| Eligibility |
Inclusion Criteria:
- Part A: Patients between >= 12 months and < 18 years of age
- Part B:
- 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
- Any (non-CNS primary) solid tumor including lymphoma with inactivating
alterations of any of the DNA Damage Repair (DDR) genes: ATM, ATRX, BRCA1, BRCA2,
CDK12, CHEK1, CHEK2, FANCA, MSH2, MRE11, PALB2, PARP1, POLD1, RAD51, or XRCC2
- Part B: Any (non-CNS primary) solid tumor diagnosis including lymphoma which meets one
of the following criteria:
- B1, EWS Cohort:
- 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.)
- B2, PAX3-FOXO1 ARMS Cohort:
- 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
- B3, DDR Non-statistical Cohort:
- Any (non-CNS primary) solid tumor including lymphoma with inactivating
alterations of any of the DNA Damage Repair (DDR) genes: ATM, ATRX, BRCA1,
BRCA2, CDK12, CHEK1, CHEK2, FANCA, MSH2, MRE11, PALB2, PARP1, POLD1, RAD51,
or XRCC2
- All the genes on the DDR panel are annotated with OncoKB, a precision oncology
knowledge base which is publicly available here: https://www.oncokb.org/. Alterations
which are categorized either 'Oncogenic' or 'Likely Oncogenic' would be considered
sufficient for eligibility on either the phase 1 or phase 2 portions of this study.
Alterations which are not annotated in OncoKB will need to be reviewed with locally
qualified experts in molecular pathology, such as via an established molecular tumor
board, in order to determine the likely oncogenicity AND will require approval by the
study chair, Dr. Michael Ortiz. If such experts are not available at any institution,
the study chair will review
- In cases where multiple mutations are present or multiple samples are available,
either at different locations or different points in time, the presence of a single
qualifying genomic alteration in any of those samples will is considered sufficient
for eligibility on the phase 2 portions of this study
- Qualifying aberrations must be detected in either DNA or ribonucleic acid (RNA) in any
tumor tissue sample (i.e. detection of a variant on circulating tumor DNA/RNA is not
sufficient to qualify) using a somatic (and/or germline) mutational testing approach
with either a targeted panel or whole exome/genome sequencing in the context of a
Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory setting. Any
CLIA certified laboratory is acceptable to use
- Part A: Patients must have either measurable or evaluable disease
- Part B (1, 2, 3): Patients must have measurable disease
- Patients with a prior history of CNS metastases may enroll on study provided there is
no current evidence of active disease at the time of enrollment
- Patient's current disease state must be one for which there is no known curative
therapy or therapy proven to prolong survival with an acceptable quality of life
- Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1 or 2. Use Karnofsky >= 50% for patients > 16 years of age
and Lansky >= 50% for patients =< 16 years of age. Note that neurologic deficits in
patients with tumors previously metastatic to the CNS (or other non-oncologic reasons)
must have been stable for at least 7 days prior to study enrollment. Patients who are
unable to walk because of paralysis, but who are up in a wheelchair, will be
considered ambulatory for the purpose of assessing the performance score
- Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer therapy and must meet the following minimum duration from prior
anti-cancer directed therapy prior to enrollment. If after the required timeframe, the
numerical eligibility criteria are met, e.g., blood count criteria, the patient is
considered to have recovered adequately
- Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive:
>= 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior
nitrosourea)
- Anti-cancer agents not known to be myelosuppressive (e.g., not associated with
reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the
last dose of agent
- Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,
and toxicity related to prior antibody therapy must be recovered to grade =< 1
- Corticosteroids: If used to modify immune adverse events related to prior
therapy, >= 14 days must have elapsed since last dose of corticosteroid
- Hematopoietic growth factors: >= 14 days after the last dose of a long-acting
growth factor (e.g., pegfilgrastim) or 7 days for short acting growth factor. For
agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur
- Interleukins, interferons and cytokines (other than hematopoietic growth
factors): >= 21 days after the completion of interleukins, interferon or
cytokines (other than hematopoietic growth factors)
- Stem cell Infusions (with or without total-body irradiation [TBI]):
- Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem
cell infusion including donor lymphocyte infusions (DLI) or boost infusion:
>= 84 days after infusion and no evidence of graft versus host disease
(GVHD)
- Autologous stem cell infusion including boost infusion: >= 30 days
- Cellular therapy: >= 42 days after the completion of any type of cellular therapy
(e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.)
- Radiation therapy (XRT)/external beam irradiation including protons: >= 14 days
after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >=
50% of the pelvis; >= 42 days if other substantial bone marrow (BM) radiation
- Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I MIBG): >= 42 days
after systemically administered radiopharmaceutical therapy
- Study specific prior therapy: Patients must not have received prior exposure to
BAY 1895344 (elimusertib) or any other specific ATR inhibitors including
berzosertib (M6620, VX-970), ceralasertib (AZD6738), M4344 (VX-803), M1774, and
RP-3500. Treatment with other DNA damage repair inhibitors which do not
specifically inhibit ATR (e.g. PARP inhibitors, WEE1 inhibitors, CHEK1
inhibitors, etc.) does not exclude them from eligibility on this study
- For patients with solid tumors without known bone marrow involvement
- Peripheral absolute neutrophil count (ANC) >= 1000/uL
- For patients with solid tumors without known bone marrow involvement
- Platelet count >= 100,000/uL (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment)
- For patients with solid tumors without known bone marrow involvement
- Hemoglobin >= 8.0 g/dL at baseline (may receive red blood cell [RBC]
transfusions)
- Patients with known or possible bone marrow metastatic disease will be eligible for
study provided they meet the blood counts in above inclusion criteria (may receive
transfusions provided they are not known to be refractory to red cell or platelet
transfusions). These patients will not be evaluable for hematologic toxicity. At least
5 of every cohort of 6 patients must be evaluable for hematologic toxicity for the
dose-escalation part of the study. If dose-limiting hematologic toxicity is observed,
all subsequent patients enrolled must be evaluable for hematologic toxicity
- Serum creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or a creatinine based on age/gender as follows:
- Age: 1 to < 2 years; Maximum serum creatinine (mg/dL): 0.6 (male); 0.6 (female)
- Age: 2 to < 6 years; Maximum serum creatinine (mg/dL): 0.8 (male); 0.8 (female)
- Age: 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 (male); 1 (female)
- Age: 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female)
- Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)
- Age: >= 16 years; Maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)
- Bilirubin (sum of conjugated + unconjugated or total) =< 1.5 x upper limit of normal
(ULN) for age
- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135
U/L. For the purpose of this study, the ULN for SGPT is 45 U/L
- Patients with seizure disorder may be enrolled if on anticonvulsants and well
controlled as evidenced by no increase in seizure frequency in the prior 7 days. For
patients a history of seizure but not on anticonvulsants, no seizure in the past 3
months
- Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE]
version [v]5) resulting from prior therapy must be =< grade 2, with the exception of
decreased tendon reflex (DTR). Any grade of DTR is eligible
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
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