A Phase 1 Safety Study of Evexomostat (SDX-7320) in Patients with Late-Stage Cancer: An Antiangiogenic, Insulin-Sensitizing Drug Conjugate Targeting METAP2.

PURPOSE

To investigate the safety and tolerability of evexomostat (SDX-7320) in patients with late-stage cancer.

PATIENTS AND METHODS

This phase 1 dose-escalation safety study used an accelerated titration followed by a 3 + 3 design on 7- or 14-day administration, with dose expansion at the recommended phase 2 dose in 32 patients with late-stage, solid tumors. Measurements included standard assessments of safety, tolerability, target engagement in whole blood, plasma levels of protein biomarkers, and drug exposure. Tumor response was measured using RECIST v.1.1.

RESULTS

Thirty-two patients were dosed with evexomostat (SDX-7320), starting at 1.7 mg/m2 once per week and escalated to 65 mg/m2 (once every 2 weeks, 28 days/cycle). Dose escalation and expansion confirmed the maximum tolerated dose at 49 mg/m2 once every 2 weeks with reversible thrombocytopenia as the dose-limiting toxicity. Most treatment-emergent adverse events were of grade 1 or 2 in severity and nonserious, with no grade 5 adverse events. Eighty percent of patients (n = 20/25 evaluable) had stable disease, and the average treatment duration was 87 days (3.1 cycles). Key angiogenic biomarkers VEGF-C and bFGF (FGF2) improved in response to evexomostat. Patients with baseline insulin resistance (i.e., fasting insulin >20 µU/mL; n = 11) exhibited significant decreased fasting insulin after treatment. Decreases in leptin were observed in 27/31 patients (87%), whereas adiponectin increased in 28/31 patients (90%). Plasma lipid profiles showed increased high-density lipoprotein (HDL) and decreased low-density lipoprotein (LDL) cholesterol.

CONCLUSIONS

Evexomostat (SDX-7320) was well-tolerated with prolonged stable disease and metastatic control in an open-label, phase I safety study. Improvements were observed in angiogenic and metabolic biomarkers.

SIGNIFICANCE

Obesity and insulin resistance are known to promote tumor growth and accelerate the mortality of patients with cancer. Evexomostat is a novel antiangiogenic and antimetastatic drug candidate which also has insulin-sensitizing and antiobesity properties that is being developed for use in combination with standard-of-care therapies for obese patients with cancer.