Abstract CT149: SNDX-6352-0502 - A phase 1, open-label, dose escalation trial to investigate the safety, tolerability, pharmacokinetics and pharmacodynamic activity of SNDX-6352 monotherapy in patients with unresectable, recurrent, locally-advanced, or metastatic solid tumors
Authors: Azad Nilo , Rasco Drew , Sharma Sunil , Taylor Matthew , Quaranto Christine , Tamang David L. , Nordness Robert , Meyers Michael L. , Sankoh Serap , Ordentlich Peter , Tolcher Anthony W. 
Published: September 2020

Abstract
Background: Immunosuppressive tumor associated macrophages (TAMs) have been shown to correlate with poor prognosis. SNDX-6352 is a humanized, high-affinity monoclonal IgG4 antibody that blocks dual ligand activation of colony stimulating factor- 1 receptor (CSF-1R), which regulates monocyte migration, proliferation and differentiation into TAMs. By inhibiting and reducing TAM numbers, SNDX-6352 may slow tumor growth and enhance anti-tumor immunotherapeutic approaches.
Methods: SNDX-6352-0502 was a multi-center Phase 1 study consisting of Phase 1a (monotherapy) and Phase 1b (combination with durvalumab) in patients with pretreated, advanced solid tumors. The primary objective was determining the MTD and RP2D of SNDX-6352 alone and in combination with durvalumab. Dose regimens of 1, 2, 3 and 6 mg/kg bi-weekly (q2wks) and 6 mg/kg once monthly (q4wks) were administered in 1a, and 1, 2, and 3 mg/kg bi-weekly in 1b. Drug pharmacokinetics (PK) and pharmacodynamic (PD) biomarkers were measured.
Results: Thirty-two patients with advanced solid tumors were enrolled with a median age of 61. The median number of prior therapies was 5 (range 2-12) and 72% of patients had ECOG performance status of 1. Median exposure in terms of cycles was 2, maximum was 10. Three patients had SD greater than 4 months. Most common (&gt; 10%) treatment-related AEs were fatigue (31%), periorbital edema (31%) aspartate aminotransferase increased (22%), blood creatinine phosphokinase increased (22%) nausea (13%) and decreased appetite (13%). Grade 3/4 related AEs were observed in 12 patients (38%) with ≥ 2 events in CPK (5), amylase (3), AST (3) and lipase (2). One possibly related SAE of pneumonitis at 6 mg/kg q2wks was reported. DLTs reported in two subjects were G3 fatigue at 2 mg/kg and G3 pneumonitis at 6 mg/kg q2wks. Laboratory abnormalities included increases in blood creatinine phosphokinase, ALT, AST, amylase, and lipase. These abnormalities were all asymptomatic and are consistent with the known class effect of CSF-1Ri. There was no evidence of hepatocellular toxicity. Plasma concentrations of SNDX-6352 increased in a dose-proportional manner with drug accumulation observed at &gt; 1 mg/kg. Plasma CSF1 and IL-34 concentrations increased with treatment and remained elevated at all doses &gt; 1 mg/kg. CSF1 receptor occupancy was saturated at 4 hours post-dose in all treatment cohorts. Circulating non-classical monocytes (CD14+CD16hi) were ablated at all dose levels within 24 hrs and remained suppressed at all doses &gt;1 mg/kg.
Conclusion: SNDX-6352 demonstrates tolerability at the highest dose level evaluated (6 mg/kg) with robust PD biomarker modulation at doses as low as 1 mg/kg. A RP2D of 6mg/kg q4wks will be explored in future solid tumor studies.
Citation Format: Nilo Azad, Drew Rasco, Sunil Sharma, Matthew Taylor, Christine Quaranto, David L. Tamang, Robert Nordness, Michael L. Meyers, Serap Sankoh, Peter Ordentlich, Anthony W. Tolcher. SNDX-6352-0502 - A phase 1, open-label, dose escalation trial to investigate the safety, tolerability, pharmacokinetics and pharmacodynamic activity of SNDX-6352 monotherapy in patients with unresectable, recurrent, locally-advanced, or metastatic solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT149.