Abstract CT153: SDX-7320 elicits improvements in tumor-related and metabolic biomarkers: Results of a phase 1 dose-escalation study in patients with advanced refractory or late-stage solid tumors
Authors: Mita Monica M. , Bendell Johanna , Mita Alain C. , Gordon Michael , Sachdev Jasgit , Carver Bradley J. , Shanahan James , Mayes Benjamin , Awerkamp Kris , Browning David , Salomon Neal , Sullivan Kimberly , Anderson-Villaluz Alfred , Johnson Joe , Petersen John S. , Turnquist David J. , Cornelius Peter 
Published: September 2020

Abstract
Background and Rationale: Metabo-oncology is the study of specific tumor types whose growth and/or metastasis is accelerated by metabolic dysfunction, often associated with hyper-adiposity. In this setting the metabolic hormones leptin, adiponectin and insulin are potential mediators. SDX-7320 is a novel methionine aminopeptidase type 2 inhibitor (MetAP2) being developed for use in combination with other anti-cancer agents to treat the metabo-oncology patient population.
Study Design: This first-in-human study used a 3+3 design with dose expansion at the RP2D. Measurements included standard assessments of safety, tolerability, as well as inhibition of MetAP2 in whole blood, plasma levels of protein biomarkers and drug exposure. Tumor response was measured using RECIST v.1.1.
Results: 32 patients with an average of 5.3 prior treatment regimens were dosed. Sub-cutaneous dosing of SDX-7320 began at 1.7 mg/m2 once per week (Q7D, 28 days/cycle) and was escalated to 49 mg/m2. Repeated Q7D administration at 49 mg/m2 resulted in dose-limiting (G3-G4) thrombocytopenia. Expansion at 49 mg/m2 confirmed thrombocytopenia as the dose-limiting toxicity (DLT), reversible upon cessation of dosing. Dose-escalation was re-initiated at 36 mg/m2 every two weeks (Q14D). Repeated dosing at 65 mg/m2 (Q14D) resulted in G3 reversible thrombocytopenia. Expansion at 49 mg/m2 (Q14D) confirmed that this was the maximum tolerated dose (MTD) on a Q14D schedule. No deaths or Grade 5 TEAEs attributable to SDX-7320 were reported. Six patients had a combined total of 9 Grade 3/4 TEAEs considered by the Investigator to be at least possibly SDX-7320-related: thrombocytopenia (4 patients) and single cases of anemia, anorexia, fatigue, QTc prolonged, and vasculitis. Fourteen patients (44% had stable disease &gt2 cycles and three patients had stable disease for ≥6 cycles. Inhibition of MetAP2 in whole blood was 100% at all doses evaluated while the time to reach 100% inhibition was inversely related to dose. When stratified for elevated baseline levels, the following biomarkers declined after initiating SDX-7320 (average of each patient's maximum % change relative to baseline +/- SD): bFGF (-53 +/- 76%), VEGF-C (-35 +/- 39%), and insulin (-55 +/- 30%). Without stratification, leptin levels declined (-51 +/-29%) and levels of adiponectin increased after SDX-7320 (+74 +/- 63% relative to baseline).
Conclusions and Next Steps : SDX-7320 was well-tolerated with prolonged stable disease in an open-label, phase I first-in-human study. Improvements were observed in both tumor-related and metabolic biomarkers. Additional studies of SDX-7320 (in combination with other anti-cancer agents) in patients with solid tumors sensitive to metabolic hormones are scheduled. SDX-7320 is the first novel agent in clinical development to treat the metabo-oncology patient population.
Citation Format: Monica M. Mita, Johanna Bendell, Alain C. Mita, Michael Gordon, Jasgit Sachdev, Bradley J. Carver, James Shanahan, Benjamin Mayes, Kris Awerkamp, David Browning, Neal Salomon, Kimberly Sullivan, Alfred Anderson-Villaluz, Joe Johnson, John S. Petersen, David J. Turnquist, Peter Cornelius. SDX-7320 elicits improvements in tumor-related and metabolic biomarkers: Results of a phase 1 dose-escalation study in patients with advanced refractory or late-stage 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 CT153.