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).
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
64
second-generation histone deacetylase (HDAC) inhibitor, nanatinostat (previously referred to as either VRx-3996 or CHR-3396)
Number (Proportion) of Participants With Adverse Events (AEs)
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
Time frame: Up to approximately 2 years
Number (Proportion) of Participants With Dose-Limiting Toxicities (DLTs) in Phase 1b
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
Time frame: Cycle 1 (28 days)
Overall Response Rate
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)
Time frame: Up to approximately 2 years
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Duration of Response
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 frame: Up to approximately 2 years
Time to Response
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)
Time frame: Up to approximately 2 years
Progression-Free Survival
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)
Time frame: Up to approximately 2 years
Disease Control Rate
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)
Time frame: Up to approximately 2 years
Overall Survival
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)
Time frame: Up to approximately 2 years
Cmax (ng/mL) of VRx-3996
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)
Time frame: Phase 1b: Cycle 1 Day 1 and Phase 2: multiple doses through Cycle 2 Day 1
Cmax (ng/mL) of Valganciclovir
PK assessment of valganciclovir pre-dose and at hours 0.5, 1, 2, 4, and 6 post-dose on C1D1 and C2D1
Time frame: Phase 1b: Cycle 1 Day 1 and Phase 2: multiple doses through Cycle 2 Day 1
Area Under Curve (AUC) 0-t of VRx-3996
PK assessment of VRx-3996 pre-dose and at hours 0.5, 1, 2, 4, and 6 post-dose on C1D1 and C2D1
Time frame: Phase 1b: Cycle 1 Day 1 and Phase 2: multiple doses through Cycle 2 Day 1
AUC 0-t of of Valganciclovir
PK assessment of valganciclovir pre-dose and at hours 0.5, 1, 2, 4, and 6 post-dose on C1D1 and C2D1
Time frame: Phase 1b: Cycle 1 Day 1 and Phase 2: multiple doses through Cycle 2 Day 1
Half-life of VRx-3996
PK assessment of VRx-3996 pre-dose and at hours 0.5, 1, 2, 4, and 6 post-dose on C1D1 and C2D1
Time frame: Phase 1b: Cycle 1 Day 1 and Phase 2: multiple doses through Cycle 2 Day 1
Half-life of Valganciclovir
PK assessment of valganciclovir pre-dose and at hours 0.5, 1, 2, 4, and 6 post-dose on C1D1 and C2D1
Time frame: Phase 1b: Cycle 1 Day 1 and Phase 2: multiple doses through Cycle 2 Day 1