Safety and Efficacy of Repeat Administration of Ad/PNP and Fludarabine Phosphate in Patients With Local Head/Neck Cancer

1. Mechanism of action. The study drug, Ad/PNP-F-araAMP (Fludarabine phosphate) consists of
a nonreplicating adenoviral vector expressing the E. coli purine nucleoside
phosphorylase (PNP) injected intratumorally followed by intravenous administration of
F-araAMP. This combination generates 2-fluoroadenine (F-Ade) within the tumor resulting
in focal chemotherapeutic activity.

F-araAMP is an agent that is rapidly cleaved by plasma phosphatases to fludarabine,
which is the primary circulating form of the drug and has activity against certain
hematological malignancies, but not against solid tumors such as head and neck squamous
cell carcinoma (HNSCC). Fludarabine (F-araA) is an adenosine analog and substrate for E.
coli PNP, which cleaves the glycosidic bond of F-araA to generate F-Ade. The F-Ade
metabolite has shown pronounced activity against human tumor xenografts in mice.

Many refractory tumors are refractory precisely because they have a very low growth
fraction, i.e., a relatively small percentage of tumor cells dividing at any particular
point in time. In nonclinical studies, significant in vivo antitumor activity has been
demonstrated by F-Ade generation from F-araAMP in tumors in which 2.5 to 10% of cells
express the E. coli PNP gene. In addition, anti-tumor effect was seen in patients with
advanced solid tumors (melanoma and head and neck cancer) in the higher dose cohorts
during a Phase 1 study (see next section).

2. Tumor response with Ad/PNP-F-araAMP in Phase 1 Study. The safety and efficacy of
Ad/PNP-F-araAMP has been evaluated in a Phase 1 study, PNP-001. Four escalating dose
levels were evaluated in 10 subjects with head and neck cancer and 2 subjects with
melanoma; clinical activity was observed at the highest dose levels following 3
intratumoral injections of Ad/PNP over 2 days and IV F-araAMP phosphate over 3 days. The
overall response rate (CR+PR) was approximately 67% in the 2 highest dose cohorts,
Cohorts 3 and 4. Results suggest a dose response effect. The duration of response in the
injected tumor was limited, with 4 of 5 responding tumors having disease progression of
the injected lesion prior to last follow-up on Day 56, suggesting that repeat
administration should be evaluated. Ad/PNP + F-araAMP was well tolerated. No subject
experienced a dose-limiting toxicity and none of the subjects discontinued study
treatment. Overall, the activity and safety profile of Ad/PNP seen in the Phase 1 study
supports further clinical evaluation of repeat administration of Ad/PNP (IT) and
F-araAMP phosphate infusion for patients with HNSCC.

3. Purpose of the Study. Based upon the tumor response seen with a single administration of
the two highest dose levels of Ad/PNP-F-araAMP in the Phase 1 study, PNP plans to
investigate the safety and assess anti-tumor activity of repeat cycles of injection of
Ad/PNP + F-araAMP in patients with advanced head and neck cancer. Subjects in the study
will have RECIST 1.1 measurable HNSCC which is amenable to local injection for which
there is no effective curative or palliative treatment option. This study population was
selected since results from this Phase 1/2 trial are intended to support the safety of
repeat dosing in further clinical investigation.

4. Study Design. The trial is designed as a single-arm study to evaluate the safety of
repeat cycles of Ad/PNP and F-araAMP in patients with recurrent HNSCC with tumor(s)
accessible for injection. Ad/PNP will be injected intratumorally twice on Day 1 and once
on Day 2 followed by infusion of F-araAMP daily on Days 3, 4, and 5. Subjects will
receive repeat administration of Ad/PNP-F-araAMP every 4 weeks (i.e., each cycle) for 5
cycles or until injected tumor progresses, unacceptable toxicity occurs, no tumor is
present for injection, or patient death. Tumor response in the injected tumor(s) will be
assessed by physical examination as well as by radiographic imaging. All subjects will
be monitored for adverse events during study participation.

Inclusion Criteria:

1. Provided Informed Consent

2. Age ≥ 18 years

3. Patients with histologically or cytologically confirmed diagnosis of recurrent HNSCC
for whom there is no curative treatment option. For the purposes of trial eligibility,
HNSCC may include, in addition to the usual mucosal sites, cutaneous squamous cell
primary sites and squamous cell carcinoma of unknown primary presenting with neck
lymph nodal disease, and nasopharyngeal carcinoma.

4. All standard or approved treatment options that would provide substantive palliation
must have failed, been exhausted, or patient not eligible or willing to use them (for
example neuropathy, nephropathy , or hearing loss precluding the use of cisplatin)

5. Tumor mass (primary tumor and/or lymphadenopathy) technically suitable for IT
injections (otolaryngologist will determine feasibility). Patients with nodal disease
(or metastatic disease) that is needle accessible are eligible. Patients with
additional tumors (including distant metastatic disease) beyond the IT injection
accessible tumor(s) that are not accessible for intratumoral injection are eligible
only if the patient has no other curative treatment option for the metastatic disease
and treatment of local disease may provide the patient some benefit or palliation.

6. Eastern Cooperative Oncology Group performance status of ≤ 2

7. In the judgment of the Investigator, the patient has recovered sufficiently from any
previous significant therapy side effects or toxicities prior to Ad/PNP
administration.

8. Absolute neutrophil count ≥ 1,500 cells/ul; hemoglobin ≥ 9 g/dl, platelets ≥
100,000/ul

9. Serum creatinine ≤ 1.5 mg/dl, or calculated creatinine clearance ≥ 60 ml/min

10. Bilirubin ≤ upper limit of normal, alanine aminotransferase ≤ 1.5 x upper limit of
normal and/or aspartate aminotransferase ≤ 1.5 x upper limit of normal, alkaline
phosphatase ≤ 2.5 x upper limit of normal

11. Prothrombin time (PT)/international normalized ratio (INR) ≤ 1.5 x upper limit of
normal

12. Activated partial thromboplastin (aPTT) time ≤ 1.5 x upper limit of normal

13. Female patients must have a negative urine or serum pregnancy at screening (pregnancy
test is not required for patients with bilateral oophorectomy and/or hysterectomy or
for those patients who are > 1 year postmenopausal)

14. All patients of reproductive potential must agree to use a medically acceptable form
of contraception (eg, hormonal birth control, double-barrier method) or abstinence.

Exclusion Criteria:

1. Prior history or current diagnosis of leukemia

2. Have received any gene therapy products or oncolytic viral therapy

3. Receiving allopurinol

4. Received an investigational drug within 30 days prior to first injection of Ad/PNP

5. Received radiation treatment < 4 weeks prior to first injection of Ad/PNP, and does
not have any RECIST 1.1 evaluable lesions that are outside the radiation field. (If
the patient has RECIST 1.1 evaluable lesions outside the radiation field then they can
be included.)

6. Received chemotherapy (systemic anticancer treatment) < 4 weeks prior to first
injection of Ad/PNP and has not recovered from all the related side effects. (If the
patients has recovered from related side effects or has reached a new baseline then
can be included)

7. Has significant baseline neuropathy (> grade 2 based on CTCAE v4.0)

8. Uncontrolled intercurrent disease (e.g., diabetes, hypertension, thyroid disease,
active infection)

9. Had within 6 months prior to enrollment: Myocardial infarction, cerebral vascular
accident, uncontrolled congestive heart failure, significant liver disease, unstable
angina

10. Fever (temperature > 38.1 degrees C orally)

11. Receiving chronic systemic corticosteroids (> 3 weeks) or any chronic
immunosuppressive medications within 14 days prior to first injection of Ad/PNP.
Subjects receiving short courses of corticosteroids are considered eligible for the
study.

12. Receiving anticoagulants other than those to maintain patency of venous lines

13. Women who are pregnant or breast feeding

14. History of HIV infection. No requirement for testing.