Study of Dasatinib (BMS-354825) in Patients With Solid Tumors

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I Study of BMS-354825 in Patients With Solid Tumors

Conditions
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Tumors

Intervention / Treatment
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* Drug: Dasatinib
* Drug: Dasatinib
* Drug: Dasatinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dasatinib (100 mg)<br> | Drug: Dasatinib<br>* tablets, Oral, 100 mg, once daily for 4 weeks<br>* Other names: BMS-354825;|
| Experimental: Dasatinib (150 mg)<br> | Drug: Dasatinib<br>* tablets, Oral, 150 mg, once daily, 4 weeks<br>* Other names: BMS-354825;|
| Experimental: Dasatinib (200 mg)<br> | Drug: Dasatinib<br>* tablets, Oral, 200 mg, once daily for 4 weeks<br>* Other names: BMS-354825;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From start of the treatment i.e.Day 1 to end of Cycle 1 i.e. Day 30 (4 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From start of study drug therapy up to 30 days after the last dose. | 
| 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. | From start of study drug therapy up to 30 days after the last dose. | 
| 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. | From start of study drug therapy up to 30 days after the last dose. | 
| 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. | From start of study drug therapy up to 30 days after the last dose. | 
| 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. | From start of study drug therapy up to 30 days after the last dose. | 
| 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. | From screening, Day 1 in each treatment course and at the end of study | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | Baseline, Day 1, Day 14 and Day 28 | 
| Maximum Plasma Concentration (Cmax) of Dasatinib | Cmax was obtained from the plasma concentration versus time data after oral administration 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 [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. | 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[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. | 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 | 
| 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. | 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 | 
| Terminal Elimination Half-life (T-half) of Dasatinib | T-half of dasatinib was calculated using plasma concentration versus time data. | 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 | 
| 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. | 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 | 
| Mean Apparent Oral Clearance (CLo) of Dasatinib | Apparent oral clearance was obtained from the plasma concentration versus time data. | 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 | 
| Mean Apparent Volume of Distribution (Vz/F) of Dasatinib | Apparent volume of distribution after oral dosing was obtained from plasma concentration versus time data. | 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 | 
| Cmax of Metabolite BMS-582691 | Maximum plasma concentration was obtained from plasma concentration versus time data 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) 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). | 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 BMS-582691 | Tmax of the metabolite was obtained using plasma concentration versus time data 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 | 
| 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). | 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. | 
| 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. | 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 | 
| 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). | Serum samples were assessed at baseline (Day -1) and on Days 14 and 28 | 
| 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. | Serum samples were assessed on baseline (Day -1), and pre-dose on Days 14, 28 | 
| 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. | Plasma samples were collected on baseline (Day -1), 0 hour (pre-dose), 1 and 4 hours (post-dose) on Days 1, 14 and 28 | 
| 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. | Within 4 weeks of first study drug administration, thereafter recorded every 4 or 8 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid tumors (including relapsed disease) that are refractory to standard therapies or for which no effective standard therapy exists