Summary

Primary Objective: The primary objective of the study is to evaluate the safety of repeat
administration of a dose level of Ad/PNP plus fludarabine phosphate (F-araAMP) which
demonstrated anti-tumor activity in patients with advanced head and neck cancer in a
completed phase I study.

Secondary Objective: The secondary objective is to evaluate the antitumor activity of
repeat administration of Ad/PNP plus F-araAMP.

FDA Office of Orphan Drugs Division is a source of funding for the overall project.

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.

Eligibility

1. Provided Informed Consent
2. Age = 18 years
3. Patients with histologically or cytologically confirmed diagnosis of recurrent cancer of the head and neck region for whom there is no curative treatment option. For the purposes of trial eligibility, cancers of the head and neck shall include, in addition to head and neck squamous cell carcinoma (HNSCC), cutaneous squamous cell primary sites and squamous cell carcinoma of unknown primary presenting with neck lymph nodal disease, as well as nasopharyngeal carcinoma, and salivary gland tumors.
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) measurable by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and technically suitable for intratumoral 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 intratumoral injection accessible tumor(s) that are not accessible for intratumoral injection are eligible ONLY if the patient has no other 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.