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

Study Overview
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Brief Summary
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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.

Official Title
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Parallel Phase I Study of Ixabepilone Plus Lapatinib and Ixabepilone Plus Lapatinib Plus Capecitabine in Subjects With HER2 Positive Locally Advanced or Metastatic Breast Cancer

Conditions
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Locally Advanced or Metastatic Breast Cancer

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Ixabepilone, 32 mg/m^2 + Lapatinib, 1000 mg<br>Dose Level 1 | Drug: Ixabepilone, 32 mg/m^2 + Lapatinib, 1000 mg<br>* Lapatinib, 1000 mg, administered orally, once a day, every day, for 7 to 14 consecutive days as a lead-in period prior to the first administration of ixabepilone (Day 1). Following the lapatinib lead-in phase of Cycle 1, and on Day 1 of subsequent cycles, ixabepilone, 32 mg/m^2, administered as a 3-hour IV infusion. Lapatinib, 1000 mg, administered orally, once a day, every day, for a 21-day cycle.<br>|
| Experimental: Ixabepilone, 32 mg/m^2 + Lapatinib, 1250 mg<br>Dose Level 2 | Drug: Ixabepilone, 32 mg/m^2 + Lapatinib, 1250 mg<br>* Initiated a minimum of 14 days following Day 1 of previous cohort (ixabepilone, 32 mg/m^2 + lapatinib, 1000 mg). Lapatinib, 1250 mg, administered orally once a day, every day, for 7 to 14 consecutive days as a lead-in period prior to the first administration of ixabepilone. Following the lapatinib lead-in phase of Cycle 1, and on Day 1 of subsequent cycles, ixabepilone, 32 mg/m^2, administered as a 3-hour IV infusion. Lapatinib administered, 1250 mg, orally, once a day, every day, for a 21-day cycle.<br>|
| Experimental: Ixabepilone, 40 mg/m^2 + Lapatinib, 1250 mg<br>Dose Level 3 | Drug: Ixabepilone, 40 mg/m^2 + Lapatinib, 1250 mg<br>* Initiated a minimum of 14 days following Day 1 of previous cohort (ixabepilone, 32 mg/m^2 + lapatinib, 1250 mg). Lapatinib, 1250 mg, administered orally once a day, every day, for 7 to 14 consecutive days as a lead-in period prior to the first administration of ixabepilone. Following the lapatinib lead-in phase of Cycle 1, and on Day 1 of subsequent cycles, ixabepilone, 40 mg/m^2, administered as a 3-hour IV infusion. Lapatinib, 1250 mg, administered orally, once a day, every day, for a 21-day cycle.<br>|
| Experimental: Ixabepilone + Lapatinib + Capecitabine<br>Triplet Combination | Drug: Ixabepilone + Lapatinib + Capecitabine<br>* Planned escalating doses of the triplet combination of ixabepilone, lapatinib, and capecitabine. No participants were enrolled in this arm due to premature termination of the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) of Ixabepilone When Administered With Lapatinib | 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. | Days 1 through 21 | 
| MTD and RP2D of Ixabepilone When Administered With Lapatinib Plus Capecitabine | 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. | Days 1 through 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 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. | Baseline to Day 21, continuously | 
| Number of Participants With DLT | 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. | Baseline to Day 21, continuously | 
| Number of Participants With Abnormalities in Hematology Laboratory Results by Worst CTC Grade | 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. | Baseline and weekly from Days 1 to 21 (Cycle 1) | 
| Number of Participants With Abnormalities in Serum Chemistry Laboratory Results by Worst CTC Grade | 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 | At baseline and within 72 hours of Day 1 of 21-day cycle | 
| Maximum 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 | 
| Time to Peak Concentration of Ixabepilone |  | Day 1 of 21-day cycle | 
| Volume of Distribution at Steady State of Ixabepilone |  | Day 1 of 21-day cycle | 
| Overall Tumor Response By Number of Participants | 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. | Baseline and Day 21 (21-day cycle) | 
| Duration of Response of Combination Treatment With Ixabepilone Plus Lapatinib | 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. | First occurrence of PR or CR to PD or Death (no average, as no data available) |