | Number of Participants With Grade 3 or 4 Hematology Abnormalities | Low neutrophils count | 0 participants |
| Dasatinib 150 mg | Number of Participants With Grade 3 or 4 Hematology Abnormalities | Low lymphocyte count | 1 participants |
| Dasatinib 200 mg | Number of Participants With Grade 3 or 4 Hematology Abnormalities | Low neutrophils count | 0 participants |
| Dasatinib 200 mg | Number of Participants With Grade 3 or 4 Hematology Abnormalities | Low lymphocyte count | 2 participants |
Secondary
Number of Participants With Sarcoma (Src) and Phosphorylated Src (pSRc) Protein Expression in Peripheral Blood Mononuclear Cells (PBMC)
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.
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
Population: All treated participants with adequate pharmacodynamic profiles. Participants could not be evaluated as the test was discontinued due to difficulty in appropriate measurements.
Secondary
Terminal Elimination Half-life (T-half) of Dasatinib
T-half of dasatinib was calculated using plasma concentration versus time data.
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
Population: All treated participants with adequate PK profiles (PK population). The 'n' signifies those participants who received study drug and were evaluated for this measure (each group respectively).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dasatinib 100 mg | Terminal Elimination Half-life (T-half) of Dasatinib | Day 14 (n = 5, 4, 2) | 5.75 hours | Standard Deviation 1.67 |
| Dasatinib 100 mg | Terminal Elimination Half-life (T-half) of Dasatinib | Day 1 (n = 9, 3, 4) | 4.77 hours | Standard Deviation 0.61 |
| Dasatinib 100 mg | Terminal Elimination Half-life (T-half) of Dasatinib | Day 28 (n= 3, 2, 2) | 4.36 hours | Standard Deviation 1.19 |
| Dasatinib 150 mg | Terminal Elimination Half-life (T-half) of Dasatinib | Day 14 (n = 5, 4, 2) | 5.04 hours | Standard Deviation 0.19 |
| Dasatinib 150 mg | Terminal Elimination Half-life (T-half) of Dasatinib | Day 1 (n = 9, 3, 4) | 4.68 hours | Standard Deviation 0.84 |
| Dasatinib 150 mg | Terminal Elimination Half-life (T-half) of Dasatinib | Day 28 (n= 3, 2, 2) | 8.33 hours | Standard Deviation 2.78 |
| Dasatinib 200 mg | Terminal Elimination Half-life (T-half) of Dasatinib | Day 1 (n = 9, 3, 4) | 7.62 hours | Standard Deviation 4.11 |
| Dasatinib 200 mg | Terminal Elimination Half-life (T-half) of Dasatinib | Day 28 (n= 3, 2, 2) | 7.66 hours | Standard Deviation 4.24 |
| Dasatinib 200 mg | Terminal Elimination Half-life (T-half) of Dasatinib | Day 14 (n = 5, 4, 2) | 7.95 hours | Standard Deviation 5.62 |
Secondary
Time to Reach Maximum Observed Plasma Concentration of Dasatinib (Tmax)
Tmax, time to reach maximum observed plasma concentration of dasatinib was obtained directly from the plasma concentration versus time data.
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
Population: All treated participants with adequate PK profiles (PK population). The 'n' signifies those participants who received study drug and were evaluated for this measure (each group respectively).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dasatinib 100 mg | Time to Reach Maximum Observed Plasma Concentration of Dasatinib (Tmax) | Day 14 (n = 5, 4, 2) | 1.0 hours |
| Dasatinib 100 mg | Time to Reach Maximum Observed Plasma Concentration of Dasatinib (Tmax) | Day 1 (n = 9, 3, 4) | 1.0 hours |
| Dasatinib 100 mg | Time to Reach Maximum Observed Plasma Concentration of Dasatinib (Tmax) | Day 28 (n= 3, 2, 2) | 0.5 hours |
| Dasatinib 150 mg | Time to Reach Maximum Observed Plasma Concentration of Dasatinib (Tmax) | Day 14 (n = 5, 4, 2) | 1.0 hours |
| Dasatinib 150 mg | Time to Reach Maximum Observed Plasma Concentration of Dasatinib (Tmax) | Day 1 (n = 9, 3, 4) | 1.0 hours |
| Dasatinib 150 mg | Time to Reach Maximum Observed Plasma Concentration of Dasatinib (Tmax) | Day 28 (n= 3, 2, 2) | 0.5 hours |
| Dasatinib 200 mg | Time to Reach Maximum Observed Plasma Concentration of Dasatinib (Tmax) | Day 1 (n = 9, 3, 4) | 1.3 hours |
| Dasatinib 200 mg | Time to Reach Maximum Observed Plasma Concentration of Dasatinib (Tmax) | Day 28 (n= 3, 2, 2) | 3.3 hours |
| Dasatinib 200 mg | Time to Reach Maximum Observed Plasma Concentration of Dasatinib (Tmax) | Day 14 (n = 5, 4, 2) | 2.3 hours |
Secondary
Tmax of the Metabolite BMS-582691
Tmax of the metabolite was obtained using plasma concentration versus time data 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
Population: All treated participants with adequate PK profiles (PK population). The 'n' signifies those participants who received study drug and were evaluated for this measure (each group respectively).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dasatinib 100 mg | Tmax of the Metabolite BMS-582691 | Day 14 (n = 5, 4, 2) | 1.0 hours |
| Dasatinib 100 mg | Tmax of the Metabolite BMS-582691 | Day 1 (n = 8, 3, 3) | 1.5 hours |
| Dasatinib 100 mg | Tmax of the Metabolite BMS-582691 | Day 28 (n= 3, 1, 2) | 1.5 hours |
| Dasatinib 150 mg | Tmax of the Metabolite BMS-582691 | Day 14 (n = 5, 4, 2) | 1.8 hours |
| Dasatinib 150 mg | Tmax of the Metabolite BMS-582691 | Day 1 (n = 8, 3, 3) | 1.5 hours |
| Dasatinib 150 mg | Tmax of the Metabolite BMS-582691 | Day 28 (n= 3, 1, 2) | 1.0 hours |
| Dasatinib 200 mg | Tmax of the Metabolite BMS-582691 | Day 1 (n = 8, 3, 3) | 2.0 hours |
| Dasatinib 200 mg | Tmax of the Metabolite BMS-582691 | Day 28 (n= 3, 1, 2) | 1.8 hours |
| Dasatinib 200 mg | Tmax of the Metabolite BMS-582691 | Day 14 (n = 5, 4, 2) | 3.0 hours |