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

Abstract

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.

• Authors: Monica M Mita, Patricia M LoRusso, Kyriakos P Papadopoulos, Michael S Gordon, Alain C Mita, Roberta Ferraldeschi, Harold Keer, Aram Oganesian, Xiang Yao Su, Simone Jueliger, Anthony W Tolcher
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 12 Pg. 2819-2826 (06 15 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 31900279 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Apoptosis Regulatory Proteins
• Morpholines
• Piperazines
• Pyrroles
• ASTX-660

Topics

• Adult
• Aged
• Apoptosis Regulatory Proteins (antagonists & inhibitors)
• Female
• Follow-Up Studies
• Humans
• Lymphoma (drug therapy, pathology)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Morpholines (therapeutic use)
• Neoplasms (drug therapy, pathology)
• Piperazines (therapeutic use)
• Prognosis
• Pyrroles (therapeutic use)