A Phase 1/ 2 Study of BAY 1895344 (Elimusertib, NSC#810486) in Pediatric Patients With Relapsed or Refractory Solid Tumors
Overview
- Phase
- Phase 1
- Status
- Active, not recruiting
- Enrollment
- 31
- Locations
- 29
- Primary Endpoint
- Response of BAY 1895344 (elimusertib)
Overview
Brief Summary
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.
Detailed Description
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 Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 12 Months to 30 Years (Child, Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Part A: Patients between \>= 12 months and \< 18 years of age
- •Patients between \>= 12 months and =\< 30 years of age for the phase 2 expansion cohorts for both EWS and PAX3-FOXO1 ARMS.
- •Patients between \>= 12 months and =\< 21 years of age for the phase 2 DDR expansion cohort
- •The Phase 2 cohorts will initially open concurrently with the Phase 1 portion but will only enroll patients at least 18 years of age. Patients \< 18 years of age will be included in the Phase 2 cohorts only after the RP2D/MTD has been estimated in the Phase 1 portion
- •All patients for both Parts A and B must have a minimum body surface area (BSA) \>= 0.74 m\^2
- •All patients for both Parts A and B must have the ability to swallow BAY 1895344 (elimusertib) tablets intact
- •Patients with recurrent or refractory solid tumors. Patients must have had histologic verification of malignancy at original diagnosis or relapse
- •Part A: Any (non-CNS primary) solid tumor diagnosis including lymphoma which meets one of the following criteria:
- •Any Ewing Sarcoma (histological confirmation alone is adequate) or any EWS-fusion positive solid tumor (i.e. including related Ewing's family of tumors with EWS fusions such as EWS-WT1, EWS-ATF1, etc.)
- •Alveolar rhabdomyosarcoma (ARMS) with the PAX3-FOXO1 fusion. This does not include PAX7-FOXO1 or other variant fusion ARMS. Please note that a FISH showing FOXO1 breakapart is NOT sufficient for eligibility onto this cohort since it cannot distinguish between FOXO1 partners
Exclusion Criteria
- •Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, OR because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control, including a medically accepted barrier or contraceptive method (e.g., male or female condom) for the duration of the study and for 3 months + 2 days for males and 6 months + 2 days for females after receiving the last dose of BAY 1895344 (elimusertib) on the study. Abstinence is an acceptable method of birth control. Female patients must not breastfeed during treatment and until 4 months after last study drug administration
- •Corticosteroids: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. If used to modify immune adverse events related to prior therapy, \>= 14 days must have elapsed since last dose of corticosteroid
- •Patients who are currently receiving another investigational drug are not eligible
- •Patients who are currently receiving other anti-cancer agents are not eligible
- •Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
- •Patients who are currently receiving drugs that are strong inducers or inhibitors of CYP3A4 are not eligible. Strong inducers or inhibitors of CYP3A4 should be avoided from 14 days prior to enrollment to the end of the study. Drugs that are considered sensitive or narrow therapeutic range CYP3A4 substrates should be avoided for the duration of protocol therapy
- •Dedicated CNS imaging is not required but patients with current active CNS metastasis whether symptomatic or discovered incidentally without clinical symptoms, will be excluded from study participation
- •Patients who have an uncontrolled infection are not eligible
- •Patients who have received a prior solid organ transplantation are not eligible
- •Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
Arms & Interventions
Treatment (elimusertib)
Patients receive elimusertib PO 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.
Intervention: Elimusertib (Drug)
Outcomes
Primary Outcomes
Response of BAY 1895344 (elimusertib)
Time Frame: Up to 60 months
Frequency (%) of patients with best response of complete response or partial response among response-evaluable patients stratified by Phase 2 cohort.
Frequency of Cycle 1 Dose Limiting Toxicities for BAY 1895344 (Elimusertib) During Dose Escalation
Time Frame: Up to 28 days (cycle 1)
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).
Response of BAY 1895344 (Elimusertib)
Time Frame: Through study completion, up to 37 months
Frequency (%) of patients with best response of complete response or partial response among response-evaluable patients stratified by Phase 2 cohort.
Secondary Outcomes
- Incidence of adverse events of BAY 1895344 (elimusertib)(Up to 60 months)
- Area under the drug concentration time curve of BAY 1895344 (elimusertib)(Up to 28 days)
- Influence of ALT on activity of BAY 1895344(Up to 28 days)
- Influence of tumor tissue expression of R-loops on activity of BAY 1895344(Up to 28 days)
- Response of BAY 1895344 (elimusertib) in children < 18 years(Up to 60 months)
- Response of BAY 1895344 in pediatric patients with non-CNS solid tumors or lymphomas(Up to 60 months)
- Incidence of Adverse Events of BAY 1895344 (Elimusertib)(Through study completion, up to 37 months)
- Area Under the Drug Concentration Time Curve of BAY 1895344 (Elimusertib)(Up to 28 days)
- Change in Phosphorylated (p)ATR of BAY 1895344 (Elimusertib)(Up to 28 days)
- Change in pH2AX of BAY 1895344 (Elimusertib)(Up to 28 days)
- Change in pKAP1 of BAY 1895344 (Elimusertib)(Up to 28 days)
- Influence of ALT on Activity of BAY 1895344(Up to 28 days)
- Influence of Tumor Tissue Expression of ATM on Activity of BAY 1895344(Up to 28 days)
- Influence of Tumor Tissue Expression of PGBD5 on Activity of BAY 1895344(Up to 28 days)
- Influence of Tumor Tissue Expression of R-loops on Activity of BAY 1895344(Up to 28 days)
- Response of BAY 1895344 (Elimusertib) in Children < 18 Years(Up to 60 months)
- Response of BAY 1895344 in Pediatric Patients With Non-CNS Solid Tumors or Lymphomas(Up to 60 months)