ATRIN Eligibility Criteria

Inclusion Criteria

For a subject to be eligible for this study, s/he must meet ALL of the following criteria:
1. 12 years of age or older
2. Subjects may be enrolled with advanced solid tumor that has at least one of the following DDR mutations documented in the past medical record or confirmed during the screening period. Gene mutations in tumor tissue must be determined by a CLIA-certified NGS method (such as, e.g., FoundationOne CDx NGS assay ). DDR genomic variants will be reviewed during eligibility and documented in the CRF.
- ATM, FANCC, MRE11A, BRCA2, MLH1, PARP1, BRCA1, PMS2, checkpoint kinase1 (CHEK1), checkpoint kinase2 (CHEK2), RAD51C, poly-ADP ribose polymerase 2 (PARP2), methylthioadenosine phosphorylase (MTAP), MUTYH, ERCC4, poly-ADP ribose polymerase 3 (PARP3), ataxia telangiectasia and Rad3-related kinase (ATR), FANCG, RAD51B, FANCA, RAD51, RAD51D, BRCA1 interacting protein 1 (BRIP1), FANCL, RAD52, mutS homolog 6 (MSH6), POLE, RAD54L, partner and localizer of BRCA2 (PALB2), polymerase delta 1 (POLD1), XRCC2, mutS homolog 2 (MSH2), NBN, cyclin dependent kinase 12 (CDK12), AT-rich interactive domain-containing protein 1A (ARID1A), ATRX, CDKN2A, p53, Rb, Myc, CyclinE and PD-L1.
- Or advanced MCC.
3. Measurable disease defined by RECIST 1.1 or, for mCRPC subjects, by PCWG3 criteria.
4. Subject must have failed (demonstrated progression or intolerable safety events) at least one prior approved standard of care (SOC) therapy prior to entry into the study.
5. Life expectancy ≥ 3 months.
6. Subject must be capable of oral administration of study medication.
7. Signed written informed consent
8. Adequate bone marrow, renal, and liver function as manifested by any of the following:
a. Complete blood cell count (CBC): ANC ≥ 1,500/mm3, platelets ≥ 100,000/mm3, hemoglobin ≥ 9.0 g/dL,
b. Coagulation profile with prothrombin time (PT) and international normalized ratio (INR), each ≤ 1.5 x upper limit of normal (ULN),
c. Creatinine clearance ≥ 60 mL/min calculated by Cockcroft-Gault formula,
d. Proteinuria < 200 mg by 24- hour urine collection (only required if dipstick indicates proteinuria ≥1+) without evidence of active sediment or clinically significant hematuria.
e. Serum bilirubin < 1.5 x ULN, AST and ALT ≤ 2.5 x ULN.
9. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
10. If female, is not pregnant or breastfeeding based on the following:
a. a negative serum pregnancy test (ß-hCG) at Screening and negative urine pregnancy test at Baseline; or
b. is of nonchildbearing potential defined as clinically infertile as the result of surgical sterilization (hysterectomy, bilateral tubal ligation, and/or bilateral oophorectomy); or
c. is confirmed postmenopausal status (defined as either having amenorrhea for ≥ 12 consecutive months without another cause and documented serum follicle-stimulating hormone [FSH] level > 40 mIU/mL or another documented medical condition (e.g., was born without a uterus)), or agree to the use of highly effective contraceptive methods at screening until 45 days or 5 half-lives (whichever is longer) after the last day of study drug.
NOTE: The following are considered highly effective contraceptive methods: hormonal oral contraceptives, injectables, and patches; intrauterine devices; double-barrier methods (synthetic condom, diaphragm, or cervical cap used with spermicidal foam, cream, or gel); and male partner sterilization.
11. If male (with or without vasectomy), agree to the use of highly effective contraceptive methods (as listed in Criterion #10 above) at screening until 45 days or 5 half-lives (whichever is longer) after the last day of study drug.


Exclusion Criteria

Subjects must NOT meet any of the following exclusion criteria to be eligible for enrollment:
1. Subject has had a cytotoxic chemotherapy, immunotherapy, radiotherapy or other targeted therapies within 4 weeks (6 weeks in cases of mitomycin C, nitrosourea, lomustine) or at least 5 half-lives (whichever is shorter, but no less than 2 weeks) before the study drug administration, and all investigated medicinal product (IMP) related AEs (excluding alopecia) have not either returned to baseline or stabilized.
2. Surgical procedure performed within 7 days prior to first scheduled dose of ATRN-119.
3. Concomitant treatment with strong inhibitors or inducers of CYP3A4 and CYP2D6.
4. Known human immunodeficiency virus infection (HIV).
5. Subjects with active viral or bacterial infections and/or receiving systemic antibiotics or anti-viral medications.
6. Current or past diagnosis of leukemia within the past 5 years.
7. Prior radiotherapy at the target lesion unless there is evidence of disease progression.
8. Known CNS metastases or clinical evidence of CNS involvement that is not stable for previous 1 month by radiology documentation (magnetic resonance imaging [MRI] brain).
9. History of non-malignant gastronintestinal (GI) bleeding, gastric stress ulcerations, or peptic ulcer disease within the past 3-months that, in the opinion of the Investigator, may place the patient at risk of side effects on an anti-angiogenesis product.
10. Patient has uncontrolled hypertension at time of enrollment.
11. Complete left bundle branch block (LBBB), bifascicular block (right bundle branch block [RBBB] with either left anterior hemiblock or left posterior hemiblock).
12. Any clinically significant ST segment and/or T-wave abnormalities.
13. Presence of unstable atrial fibrillation (ventricular response rate > 100 bpm). Patients with stable atrial fibrillation are allowed in the study provided they do not meet another exclusion criteria.
14. Myocardial infarction or unstable angina pectoris within 6 months prior to starting study medication.
15. Congestive heart failure (New York Heart Association class III-IV).
16. History of other significant cardiovascular disease or vascular disease within the last 6 months (e.g., such as hypertensive crisis, hypertensive encephalopathy, stroke or transient ischemic attack [TIA], or significant peripheral vascular disease).
17. QTcF >470 msec for male and female subjects, based on the average of three ECG measurements at the screening visit.
18. Echocardiogram or multiple gated acquisition scanning (MUGA) (within 2 months) with left ventricular ejection fraction (LVEF) <50%.
19. History of clinically significant glomerulonephritis, biopsy proven tubulointerstitialnephritis, crystal nephropathy, or other renal insufficiencies.
20. Treatment with an investigational agent within the longest time frame of either 5 half-lives or 30 days of initiating study drug.
21. Medical illness that, in the opinion of the Investigator, may impact the safety of the subject or objectives of the study. Known recreational substance use or psychiatric illness that, in the opinion of the Investigator, may affect compliance with scheduled visits.
22. Known hypersensitivity to ATRN-119 or components of the formulation.
23. History of clinically significant renal impairment.
24. History of clinically significant liver disease, liver impairment or any other liver anomality which may affect drug metabolism.