Trastuzumab, Cyclophosphamide, and an Allogeneic GM-CSF-secreting Breast Tumor Vaccine for the Treatment of HER-2/Neu-Overexpressing Metastatic Breast Cancer

NCT00399529 | Completed Phase 2 Results DMC

• 2 other identifiers: J05118RAC 0605-778
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

This is a feasibility study to examine combination therapy with Trastuzumab (T), Cyclophosphamide (CY), and an allogeneic GM-CSF-secreting whole cell breast cancer vaccine in patients with Stage IV HER-2/neu-overexpressing breast cancer. The main purposes of this study are to test the safety, clinical benefit, and bioactivity of vaccine therapy in combination with Cyclophosphamide and Trastuzumab in patients with HER-2/neu-overexpressing Stage IV breast cancer. This study will also to test whether the Cyclophosphamide can eliminate the suppressive influence of regulatory T cells, and whether Trastuzumab can increase antigen processing and presentation. These drug activities may make the immune system react better and enhance the effects of the vaccine in treating breast cancer. The vaccine consists of two irradiated allogeneic mammary carcinoma cell lines genetically modified to secrete human granulocyte-macrophage colony stimulating factor (GM-CSF). This open label, single arm study is designed to recruit up to 40 subjects to identify 20 research subjects with HER-2/neu-overexpressing Stage IV breast cancer eligible for study treatment.

Conditions

Breast Neoplasms

Keywords

Stage IV HER-2/neu overexpressing breast cancer

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Adverse Events

  Safety is measured as the number of patients that experienced adverse events related to study drug.

  From first dose through 30 days after last dose of study drug, up to 9 months

• Number of Participants With Clinical Benefit

  Clinical benefit is defined as the proportion of patients achieving complete response, partial response, or stable disease by RECIST. Complete response (CR) is defined as total disappearance of all clinical evidence of reversible disease. A partial response (PR) is defined as a \>=30% reduction in tumor target lesions. Stable disease (SD) is defined as disease status that fails to qualify as as a response (CR or PR) or progressive disease (increase of at least 20% in tumor target lesions).

  At 6 and 12 months from start of treatment

Secondary Outcomes (1)

• Number of Participants With Delayed Type Hypersensitivity (Immunological Response)

  30 days after each vaccine, up to 9 months

Study Arms (1)

Allo GM-CSF-secreting vaccine, Trastuzumab, Cyclophosphamide

EXPERIMENTAL

Allogeneic GM-CSF-secreting breast cancer vaccine : the vaccine containing a mixture of two GM-CSF-secreting allogeneic breast cancer cell lines (two parts 2T47D-V and one part 3SKBR3-7 mixed in a fixed dose of 5 X 10\^8 cells for each patient and each vaccination cycle) given intradermally every 4-6 weeks for 3 cycles and then a 4th dose given 6-8 months after beginning the study. Trastuzumab : An initial loading dose of 4 mg/kg for participants beginning treatment with Trastuzumab, otherwise 2 mg/kg given every week intravenously Cyclophosphamide : 300 mg/m\^2 given intravenously every 4-6 weeks for 3 cycles and then once 6-8 months after beginning the study

Biological: Allogeneic GM-CSF-secreting breast cancer vaccine; Drug: Trastuzumab; Drug: Cyclophosphamide

Interventions

Allogeneic GM-CSF-secreting breast cancer vaccine BIOLOGICAL

the vaccine containing a mixture of two GM-CSF-secreting allogeneic breast cancer cell lines (two parts 2T47D-V and one part 3SKBR3-7 mixed in a fixed dose of 5 X 108 cells for each patient and each vaccination cycle) on day 0.

Also known as: two parts 2T47D-V, one part 3SKBR3-7

Allo GM-CSF-secreting vaccine, Trastuzumab, Cyclophosphamide

Trastuzumab DRUG

Trastuzumab is a humanized monoclonal antibody specific for the extracellular domain of HER-2/neu that is now one component of the standard of care for both early and late stage HER-2/neu-overexpressing breast cancers. It exerts a pleiotropic antitumor effect by multiple mechanisms. The antibody decreases heterodimer formation with other members of the epidermal growth factor receptor (EGFR) family, thereby indirectly inhibiting signaling through the Ras/Raf/mitogen-activated protein kinases (MAPK) and Phosphatidylinositol 3-kinase(PI3K)/protein kinase B (Akt) pathways. It also inhibits tumor neovascularization, and augments apoptosis both in vitro and in vivo. Trastuzumab prevents cleavage of the extracellular domain of HER-2/neu, thus abrogating the constitutive activation of the remaining membrane-associated intracellular domain.

Also known as: Herceptin

Allo GM-CSF-secreting vaccine, Trastuzumab, Cyclophosphamide

Cyclophosphamide DRUG

The doses of Cyclophosphamide are based on previously reported clinical experience as well as our own preclinical data demonstrating augmented vaccine efficacy with CY-modulated vaccination. In particular, 300 mg/m2

Also known as: Cytoxan

Allo GM-CSF-secreting vaccine, Trastuzumab, Cyclophosphamide

Eligibility Criteria

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

You may qualify if:

• Patients with histologically confirmed HER-2/neu-overexpressing adenocarcinoma of the breast; this is defined as HER-2+ by immunohistochemistry (IHC) 3+ staining or Fluorescence In-Situ Hybridization (FISH). Prior adjuvant Trastuzumab therapy is permitted. Patients must not be eligible for therapy of known curative potential for metastatic breast cancer if it is identified during the course of the study.
• Patients may have measurable or evaluable disease.
• Stable central nervous system (CNS) disease that has been adequately treated and is not under active treatment allowed.
• Age 18 years or older.
• Able to give informed consent.
• Patients with an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1.
• No systemic oral steroids administered within 28 days prior to initiating treatment on protocol. Topical, ocular, and nasal steroids are allowed, as are those applied to mucus membranes.
• No prior or currently active autoimmune disease requiring management with systemic immunosuppression. This includes inflammatory bowel disease, systemic vasculitis, scleroderma, psoriasis, multiple sclerosis, hemolytic anemia or immune-mediated thrombocytopenia, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, sarcoidosis, or other rheumatologic disease. Asthma or chronic obstructive pulmonary disease that does not require daily systemic corticosteroids is acceptable.
• Not pregnant, and on appropriate birth control if of child-bearing potential.
• No history of other malignancies within the prior five years (excluding a history of carcinoma in situ of the cervix, superficial non-melanoma skin cancer, and superficial bladder cancer).
• Adequate bone marrow reserve with absolute neutrophil count (ANC) \> 1000 and platelets \> 100,000.
• Adequate renal function with serum creatinine \< 2.0.
• Adequate hepatic reserve with serum bilirubin \< 2.0, aspartate transaminase (AST) and alanine aminotransferase (ALT) \< 2X the upper limit of normal, and alkaline phosphatase \< 5X the upper limit of normal. Serum bilirubin \> 2.0 is acceptable in the setting of known Gilbert's syndrome.
• Adequate cardiac reserve with a cardiac ejection fraction within the lower limit of facility normal by MUGA, or 45% by echocardiogram.
• No active major medical or psychosocial problems that could be complicated by study participation.

You may not qualify if:

• No histologic documentation of breast adenocarcinoma.
• Breast adenocarcinoma that is not amplified for HER-2/neu gene expression by at least 2-fold by FISH analysis, or that is less than IHC 3+ when FISH negative.
• Cardiac dysfunction documented by an ejection fraction less than the lower limit of the facility normal by multi-gated acquisition (MUGA) scan, or 45% by echocardiogram.
• Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest.
• History of autoimmune disease as detailed above.
• Systemic oral corticosteroid treatment within 28 days prior to initiating treatment on study.
• Uncontrolled medical problems.
• Evidence of active acute or chronic infection.
• Chemotherapy, radiation therapy, or biologic therapy (except Trastuzumab) within 28 days prior to initiating treatment on study. Hormonal therapy and supportive therapy with bisphosphonates will be allowed.
• Participation in an investigational new drug trial within 28 days prior to initiating treatment on study.
• Pregnant or breast feeding.
• Hepatic, renal, or bone marrow dysfunction as detailed above.
• Concurrent malignancy or history of other malignancy within the last five years except as noted above.
• Corn allergy.
• Known severe hypersensitivity to Trastuzumab (excluding mild to moderate infusion reactions that are easily managed and do not recur).

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead
• American Cancer Society, Inc.: collaborator
• Avon Foundation: collaborator
• Cancer Treatment Research Foundation: collaborator
• The Commonwealth Fund: collaborator
• United States Department of Defense: collaborator
• Genentech, Inc.: collaborator

Study Sites (1)

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21231, United States

Location

Related Publications (1)

• Chen G, Gupta R, Petrik S, Laiko M, Leatherman JM, Asquith JM, Daphtary MM, Garrett-Mayer E, Davidson NE, Hirt K, Berg M, Uram JN, Dauses T, Fetting J, Duus EM, Atay-Rosenthal S, Ye X, Wolff AC, Stearns V, Jaffee EM, Emens LA. A feasibility study of cyclophosphamide, trastuzumab, and an allogeneic GM-CSF-secreting breast tumor vaccine for HER2+ metastatic breast cancer. Cancer Immunol Res. 2014 Oct;2(10):949-61. doi: 10.1158/2326-6066.CIR-14-0058. Epub 2014 Aug 12.

  PMID: 25116755 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Trastuzumab; Cyclophosphamide

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

• Title: Dr. Leisha Emens
• Organization: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

emensla@upmc.edu

412-623-3239

Study Officials

• Leisha A Emens, M.D.,Ph.D.

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 13, 2006
• First Posted: November 15, 2006
• Study Start: September 1, 2006
• Primary Completion: February 1, 2010
• Study Completion: February 1, 2010
• Last Updated: April 22, 2020
• Results First Posted: April 13, 2020

Record last verified: 2020-04

Locations

US (1)