TVEC and Preop Radiation for Sarcoma

This is a single-arm open-label phase Ib and phase II clinical study assessing the safety and
relative efficacy of concurrent talimogene laherparepvec in combination with radiotherapy in
patients with soft tissue sarcomas. Patients will be treated with neoadjuvant radiation and
weekly intratumoral injections of talimogene laherparepvec. Weekly injections of talimogene
laherparepvec will be continued until surgery. Surgery will be performed 4-6 weeks from the
end of radiation therapy to allow for resolution of acute toxicities per current standard of
care.

Inclusion Criteria:

1. Subject has provided informed consent.

2. Histologically confirmed diagnosis of locally advanced STS that is unresectable with
clear wide margins, for which preoperative radiotherapy is considered appropriate.

EXAMPLES:

- Resectable stage IIB, III, and IV disease that are not suitable for surgically
resection alone due to inability to achieve clear margins.

- Including metastatic (stage IV) disease for which radiotherapy and surgical
resection are indicated.

- Except certain histologic subtypes: GIST, Desmoid, Ewing sarcoma, Kaposi sarcoma,
and bone sarcomas.

3. Previous treatment: prior systemic anti-cancer treatment consisting of chemotherapy,
immunotherapy, or targeted therapy are allowed provided therapy completed at least 1
year prior to enrollment.

- No prior Talimogene laherparepvec or tumor vaccines allowed.

- No prior radiation to the same tumor bed allowed.

4. Age ≥18 years.

5. Both men and women of all races and ethnic groups are eligible for this trial.

6. ECOG performance status ≤1.

7. Patient must have measurable disease:

- Tumor size at least ≥ 5 cm in the longest diameter as measured by CT scan or MRI
for which radiation is feasible.

7.1 Patient must have injectable disease (direct injection or ultrasound guided).

Exclusion Criteria:

1. Certain histologic subtypes: GIST, Desmoid, Ewing sarcoma, Kaposi sarcoma, and bone
sarcomas

2. History or evidence of sarcoma associated with immunodeficiency states (e.g.:
Hereditary immune deficiency, HIV, organ transplant or leukemia).

3. Subjects with retroperitoneal and visceral sarcoma.

4. History or evidence of gastrointestinal inflammatory bowel disease (ulcerative colitis
or Crohn's disease) or other symptomatic autoimmune disease including, inflammatory
bowel disease, or history of any poorly controlled or severe systemic autoimmune
disease (i.e., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, type I
diabetes, or autoimmune vasculitis).

5. History of other malignancy within the past 3 years except treated with curative
intent and no known active disease present and has not received chemotherapy for ≥ 1
year before enrollment/randomization and low risk for recurrence.

6. History of prior or current autoimmune disease.

7. History of prior or current splenectomy or splenic irradiation.

8. Active herpetic skin lesions.

9. Require intermittent or chronic treatment with an anti-herpetic drug (e.g.,
acyclovir), other than intermittent topical use.

10. Any non-oncology vaccine therapies used for the prevention of infectious disease
within 28 days prior to enrollment and during treatment period.

11. Concomitant treatment with therapeutic anticoagulants such as warfarin.

12. Known human immunodeficiency virus (HIV) disease (requires negative test for
clinically suspected HIV infection).

13. Acute or chronic hepatitis B or hepatitis C infection (requires negative test for
clinically suspected hepatitis B or hepatitis C infection.

- Evidence of hepatitis B -

- Positive HBV surface antigen (indicative for chronic hepatitis B or recent
acute hepatitis B).

- Negative HBV surface antigen but positive HBV total core antibody
(indicative for resolved hepatitis B infection or occult hepatitis B) and
detectable copies of HBV DNA by PCR (detectable HBV DNA copies suggest
occult hepatitis B).

- Evidence of hepatitis C -

- Positive HCV antibody and positive HCV RNA by PCR (undetectable RNA copies
suggest past and resolved hepatitis C infection).

14. Female subjects who are pregnant or breast-feeding, or planning to become pregnant
during study treatment and through 3 months after the last dose of study treatment.

15. Female subjects of childbearing potential or male subjects who are unwilling to use 2
highly effective methods of contraception during study treatment and through 3 months
after the last dose of study treatment.

16. Currently receiving treatment in another investigational device or drug study, or less
than 30 days since ending treatment on another investigational device or drug
study(s).

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

18. Subject previously has entered this study.

19. Patients who are receiving any other investigational agents.

20. Evidence of CNS metastases.

21. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to talimogene laherparepvec.

22. 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.

23. Patients on or requiring immunosuppressive therapies.

24. Any of the following laboratory abnormalities:

- Hemoglobin < 9.0 g/dL

- Absolute neutrophil count (ANC) < 1500 per mm3

- Platelet count < 100,000 per mm3

- Total bilirubin > 1.5 × ULN

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × ULN

- Alkaline phosphatase > 2.5 × ULN

- PT (or INR) and PTT (or aPTT) > 1.5 × ULN

- Creatinine > 2.0 × ULN