SV-BR-1-GM in Metastatic or Locally Recurrent Breast Cancer

Study Overview
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Brief Summary
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This is a single arm, open label study of SV-BR-1-GM, a targeted immunotherapy for breast cancer. Eligible patients will have histological confirmation of breast cancer with recurrent and/or metastatic lesions. The treatment regimen includes a pre-treatment with low-dose cyclophosphamide 2-3 days before the inoculation; inoculation in 4 sites on the thighs and upper back; and post-treatment inoculation of Interferon-alpha-2b into the sites of inoculation  2 and  4 days after the inoculation. These is repeated every 2 weeks for one month (3 treatments), then monthly for up to one year. Standard tumor assessments are performed at baseline and then every 2-3 months.

Detailed Description
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This is a single arm, open label study of SV-BR-1-GM in recurrent and/or metastatic breast cancer. The detailed treatment regimen follows: Pre-Inoculation Regimen: Cyclophosphamide (Cytoxan) 300 mg/m^2 I.V., 1x only, will be given 48-72 hours before each SV-BR-1-GM inoculation, with an antiemetic of the provider's choice (steroids prohibited). If the patient is not tolerating the cyclophosphamide, a lower dose may be used (e.g. 200 or 150 mg/m^2) or it may be withheld, with the Sponsor's approval. Innoculation Day Standard Operating Procedures: Inquire regarding events of past weeks, change in medications, pain scale, ECOG scale, and review of systems. Check injection sites. Perform DTH skin test intra-dermally with the SV-BR-1 parent cell line ( 1 x 10^6 irradiated tumor cells). Observe about 20 minutes for acute hypersensitivity. Grade III or higher acute hypersensitivity will abort therapy. Inject SV-BR-1-GM intra-dermally into 4 sites in thighs and upper back (0.5 mL each). Monitor patients for 60 minutes. Vital signs will be assessed and medical attention will be warranted if unstable. SV-BR-1-GM Preparation & Inoculation Regimen: Each inoculation will be administered via intra-dermal injection at the investigational sites. Subjects will receive 15-25 x 10^6 viable, irradiated transfected breast tumor cells in a total volume of 2.0 ml Ringer's lactate. SV-BR-1-GM cells will be irradiated to ensure cell replication incompetency. SV-BR-1-GM will be divided into four aliquots of 0.5 mL each and injected intra-dermally; one each into the anterior skin of the subject's right and left thighs and over the right and left upper back . Application of anesthetic lidocaine crème may be used if necessary for control of local pain before inoculation. Subjects will be monitored for 60 minutes. After at least 10 subjects have been treated safely with this regimen, the dose of SV-BR-1-GM may be escalated or decreased in subsequent patients based on the emerging data. Post-Inoculation Regimen: 2 days (± 1 day) after inoculation, and again 4 days (± 1 day) later after inoculation, the patient will return to the principal investigator's office to receive Interferon-alpha-2b (Merck) in 0.1 mL saline, prepared as follows: These will also be provided by the sponsor and injected intra-dermally to each inoculation site, beneath the thickest area. Again, subjects will be observed about 20 minutes. The DTH response will also be recorded at the 2 days (± 1 day) visit. This cycle will be performed every 2 weeks for the first month of treatment (3 inoculations), and then every month for up to one year.

Official Title
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A Phase I/IIa Study of SV-BR-1-GM in Metastatic or Locally Recurrent Breast Cancer Patients

Conditions
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Breastcancer, Breast Neoplasm

Intervention / Treatment
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* Biological: SV-BR-1-GM
* Drug: Cyclophosphamide
* Biological: Interferon-alpha-2b


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Have histological confirmation of breast cancer with recurrent and/or metastatic lesions via investigational site. Patients with new or progressive breast cancer metastatic to brain will be eligible provided: There is no need for steroids and patients have not had steroids at least 2 weeks No individual tumor size is >50 mm3 ECOG status <3 Tumor is not impinging on Middle Cerebral Artery/speech-motor strip If surgically debulked, must be healed from surgery and at least 3 weeks have elapsed since general anesthesia Patients consent to MRI studies at 3-4 week intervals until evidence of tumor regression on at least 2 imaging studies. In no case, will the interval between MRI studies be longer than 3 months. MRI study may be introduced at any time should the patients develop new or clearly worsening symptoms and/or introduction of steroids 2. Have evidence of persistent, recurrent, or progressive disease for which there is no known or established treatment available with curative intent, after failing at least one course of community standard systemic treatment with chemotherapy (and endocrine therapy if appropriate) 3. Be 18 years of age or older and female 4. Have expected survival of at least 4 months 5. Have adequate performance status (ECOG 0-2) 6. Patients may be maintained on hormonal therapy provided there is clear evidence of tumor progression 7. Have provided written informed consent. Exclusion Criteria: Concurrent or recent chemotherapy (within 3 weeks), XRT within 3 weeks, may have had immunotherapy in the past (off within 3 weeks), or general anesthesia/major surgery (within 3 weeks). Patients must have recovered from all known or expected toxicities from previous treatment and passed a treatment-free washout period of 3 weeks before starting this program (8 weeks for persons receiving nitrosourea or mitomycin). History of clinical hypersensitivity to GM-CSF, Interferon-alpha-2b (Merck), yeast, beef, or to any components used in the preparation of the experimental vaccine. BUN >30 and a creatinine >2. Absolute granulocyte count < 1000; platelets <100,000. Bilirubin >2.0; alkaline phosphatase >5x upper limit of normal (ULN); ALT/AST >2x ULN. Proteinuria >1+ on urinalysis or >1 gm/24hr. Left ventricular ejection fraction (LVEF as determined by cardiac echo or MUGA scan) below the normal limits of the institutions specific testing range. This assessment may be repeated once at the discretion of the Investigator with the approval of the Sponsor. New York Heart Association stage 3 or 4 cardiac disease. A pleural effusion of moderate severity or worse. Any woman of childbearing potential, unless she: Agrees to take measures to avoid becoming pregnant during the study and Has a negative serum pregnancy test within 7 days prior to starting treatment. Women who are pregnant or nursing. Patients with concurrent second malignancy. Persons with previous malignancies effectively treated and not requiring treatment for >24 months are eligible, provided there is unambiguous documentation that current local recurrence or metastatic site represents recurrence of the primary breast malignancy. Patients who are HIV positive (by self-report) or have clinical or laboratory features indicative of AIDS. 14. Patients who require systemic steroids at a dose equivalent of >10 mg/day of prednisone. Beta-blocker therapy, while not exclusionary, is discouraged and alternatives should be sought if possible. The beta-blocker might compromise use of epinephrine for the rare possibility of anaphylaxis. Anticoagulants must be approved by the Investigator with notification of the Sponsor. Patients who are on treatment for rheumatological or autoimmune disease unless approved by the Investigator in consultation with the Sponsor (e.g., as for replacement therapy for autoimmune thyroiditis or diabetes). Patients with severe psychiatric (i.e. schizophrenia, bipolar, or borderline personality disorder) or other clinically progressive major medical problems, unless approved by the PI. Male breast cancer patients. Patients may not be on a concurrent clinical trial, unless approved by PI.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SV-BR-1-GM Monotherapy<br>Pretreatment with low dose cyclophosphamide 2-3 days prior to SV-BR-1-GM inoculation; SV-BR-1-GM inoculation intradermally in 4 sites on the upper back (x2) and thighs (x2); Post-inoculation low dose Interferon-alpha-2b into the vaccination sites  2 and  4 days after SV-BR-1-GM inoculation | Biological: SV-BR-1-GM<br>* See above<br>Drug: Cyclophosphamide<br>* Low dose pre-treatment to reduce regulatory T cells<br>* Other names: Cytoxan;Biological: Interferon-alpha-2b<br>* Low dose given in the vaccine site to boost the immune response<br>* Other names: Intron A;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Treatment Emergent Adverse Events Occurring in Two or More Patients [Safety] | To evaluate the number of patients with toxicity events while on SV-BR-1-GM, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) | Through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Treatment Emergent Adverse Events [Safety] | To evaluate the duration of toxicity events while on SV-BR-1-GM, as defined by CTCAE | Through study completion, an average of 1 year | 
| Number of Participants With an Adverse Event Related to SV-BR-1-GM Administration [Safety] | To evaluate the number of participants with an adverse event related to SV-BR-1-GM administration, as defined by CTCAE | Through study completion, an average of 1 year | 
| Objective Tumor Response Rate | Objective response rate (ORR), defined as complete response (CR) or partial response (PR) per response evaluation criteria in solid tumors (RECIST) and immune-related RECIST (iRECIST) criteria. | Through study completion, an average of 1 year | 
| Rate of Non-progression of Tumors | Non-progressive rate, defined as CR, PR or stable disease (SD) per RECIST and iRECIST criteria | Through study completion, an average of 1 year | 
| Durability of Tumor Response | Durability of response, as defined as complete response (disappearance of all tumors), partial response (30% or greater reduction in the sum of diameters of target lesions (tumors) with stable disease in non-target lesions) or stable disease (less than 20% increase in the sum of diameters of target lesions with no new lesions appearing) by evaluating those patients eligible to complete the optional treatments from 9-12 months | Through study completion, an average of 1 year |