Phase 1, open-label, dose-escalation study of M3814 + avelumab ± radiotherapy (RT) in patients (pts) with advanced solid tumors.

person Johanna C. Bendell Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN info_outline Johanna C. Bendell, Michael Rahman Shafique, Bradford Perez, Sarah Chennoufi, Frank Beier, Ky Trang, Scott Joseph Antonia

Authors person Johanna C. Bendell Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN info_outline Johanna C. Bendell, Michael Rahman Shafique, Bradford Perez, Sarah Chennoufi, Frank Beier, Ky Trang, Scott Joseph Antonia Organizations Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, Moffitt Cancer Center, Tampa, FL, Merck KGaA, Darmstadt, Germany Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: DNA-dependent protein kinase (DNA-PK) regulates a key DNA damage response (DDR) pathway for double-strand break (DSB) repair. DNA-PK inhibition augments DNA DSB damage generated by many antitumor therapies, including RT. DNA damage and repair impact the interaction of tumors with the immune system; combining immune checkpoint inhibitors (CPIs) with RT + DDR-targeted agents may modulate the tumor immune microenvironment, enhancing responsiveness to CPIs. M3814 (small molecule selective DNA-PK inhibitor) has demonstrated monotherapy activity in several tumor cell lines, and M3814 + RT combined with avelumab (programmed death ligand 1 mAb) significantly delayed tumor growth vs either agent alone + RT in MC38 syngrafts. This study will evaluate the clinical utility of M3814 combined with avelumab ± RT in pts with advanced solid tumors. Methods: NCT03724890 is a 2-part first-in-man study in adult pts with advanced or metastatic solid tumors. Part A is enrolling pts with measurable/evaluable solid tumors (RECIST v1.1); Part B will enrol pts with primary or metastatic tumor(s) in the lung which is/are amenable to be irradiated. In Part A, M3814 will be given orally twice daily. In Part B, M3814 + TRT will be given once daily, 5 days/wk for 2 wk. In both parts, pts will receive avelumab iv once every 2 wk from Day 1 until disease progression/unacceptable toxicity. Part B will initiate once the Safety Monitoring Committee declares the first dose level of Part A to have acceptable safety/tolerability. Primary objectives are to define the recommended Phase 2 dose (RP2D) of M3814 when combined with avelumab (Part A) and with avelumab + TRT (Part B) via dose-limiting toxicities (DLTs) occurring during the first 3/4 (Part A/B) wk of treatment. Secondary objectives include safety/tolerability, pharmacokinetics, immunogenicity, preliminary antitumor activity (BOR, PFS, OS). Sample size for each part depends on the number of DLTs/dose levels for M3814; dose escalation will be based on a Bayesian logistic regression model with overdose control. Part A aims to include 6–24 pts (≤4 dose levels), Part B 6–18 pts (≤3 dose levels). Recruitment began in Dec 2018. Clinical trial information: NCT03724890