Paclitaxel Albumin-Stabilized Nanoparticle Formulation and Gemcitabine Hydrochloride With or Without WEE1 Inhibitor AZD1775 in Treating Patients With Previously Untreated Pancreatic Cancer That Is Metastatic or Cannot Be Removed by Surgery

PRIMARY OBJECTIVES: I. To evaluate the toxicity of combination therapy with nab-paclitaxel (paclitaxel albumin-stabilized nanoparticle formulation), gemcitabine (gemcitabine hydrochloride) and AZD1775 (WEE1 inhibitor MK-1775) in patients with treatment-naive metastatic adenocarcinoma of the pancreas or locally-advanced adenocarcinoma of the pancreas which is not surgically resectable. (Phase I) II. To determine the dose of AZD1775 to be used in combination with nab-paclitaxel and gemcitabine chemotherapy in the phase II portion of the trial. (Phase I) III. To determine the pharmacokinetics of AZD1775 in combination with nab-paclitaxel and gemcitabine. (Phase I) IV. To evaluate progression-free survival (PFS) associated with nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the pancreas. (Phase II) SECONDARY OBJECTIVES: I. To evaluate overall survival (OS) associated with nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the pancreas. (Phase II) II. To evaluate response rate (complete response \[CR\] + partial response \[PR\]) associated with nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the pancreas. (Phase II) III. To evaluate disease control rate (CR + PR + stable disease \[SD\]) associated with nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the pancreas. (Phase II) TERTIARY OBJECTIVES: I. To evaluate the ability of AZD1775 to inhibit Wee1 and increase deoxyribonucleic acid (DNA) damage and tumor cell death when combined with nab-paclitaxel/gemcitabine compared to nab-paclitaxel/gemcitabine/placebo. (Phase II) II. To evaluate if biomarker changes in tumor tissue associated with Wee1 inhibition may also be present in hair follicles. (Phase II) III. To evaluate the change in tumor fludeoxyglucose (FDG) uptake (maximum standardized uptake value \[SUVmax\]) between baseline FDG-positron emission tomography (PET) and week 4 FDG-PET as a predictor of response using Response Evaluation Criteria in Solid Tumors (RECIST) as the reference standard for response. (Phase II) IV. To evaluate the change in tumor FDG uptake (SUVmax) between baseline FDG-PET and week 4 FDG-PET as a predictor of progression-free survival. (Phase II) V. To compare the change in tumor FDG uptake (SUVmax) between baseline FDG-PET and week 4 FDG-PET between the patients from treatment arms C and D. (Phase II) VI. To evaluate if an early increase in tumor fluorothymidine (FLT) uptake (FLT-flare) is observed within 24 hours after initiation of treatment with nab-paclitaxel/gemcitabine/placebo. (Phase II) VII. To evaluate if an early (within 24 hours \[h\]) increase in tumor FLT uptake (FLT-flare) is abrogated after initiation of treatment with nab-paclitaxel/gemcitabine/AZD1775. (Phase II) VIII. To compare the change in tumor FLT uptake (SUVmax) from baseline to 24 hours after initiation of treatment between the patients from treatment arms C and D. (Phase II) OUTLINE: This is a phase I, dose escalation study of WEE1 inhibitor AZD1775 followed by a randomized phase II study. Patients in phase I are assigned to arm A or B and patients in phase II are randomized to arm C or D. ARM A (PHASE I, DOSE LEVEL 1): Patients receive paclitaxel albumin-stabilized nanoparticle formulation intravenously (IV) over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive WEE1 inhibitor AZD1775 orally (PO) daily on days 1, 2, 8, 9, 15, and 16. ARM B (PHASE I, DOSE LEVEL -2): Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A. ARMS C - G (PHASE I, DOSE LEVEL -1 to DOSE LEVEL 4): Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A at various dose levels. These arms did not enroll any patients. ARM H (PHASE II, Control): Patients receive paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride as in Arm A. The study did not move forward to the phase II part. ARM I (PHASE II, WEE1 INHIBITOR AZD1775): Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A. The study did not move forward to the phase II part. In all arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years.