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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

Primary Purpose

Locally Advanced or Metastatic Breast Cancer

Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Ixabepilone, 32 mg/m^2 + Lapatinib, 1000 mg
Ixabepilone, 32 mg/m^2 + Lapatinib, 1250 mg
Ixabepilone, 40 mg/m^2 + Lapatinib, 1250 mg
Ixabepilone + Lapatinib + Capecitabine
Sponsored by
R-Pharm
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Locally Advanced or Metastatic Breast Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

  • The Cancer Institute Of New Jersey
  • Local Institution
  • Local Institution

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Ixabepilone, 32 mg/m^2 + Lapatinib, 1000 mg

Ixabepilone, 32 mg/m^2 + Lapatinib, 1250 mg

Ixabepilone, 40 mg/m^2 + Lapatinib, 1250 mg

Ixabepilone + Lapatinib + Capecitabine

Arm Description

Dose Level 1

Dose Level 2

Dose Level 3

Triplet Combination

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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.
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.
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.
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
Maximum Concentration of Ixabepilone
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
Terminal Half-life of Ixabepilone
Time to Peak Concentration of Ixabepilone
Volume of Distribution at Steady State of Ixabepilone
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.
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.

Full Information

First Posted
March 5, 2008
Last Updated
February 9, 2016
Sponsor
R-Pharm
Collaborators
GlaxoSmithKline
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1. Study Identification

Unique Protocol Identification Number
NCT00634088
Brief Title
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
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
February 2016
Overall Recruitment Status
Terminated
Why Stopped
Slow Accrual
Study Start Date
June 2008 (undefined)
Primary Completion Date
June 2010 (Actual)
Study Completion Date
June 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
R-Pharm
Collaborators
GlaxoSmithKline

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Locally Advanced or Metastatic Breast Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
13 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ixabepilone, 32 mg/m^2 + Lapatinib, 1000 mg
Arm Type
Experimental
Arm Description
Dose Level 1
Arm Title
Ixabepilone, 32 mg/m^2 + Lapatinib, 1250 mg
Arm Type
Experimental
Arm Description
Dose Level 2
Arm Title
Ixabepilone, 40 mg/m^2 + Lapatinib, 1250 mg
Arm Type
Experimental
Arm Description
Dose Level 3
Arm Title
Ixabepilone + Lapatinib + Capecitabine
Arm Type
Experimental
Arm Description
Triplet Combination
Intervention Type
Drug
Intervention Name(s)
Ixabepilone, 32 mg/m^2 + Lapatinib, 1000 mg
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Ixabepilone, 32 mg/m^2 + Lapatinib, 1250 mg
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Ixabepilone, 40 mg/m^2 + Lapatinib, 1250 mg
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Ixabepilone + Lapatinib + Capecitabine
Intervention Description
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.
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) of Ixabepilone When Administered With Lapatinib
Description
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
Title
MTD and RP2D of Ixabepilone When Administered With Lapatinib Plus Capecitabine
Description
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
Secondary Outcome Measure Information:
Title
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)
Description
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
Title
Number of Participants With DLT
Description
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
Title
Number of Participants With Abnormalities in Hematology Laboratory Results by Worst CTC Grade
Description
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)
Title
Number of Participants With Abnormalities in Serum Chemistry Laboratory Results by Worst CTC Grade
Description
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
Title
Maximum Concentration of Ixabepilone
Time Frame
Day 1 of 21-day cycle
Title
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
Time Frame
Day 1 of 21-day cycle
Title
Terminal Half-life of Ixabepilone
Time Frame
Day 1 of 21-day cycle
Title
Time to Peak Concentration of Ixabepilone
Time Frame
Day 1 of 21-day cycle
Title
Volume of Distribution at Steady State of Ixabepilone
Time Frame
Day 1 of 21-day cycle
Title
Overall Tumor Response By Number of Participants
Description
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)
Title
Duration of Response of Combination Treatment With Ixabepilone Plus Lapatinib
Description
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)

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bristol-Myers Squibb
Organizational Affiliation
Bristol-Myers Squibb
Official's Role
Study Director
Facility Information:
Facility Name
The Cancer Institute Of New Jersey
City
New Brunswick
State/Province
New Jersey
ZIP/Postal Code
08901
Country
United States
Facility Name
Local Institution
City
Brisbane
State/Province
Queensland
ZIP/Postal Code
4101
Country
Australia
Facility Name
Local Institution
City
Modena
ZIP/Postal Code
41100
Country
Italy

12. IPD Sharing Statement

Learn more about this trial

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

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