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

Phase 1/2, Open-label Study Evaluating Safety of Repeat Administration of Ad/PNP-F-araAMP (Ad/PNP Administered Intratumorally Followed by Intravenous Fludarabine Phosphate) in Subjects With Recurrent, Local Head and Neck Cancer

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.

Study Overview

• Status: Recruiting
• Conditions: Recurrent Head and Neck Cancer
• Intervention / Treatment: Biological: Ad/PNP; Drug: Fludarabine Phosphate

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Chief Medical Officer; Phone Number: 678-384-7220; Email: info@geovax.com
• Study Contact Backup: Name: Director Clinical Operations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Recruiting
      • Stanford University
      • Contact: Luis Martinez Ramirez; Phone Number: 650-736-2344; Email: martluis@stanford.edu
      • Contact: A. Dimitrios Colevas, MD; Phone Number: 650-724-9707; Email: colevas@stanford.edu
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Winship Cancer Institute - Emory University School of Medicine
      • Contact: Madison Miller Stallings; Phone Number: 404-686-1794; Email: madison.miller.stallings@emory.edu
      • Contact: Nicole C. Schmitt, MD, FACS; Phone Number: 404-778-1900; Email: nicole.cherie.schmitt@emory.edu
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Recruiting
      • Thomas Jefferson University
      • Contact: Camilo Henao, MPH; Phone Number: 215-955-9959; Email: Camilo.Henao@jefferson.edu
      • Contact: Joseph M Curry, MD, FACS; Phone Number: 215-955-6760; Email: joseph.curry@jefferson.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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.

Exclusion Criteria:

1. Prior history or current diagnosis of leukemia
2. Have received any gene therapy products or oncolytic viral therapy
3. Receiving allopurinol
4. Received an investigational drug within 30 days prior to first injection of Ad/PNP
5. 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.)
6. 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 patient has recovered from all related side effects or has reached a new baseline, then they may begin receiving treatment at sooner than 4 weeks)
7. Have significant baseline neuropathy (> Grade 2 based on Common Terminology Criteria for Adverse events [CTCAE] v5.0)
8. Uncontrolled intercurrent disease (e.g., diabetes, hypertension, thyroid disease, active infection)
9. Had within 6 months prior to enrollment: Myocardial infarction, cerebral vascular accident, uncontrolled congestive heart failure, significant liver disease, unstable angina
10. Fever (temperature > 38.1 degrees C orally)
11. 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.
12. Receiving anticoagulants other than those to maintain patency of venous lines
13. Women who are pregnant or breast feeding
14. History of HIV infection. No requirement for testing.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ad/PNP + fludarabine phosphate, 5 cycles	Biological: Ad/PNP; Ad/PNP is a replication defective adenoviral vector expressing E. coli Purine Nucleoside Phosphorylase; Other Names: Gedeptin; Drug: Fludarabine Phosphate; Fludarabine phosphate is an anticancer agent currently used to treatment patients with chronic lymphocytic leukemia.; Other Names: Fludara

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety as measured by the number of adverse events Grade 2 and above that are considered by investigator to be definitely, probably, or possibly related to study treatment, graded according to Common Terminology Criteria for Adverse Effects v. 4.0	Adverse events Grade 2 and above that are considered by investigator to be definitely, probably, or possibly related to study treatment will be collected from initial dose through 60 days after last dose of study drug. Outcome measure will be reported as the number of events for each dose group, and all safety events will be summarized with descriptive statistics.	up to 60 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Overall Response (ORR) per RECIST 1.1.	Best durable overall response (ORR) defined as CR or partial response determined by RECIST 1.1 persisting for at least 4 weeks	Six months
Progression Free Survival (PFS)	Progression Free Survival (PFS) defined as time from first intratrumoral injection to date of progression or to death, whichever occurs first.	Six months
Duration of treatment response	Duration of treatment response defined as time from first documentation of CR or PR until first occurrence of disease progression or death.	Six months

Collaborators and Investigators

• Sponsor: GeoVax, Inc.
• Collaborators: Emory University; Stanford University; Thomas Jefferson University
• Investigators: Principal Investigator: A. Dimitrios Colevas, MD, Stanford University

Publications and helpful links

General Publications

• Parker WB, Sorscher EJ. Use of E. coli Purine Nucleoside Phosphorylase in the Treatment of Solid Tumors. Curr Pharm Des. 2017 Nov 8:10.2174/1381612823666171109101851. doi: 10.2174/1381612823666171109101851. Online ahead of print.
• Rosenthal EL, Chung TK, Parker WB, Allan PW, Clemons L, Lowman D, Hong J, Hunt FR, Richman J, Conry RM, Mannion K, Carroll WR, Nabell L, Sorscher EJ. Phase I dose-escalating trial of Escherichia coli purine nucleoside phosphorylase and fludarabine gene therapy for advanced solid tumors. Ann Oncol. 2015 Jul;26(7):1481-7. doi: 10.1093/annonc/mdv196. Epub 2015 Apr 21.

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2019
• Primary Completion (Estimated): May 1, 2024
• Study Completion (Estimated): August 1, 2025

Study Registration Dates

• First Submitted: October 19, 2018
• First Submitted That Met QC Criteria: November 26, 2018
• First Posted (Actual): November 27, 2018

Study Record Updates

• Last Update Posted (Estimated): August 31, 2023
• Last Update Submitted That Met QC Criteria: August 30, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Fludarabine; Adenovirus; Head & neck squamous cell carcinoma
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Fludarabine; Fludarabine phosphate
• Other Study ID Numbers: PNP-002; R01FD005746-01A1 (U.S. FDA Grant/Contract); 14271 (Registry Identifier: IND)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No