Abstract 4700: The novel and selective PI3Kδ inhibitor, RV1001, displays single agent biologic activity in spontaneous canine NHL

Abstract

Abstract Background: Non-Hodgkin's lymphoma (NHL) is the most common cancer in dogs with over 70,000 new cases diagnosed each year. Evidence suggests that canine NHL is an excellent spontaneous large animal model of human NHL, particularly for the evaluation of new therapeutics. The purpose of this work was to establish the preclinical profile and clinical efficacy of the novel, potent, and selective PI3Kδ inhibitor RV1001 in canine NHL with ultimate goal of informing the development of such inhibitors in human NHL. Methods: Activity of RV1001 on individual PI3K isoforms was determined using a Homogenous Time Resolved Fluorescence assay (Millipore, Billerica, MA). Potency of the compound on the delta isoform was further corroborated in anti-FcϵR1 induced CD63 expression studies using human whole blood. Ability of RV1001 to arrest growth across several cell lines was determined by a MTT assay. Inhibition of endogenous pAKT in cell lines and primary canine NHL cells was determined by Western blotting. A phase I study of RV1001 was performed in dogs with T and B naïve and drug resistant NHL to assess safety, pharmacokinetic profile and response to therapy. Results: RV1001 demonstrated significant potency against PI3Kδ (39.3 nM) with several fold selectivity over the α (>250), β (>30), and γ (>20) isoforms. In addition, RV1001 inhibited anti-FcϵR1 induced CD63 expression, a marker of PI3Kδ signaling, in human whole blood basophils with an EC50 of 94.7 nM. Proliferation assays in leukemic cells indicated that the compound arrested growth at concentrations between 1.5 and 13 μM. Reduced PI3Kδ signaling was manifested by a reduction in pAKT with half-maximal inhibition noticed between 10 and 100 nM. Oral administration of 100 mg/kg RV1001 to healthy dogs over a 14-day period resulted in significant accumulation (Cmax = 70 μM on Day 1 versus 186 μM on Day 14; PI3Kδ = 69 μM on Day 14). To date, 9 dogs have been entered into the Phase I clinical trial beginning at a dose of 10 mg/kg SID using a standard 3×3 design. One dog with T cell NHL has had a durable complete response to therapy (10 mg/kg), and 3 additional dogs have had partial responses (15 mg/kg n = 2 and 25 mg/kg n = 1) for an objective response rate of 44%. Adverse events associated with RV1001 administration include grade 1 anorexia and grade 3 and 4 LFT elevation. Pharmacokinetic analyses revealed Cmax concentrations of 10-25 μM with AUC0-t ranging from 50 to 100 μM.hr with accumulation evident after 3-4 weeks of dosing. Exploration of alternative dosing regimens is ongoing to eliminate the drug accumulation and thus circumvent the observed hepatotoxicity. Conclusions: RV1001 exhibits potent activity against PI3Kδ with associated inhibition of AKT phosphorylation, excellent oral bioavailability, and strong single agent efficacy in dogs with both B and T NHL. Data generated from these studies will have broad applicability to the further development of isoform specific PI3K inhibitors in people with NHL. Citation Format: Cheryl A. London, Sarah B. Rippy, Misty D. Bear, Kim Cronin, Andrew H. Abbo, Kumar V. Penmetsa, Srikant Viswanadha, Swaroop Vakkalanka. The novel and selective PI3Kδ inhibitor, RV1001, displays single agent biologic activity in spontaneous canine NHL. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4700. doi:10.1158/1538-7445.AM2015-4700