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

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 Tablet Pharmacokinetic (PK) cohort to investigate the PK parameters of the tablet formulation.

• VRx-3996 and valganciclovir (Combination product), also known as nanatinostat, ganciclovir, Chroma (CHR)-3996: second-generation histone deacetylase (HDAC) inhibitor, nanatinostat (previously referred to as either VRx-3996 or CHR-3396)

Primary outcomes

• Number (Proportion) of Participants With Adverse Events (AEs) [Up to approximately 2 years]: Number (percentage) of patients experiencing at least one treatment-emergent adverse event, defined as those untoward medical events with onset after the first dose of study drug or existing events that worsened after the first dose during the study
• Number (Proportion) of Participants With Dose-Limiting Toxicities (DLTs) in Phase 1b [Cycle 1 (28 days)]: Number (percentage) of patients experiencing a DLT during the first cycle (28 days) of study treatment in Phase 1b, defined as an adverse event (AE) or clinically significant abnormal laboratory value that was at least possibly related to study drugs and was not primarily related to disease, disease progression, concomitant medication(s), or intercurrent illness. In addition, to be considered a DLT, the AE had to meet at least one of the following criteria: * Grade 4 anemia unexplained by underlying disease * Grade 4 febrile neutropenia * Grade 4 neutropenia lasting >5 days * Any other Grade 4 hematologic toxicity (thrombocytopenia, neutropenia, febrile neutropenia, anemia) of any duration * Grade 4 or higher tumor lysis syndrome * Grade 3 or higher thrombocytopenia (with or without bleeding) * Any requirement for platelet transfusion * Grade 3 or higher non-hematologic toxicity despite adequate supportive care * Results in a dose hold of >7 consecutive days
• Overall Response Rate [Up to approximately 2 years]: Number (percentage) of patients with a best overall complete response (CR) or partial response (PR) according to the Lugano 2014 criteria (Cheson, Bruce D. et al. J Clin Oncology 2014;32(27):3059-68), where CR included complete metabolic response (no/minimal fluorodeoxyglucose \[FDG\] uptake) and radiologic response (target lesions regress to ≤1.5 cm in longest transverse diameter of a lesion) and no new lesions, and PR included partial metabolic response (reduced FDG uptake compared with baseline) or radiologic response (target lesions ≤ 50% decrease in the sum of the product of perpendicular diameters of up to 6 target measurable nodes and extranodal sites)

Secondary outcomes

• Duration of Response [Up to approximately 2 years]: Interval of time from date of first observed complete or partial response per Lugano 2014 criteria (Cheson BD et al. J Clin Oncology 2014;32(27):3059-68) to the date of documented disease progression or death due to any cause, where disease progression is defined by Lugano 2014 criteria (Cheson BD et al. J Clin Oncology 2014;32(27):3059-68) as progressive metabolic disease (increase in fluorodeoxyglucose \[FDG\] uptake from baseline or new FDG-avid foci consistent with lymphoma) or progressive radiologic response (increase in the product of perpendicular diameters of a single node by ≥ 50% or emergence of a new lesion)
• Time to Response [Up to approximately 2 years]: Interval of time from the start of study drug treatment to the first documentation of CR or PR per Lugano 2014 criteria (Cheson BD et al. J Clin Oncology 2014;32(27):3059-68)
• Progression-Free Survival [Up to approximately 2 years]: Interval of time from the date of first study drug administration to the documented date of disease progression or death, whichever occurred first, where disease progression is defined by Lugano 2014 criteria (Cheson BD et al. J Clin Oncology 2014;32(27):3059-68) as progressive metabolic disease (increase in fluorodeoxyglucose \[FDG\] uptake from baseline or new FDG-avid foci consistent with lymphoma) or progressive radiologic response (increase in the product of perpendicular diameters of a single node by ≥ 50% or emergence of a new lesion)
• Disease Control Rate [Up to approximately 2 years]: Number (percentage) of patients with CR, PR, or stable disease (SD) per Lugano 2014 criteria (Cheson BD et al. J Clin Oncology 2014;32(27):3059-68)
• Overall Survival [Up to approximately 2 years]: Interval of time from date of first study drug treatment to date of death, for any reason (patients without documentation of death at the time of analysis were censored at the date the patient was last known to be alive)
• Cmax (ng/mL) of VRx-3996 [Phase 1b: Cycle 1 Day 1 and Phase 2: multiple doses through Cycle 2 Day 1]: Pharmacokinetic (PK) assessment of VRx-3996 pre-dose and at hours 0.5, 1, 2, 4, and 6 post-dose on cycle 1 day 1 (C1D1) and cycle 2 day 2 (C2D1)
• Cmax (ng/mL) of Valganciclovir [Phase 1b: Cycle 1 Day 1 and Phase 2: multiple doses through Cycle 2 Day 1]: PK assessment of valganciclovir pre-dose and at hours 0.5, 1, 2, 4, and 6 post-dose on C1D1 and C2D1
• Area Under Curve (AUC) 0-t of VRx-3996 [Phase 1b: Cycle 1 Day 1 and Phase 2: multiple doses through Cycle 2 Day 1]: PK assessment of VRx-3996 pre-dose and at hours 0.5, 1, 2, 4, and 6 post-dose on C1D1 and C2D1
• AUC 0-t of of Valganciclovir [Phase 1b: Cycle 1 Day 1 and Phase 2: multiple doses through Cycle 2 Day 1]: PK assessment of valganciclovir pre-dose and at hours 0.5, 1, 2, 4, and 6 post-dose on C1D1 and C2D1
• Half-life of VRx-3996 [Phase 1b: Cycle 1 Day 1 and Phase 2: multiple doses through Cycle 2 Day 1]: PK assessment of VRx-3996 pre-dose and at hours 0.5, 1, 2, 4, and 6 post-dose on C1D1 and C2D1
• Half-life of Valganciclovir [Phase 1b: Cycle 1 Day 1 and Phase 2: multiple doses through Cycle 2 Day 1]: PK assessment of valganciclovir pre-dose and at hours 0.5, 1, 2, 4, and 6 post-dose on C1D1 and C2D1

Sex: All, ages: 18 Years to any

Key Inclusion Criteria:

* Relapsed/refractory, pathologically confirmed Epstein-Barr Virus positive (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 central nervous system (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 quantitative polymerase chain reaction (qPCR)
* Known history of human herpes virus (HHV)-6 chromosomal integration
* Known history of HIV infection

Participant flow

Outcome results

• Number (Proportion) of Participants With Adverse Events (AEs) (Primary), Count of participants, Participants: Phase 1b Dose Escalation Cohort 1 7; Phase 1b Dose Escalation Cohort 2a 5; Phase 1b Dose Escalation Cohort 2b 4; Phase 1b Dose Escalation Cohort 2c 4; Phase 1b Dose Escalation Cohort 3 5; Phase 2 Dose Expansion - Capsule 30; Phase 2 Dose Expansion - Tablet 9
• Number (Proportion) of Participants With Dose-Limiting Toxicities (DLTs) in Phase 1b (Primary), Count of participants, Participants: Phase 1b Dose Escalation Cohort 1 4; Phase 1b Dose Escalation Cohort 2a 0; Phase 1b Dose Escalation Cohort 2b 0; Phase 1b Dose Escalation Cohort 2c 0; Phase 1b Dose Escalation Cohort 3 (RP2D) 0
• Overall Response Rate (Primary), Count of participants, Participants: Phase 1b Dose Escalation Cohort 1 2; Phase 1b Dose Escalation Cohort 2a 1; Phase 1b Dose Escalation Cohort 2b 0; Phase 1b Dose Escalation Cohort 2c 0; Phase 1b Dose Escalation Cohort 3 1; Phase 2 Dose Expansion - Capsule 3; Phase 2 Dose Expansion - Tablet 1
• Duration of Response (Secondary), Median, days: Phase 1b Dose Escalation Cohort 1 825.5 (160.0 to NA); Phase 1b Dose Escalation Cohort 2a 116.5 (34.0 to NA); Phase 1b Dose Escalation Cohort 2b 113.0 (NA to NA); Phase 1b Dose Escalation Cohort 2c ; Phase 1b Dose Escalation Cohort 3 NA (127.0 to NA); Phase 2 Dose Expansion - Capsule 634.0 (80.0 to NA); Phase 2 Dose Expansion - Tablet NA (57.0 to NA)
• Time to Response (Secondary), Median, days: Phase 1b Dose Escalation Cohort 1 NA (33.0 to NA); Phase 1b Dose Escalation Cohort 2a 52.5 (51.0 to NA); Phase 1b Dose Escalation Cohort 2b NA (50.0 to NA); Phase 1b Dose Escalation Cohort 2c ; Phase 1b Dose Escalation Cohort 3 NA (57.0 to NA); Phase 2 Expansion - Capsule 162.0 (58.0 to NA); Phase 2 Expansion - Tablet NA (58.0 to NA)
• Progression-Free Survival (Secondary), Median, days: Phase 1b Dose Escalation Cohort 1 209.0 (57.0 to NA); Phase 1b Dose Escalation Cohort 2a 168.0 (87.0 to NA); Phase 1b Dose Escalation Cohort 2b 107.5 (53.0 to NA); Phase 1b Dose Escalation Cohort 2c 55.5 (15.0 to NA); Phase 1b Dose Escalation Cohort 3 185.0 (10.0 to NA); Phase 2 Expansion - Capsule 66.0 (56.0 to 220.0); Phase 2 Expansion - Tablet 52.5 (34.0 to 114.0)
• Disease Control Rate (Secondary), Count of participants, Participants: Phase 1b Dose Escalation Cohort 1 4; Phase 1b Dose Escalation Cohort 2a 2; Phase 1b Dose Escalation Cohort 2b 1; Phase 1b Dose Escalation Cohort 2c 1; Phase 1b Dose Escalation Cohort 3 4; Phase 2 Expansion - Capsule 12; Phase 2 Expansion - Tablet 3
• Overall Survival (Secondary), Median, days: Phase 1b Dose Escalation Cohort 1 227.0 (122.0 to NA); Phase 1b Dose Escalation Cohort 2a 578.0 (486.0 to NA); Phase 1b Dose Escalation Cohort 2b NA (328.0 to NA); Phase 1b Dose Escalation Cohort 2c 168.5 (32.0 to NA); Phase 1b Dose Escalation Cohort 3 496.0 (49.0 to NA); Phase 2 Expansion - Capsule 801.0 (315.0 to NA); Phase 2 Expansion - Tablet NA (106.0 to NA)
• Cmax (ng/mL) of VRx-3996 (Secondary), Mean, ng/mL: Phase 1b Dose Escalation Cohort 2a 29.8 +/- 26.7; Phase 1b Dose Escalation Cohorts 1, 2b and 2c 83.3 +/- 38.1; Phase 1b Dose Escalation Cohort 3 214 +/- 140; Phase 2 RP2D - Capsule 196 +/- 166; Phase 2 RP2D - Tablet 298 +/- 137
• Cmax (ng/mL) of Valganciclovir (Secondary), Mean, ng/mL: Phase 1b Dose Escalation - 450 mg 4230 +/- 1348; Phase 1b Dose Escalation - 900 mg 6712 +/- 1495; Phase 2 RP2D - Capsule (VRx-3996) 7300 +/- 2790; Phase 2 RP2D - Tablet (VRx-3996) 14900 +/- 8380
• Area Under Curve (AUC) 0-t of VRx-3996 (Secondary), Mean, h*ng/mL: Phase 1b Dose Escalation Cohort 2a 128 +/- 67.0; Phase 1b Dose Escalation Cohorts 1, 2b and 2c 229 +/- 76.4; Phase 1b Dose Escalation Cohort 3 340 +/- 384; Phase 2 RP2D - Capsule 417 +/- 299; Phase 2 RP2D - Tablet 587 +/- 212
• AUC 0-t of of Valganciclovir (Secondary), Mean, h*ng/mL: Phase 1b Dose Escalation - 450 mg 15600 +/- 4160; Phase 1b Dose Escalation - 900 mg 24400 +/- 9300; Phase 2 RP2D - Capsule (VRx-3996) 25200 +/- 10400; Phase 2 RP2D - Tablet (VRx-3996) 49700 +/- 29100
• Half-life of VRx-3996 (Secondary), Mean, hours: Phase 1b Dose Escalation Cohort 2a 1.89 +/- 0.252; Phase 1b Dose Escalation Cohorts 1, 2b and 2c 1.44 +/- 0.466; Phase 1b Dose Escalation Cohort 3 ; Phase 2 RP2D - Capsule 1.46 +/- 0.589; Phase 2 RP2D - Tablet 1.43 +/- 0.287
• Half-life of Valganciclovir (Secondary), Mean, hours: Phase 1b Dose Escalation - 450 mg 3.56 +/- 1.06; Phase 1b Dose Escalation - 900 mg 3.13 +/- 1.43; Phase 2 RP2D - Capsule (VRx-3996) 3.32 +/- 1.10; Phase 2 RP2D - Tablet (VRx-3996) 2.17 +/- 1.68

Adverse events

Time frame: Up to approximately 2 years

Serious adverse events by term

Other adverse events by term

• Results publication: Haverkos B, Alpdogan O, Baiocchi R, Brammer JE, Feldman TA, Capra M, Brem EA, Nair S, Scheinberg P, Pereira J, Shune L, Joffe E, Young P, Spruill S, Katkov A, McRae R, Royston I, Faller DV, Rojkjaer L, Porcu P. Targeted therapy with nanatinostat and valganciclovir in recurrent EBV-positive lymphoid malignancies: a phase 1b/2 study. Blood Adv. 2023 Oct 24;7(20):6339-6350. doi: 10.1182/bloodadvances.2023010330. PMID 37530631

• Study Protocol (PDF, 2021-01-07)
• Statistical Analysis Plan (PDF, 2023-05-01)

• Jill DeFratis Robinson, Study director, Viracta Therapeutics