Talimogene Laherparepvec, Nivolumab and Trabectedin for Sarcoma

This is a Phase 2 study using talimogene laherparepvec, nivolumab, and trabectedin as first,
second or third line therapy for advanced sarcoma, including desmoid tumor and chordoma. The
primary objective is to determine progression-free survival (PFS) at month 12. The secondary
objectives are (1) To evaluate the best overall response (BOR) and duration of response (DOR)
by RECIST v1.1 via CT scan or MRI at 6,12,18, and 24 weeks post treatment, (2) To determine
progression-free survival rate (PFS) at 6 and 9 months, (3) To determine overall survival
rate at 6, 9, and 12 months, (4) To determine the incidence of conversion of an unresectable
tumor to a resectable tumor, and (5) To evaluate the incidence of adverse events related to
TALIMOGENE LAHERPAREPVEC in combination with nivolumab and trabectedin. The exploraratory
objective is to correlate response with immune cell trafficking in the tumor microenvironment
(TME) of resected tumors.

The primary endpoint is Progression free survival at month 12. The secondary endpoints are:
1) Best overall response (BOR) and duration of response (DOR) by RECIST v1.1 via CT scan or
MRI at 6,12,18 and 24 weeks post treatment, 2) PFS rate at 6 and 9 months

• Overall survival rate at 6, 9, and 12 months, 3) Incidence of conversion of an unresectable
tumor to a resectable tumor, 4) Incidence of adverse events related to TALIMOGENE
LAHERPAREPVEC in combination with nivolumab and trabectedin. The exploratory endpoint is
correlation of response with immune cell trafficking in the tumor microenvironment of
resected tumors.

Forty male and female subjects > 18 years of age, of any ethnicity, with advanced sarcoma,
including desmoid tumor and chordoma will be treated.

Inclusion Criteria:

- Individuals must meet all of the inclusion criteria in order to be eligible to
participate in the study, as follows:

- Male or Female ≥ 18 years of age

- Pathologically confirmed diagnosis of locally advanced unresectable or metastatic
sarcoma including desmoid tumor and chordoma

- Ability to understand the purposes and risks of the study and has signed and
dated a written informed consent form approved by the Investigator's IRB/Ethics
Committee

- Willingness to comply with all study procedures and availability for the duration
of the study.

- Previously untreated or treated patient with measurable disease by RECIST v1.1,
and at least, one accessible tumor for intratumoral injection of TALIMOGENE
LAHERPAREPVEC

- ECOG performance status ≤ 1

- Life expectancy of at least 3 months

- Acceptable liver function: Bilirubin <1.5 times upper limit of normal (ULN;
except subjects with Gilbert Syndrome who must have a total bilirubin level < 3.0
ULN); AST (SGOT), ALT (SGPT) and alk phos < 2.5 x ULN (< 5 x ULN if liver
metastases present)

- Acceptable renal function: Creatinine < 1.5 times ULN

- Acceptable hematologic status: ANC >1500 cells/μL or greater; Platelet count
>100,000/μL or greater; Hemoglobin > 9.0 g/dL or greater

- INR and PT < 1.5 ULN unless taking anti-coagulation, in which case PT, INR and
aPTT must be within therapeutic range of intended use of anticoagulants

- All women of childbearing potential must have a negative urine or serum pregnancy
test within 72 hours of enrollment. If urine test is positive or cannot be
confirmed as negative, a serum pregnancy test will be required; all subjects must
agree to use highly effective means of contraception (surgical sterilization or
the use of barrier contraception with either a condom or diaphragm in conjunction
with spermicidal gel or an IUD) with their partner from entry into the study
through 5 months for women and 7 months for men after the last dose.

Exclusion Criteria:

- All individuals meeting any of the exclusion criteria at baseline will be excluded
from study participation, as follows:

- Known active central nervous system (CNS) 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 of prednisone or equivalent. The exception does not include
carcinomatosus meningitis which is excluded regardless of clinical stability.

- History or evidence of active autoimmune disease that requires systemic treatment
(ie, with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.)
is not considered a form of systemic treatment.

- Evidence of clinically significant immunosuppression such as the following: -
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 7 days prior to study treatment.

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

- Requires intermittent or chronic systemic (intravenous or oral) treatment with an
antiherpetic drug (e.g., acyclovir), other than intermittent topical use.

- Previous treatment with TALIMOGENE LAHERPAREPVEC or any other oncolytic virus.

- Received live vaccine within 28 days prior to study treatment.

- Prior immunosuppressive, chemotherapy, radiotherapy (in which the field
encompassed a planned injection site), biological cancer therapy, or major
surgery within 28 days prior to study treatment or has not recovered to CTCAE
grade 1 or better from adverse event due to cancer therapy administered more than
28 days prior to study treatment. Adjuvant hormonal therapy is allowed if
appropriate for planned study.

- Prior radiotherapy in which the field does not overlap the injection sites or
nonimmunosuppressive targeted therapy within 14 days prior to study treatment or
has not recovered to CTCAE grade 1 or better from adverse event due to cancer
therapy administered more than 14 days prior to study treatment

- Currently receiving treatment with another investigational device or drug study,
or < 28 days since ending treatment with another investigational device or drug
study(s).

- Other investigational procedures while participating in this study are excluded.

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

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

- Known to have human immunodeficiency virus (HIV) infection.

- History of other malignancy within the past 5 years with the following
exceptions:

- Adequately treated non melanoma skin cancer without evidence of disease at
the time of enrollment;

- Adequately treated cervical carcinoma in situ without evidence of disease at
the time of enrollment;

- Adequately treated breast ductal carcinoma in situ without evidence of
disease at the time of enrollment;

- Prostatic intraepithelial neoplasia without evidence of prostate cancer at
the time of enrollment.

- Subject has known sensitivity to TALIMOGENE LAHERPAREPVEC, NIVOLUMAB or
TRABECTEDIN or any of its components to be administered during dosing.

- Female subject is pregnant or breast-feeding or planning to become pregnant
during study treatment and through 3 months after the last dose of TALIMOGENE
LAHERPAREPVEC, NIVOLUMAB or TRABECTEDIN.

- 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, NIVOLUMAB or TRABECTEDIN.

- 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.

- 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
such as immunosuppressed individuals, individuals known to have HIV infection,
pregnant women, or infants under the age of 3 months, during TALIMOGENE
LAHERPAREPVEC treatment and through 30 days after the last dose of TALIMOGENE
LAHERPAREPVEC.