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

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

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.

Study Overview

• Status: Terminated
• Conditions: Locally Advanced or Metastatic Breast Cancer
• Intervention / Treatment: 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

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • Brisbane, Queensland, Australia, 4101
      • Local Institution
• Italy
  • Modena, Italy, 41100
    • Local Institution
• United States
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • The Cancer Institute of New Jersey

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ixabepilone, 32 mg/m^2 + Lapatinib, 1000 mg; Dose Level 1	Drug: Ixabepilone, 32 mg/m^2 + Lapatinib, 1000 mg; 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.
Experimental: Ixabepilone, 32 mg/m^2 + Lapatinib, 1250 mg; Dose Level 2	Drug: Ixabepilone, 32 mg/m^2 + Lapatinib, 1250 mg; 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.
Experimental: Ixabepilone, 40 mg/m^2 + Lapatinib, 1250 mg; Dose Level 3	Drug: Ixabepilone, 40 mg/m^2 + Lapatinib, 1250 mg; 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.
Experimental: Ixabepilone + Lapatinib + Capecitabine; Triplet Combination	Drug: Ixabepilone + Lapatinib + Capecitabine; 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.

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: R-Pharm
• Collaborators: GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): June 1, 2010
• Study Completion (Actual): June 1, 2010

Study Registration Dates

• First Submitted: March 5, 2008
• First Submitted That Met QC Criteria: March 11, 2008
• First Posted (Estimate): March 12, 2008

Study Record Updates

• Last Update Posted (Estimate): March 10, 2016
• Last Update Submitted That Met QC Criteria: February 9, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protein Kinase Inhibitors; Capecitabine; Lapatinib; Epothilones
• Other Study ID Numbers: CA163-144; EURDRACT: 2007-004123-38