A phase 1b/2 study of nanatinostat and valganciclovir in patients with advanced Epstein-Barr virus positive (EBV<sup>+</sup>) solid tumors and in combination with pembrolizumab in patients with recurrent/metastatic nasopharyngeal carcinoma (RM-NPC).
Bibliographic record
Abstract
TPS6107 Background: Epstein-Barr virus (EBV) is linked to the development and pathogenesis of nasopharyngeal carcinoma (NPC). Most patients present with advanced stage disease at diagnosis (Li 2014); first-line chemoradiation is commonly followed by recurrence and poor prognosis emphasizing the need for new treatment options. Targeting EBV in NPC represents a novel therapeutic approach. EBV is predominantly latent in NPC; pre-clinical studies demonstrated that induction of the viral lytic phase by histone deacetylase inhibitors (HDACi) renders EBV+ tumor cells susceptible to the cytotoxic activity of ganciclovir (GCV) (Hui 2016). Nanatinostat (Nstat), a potent Class-I HDACi, induces the expression of the lytic BGLF4 protein kinase in EBV+ tumor cells, which activates the nucleoside analog GCV via phosphorylation. Phosphorylated GCV becomes incorporated into the cellular DNA causing chain termination and apoptosis. The all-oral combination of Nstat and valganciclovir (VGCV), a pro-drug of GCV, has demonstrated favorable safety and preliminary efficacy in a phase 1/2 study in patients with recurrent EBV+ lymphoma (NCT03397706). This phase 1b/2, open-label, multicenter study will evaluate the safety, tolerability, pharmacokinetics, and preliminary activity of Nstat + VGCV in patients with advanced EBV+ solid tumors. Additionally, the combination of pembrolizumab together with Nstat + VGCV will be evaluated in recurrent/metastatic NPC (RM-NPC) patients. NPC frequently exhibits high PD-L1 expression levels; however, PD-1 inhibitors resulted in limited response rates ranging from 20-30% in the RM-NPC setting. Methods: Phase 1b utilizes a 3+3 dose escalation design to determine the recommended Phase 2 dose (RP2D) of Nstat + VGCV in patients with EBV+ RM-NPC. In Phase 2, up to 60 patients with EBV+ RM-NPC will be randomized 1:1 to receive Nstat + VGCV at the RP2D with or without pembrolizumab to evaluate safety, tolerability, overall response rate, and potential pharmacodynamic markers of drug activity, including plasma EBV DNA levels. Additionally, patients with EBV+ solid tumors other than RM-NPC will receive Nstat + VGCV at the RP2D in a separate Phase 1b dose expansion cohort. Patients eligible for the phase 1b dose escalation and phase 2 will have EBV+ RM-NPC with 1-3 prior lines of platinum-based chemotherapy and no available curative therapies. Patients with advanced EBV+ non-NPC solid tumors (gastric cancer, lymphoepithelioma-like carcinoma, leiomyosarcoma) and no curative therapies are eligible for the phase 1b expansion cohort. All patients must have measurable disease per RECIST v1.1 and adequate bone marrow, liver, and renal function. Enrollment began in January 2022. Clinical trial information: NCT05166577.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.009 | 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".