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Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III, Phase II Treatment Active 18 and over Other D-0140 NCT00169104

Trial Description

Summary

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.

Further Study Information

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 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.

Trial Contact Information

Trial Lead Organizations/Sponsors

Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center

Gary N Schwartz, MD

Principal Investigator

Gary N Schwartz, MD		Ph: (603) 653-6181
		Email: gary.n.schwartz@hitchcock.org

Michelle L Greene, MS		Ph: (603) 653-6196
		Email: michelle.l.greene@hitchcock.org

U.S.A.
New Hampshire
	Lebanon
	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center
		Gary N Schwartz, MD	Ph: 603-653-6181
			Email: gary.n.schwartz@hitchcock.org
		Michelle L Greene, BS	Ph: (603) 653-6196
			Email: michelle.l.greene@hitchcock.org
		Gary N. Schwartz	Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00169104
Information obtained from ClinicalTrials.gov on August 04, 2008