Phase I Study of Dasatinib (BMS-354825) and Capecitabine for Women With Advanced Breast Cancer

Safety was assessed from first dose of study drug through at least 30 days after the last dose, until resolution of drug-related toxicity or when toxicity was deemed irreversible, whichever was longer. An adverse event (AE) was considered a dose limiting toxicity (DLT) if it occurred in the first 21 days and was at least possibly related to study drugs and were: Clinically-evident toxicity of Grade \>= 3, or of Grade 2 which required interruption of treatment for \>= 7 days (consecutive or non-consecutive); non-hematologic abnormal laboratory value of Grade \>= 3, or hematologic toxicity of Grade 4, which persisted 7 days; any grade toxicity which in the judgment of the investigator required a dose reduction or removal from further study therapy.

Time frame: Day 1 to 30 days post last dose

Population: Safety Population: All participants who received at least one dose of study drug. DLTs: Grade 3 headache, Grade 3 pneumonia, Grade 3 diarrhea in Dosing arms, 1, 2, and 3, respectively. DLTs in dose arm 4: 1 participant with Grade 3 pneumonia and pain and 1 participant with Grade 4 neutropenia and diarrhea plus Grade 3 vomiting and mucositis.

CTC, Version 3 used to assess parameters. (ULN)=upper limit of normal: (ALT)= alanine transaminase; (AST)=aspartate aminotransferase; (ALP)=alkaline phosphatase. ALT Grade (Gr)1:\>ULN to 2.5\*ULN; Gr 2: \>2.5 to 5.0\*ULN; Gr 3: \>5.0 to 20.0\*ULN; Gr 4: \>20.0\*ULN. AST Gr 1: \>ULN to 2.5\*ULN; Gr 2: \>2.5 to 5.0\*ULN; Gr 3: \>5.0 to 20.0\*ULN; Gr 4: \>20.0\*ULN. Total bilirubin Gr 1: \>ULN to 1.5\*ULN; Gr 2: \>1.5 to 3.0\*ULN; Gr 3: \>3.0 to 10.0\*ULN; Gr 4: \>10.0\*ULN. ALP (U/L) Gr1:\>ULN to 2.5\*ULN, Gr2:\>2.5 to 5.0\*ULN, Gr3:\>5.0 to 20.0\*ULN, Gr4:\>20.0\*ULN. Albumin (low) Gr 1:\<LLN - 3 grams per deciliter (g/dL)to \<LLN - 3 g/dL; Gr 2: \<3 - 2 g/dL to \< 3.0 - 2.0 g/dL; Gr 3: \< 2 g/dL to \<2 g/L. Participants with a baseline chemistry lab value of Gr 0 but who had Gr 3 - 4 chemistry value while on-study are presented below.

Time frame: Day 1 to 30 days post last dose

Population: Safety Population: All participants with at least 1 dose of study drug. N=number of participants with Grade 0 values at baseline in each dosing arm, respectively.

National Cancer Institute Common terminology criteria (CTC), Version 3 used to assess parameters. Lower limit of normal (LLN). CTC criteria: Absolute neutrophil count (ANC). Leukocytes (White blood cells) Grade (Gr) 1:\<LLN to 3.0\*10\^9/L, Gr 2:\<3.0 to 2.0\*10\^9/L, Gr 3:\<2.0 to 1.0\*10\^9/L, Gr 4:\<1.0\*10\^9/L. ANC Gr 1:\<LLN to 1.5\*10\^9/L, Gr 2:\<1.5 to 1.0\*10\^9/L, Gr 3:\<1.0 to 0.5\*10\^9/L, Gr 4:\<0.5\*10\^9/L. Platelet count Gr 1:LLN to 75.0\*10\^9/L, Gr 2:\<75.0 to 50.0\*10\^9/L, Gr 3:\<50.0 to 25.0\*10\^9/L, Gr 4:\<25.0 to 10\^9/L. Hemoglobin Gr 1:\<LLN to 10.0 g/dL, Gr 2:\<10.0 to 8.0 g/dL, Gr 3:\<8.0 to 6.5 g/dL, Gr 4:\<6.5 g/dL. Participants with a baseline hematology lab value of Gr 0 but who had Gr 3 - 4 hematology value while on-study are presented below.

Time frame: Day 1 up to 30 days post last dose

Population: Safety Population: All participants with at least 1 dose of study drug. N=number of participants with Grade 0 values at baseline in each dosing arm, respectively.

Adverse events (AEs) were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Serious AE (SAE)=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death.

Time frame: Day 1 up to 30 days post last dose

Population: Safety Population: all participants receiving at least one dose of study drug.

Complete Response (CR): disappearance of all target and non-target lesions, with confirmation at \>=4 weeks interval; Partial Response (PR): \>= 30% decrease in sum of longest diameter (LDs) of target lesions, taking as reference the baseline sum LD, with confirmation at \>= 4 weeks interval. Progressive Disease (PD): Appearance of new lesion(s), or \>=20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since treatment start, or unequivocal progression of existing non-target lesions. Stable disease was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, without unequivocal progression of non-target lesions, after \>=6 weeks on study. Radiological tumor assessment by computed tomography (CT) or magnetic resonance imaging (MRI) occurred every 6 weeks. For those patients who were on treatment \> 24 weeks, the tumor assessment occurred every 9 weeks.

Time frame: Day 1 to 30 days post last dose

Population: All participants with at least one measurable lesion at baseline, who received at least one dose of the combination therapy and have at least one on-study tumor assessment or stopped study treatment prior to first assessment, were evaluated. Those who stopped drug prior to tumor assessment for reasons unrelated to disease or drug were excluded.

Objective response rate was the percentage of participants, (n/N; number with objective response per Number evaluated) whose best response is either a Complete Response (CR) or a Partial Response (PR). Disease control rate was defined as percentage (n/N) of participants with stable disease greater than (\>) 6 months, PR, or CR. Efficacy Evaluable Population: All participants with at least one measurable lesion at baseline, who received at least one dose of combination study drug and have at least one on-study tumor assessment or stopped study treatment prior to first assessment, were evaluated. Those who stop treatment prior to tumor assessment for reasons unrelated to disease or drug were excluded.

Time frame: Day 1 up to 30 days post last dose

Population: n=number of participants with ORR: 2, 1, 0, 6 in dosing arms 1, 2, 3, and 4, respectively. n= number of participants with Disease control: 3, 2, 2, 14 in dosing arms 1, 2, 3, and 4, respectively.