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

  • Clin Cancer Res. 2020 Jun 15;26(12):2819-2826. doi: 10.1158/1078-0432.CCR-19-1430.
Monica M Mita  1 ,  Patricia M LoRusso  2 ,  Kyriakos P Papadopoulos  3 ,  Michael S Gordon  4 ,  Alain C Mita  5 ,  Roberta Ferraldeschi  6  7 ,  Harold Keer  6 ,  Aram Oganesian  6 ,  Xiang Yao Su  6 ,  Simone Jueliger  7 ,  Anthony W Tolcher  3
Affiliations
  • 1. Experimental Therapeutics, Cedars-Sinai, Los Angeles, California. [email protected].
  • 2. Medical Oncology, Yale Cancer Center, New Haven, Connecticut.
  • 3. Clinical Research, South Texas Accelerated Research Therapeutics (START), San Antonio, Texas.
  • 4. HonorHealth Research Institute, Scottsdale, Arizona.
  • 5. Experimental Therapeutics, Cedars-Sinai, Los Angeles, California.
  • 6. Astex Pharmaceuticals, Inc., Pleasanton, California.
  • 7. Astex Pharmaceuticals, Cambridge, United Kingdom.
PMID: 31900279 DOI: 10.1158/1078-0432.CCR-19-1430
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.

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