This phase I/II trial tests the safety, best dose, and whether elimusertib works in treating patients with solid tumors that have come back (relapsed) or does not respond to treatment (refractory). Elimusertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
31
Given PO
Children's Hospital of Alabama
Birmingham, Alabama, United States
Children's Hospital Los Angeles
Los Angeles, California, United States
Children's Hospital of Orange County
Orange, California, United States
UCSF Medical Center-Mission Bay
San Francisco, California, United States
Children's Hospital Colorado
Aurora, Colorado, United States
Frequency of Cycle 1 Dose Limiting Toxicities for BAY 1895344 (Elimusertib) During Dose Escalation
Frequency (%) of patients experiencing a cycle 1 dose limiting toxicity among toxicity-evaluable patients stratified by dose level during the dose escalation part of the study (Part A).
Time frame: Up to 28 days (cycle 1)
Response of BAY 1895344 (Elimusertib)
Frequency (%) of patients with best response of complete response or partial response among response-evaluable patients stratified by Phase 2 cohort.
Time frame: Through study completion, up to 37 months
Incidence of Adverse Events of BAY 1895344 (Elimusertib)
Frequency (%) of patients with adverse events stratified by study part and dose level.
Time frame: Through study completion, up to 37 months
Area Under the Drug Concentration Time Curve of BAY 1895344 (Elimusertib)
Median (min, max) of the area under the drug concentration time curve (AUC) in cycle 1 stratified by study part and dose level.
Time frame: Up to 28 days
Change in Phosphorylated (p)ATR of BAY 1895344 (Elimusertib)
Median (min, max) of the change in (p)ATR stratified by study part and dose level.
Time frame: Up to 28 days
Change in pH2AX of BAY 1895344 (Elimusertib)
Median (min, max) of the change in pH2AX stratified by study part and dose level.
Time frame: Up to 28 days
Change in pKAP1 of BAY 1895344 (Elimusertib)
Median (min, max) of the change in pKAP1 stratified by study part and dose level.
Time frame: Up to 28 days
Influence of ALT on Activity of BAY 1895344
Median (min, max) of ALT in responders (CR or PR) versus non-responders among all response-evaluable patients.
Time frame: Up to 28 days
Influence of Tumor Tissue Expression of ATM on Activity of BAY 1895344
Median (min, max) of ATM in responders (CR or PR) versus non-responders among all response-evaluable patients.
Time frame: Up to 28 days
Influence of Tumor Tissue Expression of PGBD5 on Activity of BAY 1895344
Median (min, max) of PGBD5 in responders (CR or PR) versus non-responders among all response-evaluable patients.
Time frame: Up to 28 days
Influence of Tumor Tissue Expression of R-loops on Activity of BAY 1895344
Median (min, max) of R-loops in responders (CR or PR) versus non-responders among all response-evaluable patients.
Time frame: Up to 28 days
Response of BAY 1895344 (Elimusertib) in Children < 18 Years
Frequency (%) of patients with best response of complete response or partial response among response-evaluable patients in the dose escalation part of the study (Part A).
Time frame: Up to 60 months
Response of BAY 1895344 in Pediatric Patients With Non-CNS Solid Tumors or Lymphomas
Frequency of patients with best response of complete response or partial response among response-evaluable patients with non-CNS solid tumors or lymphomas with specific deleterious alternations in DDR pathway.
Time frame: Up to 60 months
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Children's National Medical Center
Washington D.C., District of Columbia, United States
Johns Hopkins All Children's Hospital
St. Petersburg, Florida, United States
Lurie Children's Hospital-Chicago
Chicago, Illinois, United States
Riley Hospital for Children
Indianapolis, Indiana, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States
...and 19 more locations