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

Phase 1

Terminated

Conditions: Locally Advanced or Metastatic Breast Cancer

Interventions: Drug: Ixabepilone, 32 mg/m^2 + Lapatinib, 1000 mg
Drug: Ixabepilone, 32 mg/m^2 + Lapatinib, 1250 mg
Drug: Ixabepilone, 40 mg/m^2 + Lapatinib, 1250 mg
Drug: Ixabepilone + Lapatinib + Capecitabine

Registration Number: NCT00634088

Lead Sponsor: R-Pharm

Brief Summary: The purpose of this study is to determine the safety and preliminary effectiveness of ixabepilone plus lapatinib with and without capecitabine in the treatment of human epidermal growth factor receptor 2 (HER2)-positive or metastatic breast cancer.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: Female

Target Recruitment: 13

Inclusion Criteria

Females aged 18 years or older with histologic or cytologic diagnosis of adenocarcinoma originating in the breast
Radiologic or pathologic evidence that the cancer is metastatic or locally advanced (a T4 tumor and stage IIIB/IIIC disease) and not curable by local measures, such as radiation or surgery
Positive status for human epidermal growth factor receptor 2
Measurable disease as per Response Evaluation Criteria In Solid Tumors guidelines
Karnofsky performance status of 70 to 100
Life expectancy of at least 3 months

Exclusion Criteria

Prior radiation must not have included 30% or more of major bone-marrow containing areas, such as the pelvis and lumbar spine
Common Terminology Criteria Grade 2 or greater neuropathy
Inadequate hematologic, hepatic, or renal function
Known prior severe hypersensitivity reactions to agents containing Cremophor® EL or known hypersensitivity or prior intolerance to fluoropyrimidine
Known or suspected dihydropyrimidine dehydrogenase deficiency
More than 3 prior chemotherapy regimens in the metastatic setting
Prior treatment with an epothilone or lapatinib; prior treatment with capecitabine within the past 6 months

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ixabepilone, 32 mg/m^2 + Lapatinib, 1000 mg	Ixabepilone, 32 mg/m^2 + Lapatinib, 1000 mg	Dose Level 1
Ixabepilone, 32 mg/m^2 + Lapatinib, 1250 mg	Ixabepilone, 32 mg/m^2 + Lapatinib, 1250 mg	Dose Level 2
Ixabepilone, 40 mg/m^2 + Lapatinib, 1250 mg	Ixabepilone, 40 mg/m^2 + Lapatinib, 1250 mg	Dose Level 3
Ixabepilone + Lapatinib + Capecitabine	Ixabepilone + Lapatinib + Capecitabine	Triplet Combination

Primary Outcome Measures

Name	Time	Method
MTD and RP2D of Ixabepilone When Administered With Lapatinib Plus Capecitabine	Days 1 through 21	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.
Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) of Ixabepilone When Administered With Lapatinib	Days 1 through 21	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Abnormalities in Hematology Laboratory Results by Worst CTC Grade	Baseline and weekly from Days 1 to 21 (Cycle 1)	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.
Maximum Concentration of Ixabepilone	Day 1 of 21-day cycle
Volume of Distribution at Steady State of Ixabepilone	Day 1 of 21-day cycle
Duration of Response of Combination Treatment With Ixabepilone Plus Lapatinib	First occurrence of PR or CR to PD or Death (no average, as no data 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.
Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, Treatment-related AEs, Treatment-related AEs (Grade 3 or 4), Peripheral Neuropathy (PN), PN (Grade 3 or 4)	Baseline to Day 21, continuously	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.
Number of Participants With DLT	Baseline to Day 21, continuously	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.
Number of Participants With Abnormalities in Serum Chemistry Laboratory Results by Worst CTC Grade	At baseline and within 72 hours of Day 1 of 21-day cycle	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 to Peak Concentration of Ixabepilone	Day 1 of 21-day cycle
Area Under the Concentration-time Curve From 0 to Infinity (AUC[INF]) and AUC From 0 to Last Quantifiable Concentration (AUC[O-T] of Ixabepilone	Day 1 of 21-day cycle
Terminal Half-life of Ixabepilone	Day 1 of 21-day cycle
Overall Tumor Response By Number of Participants	Baseline and Day 21 (21-day cycle)	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.