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Closed due to achievement of primary study endpoint
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| Name | Class |
|---|---|
| Amgen | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| G-CSF | Drug | 5 mcgm/kg daily Monday through Friday weeks 3-14 |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | Buffy coat effector cells were isolated by centrifugation from heparinized blood, 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 Week 14 was compared to specific lysis at baseline for 17 patients with week 14 samples available. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Gary N Schwartz, MD | Norris Cotton Cancer Center | Principal Investigator |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| Result | 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. |
| Label | URL |
|---|---|
| Norris Cotton Cancer Center Home Page | View source |
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There was no run-in prior to randomization and the start of treatment.
Patients were enrolled between July 12, 2002 and November 2, 2007 from the Comprehensive Breast Program at the Norris Cotton Cancer Center.
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| ID | Title | Description |
|---|---|---|
| FG000 | G-CSF Arm | 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. |
| FG001 | Placebo Arm | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
A total of 23 subjects were enrolled. Four subjects dropped out in the first week of treatment and are inevaluable for any study endpoints.
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| ID | Title | Description |
|---|---|---|
| BG000 | G-CSF Arm | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | 19 subjects were evaluable for response and toxicity, but only 17 subjects had evaluable specific lysis laboratory outcomes at baseline and at Day 12. | Posted | Mean | Standard Deviation | percentage of specific lysis | Baseline and 12 days |
14 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | G-CSF | 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. G-CSF: 5 mcgm/kg daily Monday through Friday weeks 3-14 trastuzumab: 4 mcgm/kg intravenously (IV) over 90 minutes week 1, then 2 mg/kg IV over 30 minutes weeks 2-14 vinorelbine: 25 mg/m2 over 6 minutes IV weekly, weeks 3, 4, 6, 7, 9, 10, 12, 13 G-CSF: 5 mcgm/kg SQ daily for ten days, Monday through Friday of the first two weeks of the study |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Mental status change | Nervous system disorders | Systematic Assessment | Grade 3 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Thrombocytopenia | Blood and lymphatic system disorders | Systematic Assessment | Grade 3 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Gary N. Schwartz MD | Dartmouth-Hitchcock Medical Center / Norris Cotton Cancer Center | (603) 653-6181 | gary.n.schwartz@hitchcock.org |
| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
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| ID | Term |
|---|---|
| D016179 | Granulocyte Colony-Stimulating Factor |
| D000069585 | Filgrastim |
| D000068878 | Trastuzumab |
| D000077235 | Vinorelbine |
| ID | Term |
|---|---|
| D003115 | Colony-Stimulating Factors |
| D006023 | Glycoproteins |
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
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| trastuzumab | Drug | 4 mcgm/kg intravenously (IV) over 90 minutes week 1, then 2 mg/kg IV over 30 minutes weeks 2-14 |
|
|
| vinorelbine | Drug | 25 mg/m2 over 6 minutes IV weekly, weeks 3, 4, 6, 7, 9, 10, 12, 13 |
|
|
| G-CSF | Drug | 5 mcgm/kg SQ daily for ten days, Monday through Friday of the first two weeks of the study |
|
|
| saline placebo | Drug | Saline will be given SQ daily for ten days, Monday through Friday of the first two weeks of the study |
|
| 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 | 19 subjects (11 on the G-CSF arm and 8 on the placebo arm) completed 14 weeks of treatment and completed restaging at that time. Responses were evaluated by RECIST criteria. | 14 weeks |
| Safety of the Combination of Trastuzumab, G-CSF, and Vinorelbine in Subjects With Her-2 Overexpressing Metastatic Breast Cancer | Adverse events were graded per RECIST v4.0. There were two severe adverse events: Grade 3 mental status changes in one subject on the G-CSF arm, and Grade 3 febrile neutropenia in one subject on the Placebo arm. Refer to Adverse Events Table for specifics. | 14 weeks |
| Physician Decision |
|
| BG001 | Placebo Arm | 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
|
|
|
|
| Secondary | 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 | Buffy coat effector cells were isolated by centrifugation from heparinized blood, 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 Week 14 was compared to specific lysis at baseline for 17 patients with week 14 samples available. | 17 of 19 subjects had results from ADCC assays from baseline and at week 14. Because subjects on both arms of the trial received the identical treatment with 12 weeks of vinorelbine and G-CSF after the initial two week randomization, it is appropriate to pool the results of the ADCC assays at the 14 week timepoint from both arms. | Posted | Median | Standard Deviation | percentage of specific lysis | Baseline and 14 weeks |
|
|
|
| Secondary | Clinical Response Rate of the Combination of Trastuzumab, G-CSF, and Vinorelbine in Subjects With Her-2 Overexpressing Metastatic Breast Cancer | 19 subjects (11 on the G-CSF arm and 8 on the placebo arm) completed 14 weeks of treatment and completed restaging at that time. Responses were evaluated by RECIST criteria. | 19 subjects completed 14 weeks of treatment and underwent restaging at that timepoint. | Posted | Count of Participants | Participants | 14 weeks |
|
|
|
| Secondary | Safety of the Combination of Trastuzumab, G-CSF, and Vinorelbine in Subjects With Her-2 Overexpressing Metastatic Breast Cancer | Adverse events were graded per RECIST v4.0. There were two severe adverse events: Grade 3 mental status changes in one subject on the G-CSF arm, and Grade 3 febrile neutropenia in one subject on the Placebo arm. Refer to Adverse Events Table for specifics. | 19 subjects (11 on the G-CSF arm and 8 on the placebo arm) received at least two weeks of treatment on study and were evaluable for toxicity. | Posted | Count of Participants | Participants | 14 weeks |
|
|
|
| 0 |
| 11 |
| 1 |
| 11 |
| 10 |
| 11 |
| EG001 | {Placebo | 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. G-CSF: 5 mcgm/kg daily Monday through Friday weeks 3-14 trastuzumab: 4 mcgm/kg intravenously (IV) over 90 minutes week 1, then 2 mg/kg IV over 30 minutes weeks 2-14 vinorelbine: 25 mg/m2 over 6 minutes IV weekly, weeks 3, 4, 6, 7, 9, 10, 12, 13 saline placebo: Saline will be given SQ daily for ten days, Monday through Friday of the first two weeks of the study | 0 | 8 | 1 | 8 | 6 | 8 |
| Febrile neutropenia | Immune system disorders | Systematic Assessment | Grade 3 |
|
| Anemia | Blood and lymphatic system disorders | Systematic Assessment | Grade 3 |
|
| Sensory neuropathy | Nervous system disorders | Systematic Assessment | Grade 2 |
|
| Arthralgias | Musculoskeletal and connective tissue disorders | Systematic Assessment | Grade 2 |
|
| constipation | Gastrointestinal disorders | Systematic Assessment | Grade 2 |
|
| anemia | Blood and lymphatic system disorders | Systematic Assessment | Grade 2 |
|
| Tumor pain | Nervous system disorders | Systematic Assessment | Grade 2 |
|
| Mucositis | Gastrointestinal disorders | Systematic Assessment | Grade 2 |
|
| heartburn | Gastrointestinal disorders | Systematic Assessment | Grade 2 |
|
| Thrombocytopenia | Blood and lymphatic system disorders | Systematic Assessment | Grade 2 |
|
| Leukopenia | Blood and lymphatic system disorders | Systematic Assessment | Grade 4 |
|
| Leukopenia | Blood and lymphatic system disorders | Systematic Assessment | Grade 2 |
|
| Granulocytopenia | Blood and lymphatic system disorders | Systematic Assessment | Grade 4 |
|
| Granulocytopenia | Blood and lymphatic system disorders | Systematic Assessment | Grade 3 |
|
| Granulocytopenia | Blood and lymphatic system disorders | Systematic Assessment | Grade 2 |
|
| Elevated alkaline phosphatase | Investigations | Systematic Assessment | Grade 3 |
|
| Elevated alkaline phosphatase | Investigations | Systematic Assessment | Grade 2 |
|
| Elevated AST | Investigations | Systematic Assessment | Grade 3 |
|
| Elevated AST | Investigations | Systematic Assessment | Grade 2 |
|
| Elevated ALT | Investigations | Systematic Assessment | Grade 3 |
|
| Elevated ALT | Investigations | Systematic Assessment | Grade 2 |
|
The sponsor will be provided 30 days to review a manuscript and 15 days to review a poster. The sponsor may request an additional 60 days to review study results prior to their release, if the request is submitted in writing.
| D017437 |
| Skin and Connective Tissue Diseases |
| D016298 |
| Hematopoietic Cell Growth Factors |
| D016207 | Cytokines |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D011506 | Proteins |
| D001685 | Biological Factors |
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D014748 | Vinca Alkaloids |
| D046948 | Secologanin Tryptamine Alkaloids |
| D026121 | Indole Alkaloids |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D007211 | Indoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D054836 | Indolizidines |
| D007212 | Indolizines |
| Stable Disease |
|
| Disease Progression |
|
| Grade 4 leukopenia |
|
| Grade 4 granulocytopenia |
|
| Grade 3 anemia |
|
| Grade 3 thrombocytopenia |
|
| Grade 3 granulocytopenia |
|
| Grade 3 elevation in alkaline phosphatase |
|
| Grade 3 elevation in AST |
|
| Grade 3 elevation in ALT |
|
| Grade 2 sensory neuropathy |
|
| Grade 2 arthralgias |
|
| Grade 2 constipation |
|
| Grade 2 tumor pain |
|
| Grade 2 mucositis |
|
| Grade 2 heartburn |
|
| Grade 2 anemia |
|
| Grade 2 thrombocytopenia |
|
| Grade 2 leukopenia |
|
| Grade 2 granulocytopenia |
|
| Grade 2 elevation in alkaline phosphatase |
|
| Grade 2 elevation in AST |
|
| Grade 2 elevation in ALT |
|