A first-in-man phase 1 study of the DNA-dependent protein kinase inhibitor peposertib (formerly M3814) in patients with advanced solid tumours

Abstract

Background: This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase (DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/pharmacodynamic profiles and clinical activity.

Methods: Adult patients with advanced solid tumours received peposertib 100-200 mg once daily or 150-400 mg twice daily (BID) in 21-day cycles.

Results: Thirty-one patients were included (median age 66 years, 61% male). One dose-limiting toxicity, consisting of mainly gastrointestinal, non-serious adverse events (AEs) and long recovery duration, was reported at 300 mg BID. The most common peposertib-related AEs were nausea, vomiting, fatigue and pyrexia. The most common peposertib-related Grade 3 AEs were maculopapular rash and nausea. Peposertib was quickly absorbed systemically (median Tmax 1.1-2.5 h). The p-DNA-PK/t-DNA-PK ratio decreased consistently in peripheral blood mononuclear cells 3-6 h after doses ≥100 mg. The best overall response was stable disease (12 patients), lasting for ≥12 weeks in seven patients.

Conclusions: Peposertib was well-tolerated and demonstrated modest efficacy in unselected tumours. The MTD was not reached; the RP2D was declared as 400 mg BID. Further studies, mainly with peposertib/chemo-radiation, are ongoing.

Clinical trial registration: NCT02316197.

Conflict of interest statement

M.T.J.v.B., M.M.-S. and D.N. declare no potential conflicts of interest. A.A. has undertaken advisory roles and received speaker fees from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Eli Lilly, Genomic Health, Hoffmann-La Roche, Ipsen, Leo Pharma, Merck & Co., Novartis and Pfizer. M.J.A.d.J. has participated in advisory boards on behalf of Faron Pharmaceuticals. P.S. has received honoraria and has undertaken consultancy work for Deciphera. H.M.W.V. has participated in advisory boards on behalf of Lava Therapeutics and Glycostem, for which fees were paid to his institution. B.S., K.B., S.E.B. and M.K. are employees of Merck KGaA, Darmstadt, Germany. L.D. was an employee of Merck KGaA, Darmstadt, Germany, at the time of study conduct, and is currently an employee of Debiopharm International S.A., Lausanne, Switzerland. I.D.-P. is an employee of Ares Trading S.A., Eysins, Switzerland; an affiliate of Merck KGaA, Darmstadt, Germany. J.H.M.S. is patent holder on development of oral taxanes and shareholder of Modra Pharmaceuticals B.V.

Figures

Fig. 1. Patient disposition.

aFormerly M3814; bThe six patients in the RP2D cohort were aspirin-naïve; cPatients were treated until disease progression or death; dDLT, due to a combination of low grade, mainly gastrointestinal, non-serious AEs and the long duration of recovery following treatment discontinuation. BID twice daily, DLT dose-limiting toxicity, QD once daily, RP2D recommended phase 2 dose.

Fig. 2. Peposertib (formerly M3814) pharmacokinetics.

Plasma concentration–time profiles of peposertib (formerly M3814) following a QD (PK Analysis Set; n = 6) and b BID (PK Analysis Set; n = 25 [Cycle 1], n = 17 [Cycle 2]) dosing (linear scale). Dose-normalised AUC0–12 for peposertib by dose on c Cycle 1 Day 1 (QD and BID; PK Analysis Set; n = 25) and d Cycle 2 Day 1 (BID; PK Analysis Set; n = 17). AUC0–12 area under the plasma concentration–time curve from 0 to 12 h, BID twice daily, PK pharmacokinetics, QD once daily.

Fig. 3. DNA-PK inhibition by peposertib (formerly M3814).

In a typical time-course profiles of PK (grey circles) and DNA-PK inhibition (black squares) after peposertib treatment from one patient treated with peposertib 100 mg QD. DNA-PK inhibition on treatment is expressed as percentage change of p-DNA-PK/t-DNA-PK from the pre-treatment value (time h = 0). In b concentration-dependent inhibition of DNA-PK in response to peposertib treatment. Experimental concentration−response data are shown (open circles) and the line represents the Emax model fit to the data. Bleo bleomycin, DNA-PK DNA-dependent protein kinase, Emax maximum response, p-DNA-PK autophosphorylated form of DNA-PK on Ser2056, PK pharmacokinetics, QD once daily, t-DNA-PK total DNA-PK.

Fig. 4. Waterfall plot showing best percentage change in tumour size from baseline and best overall response.

Peposertib (formerly M3814) dose (mg)/frequency of administration is shown for each patient on the x axis. Dashed lines show the 20% threshold for PD and the 30% threshold for partial response. aColon. BID twice daily, MSI microsatellite instability, NSCLC non-small cell lung cancer, PD progressive disease, QD once daily, RP2D recommended phase 2 dose, SD stable disease.