M6620 and Irinotecan Hydrochloride in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

Patients must have histologically confirmed metastatic or unresectable malignancy that is refractory to standard therapy or for which no standard therapy exists and where irinotecan is deemed a reasonable treatment option

FOR PATIENTS ENROLLED IN THE EXPANSION COHORT: Patients must have known deficiencies in the deoxyribonucleic acid (DNA)-Damage Response (DDR), e.g. mutations in ATM, PALB2, BRCA1/2 or other deficiencies after discussion with the Study Chair (prioritized), or patients can be enrolled with the following tumor types regardless of known DDR deficiency: pancreatic cancer, colorectal cancer, and small cell lung cancer

Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>= 20 mm (\>= 2 cm) with conventional techniques or as \>= 10 mm (\>= 1 cm) with spiral CT scan, magnetic resonance imaging (MRI), or calipers by clinical exam

No limit on prior lines of therapy for metastatic disease; prior adjuvant or neoadjuvant chemotherapy does not count as a prior line of therapy as long as completion of the adjuvant or neoadjuvant therapy was more than 1 year prior to patient enrollment

Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of M6620 (VX-970, berzosertib) in combination with irinotecan in patients \< 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials

Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky \>= 70%)

Life expectancy of greater than 12 weeks

Leukocytes \>= 3,000/mcL

Absolute neutrophil count \>= 1,500/mcL

Platelets \>= 100,000/mcL

Total bilirubin within normal institutional limits

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional upper limit of normal (ULN); if liver involvement, =\< 5 x ULN

Creatinine clearance \>= 60 mL/min/1.73 m\^2

Patients must have archived tumor tissue from prior tumor biopsy or surgical resections available for submission that is sufficient to complete molecular profiling

FOR PATIENTS ENROLLED IN THE EXPANSION COHORT: Willingness to undergo mandatory biopsies (day -13, approximately 18 to 22 hours post end of irinotecan infusion and day 2, approximately 18 to 22 hours post end of irinotecan infusion \[= 17 to 21 hours post end of M6620 (VX-970, berzosertib)\]); patients enrolled to this cohort should have tumors deemed easily accessible for biopsies with low likelihood of complication

The effects of M6620 (VX-970, berzosertib) on the developing human fetus are unknown; for this reason and because DNA-damage response (DDR) inhibitors may have teratogenic potential, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of M6620 (VX-970, berzosertib) administration

* For this reason and because DNA-damage response (DDR) inhibitors may have teratogenic potential, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 6 months after study completion

Ability to understand and willingness to sign a written informed consent document

What this study is about