Dose Escalation & Expansion Study of Oral VRx-3996 & Valganciclovir in Subjects With EBV+ Lymphoid Malignancies
- Conditions
- Epstein-Barr Virus-Associated LymphomaLymphoproliferative Disorders
- Interventions
- Registration Number
- NCT03397706
- Lead Sponsor
- Viracta Therapeutics, Inc.
- Brief Summary
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).
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 64
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description PK Cohort Valganciclovir Assessment of VRx-3996 tablet and valganciclovir PK parameters at the RP2D Phase 1b Dose Escalation VRx-3996 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 PK Cohort VRx-3996 Assessment of VRx-3996 tablet and valganciclovir PK parameters at the RP2D Phase 2 Dose Expansion VRx-3996 VRx-3996 (RP2D: recommended phase 2 dose) and valganciclovir Phase 1b Dose Escalation Valganciclovir 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 Phase 2 Dose Expansion Valganciclovir VRx-3996 (RP2D: recommended phase 2 dose) and valganciclovir
- Primary Outcome Measures
Name Time Method 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 daysOverall 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 Outcome Measures
Name Time Method 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
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
Trial Locations
- Locations (28)
Georgia Cancer Center at Augusta University
🇺🇸Augusta, Georgia, United States
Winship Cancer Institute, Emory University
🇺🇸Atlanta, Georgia, United States
University of California, Los Angeles
🇺🇸Los Angeles, California, United States
UC Irvine Chao Family Comprehensive Cancer Center
🇺🇸Orange, California, United States
USC Norris Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
Mid Florida Hematology and Oncology Center
🇺🇸Orange City, Florida, United States
ASCLEPES Research Centers
🇺🇸Weeki Wachee, Florida, United States
Northwestern University Feinberg School of Medicine
🇺🇸Chicago, Illinois, United States
Ruth M Rothstein CORE Center
🇺🇸Chicago, Illinois, United States
The University of Kansas Cancer Center and Medical Pavilion
🇺🇸Westwood, Kansas, United States
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
🇺🇸Baltimore, Maryland, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Weill Cornell Medical College - New York Presbyterian Hospital
🇺🇸New York, New York, United States
The Ohio State University Wexner Medical Center James Cancer Hospital
🇺🇸Columbus, Ohio, United States
Texas Oncology - Baylor Sammons Cancer Center
🇺🇸Dallas, Texas, United States
Centro de Hematologia e Oncologia da Bahia (CEHON)
🇧🇷Salvador, BA, Brazil
Hospital de Cancer de Pernambuco (HCP)
🇧🇷Recife, PE, Brazil
Real e Benemerita Associacao Portuguesa de Beneficencia
🇧🇷São Paulo, SP, Brazil
Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP)
🇧🇷São Paulo, SP, Brazil
Hospital Santa Marcelina
🇧🇷São Paulo, SP, Brazil
Hospital do Cancer Mae de Deus
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Fox Chase Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
St. Vincent Healthcare Cancer Center
🇺🇸Billings, Montana, United States
John Theurer Cancer Center at Hackensack UMC
🇺🇸Hackensack, New Jersey, United States
University of Colorado Anschutz Cancer Pavilion
🇺🇸Aurora, Colorado, United States
Indiana Blood and Marrow Transplantation
🇺🇸Indianapolis, Indiana, United States
Henry Ford Hospital
🇺🇸Detroit, Michigan, United States
Thomas Jefferson University
🇺🇸Philadelphia, Pennsylvania, United States