Onvansertib in Combination With NALIRIFOX for First Line Treatment of Advanced Pancreatic Cancer

Inclusion Criteria:

• Ability of participant to understand this study, and participant willingness to signa written informed consent. Remote consenting will be allowed on a case-by-casebasis, but will not replace in-person visits for labs/physical, etc.

• Males and females age ≥ 18 years

• ECOG Performance Status 0 - 1

• Measurable disease by RECIST 1.1

• Histologically or cytologically confirmed adenocarcinoma of the exocrine pancreas

• Locally advanced unresectable or metastatic disease who are treatment naive

• No previous systemic therapy in the metastatic setting

• Participant must be willing to submit archival tissue if available and sufficient -otherwise fresh biopsy collection will be performed at screening UNLESS it is deemedmedically unsafe for the participant. If participant does not have archival tissueand is not able to undergo a fresh biopsy at this time, enrollment will be per theprincipal investigator's discretion

• Adequate organ function, defined as follows:

• Leukocytes (White Blood Cell [WBC]) > 3 K/UL

• Absolute Neutrophil Count >1.5K/UL

• Platelets >100K/UL

• Hemoglobin ≥ 9 g/dL(level must be maintained without transfusions)

• Calculated creatinine clearance ≥ 50 mL/min using the Cockcroft-Gault equation

• Total bilirubin ≤ 1.5 x ULN

• If known Gilbert's syndrome then discuss with principal investigator. Emaildocumentation of discussion and approval will be saved and documented for source.

• Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN unless livermetastases are present, in which case they must be ≤ 5 x ULN

• Women of child-bearing potential (WOCBP) and men with partners of child-bearingpotential must agree to practice sexual abstinence or to use the forms ofcontraception listed in Child-Bearing Potential/Pregnancy section.

Exclusion Criteria:

• Simultaneously enrolled in any therapeutic clinical trial

• Current or anticipating use of other anti-neoplastic or investigational agents whileparticipating in this study

• Diagnosed with a psychiatric illness or is in a social situation that would limitcompliance with study requirements

• Is pregnant or breastfeeding

• Has a known allergic reaction to any excipient contained in the study drugformulation

• Active Grade 3 (per the National Cancer Institute (NCI) Common Terminology Criteriafor Adverse Events (CTCAE), Version 5.027) or higher viral, bacterial, or fungalinfection within 2 weeks prior to the first dose of study treatment.

• Patient has had major surgery within 4 weeks prior to enrollment

• Untreated or symptomatic brain metastasis

• Gastrointestinal (GI) disorder(s) that, in the opinion of the Investigator, wouldsignificantly impede the absorption of an oral agent (e.g., intestinal occlusion,active Crohn's disease, ulcerative colitis, extensive gastric and small intestineresection)

• Unable or unwilling to swallow study drug

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, clinically significant non-healing or healing wounds, symptomaticcongestive heart failure (CHF) Class II or higher according to the New York HeartAssociation (NYHA) Functional Classification, unstable angina pectoris, clinicallysignificant cardiac arrhythmia, significant pulmonary disease (shortness of breathat rest or mild exertion), uncontrolled infection

• Known active infection with HIV, with measurable viral titer, and/or activeinfection with hepatitis B or C (patients who have had a hepatitis B virusimmunization are eligible)

• Known active infection with SARS-CoV-2 where symptoms are present

• Clinically significant ascites or pleural effusions

• Patients with a history of other malignancies except adequately treated non-melanomaskin cancer, curatively treated in-situ cancer of the cervix or prostate, or othersolid tumors curatively treated with no evidence of disease for > 2 years

• Any active disease condition that would render the protocol treatment dangerous orimpair the ability of the patient to receive study drug per PI discretion.

• Any condition (e.g., psychological, geographical, etc.) that does not permitcompliance with the protocol

• Treatment with any of the drugs listed in section with title; Prohibited orRestricted Concomitant Medications at the time of study treatment initiation.Planned concomitant use of medications known to prolong the QT/QTc intervalaccording to institutional guidelines. Use of strong CYP3A4 or CYP2C19 inhibitors orstrong CYP3A4 inducers. Patients currently receiving these agents who can beswitched to alternate therapy are not excluded. Inhibitors should be stopped atleast 1 week prior to the first dose of protocol therapy and inducers should bestopped at least 2 weeks prior to initiation of protocol therapy

• QT interval: Fridericia's correction (QTcF) > 470 milliseconds.

• A single ECG is sufficient. Triplicate may be done per PI discretion. Iftriplicate ECG completed, the QTcF should be calculated as the arithmetic meanof the QTcF on triplicate ECGs. In the case of potentially correctible causesof QT prolongation that are readily corrected (e.g., medications, hypokalemia),the triplicate ECG may be repeated once during Screening and that result may beused to determine eligibility

• Presence of risk factors for torsade de pointes, including family history ofLong QT Syndrome or uncorrected hypokalemia