Elimusertib for the Treatment of Relapsed or Refractory Solid Tumors

PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of BAY 1895344 (elimusertib) administered as an oral tablet, twice per day for 3 days on and 4 days off to patients \< 18 years of age with recurrent or refractory Ewing sarcoma (and EWS fusions), PAX3-FOXO1 alveolar rhabdomyosarcoma, and non-central nervous system (CNS) solid tumors or lymphoma with specific deleterious deoxyribonucleic acid (DNA) damage response (DDR) pathway alterations. (Phase 1/Part A) II. To define the antitumor activity of BAY 1895344 (elimusertib) in pediatric patients and young adults with recurrent or refractory Ewing sarcoma (and EWS fusions). (Phase 2/Part B) III. To define the antitumor activity of BAY 1895344 (elimusertib) in pediatric patients and young adults with recurrent or refractory PAX3-FOXO1 fusion positive alveolar rhabdomyosarcoma. (Phase 2/Part B) IV. To define and describe the toxicities of BAY 1895344 (elimusertib) administered on this schedule. (Phase 1/Part A) SECONDARY OBJECTIVES: I. To characterize the pharmacokinetics of BAY 1895344 (elimusertib) in children and adolescents with recurrent or refractory cancer. II. To assess the biologic activity of BAY 1895344 (elimusertib) by immunohistochemical assessments of phosphorylated (p)ATR, pH2AX, and pKAP1 in paired tissue samples before and after treatment with BAY 1895344 (elimusertib). III. To assess whether the activity of BAY 1895344 (elimusertib) is influenced by alternative lengthening of telomeres (ALT), as well as tumor tissue expression of ATM, PGBD5, and/or R-loops. IV. To assess whether the activity of BAY 1895344 (elimusertib) is associated with tumor mutational processes, as measured by whole genome tumor tissue sequencing. V. To preliminary determine the anti-tumor activity of BAY 1895344 (elimusertib) in children \< 18 years of age within the confines of a phase 1 study (Phase 1 and 2/Part A and B). VI. To assess the antitumor activity of BAY 1895344 (elimusertib) in pediatric patients with non-CNS solid tumors or lymphomas with specific deleterious alterations in DDR pathway genes. (Phase 2/Part B) OUTLINE: This is pediatric a phase I, dose-escalation study as well as a phase II dose expansion study in pediatric patients and young adults. Patients receive elimusertib orally (PO) twice daily (BID) on days 1-3, 8-10, 15-17, and 22-24 of each cycle. Treatment repeats every 28 days for 26 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 12 months, every 6 months for 24 months, and then annually for up to 60 months.