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.