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Clinical Trial
. 2018 Apr 24;13(4):e0195357.
doi: 10.1371/journal.pone.0195357. eCollection 2018.

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

Heather L Gardner  1 , Sarah B Rippy  2 , Misty D Bear  3 , Kim L Cronin  4 , Heather Heeb  5 , Holly Burr  6 , Claire M Cannon  7 , Kumar V Penmetsa  8 , Srikant Viswanadha  9 , Swaroop Vakkalanka  8 , Cheryl A London  10
Affiliations
Clinical Trial

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

Heather L Gardner et al. PLoS One. .

Abstract

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.

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Conflict of interest statement

Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: Kumar Penmetsa, Srikant Viswanadha, and Swaroop Vakkalanka are employees of Rhizen Pharmaceuticals SA/Incozen Therapeutics Pvt. Ltd., which provided financial support for the study. Kim Cronin is employed by New England Oncology Group, Heather Heeb is employed by Blue Pearl Kansas City, and Holly Burr is employed by Las Vegas Veterinary Specialists. Cheryl London is also a consultant for Rhizen Pharmaceuticals. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Biologic activity of RV1001 against canine primary NHL cells treated ex vivo.
Inhibition of pAKT in primary canine NHL cells treated ex vivo with RV1001 is demonstrated by western blotting.
Fig 2
Fig 2. Response to RV1001 administration in dogs with NHL.
(A) Blood samples were collected to assess plasma concentrations of RV1001 over an 8 hour period after RV1001 administration. (B) Dogs were evaluated once weekly for response assessments. Objective responses were noted in all dosing cohorts. (C) Lymph node samples were collected from dogs before and after RV1001 administration. Inhibition of pAKT was observed within 2 hours of drug administration. Dosing groups: Dog 1 (10 mg/kg); Dog 4 (15 mg/kg); Dogs 18, 19, 20, 21 (25 mg/kg M-F).
Fig 3
Fig 3. Objective response rates to RV1001 in dogs with NHL.
Waterfall plot showing the best ORR for dogs enrolled in the phase II study. Solid horizontal black line indicates a reduction in size of the target lesions of at least 30%, consistent with a partial response. * = dogs enrolled in the clinical trial at 10 mg/kg M-Th RV1001.
See this image and copyright information in PMC

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