Abstract CT242: SNDX-6352-0502: A phase 1, open-label, dose escalation trial to investigate the safety, tolerability, pharmacokinetics and pharmacodynamic activity of SNDX-6352 in combination with durvalumab in patients with unresectable, recurrent, locally-advanced, or metastatic solid tumors
Authors: Tolcher Anthony W. , Rasco Drew , Sharma Sunil , Taylor Matthew , Quaranto Christine , Tamang David L. , Nordness Robert , Meyers Michael L. , Sankoh Serap , Ordentlich Peter , Azad Nilo 
Published: September 2020

Abstract
Background: Tumor associated macrophages have been proposed to suppress the anti-tumor immune responses potentiated by immune checkpoint blockade. CSF1 receptor (CSF-1R) blockade enhances anti-PD1 or PD-L1 anti-tumor efficacy in various tumor models. SNDX-6352 is a high affinity, humanized monoclonal antibody against CSF1R. This Phase 1 study was designed to identify a recommended phase 2 dose for the combination of SNDX-6352 and the anti-PD-L1 antibody, durvalumab.
Methods: Study SNDX-6352-0502 was a multi-center Phase 1 study consisting of Phase 1a (monotherapy) and Phase 1b (combination with durvalumab). The primary objective of 1b was to define MTD or RP2D of the combination as evaluated by the incidence of DLTs. The 1b cohorts included 1, 2, and 3 mg/kg administered q2wk in combination with a fixed dose of 1500 mg durvalumab q4wk. The RP2D was determined based on safety, drug exposure, and PD biomarker changes.
Results: 12 patients with advanced solid tumors were treated with durvalumab and SNDX-6352 (3 at 1 mg/kg, 3 at 2 mg/kg, and 6 at 3 mg/kg). Median number of prior therapies was 6.5 (range 2-13). Median age at enrollment was 67 years (range 34-74), and 75% of patients had ECOG performance status of 1. Median exposure in terms of cycles was 2 (range 2-4). Nine SAEs occurred in 5/12 (42%) patients. All SAEs were assessed as unrelated to study drug and generally reflected co-morbidity in this population of patients with advanced cancer.
Most common treatment-related AEs were edema peripheral (33%), fatigue (25%), periorbital edema (25%), and hypothyroidism (25%). Grade 3 or higher treatment-related AEs were reported in 4 patients (33%). One patient had two events (anemia and pericardial effusion); amylase increased, diarrhea, and rash occurred in 1 patient each. Elevations in circulating enzymes were consistent with the known effect of the class on Kupffer-cell mediated clearance of circulating enzymes. No objective responses have been reported to date.
Plasma concentrations of SNDX-6352 increased in a dose-proportional manner with drug accumulation observed at &gt; 1mg/kg. Treatment led to elevations of plasma concentrations of CSF1R ligands, CSF1 and IL-34, which remained above pre-dose levels at 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 depleted at all dose levels after one day.
Conclusion: SNDX-6352 is a potent CSF1R antagonist that demonstrates tolerability and robust PD biomarker modulation in combination with durvalumab. The recommended phase 2 dose of 3 mg/kg administered q2wk in combination therapy will be explored in future studies.
Citation Format: Anthony W. Tolcher, Drew Rasco, Sunil Sharma, Matthew Taylor, Christine Quaranto, David L. Tamang, Robert Nordness, Michael L. Meyers, Serap Sankoh, Peter Ordentlich, Nilo Azad. SNDX-6352-0502: A phase 1, open-label, dose escalation trial to investigate the safety, tolerability, pharmacokinetics and pharmacodynamic activity of SNDX-6352 in combination with durvalumab 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 CT242.