A Phase I Study of ASTX660, an Antagonist of Inhibitors of Apoptosis Proteins, in Adults with Advanced Cancers or Lymphoma

Purpose: This first-in-human, phase I study evaluated ASTX660, an oral, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins in patients with advanced solid tumors or lymphoma. Patients and Methods: ASTX660 was administered orally once daily on a 7-day-on/7-day-off schedule in a 28-day cycle. Dose escalation followed a standard 3+3 design to determine the MTD and recommended phase II dose (RP2D). Dose expansion was conducted at the RP2D. Results: Forty-five patients received ASTX660 (range 15–270 mg/day). Dose-limiting toxicity of grade 3 increased lipase with or without increased amylase occurred in 3 patients at 270 mg/day and 1 patient at 210 mg/day. The MTD was determined to be 210 mg/day and the RP2D 180 mg/day. Common treatment-related adverse events included fatigue (33%), vomiting (31%), and nausea (27%). Grade ≥3 treatment-related adverse events occurred in 7 patients, most commonly anemia (13%), increased lipase (11%), and lymphopenia (9%). ASTX660 was rapidly absorbed, with maximum concentration achieved at approximately 0.5–1.0 hour. An approximately 2-fold accumulation in AUC exposures was observed on day 7 versus 1. ASTX660 suppressed cellular inhibitor of apoptosis protein-1 in peripheral blood mononuclear cells, which was maintained into the second cycle beyond the off-therapy week at the 180-mg/day RP2D and above. Clinical activity was seen in a patient with cutaneous T-cell lymphoma. Conclusions: ASTX660 demonstrated a manageable safety profile and exhibited evidence of pharmacodynamic and preliminary clinical activity at the 180-mg/day RP2D. The phase II part of the study is ongoing.