• Incidence of >= grade 3 toxicities for each assigned window treatment [ Time Frame: Up to 30 days ]
  Assessed per Common Terminology Criteria for Adverse Events version 5.0. The 95% CI will be reported with the point estimate of toxicity rate. All grade 3+ acute toxicities will also be summarized with its grade.
• Proportion of feasibility-evaluable participants within each study arm that have a measurable change in post-treatment tumor biology from baseline [ Time Frame: Changes in tumor biology from baseline (i.e., Day 0) and on-treatment biopsy (i.e., 10 days from start of study intervention) ]
  Will be estimated with a 95% CI.

• Incidence of >= grade 3 toxicities for the cobimetinib window therapy [ Time Frame: Up to 30 days ]
  Assessed per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The 95% CI will be reported with the point estimate of toxicity rate. All grade 3+ acute toxicities will also be summarized with its grade.
• Incidence of >= grade 3 toxicities for the olaparib window therapy [ Time Frame: Up to 30 days ]
  Assessed per CTCAE version 5.0. The 95% CI will be reported with the point estimate of toxicity rate. All grade 3+ acute toxicities will also be summarized with its grade.

PRIMARY OBJECTIVE:

I. Assess the feasibility of detecting a measurable change in tumor biology at post-treatment from baseline (i.e., before the 10-day treatment window) for all feasibility-evaluable participants.

SECONDARY OBJECTIVES:

I. Assess preliminary safety and tolerability of the proposed study agent(s) in each study arm.

II. Assess the feasibility of detecting a measurable change in tumor biology at post-treatment from baseline (i.e., before the 10-day treatment window) among participants in an assigned 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 2 arms.

ARM I: 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 II: 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.

After completion of study treatment, patients are followed up for 30 days.

• Borderline Resectable Pancreatic Adenocarcinoma
• Locally Advanced Pancreatic Ductal Adenocarcinoma
• Metastatic Pancreatic Ductal Adenocarcinoma
• Resectable Pancreatic Ductal Adenocarcinoma
• Stage I Pancreatic Cancer AJCC v8
• Stage IA Pancreatic Cancer AJCC v8
• Stage IB Pancreatic Cancer AJCC v8
• Stage II Pancreatic Cancer AJCC v8
• Stage IIA Pancreatic Cancer AJCC v8
• Stage IIB Pancreatic Cancer AJCC v8
• Stage III Pancreatic Cancer AJCC v8
• Stage IV Pancreatic Cancer AJCC v8

• Drug: Cobimetinib
  Given PO
  Other Names:

  • Cotellic
  • GDC-0973
  • MEK Inhibitor GDC-0973
  • XL518
• Drug: Olaparib
  Given PO
  Other Names:

  • AZD 2281
  • AZD-2281
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281

• Experimental: Arm I (cobimetinib)
  Patients receive cobimetinib PO QD on days 1-10 in the absence of disease progression or unacceptable toxicity. Within 12-24 hours, patients undergo biopsy or surgery.
  Intervention: Drug: Cobimetinib
• Experimental: Arm II (olaparib)
  Patients receive olaparib PO BID on days 1-10 in the absence of disease progression or unacceptable toxicity. Within 12-24 hours, patients undergo biopsy or surgery.
  Intervention: Drug: Olaparib

Inclusion Criteria:

• Ability to understand and the willingness to sign a written informed consent document
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Clinically-confirmed diagnosis of adenocarcinoma of the pancreas (resectable, borderline resectable, locally advanced, or metastatic disease at presentation) are eligible
• Participants may be treatment naive or have received prior therapy for the treatment of their pancreatic ductal adenocarcinoma (PDAC). A minimum washout period of 10-days after completing the most recent line of therapy is required before a participant can initiate treatment with study agent
• Based on available imaging, participant must have at least one disease lesion that can be biopsied in accordance with institutional standards
• Hemoglobin >= 10.0 g/dL with no blood transfusion within 28 days of starting treatment (within 4 weeks prior to initiating window treatment)
• White blood cells (WBC) > 3 x 10^9/L (within 4 weeks prior to initiating window treatment)

• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (> 1500 per mm^3) (within 4 weeks prior to initiating window treatment)

  • May be waived on a case-by-case basis for patient populations recognized to have normal baseline values below this level
• Platelet count >= 100 x 10^9/L (> 100,000 per mm^3) (within 4 weeks prior to initiating window treatment)

• Creatinine =< 1.5 x upper limit of normal (ULN), OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min/1.73m^2 for participants with creatinine levels > 1.5 x institutional ULN (within 4 weeks prior to initiating window treatment)

  • Creatinine clearance should be calculated per institutional standard. For participants with a baseline calculated creatinine clearance below normal institutional laboratory values, a measured baseline creatinine clearance should be determined. Individuals with higher values felt to be consistent with inborn errors of metabolism will be considered on a case-by-case basis
• Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 4 weeks prior to initiating window treatment)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (within 4 weeks prior to initiating window treatment)
• Participants must be willing to undergo one mandatory on-study tumor biopsies prior to initiating window treatment with assigned study agent(s)
• Participant is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
• Participant must be able to swallow tablets or capsules. A participant with any gastrointestinal disease that would impair ability to swallow, retain, or absorb drug is not eligible
• Participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Participants must agree to use an adequate method of contraception starting with the first dose of study therapy through at least 14 after the last dose of study therapy. Longer use of contraception may be required depending on study drug assignment
• No other prior invasive malignancy is allowed except for the following: adequately treated basal (or squamous cell) skin cancer, in situ breast or cervical cancer, any malignancy treated with a curative intent without evidence of disease recurrence for at least 6 months

• Individuals must not have known active hepatitis B virus (HBV). Those who have completed curative therapy for hepatitis C virus (HCV) are eligible. HCV infection permitted but patient must be Child's Pugh A. Patients with known human immunodeficiency virus (HIV) infection are eligible if they meet each of the following 3 criteria:

  • CD4 counts >= 350 mm^3
  • Serum HIV viral load of < 25,000 IU/ml and
  • Treated on a stable antiretroviral regimen
  • HIV testing is not required

Exclusion Criteria:

• Tumor not accessible for core biopsy
• Medical co-morbidities that are deemed to make risk of surgery unacceptably high as determined by institutional standards
• Recent major surgery within 4 weeks prior to starting study treatment. Minor surgery within 2 weeks of starting study treatment. Patients must be recovered from effects of surgery
• Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil)
• Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil)
• 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 the patient is receiving study medication. Strong or moderate CYP3A inhibitors and inducers should not be taken with study treatment; however, if no other suitable alternative concomitant medication is available, dose reductions may be allowed under careful monitoring
• Known severe hypersensitivity to the study agent(s) (or equivalent agents, respectively), or any excipient of these medicinal products, or history of allergic reactions attributed to compounds of similar chemical or biologic composition to the study agent(s)

• Clinically significant cardiac disease or impaired cardiac function, including any of the following:

  • Clinically significant and/or uncontrolled heart disease such as congestive heart failure (New York Heart Association grade >= 2) uncontrolled hypertension, or clinically significant arrhythmia currently requiring medical treatment
  • Corrected QT using Fridericia's formula (QTcF) > 470 msec for females, or > 450 msec for males, on screening electrocardiogram (ECG) or congenital long QT syndrome
  • Acute myocardial infarction or unstable angina pectoris < 6 months prior to screening
• Psychiatric illness/social situations that would limit compliance with study requirements
• Participants with a history of hypersensitivity reactions to study agents or their excipients
• Participant is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment