Georgia's Online Cancer Information Center

Find A Clinical Trial

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

Status
Active
Cancer Type
Head and Neck Cancer
Trial Phase
Phase I
Phase II
Eligibility
18 Years and older, Male and Female
Study Type
Treatment
NCT ID
NCT03754933
Protocol IDs
PNP-002 (primary)
NCI-2019-01328
14271
R01FD005746-01A1
Study Sponsor
GeoVax, Inc.

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.
**Clinical trials are research studies that involve people. These studies test new ways to prevent, detect, diagnose, or treat diseases. People who take part in cancer clinical trials have an opportunity to contribute to scientists’ knowledge about cancer and to help in the development of improved cancer treatments. They also receive state-of-the-art care from cancer experts... Click here to learn more about clinical trials.
Georgia CORE

 

Advancing Cancer Care through Partnerships and Innovation

Georgia CORE is a statewide nonprofit that leverages partnerships and innovation to attract more clinical trials, increase research, and promote education and early detection to improve cancer care for Georgians in rural, urban, and suburban communities across the state.