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

  • End date
    Aug 21, 2023
  • participants needed
  • sponsor
    PNP Therapeutics, Inc.
Updated on 21 March 2021


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, locoregional head/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.


  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.

Condition Recurrent Head and Neck Carcinoma, Recurrent Head and Neck Cancer
Treatment fludarabine phosphate, Ad/PNP
Clinical Study IdentifierNCT03754933
SponsorPNP Therapeutics, Inc.
Last Modified on21 March 2021


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Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have Recurrent Head and Neck Cancer?
Do you have any of these conditions: Recurrent Head and Neck Carcinoma or Recurrent Head and Neck Cancer?
Do you have any of these conditions: Recurrent Head and Neck Carcinoma or Recurrent Head and Neck Cancer?
Do you have any of these conditions: Recurrent Head and Neck Cancer or Recurrent Head and Neck Carcinoma?
Provided Informed Consent
Age 18 years
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
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)
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
Eastern Cooperative Oncology Group performance status of 2
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
Absolute neutrophil count 1,500 cells/ul; hemoglobin 9 g/dl, platelets 100,000/ul
Serum creatinine 1.5 mg/dl, or calculated creatinine clearance 60 ml/min
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
Prothrombin time (PT)/international normalized ratio (INR) 1.5 x upper limit of normal
Activated partial thromboplastin (aPTT) time 1.5 x upper limit of normal
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)
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

Prior history or current diagnosis of leukemia
Have received any gene therapy products or oncolytic viral therapy
Receiving allopurinol
Received an investigational drug within 30 days prior to first injection of Ad/PNP
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.)
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)
Has significant baseline neuropathy (> grade 2 based on CTCAE v4.0)
Uncontrolled intercurrent disease (e.g., diabetes, hypertension, thyroid disease, active infection)
Had within 6 months prior to enrollment: Myocardial infarction, cerebral vascular accident, uncontrolled congestive heart failure, significant liver disease, unstable angina
Fever (temperature > 38.1 degrees C orally)
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
Receiving anticoagulants other than those to maintain patency of venous lines
Women who are pregnant or breast feeding
History of HIV infection. No requirement for testing
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