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

This study has been terminated.
(Slow Accrual)
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00634088
First received: March 5, 2008
Last updated: October 11, 2011
Last verified: October 2011
  Purpose

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.


Condition Intervention Phase
Locally Advanced or Metastatic Breast Cancer
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
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) of Ixabepilone When Administered With Lapatinib [ Time Frame: Days 1 through 21 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Days 1 through 21 ] [ Designated as safety issue: Yes ]
    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) [ Time Frame: Baseline to Day 21, continuously ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline to Day 21, continuously ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and weekly from Days 1 to 21 (Cycle 1) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: At baseline and within 72 hours of Day 1 of 21-day cycle ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Day 1 of 21-day cycle ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Terminal Half-life of Ixabepilone [ Time Frame: Day 1 of 21-day cycle ] [ Designated as safety issue: No ]
  • Time to Peak Concentration of Ixabepilone [ Time Frame: Day 1 of 21-day cycle ] [ Designated as safety issue: No ]
  • Volume of Distribution at Steady State of Ixabepilone [ Time Frame: Day 1 of 21-day cycle ] [ Designated as safety issue: No ]
  • Overall Tumor Response By Number of Participants [ Time Frame: Baseline and Day 21 (21-day cycle) ] [ Designated as safety issue: No ]
    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 [ Time Frame: First occurrence of PR or CR to PD or Death (no average, as no data available) ] [ Designated as safety issue: No ]
    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.


Enrollment: 13
Study Start Date: June 2008
Study Completion Date: June 2010
Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00634088

Locations
United States, New Jersey
The Cancer Institute Of New Jersey
New Brunswick, New Jersey, United States, 08901
Australia, Queensland
Local Institution
Brisbane, Queensland, Australia, 4101
Italy
Local Institution
Modena, Italy, 41100
Sponsors and Collaborators
Bristol-Myers Squibb
GlaxoSmithKline
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided

Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00634088     History of Changes
Other Study ID Numbers: CA163-144, EURDRACT: 2007-004123-38
Study First Received: March 5, 2008
Results First Received: April 1, 2011
Last Updated: October 11, 2011
Health Authority: United States: Food and Drug Administration
Australia: Department of Health and Ageing Therapeutic Goods Administration
Italy: Ethics Committee

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Capecitabine
Fluorouracil
Lapatinib
Epothilones
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Protein Kinase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 21, 2014