Abstract LB-308: KPT-9274 inhibits cellular NAD and synergizes with doxorubicin to treat dogs with lymphoma
Authors: London Cheryl , Brown Megan , Warry Emma , Schuh Elizabeth , Senapedis William T. , Argueta Christian , Kashyap Trinayan , Chang Hua , Ellis Joel , Shacham Sharon , Baloglu Erkan 
Published: July 2017

Abstract
Nicotinamide adenine dinucleotide (NAD), an essential metabolite and cofactor of several biological processes (e.g. genomic stability), undergoes significant alterations during malignant transformation. In cancer cells, the high metabolic demands of proliferating cells and increased activity of NAD consuming enzymes (i.e. SIRT1 and PARP1) lead to rapid NAD turnover. NAD can be generated de novo from tryptophan or regenerated by nicotinamide phosphoribosyl transferase (NAMPT) or nicotinate phosphoribosyl transferase 1 (NAPRT1) in NAD salvage pathways. However, cancer cells rely mainly on the NAMPT-dependent pathway, making NAD depletion a promising anti-cancer therapy. KPT-9274 is a novel first-in-class orally bioavailable dual inhibitor of p21-activated kinase 4 (PAK4) and NAMPT that demonstrates potent anti-tumor activity in a variety of cancer cell lines. KPT-9274 treatment rapidly depletes cellular NAD levels, leading to ATP loss and cell death. Similarly, hyper activation of PARP1 through DNA damaging agents (e.g. doxorubicin; DOX) can lead to apoptosis. Here we present results from a phase 1 study of KPT-9274 as a single agent and in combination with DOX for the treatment of dogs with solid tumors or lymphomas.
Methods: Dogs with cancer (lymphoma, n=4; sarcoma n=6; mast cell tumor n=2) were enrolled into a prospective phase 1 dose escalation study of KPT-9274 given qod x 3 per week. Plasma samples were used for pharmacokinetics (PK) and tumor biopsies were used to assess pharmacodynamics (PDn; i.e. PAK4, NAMPT and downstream effectors). In an expansion cohort, dogs with lymphoma (n=6) received 4 doses of KPT-9274 at 2 mg/kg prior to administration of a single dose of DOX.
Results: Doses up to 4 mg/kg KPT-9274 were well tolerated with no grade ≥3 toxicities. At 4.5 mg/kg one dog exhibited severe vomiting, diarrhea, collapse, anemia and thrombocytopenia, establishing 4 mg/kg as MTD. The PK of KPT-9274 was dose proportional and in agreement with healthy dogs. PDn markers (NAD levels) in tumors showed target engagement through NAD depletion as well as changes in PAK4 pathway biomarkers using IHC. Four dogs exhibited stable disease during treatment (3 soft tissue sarcomas, 1 mast cell tumor) at doses ranging from 3 - 4.5 mg/kg. Of the 6 dogs with naïve lymphoma that received KPT-9274 and a single dose of DOX, 5 achieved a complete response, one of which lasted for over 3 months. No unexpected toxicities were noted with the combination when compared to those expected from DOX alone.
Conclusions: KPT-9274 exhibits single agent activity in canine spontaneous cancers. Moreover, the combination of KPT-9274 and DOX has substantial biologic activity against canine Non-Hodgkin lymphoma, likely through the activation of NAD consuming enzymes such as PARP1 by DOX. Importantly, the drug combination was safe with no enhanced toxicity over DOX alone. This data could be applied directly to the current trial of KPT-9274 in a Phase 1 clinical trial in patients with advanced solid malignancies or NHL (NCT02702492).
Citation Format: Cheryl London, Megan Brown, Emma Warry, Elizabeth Schuh, William T. Senapedis, Christian Argueta, Trinayan Kashyap, Hua Chang, Joel Ellis, Sharon Shacham, Erkan Baloglu. KPT-9274 inhibits cellular NAD and synergizes with doxorubicin to treat dogs with lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-308. doi:10.1158/1538-7445.AM2017-LB-308