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Phase I trial of ATM inhibitor M3541 in combination with palliative radiotherapy in patients with solid tumors
Saiama N Waqar1, Clifford Robinson2, Anthony J Olszanski3
1Division of Oncology, Washington University School of Medicine and Alvin J. Siteman Cancer Center, Saint Louis, MO, USA.
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).
Insights
The ATM inhibitor M3541 showed good tolerability with palliative radiotherapy in solid tumors. However, further development was halted due to a non-optimal pharmacokinetic profile and lack of a clear dose-response relationship.
Area of Science:
- Oncology
- Pharmacology
- Radiotherapy
Background:
- Ataxia telangiectasia mutated (ATM) kinase is crucial for DNA double-strand break (DSB) repair.
- ATM inhibitors, like M3541, are investigated to enhance radiotherapy (RT) efficacy.
- M3541 is an orally administered selective ATM inhibitor.
Purpose of the Study:
- Evaluate the maximum-tolerated dose (MTD), recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and antitumor activity of M3541 combined with palliative RT.
- Assess M3541 in patients with solid tumors receiving fractionated RT.
Main Methods:
- Phase I dose-escalation study of M3541 (50-300 mg) with fractionated palliative RT (30 Gy in 10 fractions).
- Bayesian logistic regression model used for dose escalation.
- Fifteen patients with solid tumors were enrolled.
Main Results:
- M3541 doses up to 300 mg/fraction day were well tolerated with no Grade ≥4 treatment-emergent adverse events (TEAEs).
- Three patients (20.0%) achieved confirmed complete or partial response.
- No dose-response relationship or correlation between dose and PK parameters or ATM signaling was observed.
Conclusions:
- The MTD and RP2D could not be established due to early study closure.
- Non-optimal PK profile and absence of a dose-response relationship led to discontinuation of M3541 clinical development.
- M3541 demonstrated tolerability but lacked efficacy signals for further progression in this combination setting.
