Abstract 5396
Background
Agents that generate breaks in DNA are frequently used in the treatment of cancer. These agents induce different forms of DNA damage including double-strand breaks (DSBs), which are the most lethal if left unrepaired. M3814 targets tumor cell growth and survival by inhibiting DNA-PK, which is part of a critical DSB DNA damage repair mechanism. M3814 has been explored as a single agent (A; NCT02316197) and in combination with radiotherapy (RT) (B; NCT02516813).
Methods
In both trials patients (pts) were treated with ascending doses of M3814 to establish the safety and maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) (primary endpoint) and efficacy (secondary endpoint). Dose-limiting toxicity (DLT) was evaluated after 3 (A) or 5 weeks (B). Rich pharmaco-kinetic and -dynamic (PK and Pd) sampling was performed (exploratory endpoint). In A, M3814 was continued until progression, unacceptable toxicity, pt wish, or physician decision. In B, M3814 was given during RT to tumor or metastasis in the head and neck or thoracic region, 10 x 3 Gy.
Results
Up to Apr 1, 2018, 31 pts in A and 16 pts in B have been enrolled. In A one DLT was seen (prolonged low-grade AEs), the RP2D selected was 400 mg BID. In B, dose escalation is ongoing with DLTs of grade 3 mucositis (n = 3) and grade 3 odynophagia tox (n = 1). Most frequent adverse events (AE) were in A, nausea, vomiting, decreased appetite, constipation, diarrhea, pyrexia, fatigue, and rash, in B, dysphagia, prolonged mucosal inflammation/ stomatitis and radiation skin injury. One case of radiation pneumonitis has been reported. No pts discontinued due to AE. PK analysis demonstrated high variability of exposure. Pd in surrogate tissue showed robust inhibition of the induction of phosphoDNA-PKi (pDNA-PKi) for up to 6 hours. No objective responses were reported in A, while in B durable in field responses were seen (n = 7).
Conclusions
M3814 was found to be well tolerated as monotherapy and dose escalation combination with palliative RT is ongoing. PK of the current formulation showed a high inter-pt variability, Pd suppression of pDNA-PKi was observed as predicted by modelling and simulation.
Clinical trial identification
NCT02316197 and NCT02516813.
Legal entity responsible for the study
Merck KGaA, Darmstadt, Germany.
Funding
Merck KGaA, Darmstadt, Germany.
Editorial Acknowledgement
Disclosure
M. Kuipers, B. Sarholz, G. Locatelli: Employee: Merck KGaA. P. Aftimos: Honoraria: Synthon, Boehringer Ingelheim, Macrogenics, Amgen, Novartis; Travel grants: Amgen, Merck, Roche. J. Debus: Advisory role and funding for the conduct of a clinical trial: Merck. All other authors have declared no conflicts of interest.