Talimogene Laherparepvec With Paclitaxel or Endocrine Therapy in Treating Participants With Metastatic, Unresectable, or Recurrent HER2- Negative Breast Cancer

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of intra-lesional talimogene laherparepvec
administration in combination with paclitaxel or endocrine therapy in patients with
metastatic, unresectable, or locoregionally recurrent HER2-negative breast cancer with
injectable sites of disease.

SECONDARY OBJECTIVES:

I. To evaluate the efficacy of talimogene laherparepvec in combination with paclitaxel in the
study population using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

II. To evaluate the efficacy of talimogene laherparepvec in combination with endocrine
therapy in the study population using RECIST 1.1 criteria.

OUTLINE: Participants are assigned to 1 of 2 cohorts.

COHORT I (PACLITAXEL): Participants receive talimogene laherparepvec intra-tumorally (IT)
every 2 weeks for the first 12 weeks and then every 3 weeks thereafter. Participants also
receive paclitaxel intravenously (IV) over 60 minutes on days 1, 8, 15, and 22. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.

COHORT II (ENDOCRINE THERAPY): Participants receive talimogene laherparepvec IT every 2 weeks
for the first 12 weeks and then every 3 weeks thereafter. Participants also receive letrozole
orally (PO), anastrazole PO, exemestane PO, tamoxifen PO on days 1-28 or fulvestrant
intramuscularly (IM) every 2 weeks for 3 doses then every 4 weeks for the subsequent courses.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up for 30 days.

Inclusion Criteria:

- Metastatic or locoregionally recurrent HER2-negative breast cancer; resectable disease
allowed

- Ability to understand and voluntarily sign informed consent prior to undergoing any
study-related assessments or procedures, as well as adhere to the study visit schedule
and other protocol requirements

- Histologic or cytologic confirmation of invasive breast cancer that is HER2-negative
by standard clinical criteria

- Patients who will participate in the endocrine therapy cohort must have invasive
breast cancer that is estrogen receptor (ER)+ (>= 1% ER staining by
immunohistochemistry [IHC])

- At least one accessible and injectable lesion in the locoregional area (ie. breast,
chest wall, skin nodule or mass, axillary or supraclavicular lymph node) of at least 1
centimeter (cm); (ultrasound imaging may be used as clinically indicated)

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

- Concomitant use of bisphosphonates, receptor activator of nuclear factor kappa-B
ligand (RANKL) antibody, and ovarian suppression is allowed

- Absolute neutrophil count (ANC) ≥ 1.5x10^9/L for paclitaxel cohort, and ≥ 1.0x10^9/L
for endocrine therapy cohort

- Hemoglobin (Hgb) ≥ 9 g/dL

- Platelets (plt) ≥ 100 x 10^9/L for paclitaxel cohort, and ≥ 75, 000 for endocrine
therapy cohort

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper
limit normal (ULN)

- Serum total bilirubin ≤ 1.5 x ULN

- Serum creatinine ≤ 1.5 x ULN, or 24-hour (hr) clearance ? 60 ml/min

- International normalization ratio (INR) or prothrombin time (PT) ≥ 1.5 x

- Females of child-bearing potential (FCBP) should have a negative urine or serum
pregnancy test within 72 hours prior to enrollment; if urine test is positive or
cannot be confirmed as negative, a serum pregnancy test will be required; FCBP must
also be willing to adhere to acceptable forms of birth control (a physician-approved
contraceptive method: tubal ligation; intra-uterine device; barrier contraceptive with
spermicide; or vasectomized partner) during the study treatment and through 3 months
after the last dose of talimogene laherparepvec; FCBP are defined as sexually mature
women who:

- Have not undergone a hysterectomy (the surgical removal of the uterus) or
bilateral oophorectomy (the surgical removal of both ovaries) or,

- Have not been naturally postmenopausal for at least 12 consecutive months (i.e.
has had menses at any time during the preceding 12 consecutive months)

- Must be willing to practice abstinence or use effective contraception for a
minimum of 3 months following completion of study treatment (in addition to
during study therapy)

Exclusion Criteria:

- Any significant medical condition, laboratory abnormalities, which places the subject
at unacceptable risk if he/she were to participate in the study

- Any condition that confounds the ability to interpret data from the study

- Patients must have recovered from side effects resulting from prior cancer-directed
therapy to a level of grade 1 or less (unless deemed not clinically significant by
study investigator)

- Symptomatic central nervous system metastases; subjects with brain metastases that
have been previously treated and are stable for 4 weeks off steroids are allowed;
patients must be stable off steroids for brain metastases for at least 7 days;
subjects with asymptomatic clinically insignificant brain metastases not requiring
treatment are allowed; the exception does not include carcinomatous meningitis which
is excluded regardless of clinical stability

- Patients with leptomeningeal disease

- History of symptomatic autoimmune disease or active autoimmune disease that has
required systemic treatment in the 2 weeks prior to enrollment; replacement therapy
(e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for
adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
treatment

- Evidence of immune suppression due to: a) known human immunodeficiency virus (HIV)
infection or acquired immunodeficiency syndrome (AIDS); b) known leukemia or lymphoma;
c) those who require high dose steroids (> 10 mg/day of prednisone or equivalent
within 7 days prior to enrollment) or other immunosuppressive therapies (> 2 weeks);
d) active hepatitis B or C; e) congenital or acquired cellular and/or humoral immune
deficiency; f) other signs or symptoms of immune system suppression or concurrent
opportunistic infection

- Paclitaxel arm: grade 2 or higher neuropathy

- Known history of: cardiac disease, heart failure or decreased left ventricular
ejection fraction, significant clinical arrhythmias

- Patients must not have received an investigational agent within 4 weeks or ? 5 half
lives, whichever is shorter, prior to starting study treatment

- Last dose of chemotherapy must be at least 3 weeks before first dose of study
treatment; there is no required washout for endocrine therapy

- Major surgery or radiation ≤ 2 weeks prior to starting study treatment or who have not
recovered from side effects of surgery or radiation

- Active herpetic skin lesions or prior complications of HSV-1 infection (e.g. herpetic
encephalitis or keratitis)

- Lesions with underlying infection or clinically meaningful bleeding

- Requires intermittent or chronic systemic (intravenous or oral) treatment with an
antiherpetic drug (e.g. acyclovir), other than intermittent topical use; patients
requiring anti-herpetic prophylaxis during chemotherapy are excluded

- Previous treatment with talimogene laherparepvec or any other oncolytic virus

- Prior therapy with tumor vaccine

- Received live vaccine within 28 days prior to enrollment

- Known allergic reaction to talimogene laherparepvec, paclitaxel, aromatase inhibitors,
tamoxifen, fulvestrant, or any of their components; an exception is made if the
patient will not be receiving the offending agent/component (i.e. a patient who is
allergic to paclitaxel but will be receiving endocrine therapy is eligible)

- Patients on therapeutic anticoagulation

- Women who are pregnant or breast-feeding

- FCBP who are unwilling to use acceptable method(s) of effective contraception during
study treatment and through 3 months after the last dose of talimogene laherparepvec

- Sexually active subjects and their partners unwilling to use a 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

- Subjects who are unwilling to minimize exposure with his/her blood or other body
fluids to individuals who are at higher risks for HSV 1 induced complications
(immunosuppressed individuals, HIV positive individuals, pregnant women, or children
under the age of 1 year) during talimogene laherparepvec treatment and through 30 days
after the last dose of talimogene laherparepvec