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Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

5396 - Safety, clinical activity and pharmacological biomarker evaluation of the DNA-dependent protein kinase (DNA-PK) inhibitor M3814: results from two phase I trials

Date

20 Oct 2018

Session

Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

Presenters

Morten Mau-Sorensen

Citation

Annals of Oncology (2018) 29 (suppl_8): viii649-viii669. 10.1093/annonc/mdy303

Authors

M. Mau-Sorensen1, M. van Bussel2, M. Kuipers3, D.L. Nielsen4, H.M. Verheul5, P. Aftimos6, M.J.A. de Jonge7, B. van Triest2, J. Falkenius8, J. Debus9, E. Troost10, M. Samuels11, B. Sarholz12, V. Budach13, S. Goel14, G. Locatelli15, P.F. Geertsen16

Author affiliations

  • 1 Department Of Oncology, SKACCD - Rigshospitalet, 2100 - Copenhagen/DK
  • 2 Department Of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam/NL
  • 3 Early Oncology, Merck KGaA - Germany, 64293 - Darmstadt/DE
  • 4 Department Of Oncology,, Herlev and Gentofte Hospital, 2730 - Herlev/DK
  • 5 Medical Oncology, Vrije University Medical Centre (VUMC), 1081 HV - Amsterdam/NL
  • 6 Medical Oncology Clinic, Institut Jules Bordet, Leuven/BE
  • 7 Medical Oncology, Erasmus MC Daniel den Hoed Cancer Center, 3075 EA - Rotterdam/NL
  • 8 Department Of Oncology, Karolinska University Hospital, Stockholm/SE
  • 9 Department Of Radiation oncology, Heidelberg University Hospital, 69120 - Heidelberg/DE
  • 10 Department Of Radiotherapy And Radiation oncology, University Hospital Carl Gustav Carus and Faculty of Medicine of Technische Universität Dresden, Dresden/DE
  • 11 Department Of Radiation oncology, University of Miami, Miami/US
  • 12 R&d Global Biostatistics & Epidemiology, Merck KGaA, Darmstadt/DE
  • 13 Klinik Fuer Radioonkologie, Klinik fuer Radioonkologie und Strahlentherapie Charite, Berlin/DE
  • 14 Medical Oncology, Montefiore Medical Center(East campus) - Medical Park at Eastchester Albert Einstein Cancer Center, 10461 - Bronx/US
  • 15 Global Clinical Development Unit - Oncology, Merck KGaA, 64293 - Darmstadt/DE
  • 16 Medical Oncology, Herlev Hospital, University of Copenhagen, Herlev/DK
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Resources

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.

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