Brief Summary: This early phase I trial aims to determine how cobimetinib, olaparib, LY3214996, or onvansertib works in patients with pancreatic cancer. Validation of cobimetinib, or olaparib, LY3214996, and onvansertib molecular targets will be explored by comparing pre-treatment biopsies with post-treatment specimens. This knowledge will help design future biomarker driven trials to determine whether giving cobimetinib, or olaparib, LY3214996, or onvansertib will work better than standard treatments in patients with pancreatic cancer.

Detailed Description: PRIMARY OBJECTIVE: I. Independently assess the pharmacodynamic (PD) feasibility of detecting a measurable change in tumor biology at post-treatment from baseline (i.e., before the study treatment window) for all feasibility-evaluable participants in each study arm. SECONDARY OBJECTIVES: I. Assess preliminary safety and tolerability of the proposed study agent(s) in each study arm. EXPLORATORY OBJECTIVES: I. Identify predictive biomarkers of sensitivity to assigned study agent(s). II. Identify emerging mechanism(s) of resistance to assigned study agent(s). III. Determine cellular and molecular changes in pancreatic tumor cells exposed to assigned study agent(s). IV. Identify tumor markers suggestive of combinatorial therapy that could overcome resistance to therapy. OUTLINE: Patients are assigned to 1 of 4 arms. ARM I: Patients receive olaparib PO twice daily (BID) on days 1-10 in the absence of disease progression or unacceptable toxicity. Within 12-24 hours, patients undergo biopsy or surgery as clinically appropriate per institutional standards for management of patient's disease. ARM II: Patients receive cobimetinib orally (PO) once daily (QD) on days 1-10 in the absence of disease progression or unacceptable toxicity. Within 12-24 hours, patients undergo biopsy or surgery as clinically appropriate per institutional standards for management of patient's disease. ARM IV: Patients receive onvansertib PO QD on days 1-10 in the absence of disease progression or unacceptable toxicity. Within 12-24 hours, patients undergo biopsy or surgery as clinically appropriate per institutional standards for management of patient's disease. ARM V: Patients receive azenosertib PO QD on days 1-10 in the absence of disease progression or unacceptable toxicity. Within 12-24 hours, patients undergo biopsy or surgery as clinically appropriate per institutional standards for management of patient's disease. After completion of study treatment, patients are followed up for 30 days.