Nanatinostat Plus Valganciclovir in Patients With Advanced EBV+ Solid Tumors, and in Combination With Pembrolizumab in EBV+ RM-NPC

Study Overview
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Brief Summary
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This study will evaluate the safety and efficacy of nanatinostat in combination with valganciclovir in patients with relapsed/refractory EBV-positive solid tumors and in combination with pembrolizumab in patients with recurrent/metastatic nasopharyngeal carcinoma

Detailed Description
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This is an open-label, multicenter Phase 1b/2 study evaluating nanatinostat in combination with valganciclovir alone and in combination with pembrolizumab. Nanatinostat is a selective class I HDAC inhibitor which induces EBV early lytic phase protein generation, activating (val)ganciclovir to its cytotoxic form. The Phase 1b dose escalation portion is designed to evaluate safety and to determine the recommended Phase 2 dose (RP2D) in patients with EBV+ RM-NPC followed by a Project Optimus | FDA (https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus) cohort to confirm the RP2D. Up to 60 patients with EBV+ RM-NPC will be randomized 1:1 to receive nanatinostat in combination with valganciclovir at the confirmed RP2D with or without pembrolizumab to evaluate safety, overall response rate, and potential pharmacodynamic markers in the Phase 2 dose expansion part of the study. Additionally, patients with other EBV+ solid tumors will be enrolled to receive nanatinostat in combination with valganciclovir at the RP2D in a Phase 1b cohort.

Official Title
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An Open-Label, Multicenter Phase 1b/2 Study of Nanatinostat and Valganciclovir in Patients With Advanced Epstein-Barr Virus-Positive (EBV+) Solid Tumors and in Combination With Pembrolizumab in Patients With Recurrent/Metastatic Nasopharyngeal Carcinoma

Conditions
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Nasopharyngeal Carcinoma, EBV-Related Gastric Carcinoma, EBV-Related Leiomyosarcoma, EBV Related Carcinoma, EBV-Related Sarcoma

Intervention / Treatment
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* Drug: Nanatinostat
* Drug: Nanatinostat
* Drug: Valganciclovir
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Recurrent or metastatic EBV+ nasopharyngeal carcinoma (RM-NPC) for whom no potentially curative options are available, who have received at least 1 prior line of platinum-based chemotherapy and no more than 3 prior lines of therapy for RM-NPC. Phase 1b exploratory proof-of-concept cohort only: Advanced/metastatic EBV+ non-NPC solid tumors with no available curative therapies. Measurable disease per RECIST v1.1 ECOG performance status 0 or 1 Adequate bone marrow and liver function Key Exclusion Criteria: Anti-tumor treatment with cytotoxic drugs, biologic therapy, immunotherapy, or other investigational drugs within 4 weeks or >5 half-lives, whichever is shorter Active CNS disease Inability to take oral medication, malabsorption syndrome or any other gastrointestinal condition (nausea, diarrhea, vomiting) that may impact the absorption of nanatinostat and valganciclovir Active infection requiring systemic therapy Active autoimmune disease that has required systemic therapy with modifying agents, corticosteroids, or immunosuppressive agents Positive hepatitis B or hepatitis C

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A traditional 3+3 dose escalation design followed first by a dose optimization cohort and then by dose expansion with 1:1 randomization to receive nanatinostat and valganciclovir with or without pembrolizumab in Phase 2.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nanatinostat in combination with valganciclovir<br> | Drug: Nanatinostat<br>* Nanatinostat dose escalation starting at 20 mg orally daily, 4 days per week<br>* Other names: VRx-3996;Drug: Valganciclovir<br>* Valganciclovir starting at 900 mg orally daily<br>* Other names: Valcyte;|
| Experimental: Nanatinostat in combination with valganciclovir and pembrolizumab<br> | Drug: Nanatinostat<br>* Nanatinostat at the confirmed RP2D<br>* Other names: VRx-3996;Drug: Valganciclovir<br>* Valganciclovir starting at 900 mg orally daily<br>* Other names: Valcyte;Drug: Pembrolizumab<br>* Pembrolizumab (anti-PD-1) dosed at 200 mg intravenous (IV) every 3 weeks<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Incidence of dose-limiting toxicities (DLTs) |  | DLT period of 28 Days | 
| Phase 2: Overall response rate (ORR) |  | Approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of adverse events |  | Approximately 28 days following the last dose | 
| Duration of response (DOR) |  | Approximately 3 years | 
| Disease control rate (DCR) |  | Approximately 3 years | 
| Progression-free survival (PFS) |  | Approximately 3 years | 
| Overall survival (OS) |  | Approximately 3 years | 
| Pharmacokinetic parameter - time to maximum plasma concentration [tmax] |  | Approximately at 28 days following enrollment | 
| Pharmacokinetic parameter - maximum plasma concentration [Cmax] |  | Approximately 28 days following enrollment | 
| Pharmacokinetic parameter - area under the plasma concentration-time curve [AUC] |  | Approximately 28 days following enrollment |