The main objective of this trial is to assess the efficacy of onvansertib in combination with nanoliposomal irinotecan (nal-IRI), leucovorin, and fluorouracil (5-FU) for treatment of participants with histologically confirmed metastatic pancreatic ductal adenocarcinoma (PDAC).

Inclusion Criteria:

• Histologically or cytologically confirmed metastatic PDAC
• Has received 1 prior gemcitabine-based chemotherapy as first line therapy for metastatic disease. Progression after completion of neoadjuvant or adjuvant therapy of < 6 months in duration is considered 1 line of therapy for metastatic disease
• Has measurable disease according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), defined as at least 1 lesion that can be accurately measured in at least 1 dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as > 10 mm with spiral computed tomography (CT) scan
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
• Must be willing and able to undergo a tissue biopsy at screening; participants who, in the opinion of the investigator, do not have tissue that is accessible for biopsy are excepted from this criterion
• Women of childbearing potential: (defined as not post-menopausal for 12 months or no previous surgical sterilization) and fertile men must agree to use adequate contraception for the duration of study participation and for 4 months after the last dose of nal-IRI. Male subjects must agree to refrain from sperm donation during the study and for 4 months after the last dose of nal-IRI
• Ability to understand and the willingness to sign a written informed consent document. Signed informed consent form must be obtained prior to initiation of study evaluations and/or activities
• International Normalized Ratio (INR) < 1.5 unless on warfarin
• Participants with prior malignancy and who were treated with no evidence of active disease more than 2 years from initial diagnosis are eligible
• Age ≥ 18 years
• Participants must have adequate organ and bone marrow function

Exclusion Criteria:

• Prior treatment with irinotecan, nal-IRI, or investigational PLK1 inhibitor
• Uncontrolled intercurrent illness including symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, and myocardial infarction within 3 months of initiation of therapy
• History of interstitial pneumonitis or interstitial lung disease
• Participants with microsatellite instability-high (MSI-H) tumors with no prior immune checkpoint inhibitor exposure
• Pregnancy or lactation
• Participant has active and uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy
• QT interval with Fridericia's correction (QTcF) > 470 milliseconds. The QTcF should be calculated as the arithmetic mean of the QTcF on triplicate electrocardiograms (ECGs). In the case of potentially correctible causes of QT prolongation, (eg, medications, hypokalemia), the triplicate ECG may be repeated once during Screening and that result may be used to determine eligibility
• Planned concomitant use of medications known to prolong the QT/QTc interval
• Participant has undergone major surgical resection within 4 weeks prior to enrollment
• Participant received radiotherapy, surgery, chemotherapy, or an investigational therapy within 2 weeks prior to study entry
• Participant has serious medical risk factors involving any of the major organ systems such that the investigator considers it unsafe for the participant to receive an experimental research drugs
• Serious psychiatric or medical conditions that could interfere with treatment
• Major bleeding in the last 4 weeks
• More than 1 prior chemotherapy regimen administered in the metastatic setting
• Unable or unwilling to swallow oral medication
• Use of strong CYP3A4 or UGT1A1 inhibitors or strong CYP3A4 inducers. Participants currently receiving these agents who are able to switch to alternate therapy are not excluded. Inhibitors should be stopped at least one week prior to the first dose of protocol therapy and inducers should be stopped at least two weeks prior to initiation of protocol therapy.