Talimogene Laherparepvec in Treating Patients With Recurrent Breast Cancer That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To determine the efficacy of talimogene laherparepvec in inflammatory breast cancer or
non-inflammatory breast cancer patients with inoperable local recurrence measured by the
overall response rate.

SECONDARY OBJECTIVES:

I. To determine the efficacy of talimogene laherparepvec in inflammatory breast cancer or
non-inflammatory breast cancer patients with inoperable local recurrence measured by the
overall disease control rate.

II. To determine the rate of local overall response and disease control rate,
progression-free survival (PFS), and overall survival (OS) in all patients.

III. To determine the rate of local overall response and disease control rate, PFS, and OS in
patients without distant metastases.

IV. To determine the rate of local overall response and disease control rate, PFS, and OS in
patients with distant metastases.

V. To determine the safety of talimogene laherparepvec injection to local disease.

TERTIARY OBJECTIVES:

I. To determine the effect of talimogene laherparepvec on injection sites and distant
metastatic sites by evaluating immune function and apoptosis with immune cell surface markers
and cytokines.

II. To assess changes in the following: serum or plasma levels of interleukin (IL)-2, IL-12,
tumor necrosis factor (TNF)-alpha, and interferon (IFN)- alpha; (Reuben's Lab); phenotype for
T-cell subsets (CD3, CD4, CD8, CD25) and natural killer cell (NK-cell) subsets (CD16, CD56),
which will be determined via multiparameter fluorescence-activated cell sorting (FACS)
analysis (percentage and absolute numbers) in peripheral blood at Dr. James Reuben's
laboratory of MD Anderson; serum analysis of herpes simplex virus (HSV) type 1 serology with
immunoglobulin (Ig)G and IgM (enzyme-linked immunosorbent assay [ELISA]).

III. To assess distant tumor tissue changes by evaluating necrosis and immune cell
infiltration (T-/B-/NK-Cell, macrophage, dendritic cell) by immunohistochemistry assay (CD3,
CD4, CD8, CD20, CD16, CD56, granzyme B, cleaved caspase 3, and Ki-67) when distant tumor
sample is obtained; if the sample volume is ample, additional immunohistochemistry assays
will be performed for CD45RO, TIA-1, FoxP3, CD25, OX-40, CD57, CD1a, CD208, myeloperoxidase,
CD68, COX-2, major histocompatibility complex (MHC) class I and MHC class II in Dr. Savitri
Krishnamurthy's laboratory at MD Anderson.

OUTLINE:

Patients receive talimogene laherparepvec intratumorally (IT) on day 1. Courses repeat every
3 weeks in course 1 and every 2 weeks thereafter in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3
months for up to 1 year.

Inclusion Criteria:

- Histological confirmation of breast carcinoma

- Histological confirmation of recurrence of chest wall with or without distant
metastasis disease

- Patients may have any molecular status (estrogen receptor [ER], progesterone receptor
[PR] and human epidermal growth factor receptor 2 [HER2]) and must have failed at
least 1 systemic regimen after their diagnosis of locoregional disease

- Previous adjuvant endocrine therapy for initial breast cancer was allowed but had to
be discontinued at least 1 week before receiving the study drug

- Previous chemotherapy for local recurrence is allowed but must have been discontinued
at least 4 weeks before receiving the study drug and the patient must have recovered
from acute adverse effects

- Previous radiation therapy was allowed but must have been discontinued at least 2
months before study drug is administered, and the patient must have recovered from
acute toxic effects

- Eastern cooperative oncology group performance status (ECOG PS) 0-1

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

- Platelet count >= 100 x 10^9/L

- Hemoglobin >= 10.0 g/L

- International normalization ratio (INR) or prothrombin time (PT) 1.5 x upper limit of
normal (ULN), unless the subject is receiving anticoagulant therapy, in which case PT
and partial thromboplastin time (PTT)/ activated PTT (aPTT) must be within therapeutic
range of intended use of anticoagulants

- Calculated creatinine clearance > 30 ml/min

- Aspartate aminotransferase (AST) =< 2.5 x ULN

- Alanine aminotransferase (ALT) =< 2.5 x ULN

- Total bilirubin =< 1.5 x ULN

- Subjects must be candidate for intralesional injection into cutaneous, subcutaneous or
nodal tumors with or without image ultrasound guidance defined as one or more of the
following at least 1 injectable lesion >= 5 mm in longest diameter, multiple
injectable lesions that in aggregate have a longest diameter of >= 5 mm

- Female patients of childbearing potential must have negative urine pregnancy test no
more than 3 days prior to starting study treatment

- Patients must be able and willing to give written informed consent

Exclusion Criteria:

- Patients who have operable disease with curable intent, and/or are candidates for
radiation therapy for local control

- Patients receiving concurrent anti-cancer therapy (chemotherapy, immunotherapy,
radiation therapy, hormonal therapy, and biological therapy) while taking study
medication or have previously received talimogene laherparepvec or any other oncolytic
virus

- Patients with metastatic sites that requires chemotherapy and/or non-hormonal targeted
therapy

- Known active central nervous metastases; subjects with previously treated brain
metastases may participate provided they are stable (without evidence of progression
by imaging for at least four weeks prior to the first dose of trial treatment and any
neurologic symptoms have returned to baseline), have no evidence of new or enlarging
brain metastases, and are not using steroids > 10 mg/day pf prednisone or equivalent

- More than three lesions per organ for visceral metastases except for lung or lymph
node sites

- History or evidence of symptomatic autoimmune disease (eg, pneumonitis,
glomerulonephritis, vasculitis, or other), or history of active autoimmune disease
that has required systemic treatment (ie, use of corticosteroids, immunosuppressive
drugs or biological agents used for treatment of autoimmune diseases) in past 2 months
prior to enrollment; replacement therapy (eg, thyroxine for hypothyroidism, insulin
for diabetes or physiologic corticosteroid replacement therapy for adrenal or
pituitary insufficiency) is not considered a form of systemic treatment for autoimmune
disease

- Patients with concurrent disease or condition that would make them inappropriate for
study participation, or any serious medical disorder that would interfere with
patients' safety

- History of a second cancer, except treated basal cell or squamous cell skin cancer, in
situ cervical cancer or other cancers for which patients are disease free for at least
3 years

- Patients with initial diagnoses of stage IV disease

- Patients with active infection and requiring intravenous (IV) or oral antibiotics

- Evidence of immune suppression due to:

- Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency
syndrome (AIDS)

- Known leukemia or lymphoma

- Those who require high dose steroids or other immunosuppressive agents

- Known hepatitis B or C infection

- Congenital or acquired cellular and/or humoral immune deficiency

- Other signs or symptoms of immune system suppression

- Active herpetic skin lesions or prior complication of herpes simplex virus (HSV)-1
infections (e.g. herpetic encephalitis or keratitis)

- Currently pregnant or breast-feeding, or planning to become pregnant during study
treatment and through 3 months after the last dose of study treatment

- Female subject of childbearing potential who is unwilling to use acceptable method(s)
of effective contraception during study treatment and through 3 months after the last
dose of talimogene laherparepvec; (women of not childbearing potential:
post-menopausal [age > 55 years with cessation of menses > 12 months or < 55 years but
not spontaneous menses for at least 2 years or < 55 years and spontaneous menses
within the past 1 year, but currently amenorrheic (eg, spontaneous or secondary to
hysterectomy), and with postmenopausal gonadotropin levels (luteinizing hormone and
follicle-stimulating hormone levels > 40 IU/L) or postmenopausal estradiol levels (< 5
ng/dL) or according to the definition of "postmenopausal range" for the laboratory
involved] or who have had a hysterectomy, bilateral salpingectomy, or bilateral
oophorectomy)

- Sexually active subjects and their partners unwilling to use male or female latex
condom to avoid potential viral transmission during sexual contact while on treatment
and within 30 days after treatment with talimogene laherparepvec

- Currently enrolled in another clinical trial (exclude non-cancer treatment trial) or
received an investigational agent within 4 weeks of study initiation

- Requires intermittent or chronic treatment with antiherpetic drugs, except for topical
agents

- Patients who are known sensitive to any of the products or components to be
administered during treatment with talimogene laherparepvec

- Chronic oral or systemic steroid medication use at a dose of > 10 mg/d of prednisone
or equivalent (steroids with low systemic absorption [e.g. triamcinolone hexacetonide]
injected into joint space are allowed)