Phase I trial of ATM inhibitor M3541 in combination with palliative radiotherapy in patients with solid tumors

Saiama N. Waqar, Clifford Robinson, Anthony J. Olszanski, Alexander Spira, Melissa Hackmaster, Luisa Lucas, Laura Sponton, Hulin Jin, Ursula Hering, Damien Cronier, Marianna Grinberg, Annick Seithel-Keuth, Ivan Diaz-Padilla, Jordan Berlin

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Background. Ataxia telangiectasia mutated (ATM) kinase orchestrates DNA double strand break (DSB) repair; ATM inhibitors may therefore enhance the therapeutic effect of DSB-inducing treatments such as radiotherapy (RT). M3541 is an orally administered selective inhibitor of ATM. Methods. This phase I dose-escalation study evaluated the maximum-tolerated dose (MTD), recommended phase II dose(s) (RP2D), safety, pharmacokinetics (PK) and antitumor activity of M3541 in combination with fractionated palliative RT in patients with solid tumors. Fifteen patients received palliative RT (30 Gy in 10 fractions) and escalating doses of M3541 (50–300 mg administered on RT fraction days) guided by a Bayesian 2-parameter logistic regression model with overdose control. Results. Doses of M3541 up to 300 mg/fraction day were well tolerated. One patient (200 mg group) experienced two dose-limiting toxicities (urinary tract infection, febrile neutropenia) that resolved with antibiotics. All patients reported ≥ 1 treatment-emergent adverse event (TEAE) but none led to treatment discontinuation. No grade ≥ 4 TEAEs were reported and there was no indication of a dose effect for any TEAE. Three patients (20.0%; 95% confidence interval 4.3–48.1) had confirmed complete or partial response. M3541 total plasma levels did not increase with dose following single or repeated dosing. No relationship was observed between dose and changes in the ratio of phosphorylated to total ATM or in immune cell counts. Conclusions. The MTD and RP2D could not be established as the study closed early due to the absence of a dose–response relationship and non-optimal PK profile. No further clinical development of M3541 was pursued. (Trial registration number ClinicalTrials.gov NCT03225105. Registration date July 21, 2017).

Original languageEnglish
Pages (from-to)596-605
Number of pages10
JournalInvestigational New Drugs
Volume40
Issue number3
DOIs
StatePublished - Jun 2022

Keywords

  • ATM inhibitor
  • DNA damage response
  • DNA repair
  • M3541
  • Palliative radiotherapy
  • Solid tumor

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