Study of Talimogene Laherparepvec (T-VEC) in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDA) is an area of great unmet need. PDA accounts for 90%
of pancreatic tumors in 2016. The standard of care for pancreas cancer is cytotoxic
chemotherapy, but this is not particularly effective with best response rates reported of
20-30% and no significant long-term 5-year survival for patients who are not surgical
candidates. Talimogene laherparepvec (previously known as OncoVEXGM-CSF) is an intratumorally
delivered oncolytic immunotherapy comprised of an immune-enhanced herpes simplex virus type-1
(HSV-1) that selectively replicates in solid tumors. Talimogene laherparepvec was the first
oncolytic viral therapy to be approved by the Federal Drug Administration (FDA) for the
treatment of cancer, specifically melanoma. There is the potential that talimogene
laherparepvec could exert a systemic effect mitigating the potential of PDA to metastasize.

This is a phase 1 dose escalation study to evaluate the safety of talimogene laherparepvec in
PDA. To find out which doses are safe, all participants enrolled in this study will receive
up to 4 injections of T-Vec. At least two doses will be evaluated in this study, depending on
how many side effects are seen at each dose. Participants will not be able to pick the dose,
as this will be determined based on the study experience with participants enrolled
previously.

Inclusion Criteria:

1. Patient must have pathologically confirmed, locally advanced or metastatic pancreatic
adenocarcinoma deemed surgically unresectable by a surgeon with expertise in
pancreatic cancer

2. Disease must be refractory to or intolerant of at least first-line chemotherapy which
contains 5-fluorouracil or gemcitabine

3. The primary lesion must be accessible for endoscopic biopsy and injection as evaluated
by a gastroenterologist at NewYork Presbyterian -Columbia. Further, the patient must
be deemed able to tolerate repeated endoscopy procedures by an anesthesiologist and/or
gastroenterologist at NewYork Presbyterian-Columbia

4. Age 18 years or older

5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2

6. Radiologically measurable disease in the pancreas ≥1cm, as defined by RECIST v1.1

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

8. Females of child-bearing potential (defined as a sexually mature woman who (1) has not
undergone hysterectomy [the surgical removal of the uterus] or bilateral oophorectomy
[the surgical removal of both ovaries] or (2) has not been naturally postmenopausal
for at least 24 consecutive months [i.e., has had menses at any time during the
preceding 24 consecutive months]) must:

i. Either commit to true abstinence from heterosexual contact (which must be reviewed
on a monthly basis), or agree to use, and be able to comply with, effective
contraception ( starting therapy (including dose interruptions), and while on study medication or for
a period of 30 days following treatment completion. [Periodic abstinence (eg,
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not
acceptable methods of contraception].

ii. 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.This applies even if the subject practices true abstinence from
heterosexual contact.

9. Male subjects must practice true abstinence or agree to use a condom during sexual
contact with a pregnant female or a female of childbearing potential while
participating in the study, during dose interruptions and for 30 days following
treatment discontinuation, even if he has undergone a successful vasectomy.

10. Adequate organ and marrow function as defined below without need for hematopoietic
growth factor or transfusion support:

- Hemoglobin ≥8.0g/dl

- Platelets ≥75,000/microliter (mcL)

- Absolute neutrophil count (ANC) ≥1500/mm3 (1.5x109/L)

- Total bilirubin ≤1.5 x institutional upper limit of normal (ULN) or Direct
bilirubin ≤ ULN with total bilirubin >1.5 x ULN

- Aspartate aminotransferase (AST) (SGOT)/alanine transaminase (ALT) (SGPT) ≤1.5 x
ULN

- INR and aPTT ≤ 1.5 x ULN Unless the patient is on therapeutic anticoagulation in
which case the international normalized ratio (INR) and activated partial
thromboplastin time (aPTT) must be within the therapeutic range of intended use
of anti-coagulants

- Serum creatinine ≤1.5 x ULN or Creatinine clearance ≥60 mL/min/1.73 m2 by
Cockcroft-Gault

- Lipase ≤3 x ULN

Exclusion Criteria:

1. Cystic pancreatic cancer. Microcystic disease may be eligible

2. Patients with pancreatic metastases deemed likely to limit the patient's ability to
participate in the study for the complete duration (ie. >3 months), including but not
limited to:

1. Presence of central nervous system (CNS) metastasis including brain metastasis or
compromise resulting from extrinsic disease in the bone or dura

2. Presence of more than 5 liver metastases or one liver metastasis measuring more
than 3cm

3. Cancer antigen (CA)19-9 >3000 U/mL

4. Oxygen requirement attributable to pleural effusion or other malignant process

5. Symptomatic ascites or radiographic evidence of more than trace ascites

3. Pancreatitis that is active or within the preceding 3 months which in the judgment of
the endoscopist would make tumor injection likely to trigger severe recurrent
pancreatitis.

4. Prior chemotherapy or radiotherapy within 14 days prior to first dose of therapy or
has not recovered to CTCAE grade 1 or better from adverse event at time of enrollment
due to cancer therapy administered more than 28 days prior to enrollment. or prior
biological cancer therapy, targeted therapy, or major surgery within 28 days prior to
first dose of therapy or unresolved grade 2 or greater toxicity from prior treatment,
including chemotherapy, hormonal therapy, or radiotherapy, at the time of study
enrollment. The following ongoing treatments are permitted:

1. Hormone-replacement therapy or oral contraceptives

2. Hormone therapy for primary prevention of breast cancer

5. Patients may not receive Coumadin while on study. Patients may receive low molecular
weight heparin or novel oral anticoagulants (eg. dabigatran, apixaban, rivaroxaban)
provided that the dose is held 1-2 days before injections are given and biopsies are
performed per the protocol. Anti-platelet agents and herbal substances are allowed at
the discretion of the treating endoscopist.

6. Active herpetic skin lesions or prior complications of herpetic infection (e.g.,
herpetic keratitis or encephalitis) or requires intermittent or chronic systemic
(intravenous or oral) treatment with an antiherpetic drug (e.g., acyclovir), other
than intermittent topical use.

7. Previous treatment with talimogene laherparepvec or any other oncolytic virus

8. Prior therapy with tumor vaccine

9. 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.

10. Known to have acute or chronic active hepatitis B infection, hepatitis C infection, or
known to have human immunodeficiency virus (HIV) infection.

11. Subject has known sensitivity to talimogene laherparepvec or any of its components to
be administered during dosing.

12. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection including Tuberculosis (TB) and C. difficile, symptomatic congestive heart
failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social
situations that would limit compliance with study requirements. This includes known
clinically significant liver disease, including active viral, alcoholic, or other
hepatitis; cirrhosis; fatty liver; and inherited liver disease

13. Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to
hospitalization for complications of infection, bacteremia, or severe pneumonia

14. Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of
need for a major surgical procedure during the course of the study

15. 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. (Note: Women not of childbearing potential are
defined as: Any female who is post-menopausal [age > 55 years with cessation of menses
for 12 or more months or less than 55 years but not spontaneous menses for at least 2
years or less than 55 years and spontaneous menses within the past 1 year, but
currently amenorrheic (eg, spontaneous or secondary to hysterectomy), and with
postmenopausal gonadotropin levels (luteinizing hormone and follicle-stimulating
hormone levels > 40 IU/L) or postmenopausal estradiol levels (< 5 ng/dL) or according
to the definition of "postmenopausal range" for the laboratory involved] or who have
had a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy).

16. 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.

17. Subject who is 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 children under the age of 1 year, during talimogene laherparepvec treatment and
through 30 days after the last dose of talimogene laherparepvec.

Immunotherapy-Related Exclusion Criteria:

18. 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 for patients with prior allogeneic bone marrow transplantation or
prior solid organ transplantation.

• The use of inhaled or oral corticosteroids and mineralocorticoids (e.g.,
fludrocortisone) for patients with orthostatic hypotension or adrenocortical
insufficiency is allowed.

19. Received live vaccine within 28 days prior to enrollment.

20. Evidence of clinically significant immunosuppression such as the following:

- Primary immunodeficiency state such as Severe Combined Immunodeficiency Disease

- HIV positive

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

- Concurrent opportunistic infection