PRIMARY OBJECTIVES:
I. To explore the safety of talimogene laherparepvec in combination with nivolumab and
ipilimumab in this population assessed by the frequency and severity of adverse events (AEs)
using Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 toxicity
criteria.
SECONDARY OBJECTIVES:
I. Assess tumor response of talimogene laherparepvec in combination with nivolumab and
ipilimumab comparing to no treatment, in subjects with localized estrogen receptor (ER)
positive and triple negative infiltrating ductal breast cancer.
II. Descriptively analyze the evidence of tumor necrosis and inflammatory infiltration on
histopathological examination and immuno-oncological findings in tumor and peripheral blood
of patients treated with talimogene laherparepvec in combination with nivolumab and
ipilimumab.
EXPLORATORY OBJECTIVES:
I. Descriptively compare tumor response in patients whose tumors are PD-L1 positive (+) and
PD-L1 negative (-) at baseline.
II. Determine the baseline mutational load of patients at the start of treatment and relate
it to the response to treatment.
III. Determine if hormone receptor status correlates with tumor responses. IV. Determine the
number of tumor infiltrating lymphocytes in patient samples at the start and at the end of
treatment and relate them to tumor response.
V. Analyze T-cell receptor (TCR) repertoire in tumor infiltrating lymphocytes and peripheral
blood mononuclear cells.
OUTLINE:
Participants receive talimogene laherparepvec intratumorally on days 1, 22, and 36, nivolumab
intravenously (IV) over 60 minutes on days 1, 15, 29, and 43, and ipilimumab IV over 90
minutes on days 1 and 43 in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, participants are followed up for 30 days.
Inclusion Criteria:
- Written informed consent must be obtained from the subject/legal representative prior
to performing any protocol-related procedures, including screening evaluations
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
- Localized, palpable, biopsy proven triple negative or ER positive HER2 negative
infiltrating ductal breast cancer with size > 1.5 cm by palpation, excluding breast
cancer where neoadjuvant chemotherapy is indicated by current guidelines (i.e.
inflammatory subtype, etc.)
- Tumor that is palpable and injectable
- Hemoglobin >= 9 g/dL
- Absolute neutrophil count >= 1,500/mm^3
- Platelet count >= 100,000/mm^3
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
institutional upper limit of normal (ULN)
- Bilirubin =< 1.5 x ULN; for subjects with documented/suspected Gilbert?s disease,
bilirubin =< 3 x ULN
- Albumin >= 2.5 g/dl
- Prothrombin time (PT) / International normalized ratio (INR) and partial
thromboplastin time (PTT) =< 1.5 x institutional upper limit of normal unless the
patient is on anticoagulant therapy within 28 days prior to enrollment (if the patient
is receiving anticoagulant therapy, PT, and a PTT must be within therapeutic range of
intended use of anticoagulants)
- Patients must be willing to submit blood and tissue specimens for translational
medicine studies
- Patients must be offered the opportunity to participate in specimen banking for future
research
- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
[HCG]) within 24 hours prior to the start of study drug
- Women must not be breastfeeding
- Women of childbearing potential (WOCBP) must be willing to use either two adequate
barrier methods or a barrier method plus a hormonal method of contraception to prevent
pregnancy, or to abstain from heterosexual activity (complete abstinence) throughout
the study, starting with visit 1 through 5 months after the last dose of study
therapy. Approved contraceptive methods include, for example, intrauterine device,
diaphragm with spermicide, cervical cap with spermicide, male condoms, female condoms
with spermicide, or oral contraceptives. Spermicides alone are not an acceptable
method of contraception. Should a woman become pregnant or suspect she is pregnant
while she or her partner is participating in this study, she should inform her
treating physician immediately
- Male patients must agree to use an adequate method of contraception, or to abstain
from heterosexual activity (complete abstinence) starting with the first dose of study
drug through 7 months after the last dose of study therapy
Exclusion Criteria:
- Contraindications to tumor biopsy and injections (coagulopathy, known history of
keloid formation, etc.)
- Women who are pregnant or breastfeeding
- 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
- Inability to give informed consent
- History of malignancies except cured basal cell carcinoma, cutaneous squamous cell
carcinoma, melanoma in situ, superficial bladder cancer or carcinoma in situ of the
cervix; for other malignancies, must be documented to be free of cancer for >= 2
years. All other cases can be considered on a case by case basis at the discretion of
the principal investigator
- Any condition that might interfere with the subject?s participation in the study,
safety, or in the evaluation of the study results
- Concurrent enrollment in another clinical study, unless it is an observational
(non-interventional) clinical study or the follow-up period of an interventional study
- Prior exposure to any anti-PD-1 or anti-PD-L1 antibody, or any anti-CTLA 4 antibodies
- Patients must not have received prior treatment with talimogene laherparepvec or other
oncolytic virus agents
- Patients must not have received any live vaccine within 30 days prior to registration.
Seasonal flu vaccines that do not contain live virus are permitted
- Patients must not have an active infection requiring systemic therapy nor a viral
infection requiring intermittent treatment with an antiherpetic drug, other than
intermittent topical use
- Patients must not have active herpetic skin lesions or prior complications of herpetic
infection (e.g., herpetic keratitis or encephalitis) which requires intermittent or
chronic treatment with an anti-herpetic drug other than intermittent topical use
- Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer
treatment. Concurrent use of hormones for non-cancer-related conditions (e.g., insulin
for diabetes and hormone replacement therapy) is acceptable
- Patient must not have evidence of any clinically significant immunosuppression such as
the following: primary immunodeficiency state such as severe combined immunodeficiency
disease; concurrent opportunistic infection; receiving systemic immunosuppressive
therapy within 28 days before enrollment with the exceptions of intranasal, topical,
and inhaled corticosteroids or oral corticosteroids at physiologic doses not to exceed
10 mg/day of prednisone or equivalent
- Patients must not have known history human immunodeficiency virus (HIV)
- Clinical or laboratory evidence of an active herpetic infection and in patients who
require daily antiviral therapy such as acyclovir
- Active or prior documented autoimmune disease within the past 3 years
- NOTE: Subjects with active, known or suspected autoimmune disease such as
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune
condition only requiring hormone replacement, psoriasis not requiring systemic
treatment, or conditions not expected to recur in the absence of an external
trigger are permitted to enroll
- Active or prior documented inflammatory bowel disease
- History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required
steroids or has current ILD/pneumonitis or where suspected ILD/pneumonitis cannot be
ruled out by imaging at screening
- Exposure to any investigational drug within 7 days prior to screening visit or for
which 5 half-lives have not elapsed
- Prisoners or subjects who are involuntarily incarcerated
- Note: under certain specific circumstances a person who has been imprisoned may
be included or permitted to continue as a subject
- Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (e.g., infectious disease) illness
