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

Summary

Objectives

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.