Trastuzumab, Ixabepilone, and Carboplatin in Treating Patients With HER2/Neu-Positive Metastatic Breast Cancer

This study has been completed.
Sponsor:
Collaborator:
North Central Cancer Treatment Group
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00077376
First received: February 10, 2004
Last updated: February 26, 2013
Last verified: February 2013
  Purpose

This phase II trial is studying how well giving trastuzumab together with ixabepilone and carboplatin works in treating patients with HER2/neu-positive metastatic breast cancer. Monoclonal antibodies, such as trastuzumab, can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as ixabepilone and carboplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining trastuzumab with ixabepilone and carboplatin may kill more tumor cells.


Condition Intervention Phase
Breast Cancer
Biological: trastuzumab
Drug: carboplatin
Drug: ixabepilone
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Trial Of Trastuzumab Plus Weekly Ixabepilone (BMS-247550) And Carboplatin In Patients With HER/Neu-Positive Metastatic Breast Cancer

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Objective Response for HER2+ Patients (Best Objective Response a Patient Has Ever Experienced on Study) [ Time Frame: Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years ] [ Designated as safety issue: No ]

    To assess objective response, it is necessary to estimate the overall tumor burden at baseline to which subsequent measurements will be compared. The same method of assessment and the same technique should be used to characterize each lesion at baseline and during follow-up.

    The best overall response based on RECIST is the best response recorded from registration until disease progression/recurrence, taking as reference for progressive disease the smallest measurements recorded since registration. The best response was determined based on the tumor responses in target and nontarget lesions, with or without new lesions. To be assigned a status of complete or partial response, changes in tumor measurements must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once after study entry at a minimum interval of 8 weeks.



Secondary Outcome Measures:
  • Objective Response for All Treated Patients (the Best Response a Patient Has Ever Experienced on Study) [ Time Frame: Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years ] [ Designated as safety issue: No ]

    To assess objective response, it is necessary to estimate the overall tumor burden at baseline to which subsequent measurements will be compared. The same method of assessment and the same technique should be used to characterize each lesion at baseline and during follow-up.

    The best overall response based on RECIST is the best response recorded from registration until disease progression/recurrence, taking as reference for progressive disease the smallest measurements recorded since registration. The best response was determined based on the tumor responses in target and nontarget lesions, with or without new lesions. To be assigned a status of complete or partial response, changes in tumor measurements must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once after study entry at a minimum interval of 8 weeks.


  • Time to Disease Progression for HER2+ Patients [ Time Frame: Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years ] [ Designated as safety issue: No ]
    This interval will be measured from the date of entry on the study to the appearance of new metastatic lesions or objective tumor progression based on RECIST. Patients progression-free at last follow-up were censored.

  • Time to Disease Progression for All Treated Patients [ Time Frame: Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years ] [ Designated as safety issue: No ]
    This interval will be measured from the date of entry on the study to the appearance of new metastatic lesions or objective tumor progression based on RECIST. Patients progression-free at last follow-up were censored.

  • Time to Treatment Failure for HER2+ Patients [ Time Frame: Assessed every cycle until treatment discontinuation ] [ Designated as safety issue: Yes ]
    Time from study entry to the date at which a patient was removed from treatment due to progression, toxicity, refusal or death. If a patient was considered to be a major treatment violation or was taken off study as a non-protocol failure, the patient would be censored on the date he/she was removed from treatment.

  • Time to Treatment Failure for All Treated Patients [ Time Frame: Assessed every cycle until treatment discontinuation ] [ Designated as safety issue: Yes ]
    Time from study entry to the date at which a patient was removed from treatment due to progression, toxicity, refusal or death. If a patient was considered to be a major treatment violation or was taken off study as a non-protocol failure, the patient would be censored on the date he/she was removed from treatment.

  • Kaplan-Meier Estimate of Overall Survival at 3 Years for HER2+ Patients [ Time Frame: Assessed every 3 months for 2 years, then every 6 months for 3 years ] [ Designated as safety issue: No ]
    Survival estimate from the Kaplan-Meier curve of the proportion of patients alive at 3 years.

  • Kaplan-Meier Estimate of Overall Survival at 3 Years for All Treated Patients [ Time Frame: Assessed every 3 months for 2 years, then every 6 months for 3 years ] [ Designated as safety issue: No ]
    Survival estimate from the Kaplan-Meier curve of the proportion of patients alive at 3 years.


Enrollment: 61
Study Start Date: March 2004
Study Completion Date: March 2011
Primary Completion Date: March 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ixabepilone/Carboplatin/Trastuzumab

During the induction phase, patients were treated with Ixabepilone 15mg/m2 intravenously (IV) followed by carboplatin (IV) on days 1, 8 and 15 of a 28-day cycle for a max of 6 cycles. Trastuzumab was administered weekly (4mg/kg loading dose then 2mg/kg IV) starting on day 1. Routine premedication included H1 blocker (diphenhydramine 50 mg orally (PO) or IV), H2 blocker (ranitidine 150 mg PO or 50 mg IV or another equivalent H2 blocker), and at least a 5-HT3 antagonist and dexamethasone.

After completion of 24 weekly trastuzumab doses (induction therapy), trastuzumab was given at a dose of 6 mg/kg IV every 3 weeks (maintenance therapy) beginning one week after the 24th weekly dose. Trastuzumab was repeated every 21 days until disease progression or prohibitive toxicity.

Biological: trastuzumab

Induction therapy:

Trastuzumab was given as an IV infusion over 90 minutes on day 1 using a 4 mg/kg loading dose. Subsequent doses were given IV at a dose of 2 mg/kg over 30 minutes for 23 consecutive weekly doses.

Maintenance therapy:

After completion of 24 weekly trastuzumab doses (Induction Therapy), trastuzumab was given at a dose of 6 mg/kg IV over 90 minutes every 3 weeks (Maintenance Therapy) beginning one week after the 24th weekly dose. Repeat trastuzumab every 21 days until disease progression or prohibitive toxicity.

Other Name: Herceptin
Drug: carboplatin

Induction therapy:

Carboplatin was given by IV over 1 hour at an area under the curve (AUC) dose of 2 on day 1, 8 and 15 of each cycle for a maximum of 6 cycles. It was administered after completion of the Ixabepilone (BMS-247550) infusion. Routine premedication included at least a 5-HT3 antagonist and dexamethasone.

Other Names:
  • Paraplatin
  • Paraplatin-AQ
Drug: ixabepilone
Induction therapy Ixabepilone (BMS-247550) was given 30 minutes after completion of the trastuzumab infusion on days 1, 8, and 15 of each cycle at a dose of 15 mg/m2 IV infusion over 1 hour every 4 weeks for a maximum of 6 cycles.
Other Name: BMS-247550

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the response rate in patients with HER2/neu-positive metastatic breast cancer treated with trastuzumab (Herceptin®), ixabepilone, and carboplatin.

SECONDARY OBJECTIVES:

I. Determine the time to disease progression and time to treatment failure in patients treated with this regimen.

II. Determine the toxicity of this regimen in these patients. III. Determine the overall survival of patients treated with this regimen.

OUTLINE: This is a multicenter study.

INDUCTION THERAPY: Patients receive trastuzumab (Herceptin®) IV over 30 minutes* on days 1, 8, 15, and 22 and ixabepilone IV over 1 hour and carboplatin IV over 1 hour on days 1, 8, and 15. Treatment repeats every 28 days for up to 6 courses in the absence of unacceptable toxicity.

NOTE: *Trastuzumab is given over 90 minutes on day 1 of course 1 (induction therapy) only.

MAINTENANCE THERAPY: Patients receive trastuzumab IV over 90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 2 years and then every 6 months for 3 years from study entry.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Histologically confirmed adenocarcinoma of the breast

    • Metastatic disease
  • HER2/neu-positive (3+) disease by immunohistochemistry or fluorescent in situ hybridization
  • At least 1 objectively measurable disease parameter

    • No brain metastases as the only site of measurable disease
    • Previously irradiated tumors are not considered measurable disease, except for recurrent disease located in an area of prior adjuvant irradiation (e.g., axilla or chest wall)
  • Age >= 18
  • ECOG performance status of 0-1
  • Granulocyte count ≥ 1,500/mm^3
  • Platelet count ≥ 100,000/mm^3
  • AST and ALT ≤ 1.5 times upper limit of normal (ULN) (2.0 times ULN for patients with liver involvement by tumor)
  • Creatinine ≤ 1.5 mg/dL
  • LVEF within lower limit of normal by MUGA or echocardiogram
  • Negative pregnancy test
  • Fertile patients must use effective nonhormonal contraception
  • At least 1 week since prior hormonal therapy
  • At least 2 weeks since prior radiotherapy

Exclusion criteria:

  • Untreated brain metastases

    • Previously treated brain metastases that have responded to prior radiotherapy and/or surgery are allowed
  • New York Heart Association class III or IV heart disease
  • Pregnant or nursing
  • Prior severe (grade 3 or 4) hypersensitivity reaction to drugs formulated in polyoxyethylated castor oil (Cremophor EL)
  • Peripheral neuropathy
  • Other malignancy within the past 5 years except curatively treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
  • Prior trastuzumab (Herceptin®) for metastatic disease
  • Concurrent pegfilgrastim
  • Prior ixabepilone for metastatic disease
  • Prior carboplatin or other chemotherapy for metastatic disease
  • Prior cumulative doxorubicin dose > 360 mg/m^2
  • Prior cumulative epirubicin dose > 640 mg/m^2
  • Concurrent hormonal therapy
  • Concurrent radiotherapy, including radiotherapy for brain metastases
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00077376

  Show 202 Study Locations
Sponsors and Collaborators
North Central Cancer Treatment Group
Investigators
Study Chair: Stacy L. Moulder, MD, MSCI M.D. Anderson Cancer Center
  More Information

Additional Information:
Publications:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00077376     History of Changes
Other Study ID Numbers: NCI-2012-02946, E2103, U10CA023318, CDR0000350220
Study First Received: February 10, 2004
Results First Received: March 4, 2011
Last Updated: February 26, 2013
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):
Trastuzumab
Ixabepilone
Carboplatin
HER2/Neu-Positive
Metastatic Breast Cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Trastuzumab
Carboplatin
Epothilones
Serotonin 5-HT3 Receptor Antagonists
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on April 15, 2014