This randomized phase II trial studies how well modified irinotecan hydrochloride, leucovorin calcium, fluorouracil (FOLFIRI) and veliparib as a second line of therapy work compared to FOLFIRI in treating patients with pancreatic cancer that has come back after a period of improvement (metastatic). Drugs used in chemotherapy, such as irinotecan hydrochloride, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether modified FOLFIRI and veliparib as second line therapy is more effective than FOLFIRI alone in treating metastatic pancreatic cancer.

PRIMARY OBJECTIVES:

I. To evaluate the overall survival (OS) of metastatic pancreatic cancer patients treated with fluorouracil, irinotecan (irinotecan hydrochloride), leucovorin (leucovorin calcium), (modified FOLFIRI) and ABT-888 (veliparib) compared to a control arm of fluorouracil, irinotecan, and leucovorin (FOLFIRI).

SECONDARY OBJECTIVES:

I. To evaluate the frequency and severity of toxicity associated with each of the treatment arms in this patient population.

II. To evaluate the progression-free survival (PFS) in each of the treatment arms in this patient population.

III. To evaluate the overall response rate (confirmed and unconfirmed; complete response + partial response), disease control rate (confirmed and unconfirmed; complete response + partial response + stable disease), and duration of response in each of the treatment arms in this patient population.

TERTIARY OBJECTIVES:

I. To evaluate if breast cancer, early onset (BRCA)1 and BRCA2 mutations (somatic or germline) are associated with improved clinical outcomes (overall survival [OS], progression-free survival [PFS] and overall response rates [ORR]) in each treatment arm.

II. To evaluate the impact of homologous recombination deficiency (HRD) score on clinical outcomes in each treatment arm.

III. To evaluate the impact of genomic alterations identified by the BROCA-homologous recombinant (HR) assay, other than BRCA1/2, on clinical outcomes in each treatment arm.

IV. To bank tissue for future translational medicine studies.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive veliparib orally (PO) twice daily (BID) every 12 hours on days 1-7, irinotecan hydrochloride intravenously (IV) over 90-120 minutes on day 3, leucovorin calcium IV over 90-120 minutes on day 3, and fluorouracil IV over 46 hours on days 3-5.

ARM II: Patients receive irinotecan hydrochloride IV over 90-120 minutes on day 1, leucovorin calcium IV over 90-120 minutes on day 1, and fluorouracil IV bolus over 15 minutes on days 1 and then over 46 hours on days 1-3.

In both arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 3 years.

Inclusion Criteria:

• Patients must have histologically or cytologically documented pancreatic adenocarcinoma; patients with pancreatic neuroendocrine tumors, lymphoma of the pancreas, or ampullary cancer are not eligible
• Patients must have metastatic disease that is measurable; computed tomography (CT) scans or magnetic resonance imaging (MRI)s used to assess measurable disease must have been completed within 28 days prior to registration; CT scans or MRIs used to assess non-measurable disease must have been completed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form
• Patients must not have history of brain metastases
• Patients must have had one and only one prior regimen of systemic therapy for metastatic disease unless the patient meets the criteria below
• Prior systemic therapy and chemoradiotherapy for treatment of resectable, borderline resectable or locally advanced unresectable disease is allowed and does not count toward prior therapy for metastatic disease
• Patients who received systemic therapy with gemcitabine/nab-paclitaxel for resectable or borderline/locally advanced unresectable disease and progressed with metastatic disease within 3 months of the past dose of systemic therapy are eligible
• Patients must have completed systemic therapy at least 14 days prior to registration, any surgical procedure must have been performed at least 14 days prior to registration, and radiation therapy must be completed at least 7 days prior to registration; patients must have recovered from major side effects of prior therapies or procedures in the opinion of the local site investigator prior to registration
• Patients must not have received prior irinotecan-based chemotherapy (e.g. irinotecan hydrochloride, leucovorin calcium, fluorouracil, and oxaliplatin [FOLFIRINOX] or FOLFIRI)
• Patients must not have received prior PARP inhibitor therapy including, but not limited to ABT-888, olaparib, rucaparib, and talazoparib (BMN637)
• Patients must have a Zubrod performance status of 0-1
• Within 14 days prior to registration: Absolute neutrophil count (ANC) >= 1,500/mcL
• Within 14 days prior to registration: Hemoglobin >= 9 g/dL
• Within 14 days prior to registration: Platelets >= 100,000/mcL
• Within 14 days prior to registration: Total bilirubin =< 1.5 x institutional upper limit of normal (IULN)
• Within 14 days prior to registration: Serum albumin >= 3.0 g/dL
• Within 14 days prior to registration: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN; patients with liver metastases may have AST and ALT of =< 5.0 x IULN
• Within 14 days prior to registration: Serum creatinine =< 2.0 mg/dL
• Patients must have CA19-9 obtained within 14 days prior to registration; if CA19-9 is normal a carcinoembryonic antigen (CEA) must be tested within 14 days prior to registration
• Patients must have blood urea nitrogen (BUN), alkaline phosphatase, sodium, potassium, calcium, glucose, chloride, and bicarbonate levels obtained within 14 days prior to registration
• Patients must not have any clinically significant and uncontrolled major medical condition(s) including, but not limited to uncontrolled nausea/vomiting/diarrhea; active uncontrolled infection; symptomatic congestive heart failure (New York Heart Association [NYHA] class >= II); unstable angina pectoris or cardiac arrhythmia; psychiatric illness/social situation that would limit compliance with study requirements
• Patients must not have active seizure or history of seizure
• Patients must be able to swallow whole capsule
• Patients must have a complete physical examination and medical history within 28 days prior to registration
• Patients must not have known Gilbert's syndrome
• Patients must not have known hypersensitivity to irinotecan, fluorouracil, or leucovorin
• Patients of childbearing potential must have a negative pregnancy test within 28 days prior to registration and must not be nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method during the study and for 6 months following completion of treatment; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
• Patients must be willing and able to undergo a biopsy after signed consent and prior to registration; patients must have tumor tissue and blood samples available and be willing to submit tumor and blood samples; NOTE: core biopsy required; fine needle aspiration (FNA) is not an acceptable substitute for core biopsy
• If archival tumor is available for submission, patients must be willing to submit tumor sample
• Patients must be offered the opportunity to participate in specimen banking for future use
• Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
• As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system