Effects of Granulocyte Colony-stimulating Factor (G-CSF), Trastuzumab, and Vinorelbine on Immune Cell Function

NCT00169104 | Terminated Phase 2 Results DMC

• 1 other identifier: D-0140
• Study Type: interventional
• Target: 23
• Locations: 0 countries
• Sites: N/A

Brief 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.

Conditions

Metastatic Breast Cancer

Keywords

Breast cancer; Her-2/neu; Granulocyte Colony Stimulating Factor; Trastuzumab; Vinorelbine; Antibody-dependent cellular cytotoxicity; Effector cells

Outcome Measures

Primary Outcomes (1)

• 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

  Buffy coat effector cells were isolated by centrifugation from heparinized blood, and washed and counted. SKBR3 target cells were labeled with 51-Cr at 100 uCi per 5 x 105 cells for 1 hour at 37 C, washed and effector cells and target cells were plated at a ratio of 70:1 in 96 well microtiter plates, with trastuzumab 2 ug/ml and with no antibody. After addition of the target cells, the plate was centrifuged gently at 1200 rpm to pellet cells, the plate was incubated for 4 hours at 37C, and 100 uL of supernatant was measured on a gamma counter set for 51Cr counting for 1 minute per tube. Specific lysis in % is defined as follows: % specific lysis = (counts released into the supernatant under experimental conditions - spontaneous counts released into the supernatant) / (maximum counts released into the supernatant - spontaneous counts released into the supernatant) Specific lysis at Day 12 was compared to specific lysis at baseline between the G-CSF group and the placebo group.

  Baseline and 12 days

Secondary Outcomes (3)

• 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

  Baseline and 14 weeks

• Clinical Response Rate of the Combination of Trastuzumab, G-CSF, and Vinorelbine in Subjects With Her-2 Overexpressing Metastatic Breast Cancer

  14 weeks

• Safety of the Combination of Trastuzumab, G-CSF, and Vinorelbine in Subjects With Her-2 Overexpressing Metastatic Breast Cancer

  14 weeks

Study Arms (2)

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 at 4 mg/kg week 1, and 2 mg/kg week 2 during the first two weeks of the trial. All patients will then receive 12 weeks of trastuzumab at 2 mg/kg IV weeks 3 through 14, vinorelbine at 25 mg/m2 IV weekly weeks 3,4,6,7,9,10,12,13 and G-CSF at 5 mcgm/kg SQ daily Monday through Friday weeks 3-14.

Drug: G-CSF; Drug: trastuzumab; Drug: vinorelbine

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 at 4 mg/kg week 1, and 2 mg/kg week 2 during the first two weeks of the trial. All patients will then receive 12 weeks of trastuzumab at 2 mg/kg weeks 3-14, vinorelbine at 25 mg/m2 IV weekly weeks 3,4,6,7,9,10,12,13, and G-CSF at 5 mcgm/kg SQ daily Monday through Fridays weeks 3-14.

Drug: G-CSF; Drug: trastuzumab; Drug: vinorelbine; Drug: saline placebo

Interventions

G-CSF DRUG

5 mcgm/kg daily Monday through Friday weeks 3-14

Also known as: Neupogen

1; 2

trastuzumab DRUG

4 mcgm/kg intravenously (IV) over 90 minutes week 1, then 2 mg/kg IV over 30 minutes weeks 2-14

Also known as: Herceptin

1; 2

vinorelbine DRUG

25 mg/m2 over 6 minutes IV weekly, weeks 3, 4, 6, 7, 9, 10, 12, 13

Also known as: Navelbine

1; 2

saline placebo DRUG

Saline will be given SQ daily for ten days, Monday through Friday of the first two weeks of the study

2

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Dartmouth-Hitchcock Medical Center: lead
• Amgen: collaborator

Related Publications (1)

• 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.

  RESULT

Related Links

• Norris Cotton Cancer Center Home Page

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Granulocyte Colony-Stimulating Factor; Filgrastim; Trastuzumab; Vinorelbine

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines

Results Point of Contact

• Title: Gary N. Schwartz MD
• Organization: Dartmouth-Hitchcock Medical Center / Norris Cotton Cancer Center

gary.n.schwartz@hitchcock.org

(603) 653-6181

Study Officials

• Gary N Schwartz, MD

  Norris Cotton Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Staff Physician

Study Record Dates

• First Submitted: September 10, 2005
• First Posted: September 15, 2005
• Study Start: July 1, 2002
• Primary Completion: March 1, 2009
• Study Completion: March 1, 2009
• Last Updated: July 20, 2018
• Results First Posted: July 20, 2018

Record last verified: 2018-06