Trastuzumab, Cyclophosphamide, and Vaccine Therapy in Treating Patients With High-Risk or Metastatic Breast Cancer
Study Details
Study Description
Brief Summary
RATIONALE: Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vaccines made from gene-modified tumor cells may help the body build an immune response to kill tumor cells. Giving trastuzumab together with cyclophosphamide and vaccine therapy may kill more tumor cells.
PURPOSE: This phase II trial is studying the side effects of giving trastuzumab together with cyclophosphamide and vaccine therapy in treating patients with high-risk or metastatic breast cancer.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
OBJECTIVES:
Primary
-
To evaluate the safety of allogeneic sargramostim (GM-CSF)-secreting breast cancer vaccine in combination with trastuzumab (Herceptin®) and cyclophosphamide in patients with high-risk or metastatic HER2/neu-overexpressing breast cancer.
-
To measure the HER2/neu-specific CD4+ T-cell response by delayed-type hypersensitivity.
-
To measure the magnitude of HER2/neu-specific CD8+ T-cell responses by ELISPOT.
Secondary
-
To assess the impact of trastuzumab on immune priming in vivo by IHC.
-
To measure the impact of cyclophosphamide pretreatment on CD4+CD25+ regulatory T cells by flow cytometry.
-
To determine the time to disease progression.
Tertiary
-
To develop the tandem tetramer/CD107a cytotoxicity assay for HER2/neu-specific CD8+ T cells.
-
To measure novel T-cell responses induced by trastuzumab and cyclophosphamide-modulated vaccination.
OUTLINE: Patients receive trastuzumab (Herceptin®) IV over 30-90 minutes once weekly beginning on day -1 of the first course of vaccination and continuing until the completion of the last course of vaccination. Patients also receive cyclophosphamide IV over 30 minutes on day -1 and allogeneic sargramostim (GM-CSF)-secreting breast cancer vaccine intradermally on day 0. Treatment with cyclophosphamide and the vaccine repeats every 27-42 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive a fourth course of cyclophosphamide and vaccine approximately 6-8 months after the first course.
Patients undergo delayed-type hypersensitivity testing and blood sample collection at baseline and periodically during study for immunologic laboratory studies. Blood samples are analyzed for serum GM-CSF levels by pharmacokinetic studies and for immune monitoring by ELISPOT and flow cytometry. Skin punch biopsies are also performed periodically and analyzed by IHC.
After completion of study treatment, patients are followed periodically.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Trastuzumab, Cyclophosphamide, and a Breast Tumor Vaccine Participants receive Trastuzumab (T), Cyclophosphamide (CY), and an allogeneic GM-CSF-secreting whole cell breast cancer vaccine |
Biological: allogeneic GM-CSF-secreting breast cancer vaccine
Day 0 : Allogeneic GM-CSF-secreting Breast Cancer Vaccine administered as:
12 intradermal injections of a divided total dose of 5 x108 cells.
Biological: trastuzumab
Patient HAS received prior Trastuzumab within the last two weeks, give Trastuzumab 2 mg/kg weekly on Day -1 for 5 weeks.
Patient has NOT received Trastuzumab within the last two weeks, give On Cycle 1, Day -1 ONLY, Loading dose 4 mg/kg
Other Names:
Drug: cyclophosphamide
Cyclophosphamide 200mg/m2 IV in NS 100ml over 30 minutes on Day -1 ONLY. Note: there are no dose modifications for Cyclophosphamide.
Other Names:
Other: flow cytometry
Samples will be analyzed by flow cytometry using Cell Quest software
Other: immunoenzyme technique
Other: immunohistochemistry staining method
Measuring Immune Priming In Vivo By Vaccine Site Biopsies
Other: laboratory biomarker analysis
Other: pharmacological study
Procedure: biopsy
skin biopsy to be performed on day 3 and day 7 for cycle 1 and 3 only
|
Outcome Measures
Primary Outcome Measures
- Safety as Assessed by Number of Participants Experiencing Toxicity [4 years]
Safety as assessed by number of participants who experienced drug-related local and systemic toxicity, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v3.0) in response to CY-modulated immunization with a novel breast cancer vaccine in the setting of weekly Trastuzumab therapy.
- Number of Participants With Immunologic Response as Determined by Delayed-type Hypersensitivity (DTH) Response to HER2/Neu-derived Peptides [4 years]
Secondary Outcome Measures
- Clinical Benefit as Assessed by Number of Participants With Progression-free Survival [4 years]
Number of participants without evidence of disease progression.
Eligibility Criteria
Criteria
DISEASE CHARACTERISTICS:
-
Histologically confirmed adenocarcinoma of the breast, meeting one of the following criteria:
-
Metastatic disease
-
High-risk disease, defined as early-stage disease with pathologic involvement of locoregional lymph nodes
-
Patients who are/will be receiving standard adjuvant trastuzumab [Herceptin®] for high-risk disease will participate in this study during the single-agent trastuzumab portion of their therapy
-
No clinical or radiographical evidence of active disease
-
Not eligible for therapy of known curative potential for metastatic breast cancer
-
HER2/neu-overexpressing disease, defined as HER2/neu positive by IHC 3+ staining or by FISH+ amplification
-
Stable CNS disease allowed provided it has been adequately treated and is not under active treatment
-
Hormone receptor status not specified
PATIENT CHARACTERISTICS:
-
Menopausal status not specified
-
ECOG performance status 0-1
-
ANC > 1,000/mm^3
-
Platelet count > 100,000/mm^3
-
Serum creatinine < 2.0 mg/dL
-
Serum bilirubin ≤ 2.0 mg/dL (unless elevation is due to known Gilbert's syndrome)
-
AST/ALT ≤ 2 times upper limit of normal (ULN)
-
Alkaline phosphatase ≤ 5 times ULN
-
Not pregnant or nursing
-
Negative pregnancy test
-
Fertile patients must use effective contraception
-
Cardiac ejection fraction normal by MUGA OR ≥ 45% by ECHO
-
No other malignancies within the past 5 years, except for carcinoma in situ of the cervix, superficial nonmelanoma skin cancer, or superficial bladder cancer
-
No prior or currently active autoimmune disease* requiring management with systemic immunosuppression, including any of the following:
-
Inflammatory bowel disease
-
Systemic vasculitis
-
Scleroderma
-
Psoriasis
-
Multiple sclerosis
-
Hemolytic anemia or immune-mediated thrombocytopenia
-
Rheumatoid arthritis
-
Systemic lupus erythematosus
-
Sjögren syndrome
-
Sarcoidosis
-
Other rheumatologic disease
-
No symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest
-
HIV-negative
-
No evidence of active acute or chronic infection
-
No uncontrolled medical problems
-
No active major medical or psychosocial problems that could be complicated by study participation
-
No corn allergy
-
No known severe hypersensitivity to trastuzumab (except for mild to moderate infusion reactions that are easily managed and do not recur) NOTE: *Asthma or chronic obstructive pulmonary disease that does not require daily systemic corticosteroids allowed
PRIOR CONCURRENT THERAPY:
-
Any number of prior chemotherapy regimens for metastatic breast cancer allowed
-
Prior or concurrent trastuzumab in the adjuvant or metastatic setting allowed
-
More than 28 days since prior and no concurrent systemic oral steroids
-
Topical, ocular, or nasal steroids allowed
-
More than 28 days since prior and no concurrent chemotherapy, radiotherapy, or biologic therapy (except trastuzumab)
-
More than 28 days since prior and no concurrent participation in another investigational clinical trial involving a new drug
-
Concurrent endocrine therapy or bisphosphonates allowed
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Baltimore | Maryland | United States | 21231-2410 |
Sponsors and Collaborators
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Leisha A. Emens, MD, PhD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- J0885
- P30CA006973
- NA_00021048
- CDR0000634155
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Trastuzumab, Cyclophosphamide, and a Breast Tumor Vaccine |
|---|---|
| Arm/Group Description | Patients receive Trastuzumab (T), Cyclophosphamide (CY), and an allogeneic GM-CSF-secreting whole cell breast cancer vaccine |
| Period Title: Overall Study | |
| STARTED | 20 |
| COMPLETED | 20 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Trastuzumab, Cyclophosphamide, and a Breast Tumor Vaccine |
|---|---|
| Arm/Group Description | Patients receive Trastuzumab (T), Cyclophosphamide (CY), and an allogeneic GM-CSF-secreting whole cell breast cancer vaccine |
| Overall Participants | 20 |
| Age (years) [Mean (Full Range) ] | |
| Mean (Full Range) [years] |
47
|
| Sex: Female, Male (Count of Participants) | |
| Female |
20
100%
|
| Male |
0
0%
|
| Region of Enrollment (Count of Participants) | |
| United States |
20
100%
|
Outcome Measures
| Title | Safety as Assessed by Number of Participants Experiencing Toxicity |
|---|---|
| Description | Safety as assessed by number of participants who experienced drug-related local and systemic toxicity, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v3.0) in response to CY-modulated immunization with a novel breast cancer vaccine in the setting of weekly Trastuzumab therapy. |
| Time Frame | 4 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Trastuzumab, Cyclophosphamide, and a Breast Tumor Vaccine |
|---|---|
| Arm/Group Description | All patients receive weekly Trastuzumab, Cyclophosphamide, and a Breast Tumor Vaccine |
| Measure Participants | 20 |
| Patients with drug-related toxicity |
20
100%
|
| Patients with grade 3+ drug-related toxicity |
0
0%
|
| Patients with serious drug-related toxicity |
0
0%
|
| Title | Number of Participants With Immunologic Response as Determined by Delayed-type Hypersensitivity (DTH) Response to HER2/Neu-derived Peptides |
|---|---|
| Description | |
| Time Frame | 4 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Trastuzumab, Cyclophosphamide, and a Breast Tumor Vaccine |
|---|---|
| Arm/Group Description | Participants receive Trastuzumab (T), Cyclophosphamide (CY), and an allogeneic GM-CSF-secreting whole cell breast cancer vaccine |
| Measure Participants | 20 |
| DTH-positive at baseline |
12
60%
|
| Increased DTH from baseline |
11
55%
|
| Converted from DTH-negative to DTH-positive |
5
25%
|
| Title | Clinical Benefit as Assessed by Number of Participants With Progression-free Survival |
|---|---|
| Description | Number of participants without evidence of disease progression. |
| Time Frame | 4 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Only 13/20 participants had early stage disease, and 7/20 participants had a history of metastatic disease at the start of the study. All participants were assigned to the same treatment group. |
| Arm/Group Title | Trastuzumab, Cyclophosphamide, and a Breast Tumor Vaccine |
|---|---|
| Arm/Group Description | Participants receive Trastuzumab (T), Cyclophosphamide (CY), and an allogeneic GM-CSF-secreting whole cell breast cancer vaccine |
| Measure Participants | 20 |
| Patients with early stage disease |
12
60%
|
| Patients with metastatic disease |
6
30%
|
Adverse Events
| Time Frame | Adverse events were collected at weekly time points after each vaccine administration for the duration of the study, an average of 7 months. | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Trastuzumab, Cyclophosphamide, and a Breast Tumor Vaccine | |
| Arm/Group Description | Patients receive Trastuzumab (T), Cyclophosphamide (CY), and an allogeneic GM-CSF-secreting whole cell breast cancer vaccine | |
All Cause Mortality |
||
| Trastuzumab, Cyclophosphamide, and a Breast Tumor Vaccine | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/20 (0%) | |
Serious Adverse Events |
||
| Trastuzumab, Cyclophosphamide, and a Breast Tumor Vaccine | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/20 (0%) | |
Other (Not Including Serious) Adverse Events |
||
| Trastuzumab, Cyclophosphamide, and a Breast Tumor Vaccine | ||
| Affected / at Risk (%) | # Events | |
| Total | 20/20 (100%) | |
| Blood and lymphatic system disorders | ||
| Lymphadenopathy | 4/20 (20%) | |
| Gastrointestinal disorders | ||
| Anorexia | 5/20 (25%) | |
| Constipation | 1/20 (5%) | |
| Cramps | 1/20 (5%) | |
| Nausea | 4/20 (20%) | |
| Vomiting | 1/20 (5%) | |
| General disorders | ||
| Arthralgia | 9/20 (45%) | |
| Chills | 10/20 (50%) | |
| Fatigue | 10/20 (50%) | |
| Fever | 7/20 (35%) | |
| Flu-like symptoms | 3/20 (15%) | |
| Malaise | 2/20 (10%) | |
| Sweats | 1/20 (5%) | |
| Musculoskeletal and connective tissue disorders | ||
| Myalgia | 8/20 (40%) | |
| Pain, bone | 1/20 (5%) | |
| Nervous system disorders | ||
| Dizziness | 2/20 (10%) | |
| Headache | 8/20 (40%) | |
| Psychiatric disorders | ||
| Insomnia | 1/20 (5%) | |
| Skin and subcutaneous tissue disorders | ||
| Erythema/swelling of vaccine sites | 20/20 (100%) | |
| Pain/soreness/tenderness of vaccine sites | 20/20 (100%) | |
| Pruritus of vaccine sites | 20/20 (100%) | |
| Blister at vaccine site | 16/20 (80%) | |
| Dry skin at vaccine site | 1/20 (5%) | |
| Ecchymosis at vaccine site | 6/20 (30%) | |
| Eczema at vaccine site | 1/20 (5%) | |
| Edema at vaccine site | 1/20 (5%) | |
| Hives at vaccine site | 2/20 (10%) | |
| Hyperpigmentation at vaccine site | 1/20 (5%) | |
| Rash at vaccine site | 2/20 (10%) | |
| Warmth at vaccine site | 14/20 (70%) | |
| Blisters | 2/20 (10%) | |
| Eczema | 3/20 (15%) | |
| Erythema | 2/20 (10%) | |
| Rash | 2/20 (10%) | |
| Urticaria | 2/20 (10%) | |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr. Leisha Emens |
|---|---|
| Organization | Johns Hopkins University |
| Phone | |
| emensle@jhmi.edu |
- J0885
- P30CA006973
- NA_00021048
- CDR0000634155