Phase I Study of Ixabepilone Plus Lapatinib With or Without Capecitabine in the Treatment of Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer

The MTD is defined as the maximum dose that can be administered to 6 participants such that no more than 1 (or fewer than one third if more than 6 participants receive treatment) experiences a dose-limiting toxicity (DLT), with at least 2 experiencing a DLT at the next higher dose level. The RP2D is based on the MTD and the assessment of any relevant chronic toxicities.

Time frame: Days 1 through 21

Population: Because the study was terminated due to insufficient enrollment, MTD was not achieved.

MTD is defined as the maximum dose that can be administered to 6 participants such that no more than 1 (or fewer than one third if more than 6 participants receive treatment) experiences a DLT, with at least 2 experiencing a DLT at the next higher dose level. The RP2D is based on the MTD and the assessment of any relevant chronic toxicities.

Time frame: Days 1 through 21

Population: Because the study was terminated due to insufficient enrollment, no participants received the triplet combination.

Time frame: Day 1 of 21-day cycle

Population: Participants who received ixabepilone with lapatinib treatment and had pharmacokinetic parameters available.

Duration of response is measured from the time in months that measurement criteria are first met for PR or CR, whichever is recorded first, until the date of documented PD or death. Participants who neither relapse nor die will be censored on the date of their last tumor assessment.

Time frame: First occurrence of PR or CR to PD or Death (no average, as no data available)

Population: Because the study was terminated due to insufficient enrollment, the duration of response could not be analyzed.

Time frame: Day 1 of 21-day cycle

Population: Participants who received ixabepilone with lapatinib treatment and had pharmacokinetic parameters available.

CTC, Version 3.0 used to assess parameters. ULN=upper level of normal among all laboratory ranges. WBC (c/L): 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 (c/uL): 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 (c/uL): 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\*10\^9/L; Hemoglobin (g/dL): 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.

Time frame: Baseline and weekly from Days 1 to 21 (Cycle 1)

Population: All participants who received at least 1 dose of ixabepilone and either lapatinib or capecitabine.

CTC, Version 3.0 used to assess parameters. ULN=upper level of normal among all laboratory ranges. ALT(U/L) Gr 1:\>ULN-2.5\*ULN,Gr 2:\>2.5-5.0\*ULN,Gr 3:\>5.0-20.0\*ULN,Gr 4:\>20.0\* ULN; AST(U/L) Gr 1:\>ULN-2.5\* ULN,Gr 2:\>2.5-5.0\*ULN,Gr 3:\>5.0-20.0\*ULN,Gr 4:\>20.0\* ULN; ALP(U/L)Gr 1:\>ULN-2.5\*ULN, Gr 2:\>2.5-5.0\*ULN, Gr 3:\>5.0-20.0\*ULN, Gr 4:\>20.0\*ULN; Creatinine (mg/dL): Gr 1:\>ULN-1.5\*ULN, Gr 2:\>1.5-3.0\*ULN, Gr 3:\>3.0-6.0\*ULN, Gr 4:\>6.0\*ULN; Total bilirubin (mg/dL): Gr 1:\>ULN-1.5\*ULN, Gr 2:\>1.5-3.0\*ULN, Gr 3:\>3.0-10.0\*ULN, Gr 4:\>10.0\*ULN

Time frame: At baseline and within 72 hours of Day 1 of 21-day cycle

Population: All participants who received at least 1 dose of ixabepilone and either lapatinib or capecitabine.

AE=Any new untoward medical event or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. SAE=any untoward medical event that results in death, persistent or significant disability/incapacity, drug dependency or abuse; is life-threatening, important, a congenital anomaly/birth defect; or requires or prolongs existing hospitalization. Treatment related=possibly, probably, or certainly related to and of unknown relationship to study treatment. Common Terminology Criteria (CTC) Grade 3=severe; Grade 4=life-threatening or disabling.

Time frame: Baseline to Day 21, continuously

Population: All participants who received at least 1 dose of ixabepilone and either lapatinib or capecitabine.

DLT=Any of the following events, attributable to study drug and occurring within 21 days after ixabepilone administration: Grade 3 or 4 nausea, vomiting, or diarrhea despite the use of adequate medical intervention; other Grade 3 or greater nonhematologic toxicity requiring removal from study drug; recovery from study drug-related toxicity that delayed scheduled retreatment for longer than 3 weeks; Grade 4 neutropenia for 5 or more consecutive days or Grade 3 or 4 neutropenia of any duration with sepsis or fever; thrombocytopenia or bleeding requiring platelet transfusion.

Time frame: Baseline to Day 21, continuously

Population: All participants who received at least 1 dose of ixabepilone and either lapatinib or capecitabine.

Target lesion criteria: Complete Response(CR)=Disappearance of all clinical and radiologic evidence of target lesions; Partial Response (PR)=A 30% or greater decrease in the sum of longest diameter(LD) of all lesions in reference to the baseline sum LD. Stable Disease (SD)=Insufficient increase to qualify for Progressive Disease (PD) and insufficient shrinkage to qualify for PR; PD=A 20% or greater increase in the sum of LD of all target lesions, taking as reference the smallest sum LD recorded at or following baseline.

Time frame: Baseline and Day 21 (21-day cycle)

Population: All participants with measurable disease at baseline per RECIST guidelines, with the exception of those with an incorrect diagnosis.

Time frame: Day 1 of 21-day cycle

Population: Participants who received ixabepilone with lapatinib treatment and had pharmacokinetic parameters available.

Time frame: Day 1 of 21-day cycle

Population: Participants who received ixabepilone with lapatinib treatment and had pharmacokinetic parameters available.

Time frame: Day 1 of 21-day cycle

Population: Participants who received ixabepilone with lapatinib treatment and had pharmacokinetic parameters available.