Effects of Granulocyte Colony-Stimulating Factor (G-CSF), Trastuzumab, and Vinorelbine on Immune Cell Function - Full Text View

Sponsors and Collaborators:	Dartmouth-Hitchcock Medical Center Amgen
Information provided by:	Dartmouth-Hitchcock Medical Center
ClinicalTrials.gov Identifier:	NCT00169104

Purpose

Trastuzumab or Herceptin is an antibody directed against Her-2. Her-2 is a growth factor receptor which is present on the tumors of 25% of patients with breast cancer. The addition of trastuzumab to chemotherapy has been shown in a randomized clinical trial to increase the response rate to chemotherapy, the duration of response to chemotherapy, and to improve the duration of survival of patients with metastatic breast cancer. The anticancer mechanism of action of trastuzumab is unknown, but it is possible that trastuzumab acts by promoting antibody-dependent cell mediated cytotoxicity (ADCC), or direct killing of cancer cells by immune cells, triggered by antibodies bound to the surface of the cancer cell. G-CSF is a drug which is a growth factor for certain types of immune cells. G-CSF has two favorable effects on ADCC. G-CSF increases the pool of circulating cancer-killing immune cells, and G-CSF increases the strength of binding of cancer-killing immune cells to a specific part of the antibody. Therefore, priming with G-CSF significantly increases the efficiency of ADCC, and four days of treatment with G-CSF has been shown to optimize ADCC in some studies. Recent data from the investigators' laboratory indicates that chemotherapy can augment ADCC directed against tumor cells.

The investigators' hypothesis is that pre-treatment with the drug G-CSF would increase the effectiveness of chemotherapy given with trastuzumab.

Condition	Intervention	Phase
Metastatic Breast Cancer	Drug: G-CSF Drug: trastuzumab Drug: vinorelbine Drug: saline	Phase II Phase III

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer

Drug Information available for: Filgrastim Vinorelbine Vinorelbine tartrate Sargramostim Granulocyte-macrophage colony-stimulating factor Granulocyte colony-stimulating factor Immunoglobulins Globulin, Immune Sodium chloride Trastuzumab

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Investigator), Placebo Control, Parallel Assignment, Efficacy Study
Official Title:	A Phase II Trial of Trastuzumab, Neupogen, and Vinorelbine Investigating the Effects on Immune Function and Clinical Outcomes in Patients With Metastatic Breast Cancer Overexpressing Her-2/Neu

Further study details as provided by Dartmouth-Hitchcock Medical Center:

Primary Outcome Measures:

To compare antibody dependent cell-mediated cytotoxicity of effector cells isolated from subjects receiving trastuzumab with either G-CSF or a saline placebo against a Her-2 overexpressing target in vitro [ Time Frame: Two weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

To measure antibody dependent cell-mediated cytotoxicity of effector cells isolated from subjects receiving chemotherapy, trastuzumab, and G-CSF against a Her-2 overexpressing target in vitro [ Time Frame: 14 weeks ] [ Designated as safety issue: No ]
To evaluate the clinical response rate of the combination of trastuzumab, G-CSF, and vinorelbine in subjects with Her-2 overexpressing metastatic breast cancer [ Time Frame: 14 weeks ] [ Designated as safety issue: No ]
To evaluate the safety of the combination of trastuzumab, G-CSF, and vinorelbine in subjects with Her-2 overexpressing metastatic breast cancer [ Time Frame: 14 weeks ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	25
Study Start Date:	July 2002
Estimated Study Completion Date:	June 2009
Estimated Primary Completion Date:	June 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Active Comparator Subjects will receive ten doses of G-CSF at a dose of 5 mcgm/kg daily Monday through Friday for the first two weeks of the trial. All patients will also receive trastuzumab weekly during the first two weeks of the trial. All patients will then receive 12 weeks of trastuzumab, vinorelbine, and G-CSF.	Drug: G-CSF 5 mcgm/kg daily Monday through Friday weeks 3-14 Drug: trastuzumab 4 mcgm/kg intravenously (IV) over 90 minutes week 1, then 2 mg/kg IV over 30 minutes weeks 2-14 Drug: vinorelbine 25 mg/m2 over 6 minutes IV weekly, weeks 3, 4, 6, 7, 9, 10, 12, 13 Drug: G-CSF 5 mcgm/kg SQ daily for ten days, Monday through Friday of the first two weeks of the study
2: Placebo Comparator Subjects will receive ten doses of a placebo injection SQ daily Monday through Friday for the first two weeks of the trial. All patients will also receive trastuzumab weekly during the first two weeks of the trial. All patients will then receive 12 weeks of trastuzumab, vinorelbine, and G-CSF.	Drug: G-CSF 5 mcgm/kg daily Monday through Friday weeks 3-14 Drug: trastuzumab 4 mcgm/kg intravenously (IV) over 90 minutes week 1, then 2 mg/kg IV over 30 minutes weeks 2-14 Drug: vinorelbine 25 mg/m2 over 6 minutes IV weekly, weeks 3, 4, 6, 7, 9, 10, 12, 13 Drug: saline Saline will be given SQ daily for ten days, Monday through Friday of the first two weeks of the study

Detailed Description:

This is a randomized phase II study comparing trastuzumab with G-CSF against trastuzumab with placebo during the first two weeks of therapy.

Twenty five patients with metastatic breast cancer will be randomized to receive weekly trastuzumab plus either G-CSF or placebo by subcutaneous (SQ) injection daily for five days weekly for two weeks. Subsequently, all patients will receive an additional 12 weeks of weekly trastuzumab, G-CSF by SQ injection daily for five days weekly for 12 weeks, and vinorelbine once weekly at a dose of 25 mg/m2 weeks 3, 4, 6, 7, 9, 10, 12, 13. Baseline evaluation will include a history and physical exam, comprehensive metabolic panel (CMP), complete blood count (CBC), serum pregnancy test, computerized tomography (CT) scan for disease measurements, and a Multiple Uptake Gated Acquisition (MUGA) scan. The CT scan and MUGA will be repeated upon completion of the study treatment. Blood will be drawn pre-trastuzumab, 2 hours post-trastuzumab, and 48 hours post-trastuzumab on weeks 1, 2, 3, 4, and 12 to measure whole blood ADCC activity. Two additional assays for whole blood ADCC activity will be drawn at baseline pre-treatment, and following completion of protocol treatment. These assays will measure chromium release from a Her-2 positive target cell exposed to the patient's effector cells. Measurement of soluble Her-2 in patient serum will also be measured at each ADCC time point.

Eligibility

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

Criteria

Inclusion Criteria:

All patients must have pathological confirmation of carcinoma of the breast.
Patients must have metastatic breast cancer by documented clinical or radiological assessment.
Immunohistochemical analysis of HER-2/neu expression on paraffin-embedded specimens will be performed. HER-2/neu overexpression will be qualitatively scored as 0, 1+, 2+, or 3+, with 3+ indicating the strongest positivity. Fluorescence In Situ Hybridization (FISH) analyses will also be performed on these patients. Patients with 2+ to 3+ overexpression of HER-2/neu (membranous staining) are eligible, regardless of the results of the FISH analysis.
Age ≥18 years.
Karnofsky performance status ≥ 60%.
Adequate hepatic, renal, and hematologic function.
Prior treatment with trastuzumab will be allowed.
All patients must have adequate cardiac function (defined as left ventricular ejection fraction ≥ 45%) documented by echocardiogram or MUGA scan.
Premenopausal women will be required to have a negative urine or serum pregnancy test and to use an effective form of contraception.
Patients with a history of brain metastases are permitted as long as it has been at least 30 days since definitive treatment, they are clinically stable and a magnetic resonance imaging scan of the brain demonstrates control of the lesion(s).
All patients must give written informed consent indicating they are aware of the investigational nature of this treatment, as well as the risks and benefits of this protocol.

Exclusion Criteria:

No treatment with chemotherapy or trastuzumab will be allowed within four weeks of study entry.
Prior therapy with vinorelbine.
Known history of hypersensitivity to trastuzumab, Chinese hamster ovary (CHO) cell proteins, or any component of these products.
History of current unstable angina, symptomatic congestive heart failure, or myocardial infarction within the last 6 months.
Pregnant women are excluded.
History of a known hypersensitivity to E. coli-derived proteins, filgrastim, or any component of the product.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00169104

Contacts

Contact: Gary N Schwartz, MD	(603) 653-6181	gary.n.schwartz@hitchcock.org
Contact: Michelle L Greene, MS	(603) 653-6196	michelle.l.greene@hitchcock.org

Locations

United States, New Hampshire
Norris Cotton Cancer Center	Recruiting
Lebanon, New Hampshire, United States, 03756
Contact: Gary N Schwartz, MD 603-653-6181 gary.n.schwartz@hitchcock.org
Contact: Michelle L Greene, BS (603) 653-6196 michelle.l.greene@hitchcock.org
Principal Investigator: Gary N Schwartz, MD

Sponsors and Collaborators

Dartmouth-Hitchcock Medical Center

Amgen

Investigators

Principal Investigator:

Gary N Schwartz, MD

Norris Cotton Cancer Center

More Information

Norris Cotton Cancer Center Home Page This link exits the ClinicalTrials.gov site

Publications of Results:

Schwartz GN, Kaufman PA, Tretter CPG, Arrick BA, Mulrooney TJ, Connelly EM, Mellinger DL, Fisher JL, Ernstoff MS. Vinorelbine and trastuzumab enhance effector cell function in patients with Her-2/neu overexpressing metastatic breast cancer. Breast Cancer Research and Treatment 88 (Suppl 1):S128a, 2004.

Responsible Party:	Dartmouth-Hitchcock Medical Center ( Gary N. Schwartz, MD )
Study ID Numbers:	D-0140
Study First Received:	September 10, 2005
Last Updated:	December 21, 2008
ClinicalTrials.gov Identifier:	NCT00169104
Health Authority:	United States: Institutional Review Board

Keywords provided by Dartmouth-Hitchcock Medical Center:

Breast cancer
Her-2/neu
Granulocyte Colony Stimulating Factor
Trastuzumab

Vinorelbine
Antibody-dependent cellular cytotoxicity
Effector cells

Study placed in the following topic categories:

Antibodies
Vinorelbine
Skin Diseases
Trastuzumab

Breast Neoplasms
Breast Diseases
Immunoglobulins

Additional relevant MeSH terms:

Neoplasms
Neoplasms by Site
Antineoplastic Agents

Therapeutic Uses
Antineoplastic Agents, Phytogenic
Pharmacologic Actions

ClinicalTrials.gov processed this record on January 13, 2009