NCT03397706

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

Completed Phase 1, PHASE2 Results posted Last updated 20 March 2025

What this trial tests

Phase 1, PHASE2 trial testing VRx-3996 and valganciclovir in Epstein-Barr Virus-Associated Lymphoma in 64 participants. Completed in 4 May 2023.

Timeline

29 March 2018

Primary endpoint
1 April 2023

4 May 2023

Quick facts

Lead sponsor	Viracta Therapeutics, Inc.
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	sequential
Masking	none
Primary purpose	treatment
Enrollment	64
Start date	29 March 2018
Primary completion	1 April 2023
Estimated completion	4 May 2023
Sites	28 locations across United States, Brazil

Drugs / interventions tested

• VRx-3996 and valganciclovir

Conditions studied

• Epstein-Barr Virus-Associated Lymphoma — all drugs for Epstein-Barr Virus-Associated Lymphoma →
• Lymphoproliferative Disorders — all drugs for Lymphoproliferative Disorders →

Sponsor

Viracta Therapeutics, Inc. — full company profile →

Who can join

18 and older, any sex, with Epstein-Barr Virus-Associated Lymphoma or Lymphoproliferative Disorders. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number (Proportion) of Participants With Adverse Events (AEs) Primary · 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

Group	Value	95% CI
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 · 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

Group	Value	95% CI
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 · 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

Group	Value	95% CI
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
Phase 1b Dose Escalation Cohort 1	1
Phase 1b Dose Escalation Cohort 2a	1
Phase 1b Dose Escalation Cohort 2b	1
Phase 1b Dose Escalation Cohort 2c	0
Phase 1b Dose Escalation Cohort 3	2
Phase 2 Dose Expansion - Capsule	4
Phase 2 Dose Expansion - Tablet	1
Phase 1b Dose Escalation Cohort 1	1
Phase 1b Dose Escalation Cohort 2a	0
Phase 1b Dose Escalation Cohort 2b	0
Phase 1b Dose Escalation Cohort 2c	1
Phase 1b Dose Escalation Cohort 3	1
Phase 2 Dose Expansion - Capsule	5
Phase 2 Dose Expansion - Tablet	1
Phase 1b Dose Escalation Cohort 1	2
Phase 1b Dose Escalation Cohort 2a	0
Phase 1b Dose Escalation Cohort 2b	1
Phase 1b Dose Escalation Cohort 2c	3
Phase 1b Dose Escalation Cohort 3	1
Phase 2 Dose Expansion - Capsule	11
Phase 2 Dose Expansion - Tablet	5

Duration of Response Secondary · 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

Group	Value	95% CI
Phase 1b Dose Escalation Cohort 1	825.5	160.0 – NA
Phase 1b Dose Escalation Cohort 2a	116.5	34.0 – NA
Phase 1b Dose Escalation Cohort 2b	113.0	NA – NA
Phase 1b Dose Escalation Cohort 3	NA	127.0 – NA
Phase 2 Dose Expansion - Capsule	634.0	80.0 – NA
Phase 2 Dose Expansion - Tablet	NA	57.0 – NA

Time to Response Secondary · 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)

Group	Value	95% CI
Phase 1b Dose Escalation Cohort 1	NA	33.0 – NA
Phase 1b Dose Escalation Cohort 2a	52.5	51.0 – NA
Phase 1b Dose Escalation Cohort 2b	NA	50.0 – NA
Phase 1b Dose Escalation Cohort 3	NA	57.0 – NA
Phase 2 Expansion - Capsule	162.0	58.0 – NA
Phase 2 Expansion - Tablet	NA	58.0 – NA

Progression-Free Survival Secondary · 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)

Group	Value	95% CI
Phase 1b Dose Escalation Cohort 1	209.0	57.0 – NA
Phase 1b Dose Escalation Cohort 2a	168.0	87.0 – NA
Phase 1b Dose Escalation Cohort 2b	107.5	53.0 – NA
Phase 1b Dose Escalation Cohort 2c	55.5	15.0 – NA
Phase 1b Dose Escalation Cohort 3	185.0	10.0 – NA
Phase 2 Expansion - Capsule	66.0	56.0 – 220.0
Phase 2 Expansion - Tablet	52.5	34.0 – 114.0

Disease Control Rate Secondary · 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)

Group	Value	95% CI
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 · 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)

Group	Value	95% CI
Phase 1b Dose Escalation Cohort 1	227.0	122.0 – NA
Phase 1b Dose Escalation Cohort 2a	578.0	486.0 – NA
Phase 1b Dose Escalation Cohort 2b	NA	328.0 – NA
Phase 1b Dose Escalation Cohort 2c	168.5	32.0 – NA
Phase 1b Dose Escalation Cohort 3	496.0	49.0 – NA
Phase 2 Expansion - Capsule	801.0	315.0 – NA
Phase 2 Expansion - Tablet	NA	106.0 – NA

Cmax (ng/mL) of VRx-3996 Secondary · 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)

Single-dose

Group	Value	95% CI
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

Multiple-dose

Group	Value	95% CI
Phase 2 RP2D - Capsule	334	± 283
Phase 2 RP2D - Tablet	238	± 208

Cmax (ng/mL) of Valganciclovir Secondary · 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

Single-Dose

Group	Value	95% CI
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

Multiple-Dose

Group	Value	95% CI
Phase 2 RP2D - Capsule (VRx-3996)	8690	± 5800
Phase 2 RP2D - Tablet (VRx-3996)	14200	± 7060

Area Under Curve (AUC) 0-t of VRx-3996 Secondary · 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

Single-dose

Group	Value	95% CI
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

Multiple-dose

Group	Value	95% CI
Phase 2 RP2D - Capsule	638	± 418
Phase 2 RP2D - Tablet	474	± 268

AUC 0-t of of Valganciclovir Secondary · 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

Single-dose

Group	Value	95% CI
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

Multiple-dose

Group	Value	95% CI
Phase 2 RP2D - Capsule (VRx-3996)	28300	± 16400
Phase 2 RP2D - Tablet (VRx-3996)	46600	± 18000

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to approximately 2 years. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Phase 1b Dose Escalation Cohort 1

Serious: 2/7 (29%)

Deaths: 4/7

Phase 1b Dose Escalation Cohort 2a

Serious: 2/5 (40%)

Deaths: 4/5

Phase 1b Dose Escalation Cohort 2b

Serious: 2/4 (50%)

Deaths: 2/4

Phase 1b Dose Escalation Cohort 2c

Serious: 1/4 (25%)

Deaths: 4/4

Phase 1b Dose Escalation Cohort 3

Serious: 1/5 (20%)

Deaths: 3/5

Phase 2 Dose Expansion - Capsule

Serious: 11/30 (37%)

Deaths: 17/30

Phase 2 Dose Expansion - Tablet

Serious: 4/9 (44%)

Deaths: 4/9

Serious adverse events (29 terms)

Reaction	System	Phase 1b Dose Escalation C…	Phase 1b Dose Escalation C…	Phase 1b Dose Escalation C…	Phase 1b Dose Escalation C…	Phase 1b Dose Escalation C…	Phase 2 Dose Expansion - C…	Phase 2 Dose Expansion - T…
Sepsis	Infections and infestations	—	—	—	—	—	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—	—	—	—	—
Gastrointestinal haemorrhage	Gastrointestinal disorders	—	—	—	—	—	—	—
Haematochezia	Gastrointestinal disorders	—	—	—	—	—	—	—
Oral pain	Gastrointestinal disorders	—	—	—	—	—	—	—
Myelodysplastic syndrome	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—	—
Transitional cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—	—
Transitional cell carcinoma metastatic	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—	—
Tumour necrosis	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—	—
Clostridium difficile infection	Infections and infestations	—	—	—	—	—	—	—
Clostridium difficile colitis	Infections and infestations	—	—	—	—	—	—	—
Enterocolitis viral	Infections and infestations	—	—	—	—	—	—	—
Pharyngitis	Infections and infestations	—	—	—	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—	—	—	—
Atrial flutter	Cardiac disorders	—	—	—	—	—	—	—
Left ventricular failure	Cardiac disorders	—	—	—	—	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Drug hypersensitivity	Immune system disorders	—	—	—	—	—	—	—

Other adverse events (52 terms — click to expand)

Reaction	System	Phase 1b Dose Escalation C…	Phase 1b Dose Escalation C…	Phase 1b Dose Escalation C…	Phase 1b Dose Escalation C…	Phase 1b Dose Escalation C…	Phase 2 Dose Expansion - C…	Phase 2 Dose Expansion - T…
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—	—	—
Thrombocytopenia	Gastrointestinal disorders	—	—	—	—	—	—	—
Neutrophil count decreased	Investigations	—	—	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—
Chills	General disorders	—	—	—	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—	—	—	—
Muscle spasms	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—
White blood cell count decreased	Investigations	—	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—	—
Chest pain	General disorders	—	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—	—
Insomnia	Psychiatric disorders	—	—	—	—	—	—	—
Blood creatinine increased	Investigations	—	—	—	—	—	—	—
Platelet count decreased	Investigations	—	—	—	—	—	—	—
Lymphocyte count decreased	Investigations	—	—	—	—	—	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—	—	—	—	—	—
Stomatitis	Gastrointestinal disorders	—	—	—	—	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—	—	—	—	—
Toothache	Gastrointestinal disorders	—	—	—	—	—	—	—
Asthenia	General disorders	—	—	—	—	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—	—	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—	—	—	—	—
Ear pain	Ear and labyrinth disorders	—	—	—	—	—	—	—
Weight decreased	Investigations	—	—	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—	—	—
Blood alkaline phosphatase increased	Investigations	—	—	—	—	—	—	—
Hyperkalaemia	Metabolism and nutrition disorders	—	—	—	—	—	—	—
Gastroesophageal reflux disease	Gastrointestinal disorders	—	—	—	—	—	—	—
Oral pain	Gastrointestinal disorders	—	—	—	—	—	—	—

Most-reported serious reactions: Sepsis, Febrile neutropenia, Atrial fibrillation, Gastrointestinal haemorrhage, Haematochezia, Oral pain, Myelodysplastic syndrome, Transitional cell carcinoma.

Data from ClinicalTrials.gov NCT03397706 adverse events section.

Sponsor's own description

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 Epstein-Barr Virus Associated Lymphoma (EBV+ lymphomas).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Epigenetics-targeted drugs: current paradigms and future challenges.
   Dai W, Qiao X, Fang Y, Guo R, et al · · 2024 · cited 131× · PMID 39592582 · DOI 10.1038/s41392-024-02039-0
2. Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends.
   Nepali K, Liou JP. · · 2021 · cited 122× · PMID 33840388 · DOI 10.1186/s12929-021-00721-x
3. Control of viral infections by epigenetic-targeted therapy.
   Nehme Z, Pasquereau S, Herbein G. · · 2019 · cited 73× · PMID 30917875 · DOI 10.1186/s13148-019-0654-9
4. Regulation of Chemokines and Cytokines by Histone Deacetylases and an Update on Histone Decetylase Inhibitors in Human Diseases.
   Gatla HR, Muniraj N, Thevkar P, Yavvari S, et al · · 2019 · cited 68× · PMID 30841513 · DOI 10.3390/ijms20051110
5. Epstein-Barr Virus Infection in the Development of Neurological Disorders.
   Soldan SS, Lieberman PM. · · 2020 · cited 40× · PMID 33897799 · DOI 10.1016/j.ddmod.2020.01.001
6. Targeted therapy with nanatinostat and valganciclovir in recurrent EBV-positive lymphoid malignancies: a phase 1b/2 study.
   Haverkos B, Alpdogan O, Baiocchi R, Brammer JE, et al · · 2023 · cited 37× · PMID 37530631 · DOI 10.1182/bloodadvances.2023010330
7. Pharmacological targeting of the cancer epigenome.
   Mabe NW, Perry JA, Malone CF, Stegmaier K. · · 2024 · cited 36× · PMID 38937652 · DOI 10.1038/s43018-024-00777-2
8. Opportunities to Target the Life Cycle of Epstein-Barr Virus (EBV) in EBV-Associated Lymphoproliferative Disorders.
   Dugan JP, Coleman CB, Haverkos B. · · 2019 · cited 34× · PMID 30931253 · DOI 10.3389/fonc.2019.00127