Phase I/II evaluation of RV1001, a novel PI3Kδ inhibitor, in spontaneous canine lymphoma.

BACKGROUND: RV1001 is a novel, potent, and selective PI3Kδ inhibitor. The purpose of this study was to evaluate the safety and efficacy of RV1001 in canine Non-Hodgkin lymphoma (NHL). METHODS AND RESULTS: Inhibition of endogenous pAKT by RV1001 in primary canine NHL cells was determined by Western blotting. A phase I study of RV1001 was performed in 21 dogs with naïve and drug resistant T and B-cell NHL to assess safety, pharmacokinetic profile, and response to therapy. The objective response rate was 62% (complete response (CR) n = 3; partial response (PR) n = 10), and responses were observed in both naïve and chemotherapy-resistant B and T cell NHL. This study provided the recommended starting dose for a phase II, non-pivotal, exploratory, open label multi-centered clinical trial in 35 dogs with naïve and drug resistant T and B-cell NHL, to further define the efficacy and safety profile of RV1001. The objective response rate in the phase II study was 77% (CR n = 1; PR n = 26). Clinical toxicities were primarily hepatobiliary and gastrointestinal, and were responsive to dose modifications and/or temporary drug discontinuation. Hepatotoxicity was the primary dose limiting toxicity. CONCLUSIONS: RV1001 exhibits good oral bioavailability, an acceptable safety profile, and biologic activity with associated inhibition of pAKT in dogs with B and T cell NHL. Data from these studies can be leveraged to help inform the design of future studies involving isoform-selective PI3K inhibitors in humans

Predicting Solute Transport Through Green Stormwater Infrastructure With Unsteady Transit Time Distribution Theory

In this study, we explore the use of unsteady transit time distribution (TTD) theory to model solute transport in biofilters, a popular form of nature-based or “green” storm water infrastructure (GSI). TTD theory has the potential to address many unresolved challenges associated with predicting pollutant fate and transport through these systems, including unsteadiness in the water balance (time-varying inflows, outflows, and storage), unsteadiness in pollutant loading, time-dependent reactions, and scale-up to GSI networks and urban catchments. From a solution to the unsteady age conservation equation under uniform sampling, we derive an explicit expression for solute breakthrough during and after one or more storm events. The solution is calibrated and validated with breakthrough data from 17 simulated storms at a field-scale biofilter test facility in Southern California, using bromide as a conservative tracer. TTD theory closely reproduces bromide breakthrough concentrations, provided that lateral exchange with the surrounding soil is accounted for. At any given time, according to theory, more than half of the water in storage is from the most recent storm, while the rest is a mixture of penultimate and earlier storms. Thus, key management endpoints, such as the pollutant treatment credit attributable to GSI, are likely to depend on the evolving age distribution of water stored and released by these systems

Predicting Solute Transport Through Green Stormwater Infrastructure With Unsteady Transit Time Distribution Theory

In this study, we explore the use of unsteady transit time distribution (TTD) theory to model solute transport in biofilters, a popular form of nature-based or “green” storm water infrastructure (GSI). TTD theory has the potential to address many unresolved challenges associated with predicting pollutant fate and transport through these systems, including unsteadiness in the water balance (time-varying inflows, outflows, and storage), unsteadiness in pollutant loading, time-dependent reactions, and scale-up to GSI networks and urban catchments. From a solution to the unsteady age conservation equation under uniform sampling, we derive an explicit expression for solute breakthrough during and after one or more storm events. The solution is calibrated and validated with breakthrough data from 17 simulated storms at a field-scale biofilter test facility in Southern California, using bromide as a conservative tracer. TTD theory closely reproduces bromide breakthrough concentrations, provided that lateral exchange with the surrounding soil is accounted for. At any given time, according to theory, more than half of the water in storage is from the most recent storm, while the rest is a mixture of penultimate and earlier storms. Thus, key management endpoints, such as the pollutant treatment credit attributable to GSI, are likely to depend on the evolving age distribution of water stored and released by these systems