Abstract PO-005: Phase 1/2 study of Ad/PNP with fludarabine for the treatment of head & neck squamous cell carcinoma (HNSCC)
Bibliographic record
Abstract
Abstract The project pursues clinical testing of a gene-based treatment for refractory malignancy of the head and neck. Background We are evaluating intratumoral nucleoside cleavage by E. coli purine nucleoside phosphorylase (PNP) as an experimental therapy for refractory solid tumors. The approach requires delivery of PNP transgene to tumor parenchyma followed by prodrug administration, and provides “bystander” killing by a very potent purine antimetabolite (F-Ade) generated intratumorally. F-Ade is 1,000-times more potent than fluorouracil, the chemotherapeutic produced by cytosine deaminase (CD; a first-generation construct used for tumor sensitization). PNP/F-Ade has been found to be superior to CD/fluorouracil by several laboratories. In a Phase 1 study (Rosenthal et al., Ann. Oncol.), antitumor activity was observed after IT injections of a recombinant adenovirus encoding PNP (Ad/PNP), followed by IV fludarabine phosphate (F-araAMP, a prodrug converted by PNP to F-Ade). Methods Patients in the present trial have RECIST 1.1 measurable HNSCC amenable to local injection and no other palliative treatment options. A single-arm protocol is being used to evaluate safety of repeat cycles of Ad/PNP and F-araAMP. Ad/PNP is injected intratumorally twice on Day 1 and once on Day 2, followed by infusion of F-araAMP on Days 3, 4, and 5 every 4 weeks for up to 5 cycles. Results Eight patients have been enrolled to date. There have been no dose limiting toxicities, no serious adverse events (SAEs) definitively attributable to treatment, and no AEs above grade 3 severity. Up to five cycles of Ad/PNP treatment have been administered without limiting sequelae. Intratumoral expression of PNP transgene by RT-PCR has been established in treated tumors. Other correlative endpoints are in process and will be discussed. One patient exhibited tumor volume reduction by approximately 21% (as judged by CT imaging) and did not increase during five months of treatment, consistent with clinically stable disease. Two other patients completed three months of Ad/PNP with stable disease by RECIST criteria during the treatment period. Another patient’s tumor (largest dimension 3.1 cm) demonstrated 25% decrease after one treatment cycle. Challenges have included: 1) complexity of distribution of agent into large volume tumors (e.g., >100 ml) with small volume of Ad/PNP, and 2) acute swelling of tumor tissue following intratumoral virus injection in two patients, consistent with inflammatory response and/or disease progression. Conclusions Administration of Ad/PNP is safe and feasible. Injections of large volume tumors remains a challenge. The strategy is also being considered for earlier-stage HNSCC with less tumor burden, including a role similar to neoadjuvant or cytoreductive radiotherapy in combination with checkpoint blockade inhibition. A muti-center trial is planned to define MTD and feasibility in smaller tumors. Citation Format: A. Dimitrios Colevas, Eric J. Sorscher, William B. Parker, Roan Courtney Raymundo, Jeong S. Hong, Regina Rab, Camilo Henao, Nikki Schmitt, Madison Stallings, Kelly T. McKee, Eben Rosenthal, Joseph Curry. Phase 1/2 study of Ad/PNP with fludarabine for the treatment of head & neck squamous cell carcinoma (HNSCC) [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-005.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".