Talimogene Laherparepvec and Radiation Therapy in Treating Patients With Newly Diagnosed Soft Tissue Sarcoma That Can Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To estimate the pathologic complete necrosis rate (the number of patients with >= 95%
necrosis divided by the number of evaluable patients) following preoperative treatment with
talimogene laherparepvec (T-VEC) in combination with radiation in patients with localized
soft tissue sarcoma including a pre-planned interim safety analysis to assess post-surgical
wound complications.

SECONDARY OBJECTIVES:

I. To determine the toxicity of talimogene laherparepvec (T-VEC) in combination with
radiation in localized soft tissue sarcomas, during neo-adjuvant treatment and post-surgical
resection wound complications.

II. To estimate the rate of radiologic response, prior to surgery, and extent of surgical
resection.

III. To estimate time to surgery, time to progression, time to recurrence, and death.

TERTIARY OBJECTIVES:

I. To characterize the clinical outcomes within three distinct histologic subtypes:
liposarcoma (excluding myxoid liposarcoma), leiomyosarcoma and undifferentiated pleomorphic
sarcoma.

II. To characterize the percentage of tumor necrosis in treated tumors. III. To assess if the
combination of preoperative talimogene laherparepvec (T-VEC) with radiation will increase the
expression of PD-L1 in soft tissue sarcomas.

IV. To assess the impact of preoperative talimogene laherparepvec (T-VEC) with radiation on
the tumor infiltrating and circulating immune cells in patients with soft tissue sarcomas.

OUTLINE:

Patients receive talimogene laherparepvec intratumorally (IT) at weeks 1, 4, 6 and 8.
Beginning 8-10 days after start of talimogene laherparepvec, patients undergo radiation
therapy at weeks 2-6.

After completion of study treatment, patients are followed up at 60 days, every 3 months for
2 years, every 6 months for 1 year, and then every year for up to 5 years.

Inclusion Criteria:

- Newly diagnosed and histopathologically confirmed (by central pathology review)
potentially resectable soft tissue sarcomas of the extremity and trunk of the
following subtypes: liposarcoma (excluding myxoid liposarcoma), leiomyosarcoma and
undifferentiated pleomorphic sarcoma

- An incisional or core biopsy is the preferred method for diagnosis; fine needle
aspiration is not acceptable

- Sites permissible for biopsy include

- Extremities: upper (including shoulder) and lower (including hip)

- Trunk: body wall

- Patients must have localized disease with a primary tumor >= 5 cm by magnetic
resonance imaging (MRI) or computed tomography (CT) scan

- Patients must have histologically confirmed grade 2 or 3 tumors by the French
Federation of Cancer Centers Sarcoma Group (FNCLCC) sarcoma grading system

- Patients must have a primary tumor that are determined by multidisciplinary team
(medical oncology, orthopedic/surgical oncology, and radiation oncology) to require
radiation therapy for optimal management prior to surgical resection

- Patients must have a sarcoma in the extremity or trunk in location, which is
accessible to direct or ultrasound guided injections

- Karnofsky performance score >= 70

- Absolute neutrophil count (ANC) >= 1500/uL

- Absolute lymphocyte count (ALC) >= 800/uL

- Platelets >= 100,000/uL

- Hemoglobin >= 9 g/dL

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
institutional ULN

- Calculated creatinine clearance > 70 mL/min/1.73 m^2

- Patient must have a life expectancy of at least 3 months with appropriate therapy

- Patients must agree to use contraception during study treatment and for 4 months after
the end of treatment

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry,
during the study participation, and for four months after the last dose of the
drug; women of child-bearing potential must have a negative serum pregnancy test
within 14 days prior to randomization and agree to use effective contraception
throughout the treatment period and for 4 months after the last dose of study
treatment; 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

- Ability to understand and the willingness to sign a written informed consent document

- Willingness to provide mandatory tissue and blood samples for correlative studies

Exclusion Criteria:

- Patients with localized sarcomas that are not of the extremity or trunk wall
(including head/neck, retroperitoneum, visceral organs, peritoneum, pelvis within the
confines of the bony pelvis, and tumors arising in bone)

- Patients who have had prior treatment with anti-PD1 or anti-CTLA4 therapy

- Patients with grade 1 non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) tumors of any
size are not eligible

- Patients with evidence of active bleeding or bleeding diathesis will be excluded
(patients with excess of 2.5 mL of hemoptysis are not eligible)

- Patients requiring therapeutic anticoagulation

- Patients must have had no prior radiotherapy to tumor-involved sites

- Patients with gross total resection of the primary tumor prior to enrollment are not
eligible; patients who have experienced tumor recurrence after gross total tumor
resection are not eligible

- History of serious or non-healing wound, ulcer, or bone fracture

- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1)

- Use of other investigational drugs within 28 days (or five half-lives, whichever is
shorter; with a minimum of 14 days from the last dose) preceding the first dose of
talimogene laherparepvec (T-VEC) and during the study

- Previous treatment with talimogene laherparepvec (T-VEC) or any other oncolytic virus

- Patients with metastatic disease

- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to
talimogene laherparepvec (T-VEC) or any of its components

- History or evidence of active autoimmune disease (e.g., pneumonitis,
glomerulonephritis, vasculitis, or other); or history of active autoimmune disease
that has required systemic treatment (i.e., use of corticosteroids, immunosuppressive
drugs or biological agents used for treatment of autoimmune diseases) within 2 months
of enrollment; (replacement therapy [e.g., 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)

- Evidence of clinically significant immunosuppression such as

- Primary immunodeficiency state such as severe combined immunodeficiency
disease

- Concurrent opportunistic infection

- Receiving systemic immunosuppressive therapy (> 2 weeks) including oral
steroid doses > 10 mg/day of prednisone or equivalent within 2 months prior
to enrollment

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

- Viral infections requiring intermittent or chronic systemic (intravenous or oral)
treatment with an anti-herpetic drug, other than intermittent topical use (e.g.,
acyclovir)

- Other viral infections

- Known to have acute or chronic active hepatitis B or hepatitis C infection

- Known to have human immunodeficiency virus (HIV) infection

- Prior therapy with viral-based tumor vaccine

- Received live vaccine within 28 days prior to enrollment

- Patients who are unwilling to minimize exposure with his/her blood or other body
fluids to individuals who are at higher risks for herpes simplex virus (HSV)-1 induced
complications such as immunosuppressed individuals, individuals known to have HIV
infection, pregnant women, or children under the age of 1 year, during talimogene
laherparepvec (T-VEC) treatment and through 30 days after the last dose of talimogene
laherparepvec (T-VEC)

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Patients who are pregnant, breastfeeding or plan to become pregnant; sexually active
patients and their partners must be willing to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry, during the study
participation, and for four months after the last dose of T-VEC