Dose Escalation & Expansion Study of Oral VRx-3996 & Valganciclovir in Subjects With EBV-Associated Lymphoid Malignancies

Study Overview
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Brief Summary
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A two part, Phase 1b/2 study to define a recommended Phase 2 dose of VRx-3996 in combination with valganciclovir (Phase 1b) designed to evaluate the efficacy of this combination in relapsed/refractory EBV+ lymphomas.

Detailed Description
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The purpose of this study is to determine whether VRx-3996 in combination with valganciclovir is safe, determine the side effect profile, and to determine whether this therapy may help patients with EBV-related lymphomas. The study has two phases. Goals of the first phase include determining a safe and tolerable dose that can be administered in phase 2. Goals of the second phase include further evaluating the safety and tolerability of VRx-3996 in combination with valganciclovir, evaluating how the drugs are metabolized in the body, evaluating response rates and other exploratory objectives that will help the researchers evaluate how these drugs work in the body. Participants will receive daily oral doses of the two study drugs and will have multiple study visits where they will have blood collected, physical examinations, and other medical monitoring. Following completion of the Ph2, the study will enroll additional patients into a PK cohort to investigate the PK parameters of the tablet formulation.

Official Title
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A Phase 1b/2 Open-Label, Dose Escalation & Expansion Study of Orally Administered VRx-3996 & Valganciclovir in Subjects With Epstein-Barr Virus-Associated Lymphoid Malignancies

Conditions
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Epstein-Barr Virus Associated Lymphoma, Lymphoproliferative Disorders

Intervention / Treatment
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* Drug: VRx-3996
* Drug: Valganciclovir


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Relapsed/refractory, pathologically confirmed EBV+ lymphoid malignancy or lymphoproliferative disease Absence of available therapy with reasonable likelihood of cure or significant clinical benefit Adequate hematologic, hepatic and renal function as defined by laboratory assessment Key Exclusion Criteria: Known primary CNS lymphoma Known CNS metastases or leptomeningeal disease unless appropriately treated and neurologically stable for at least 4 weeks Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy Refractory graft versus host disease (GvHD) not responding to treatment Known active hepatitis B virus infection Circulating hepatitis C virus on qPCR Known history of HHV-6 chromosomal integration Known history of HIV infection

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: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1: dose escalation phase (3+3 design with definitions of dose limiting toxicity) to define a recommended phase 2 dose Phase 2: dose expansion PK Cohort
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b Dose Escalation<br>VRx-3996 (cohort 1) and valganciclovir VRx-3996 (cohort 2) and valganciclovir VRx-3996 (cohort 3) and valganciclovir VRx-3996 (cohort 4) and valganciclovir VRx-3996 (cohort 5) and valganciclovir | Drug: VRx-3996<br>* Taken orally once or twice daily<br>* Other names: Nanatinostat;Drug: Valganciclovir<br>* Taken orally once or twice daily<br>|
| Experimental: Phase 2 Dose Expansion<br>VRx-3996 (RP2D: recommended phase 2 dose) and valganciclovir | Drug: VRx-3996<br>* Taken orally once or twice daily<br>* Other names: Nanatinostat;Drug: Valganciclovir<br>* Taken orally once or twice daily<br>|
| Experimental: PK Cohort<br>Assessment of VRx-3996 tablet and valganciclovir PK parameters at the RP2D | Drug: VRx-3996<br>* Taken orally once or twice daily<br>* Other names: Nanatinostat;Drug: Valganciclovir<br>* Taken orally once or twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events and changes in clinical safety laboratory values in Dose Escalation and Cohort Expansion | Determination of a safe and tolerable Recommended Phase 2 Dose (RP2D) | Up to approximately 2 years | 
| Incidence of Dose Limiting Toxicities in Dose Escalation and Cohort Expansion |  | Up to approximately 2 years | 
| ORR as measured by stable disease (SD), partial response (PR), and complete response (CR) by radiographic assessment |  | Up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Single-dose and steady-state Cmax of VRx-3996 and valganciclovir | PK assessment of both VRx-3996 and valganciclovir pre-dose and at hours 0.5, 1, 2, 4, and 6 post-dose on C1 and C2D1 and pre-dose and at hour 2 on C1D2 ,C1D15, and C2D15 | Through Cycle 2 Day 15 (each cycle is 28 days) | 
| Single-dose and steady-state AUC of VRx-3996 and valganciclovir | PK assessment of both VRx-3996 and valganciclovir pre-dose and at hours 0.5, 1, 2, 4, and 6 post-dose on C1 and C2D1 and pre-dose and at hour 2 on C1D2 ,C1D15, and C2D15 | Through Cycle 2 Day 15 (each cycle is 28 days) | 
| Steady-state elimination half-life of VRx-3996 and valganciclovir | PK assessment of both VRx-3996 and valganciclovir pre-dose and at hours 0.5, 1, 2, 4, and 6 post-dose on C1 and C2D1 and pre-dose and at hour 2 on C1D2, C1D15, and C2D15 | Through Cycle 2 Day 15 (each cycle is 28 days) | 
| Time to response | The time from the start of first study drug administration to the first overall tumor response observed for subjects who achieved a CR or PR | Approximately 6 months | 
| Duration of response | The time interval (days) from date of the first overall response (CR or PR; achieved after study drug administration) to the date of disease progression | Up to approximately 2 years | 
| Progression-free survival | The interval between the date of first study drug administration and the date of PD or death, whichever is first reported | Up to approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EBV+ post-transplant lymphoproliferative malignancy, EBV-associated lymphoproliferative disorders associated with acquired immunodeficiency, Relapsed, refractory, EBV+ lymphoid malignancy