Talimogene Laherparepvec in Patients With Unresectable Pancreatic Cancer

Talimogene laherparepvec is a conditionally replication competent herpes simplex type-1
virus designed for use in solid tumors. It has been specifically modified to replicate in
tumors and to provide a local source of the immune-stimulating cytokine, granulocyte
macrophage colony stimulating factor (GM-CSF). It is injected directly into cancer tumors
and is believed to destroy tumor cells by direct infection of the tumor cells and an
enhanced immune response due to the release of tumor antigens and GM-CSF expression.

This was an open-label, dose-escalation study evaluating the safety and efficacy of
talimogene laherparepvec administered by direct injection into pancreatic tumors using
endoscopic ultrasound (EUS)-guided fine needle injection (FNI). Only 1 tumor mass within the
body and tail of the pancreas was injected in any participant. The protocol called for
evaluation of 4 dosing regimens in sequential cohorts of participants; however, cohort 4 was
not opened for enrollment.

Inclusion Criteria:

- cytological or histological proof of adenocarcinoma of the pancreas

- unresectable, locally advanced disease (isolated liver metastases are permitted)

- tumors of at least 1 cm diameter at screening

- measurable disease using Response Evaluation Criteria In Solid Tumors (RECIST)
criteria

- failure of either standard therapy, OR any one of the following:

- no alternative therapeutic of higher curative potential is available;

- investigator determination that patient could not tolerate alternative
therapeutic due to unacceptable toxicity; or,

- patient refusal to be treated with available alternative therapeutic

- age > 18 years

- life expectancy > 3 months

- adequate bone marrow function as indicated by:

- White blood cells (WBC) ≥ 3.0 x 10^9/L

- platelets ≥ 100 x 10^9/L

- hemoglobin ≥ 8.5 gm/dL

- adequate liver function as indicated by:

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

- alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 5 x ULN in
case of presence of liver metastasis

- ALT or AST < 2.5 x ULN in case of absence of liver metastasis

- adequate renal function as indicated by a serum creatinine level < 1.5 x ULN.

- adequate hemostasis indicated by international normalized ratio (INR) ≤ 1.5

- mentally, physically and geographically able to undergo treatment and follow-up

- provided written informed consent

- first patient in each cohort only: seropositive for herpes simplex virus type 1
(HSV1)

Exclusion Criteria:

- history of other malignancy within two years prior to screening, except for prostate
cancer (T1c, T2ab with definitive treatment, prostate-specific antigen (PSA) < 1
ng/ml, and without ongoing hormone suppression) or adequately treated in situ
carcinoma of the cervix, basal cell carcinoma, or squamous cell carcinoma of the skin

- cystic form of pancreatic cancer; microcystic disease may be eligible upon discussion
with Medical Monitor

- Common Terminology Criteria for Adverse Events (CTCAE) version 3 grade 2 or greater
clinical pancreatitis within 8 weeks prior to dosing with OncoVEX^GM-CSF

- other than metastases limited to the liver, imaging evidence of metastatic disease to
any other organ or tissue

- any serious concomitant systemic disorder that would compromise the safety of the
patient, at the discretion of the investigator

- evidence of compromised immune function including but not limited to:

- clinically significant absolute lymphocyte count < Lower Limit of Normal (LLN)

- known human immunodeficiency virus (HIV), acute or chronic active hepatitis B,
or hepatitis C infection;

- concurrently taking HIV antiviral medications (e.g. protease inhibitors,
azidothymidine, etc.)

- received intravenous (IV), intramuscular (IM) or subcutaneous (SC) human gamma
globulin within 6 months prior to dosing with OncoVEX^GM-CSF

- patients taking immunosuppressive agents (e.g. cyclosporine, tacrolimus, or oral or
systemic corticosteroids at a dose of > 10 mg/day of prednisone or equivalent).

- pregnancy, lactation or lack of effective contraception in women of child-bearing
potential (e.g., not post menopausal for > 2 years, or had tubal ligation); lack of
effective contraception in men if the partner is of child-bearing potential; women
must have been practicing an effective contraceptive method for at least three months
prior to entry in to the trial (hormonal contraception or intrauterine device in
conjunction with a barrier method); men must use a condom or be surgically sterilized

- patients with active bacterial or viral infections that require treatment with
systemic antibiotics or antiviral agents within 2 weeks prior to the first dose of
OncoVEX^GM-CSF); (note: patients with active cold sores or other HSV1 infections must
wait until those lesions have crusted over before receiving OncoVEX^GM-CSF)

- surgery requiring general or spinal anesthesia within four weeks prior to dosing with
OncoVEX^GM-CSF

- Treatment with an investigational agent within 4 weeks prior to the first dose of
OncoVEX^GM-CSF

- serum carbohydrate antigen (CA)19.9 levels > 3000 U/mL at screening

- evidence of ascites on screening abdominal computed tomography (CT) scan