Onvansertib in Combination With Gemcitabine and Nab-paclitaxel for the Treatment of Patients With Locally-advanced, Unresectable, or Metastatic Pancreatic Ductal Adenocarcinoma

Inclusion Criteria:

* Must provide written informed consent before any study-specific procedures or interventions are performed
* Must be ≥ 18 years old at the time of informed consent
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* Histologically or cytologically-proven adenocarcinoma of the exocrine pancreas with locally advanced or metastatic disease
* Must not have received prior radiotherapy, surgery, chemotherapy or investigational therapy for the treatment of metastatic disease. Prior palliative radiotherapy of metastases for alleviation of pain is permitted provided that irradiated metastases are not target lesions
* Patient must be eligible to receive GnP regimen for the treatment of their PDAC in accordance with institutional standards
* Must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
* Must have at least one disease lesion that is amenable to biopsy procedures performed per institutional standards

  * Group 1 participant must agree to undergo two (2) research biopsies
  * Group 2 participants must agree to undergo three (3) research biopsies
* Hemoglobin ≥ 8.0 g/dL
* Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L (\> 1500 per mm\^3)
* Platelet count ≥ 100 x 10\^9/L (\> 100,000 per mm\^3);
* Creatinine ≤ 1.5 x upper limit of normal (ULN), or measured or calculated creatinine clearance \> 50 mL/min/1.73 m\^2 (per Cockcroft-Gault equation)
* Aspartate aminotransferase (AST)/alanine aminotransferase (ALT): ≤ 3 x ULN, or ≤ 5 x ULN in presence of liver metastases
* Participants of childbearing potential (POCBP) must agree to abstain from sexual intercourse or use effective non-hormonal methods of contraception starting with the first dose of study therapy through 90 days from the last dose of study intervention
* POCBP may participate provided they have a negative serum pregnancy test at screening and a negative serum OR urine pregnancy test within 7 days of starting treatment
* Sperm-producing participants must agree to abstain from sexual intercourse or use effective contraception starting with the first dose through 1 month after last dose of study intervention

Exclusion Criteria:

* Concomitant use of other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy (hormone replacement therapy is acceptable), radiotherapy (except for palliative), biological therapy or other novel agent) or live virus and live bacterial vaccines while receiving study medication
* Prior treatment with a PLK1 inhibitor
* Known severe hypersensitivity to onvansertib, gemcitabine, or nab-paclitaxel, or to any excipient of these medicinal products, or history of allergic reactions attributed to compounds of similar chemical or biologic composition
* Major surgery within 6 weeks prior to enrollment
* Uncontrolled intercurrent illness including symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, and myocardial infarction within 3 months of initiating study intervention
* QT interval with Fridericia's correction (QTcF) \> 470 milliseconds

  * The QTcF should be calculated based on a mean of triplicate electrocardiogram (ECGs). In the case of potentially correctible causes of QT prolongation (e.g., medications, hypokalemia), the triplicate ECG may be repeated once during Screening and that result may be used to determine eligibility
  * Use of concomitant medications known to increase QTc or risk of Torsades. These drugs should only be used if there are no other alternatives and only with appropriate monitoring (i.e., electrocardiograms)
  * Presence of risk factors for torsade de pointes, including family history of Long QT Syndrome or uncorrected hypokalemia
* Known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
* Use of strong CYP3A4 or UGT1A1 inhibitors or strong CYP3A4 inducers. Individuals currently receiving these agents who are able to switch to alternate therapy are still eligible for participation

  * CYP3A4 or UGT1A1 inhibitors should be stopped at least one week prior to the first dose of onvansertib
  * CYP3A4 inducers should be stopped at least two weeks prior to the first dose of onvansertib
* Psychiatric illness/social situations that would limit compliance with study requirements
* Any concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, etc.)
* Participant is pregnant or breastfeeding, or expecting to conceive or sire children within the projected duration of the trial, starting with the screening visit through 90 days after the last dose of trial treatment
* Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements