Patients whose pancreatic cancers have defects in the BRCA/Fanconi DNA repair pathway or other defects in homologous repair will have cancers that respond to olaparib when given in combination with the DNA damaging agents, irinotecan, cisplatin, mitomycin C (ICM).

The trial is designed to evaluate the role of Parp inhibitor based therapy, combining the most well studied and potent Parp inhibitor currently available with a low-dose combination of DNA damaging agents to optimize the effects of Parp inhibition. To ensure optimal response rates in the trial, to enrich our population for patients likely to achieve the best clinical response to Parp inhibitor based therapy, we will recruit and enroll patients with known BRCA mutations, patients of Jewish ancestry, patients with familial pancreatic cancer, as well as with sporadic pancreatic cancer. We will test patients and their cancers for other inherited or acquired defects in homologous DNA repair. For the phase 1 study, we will enroll up to 30 patients. For the phase 2 component of the study, 100 patients with locally, advanced, unresectable or metastatic pancreatic cancer will be enrolled. An initial phase I analysis will be performed to test the safety of the ICM with Olaparib regimen at the doses we predict will be effective for the phase 2 and ensure that these doses are below the maximum tolerated dose. For this phase 1 we will use a standard 3+3 design and will test the following dose regimens in a 28 day cycle:

Dose level 1: Cisplatin/Irinotecan i.v.(day 1, 8) and Olaparib (100 mg bid p.o., Day 1 & Day 8) Dose level 2: Cisplatin/Irinotecan i.v.(day 1, 8) and Olaparib 100 bid p.o. day 1-3, day 8-10 (if this dose is not tolerated, go to Dose 5: Mitomycin + Olaparib Dose level 1) Dose level 3: Cisplatin/Irinotecan i.v.(day 1, 8) and Olaparib 200 bid p.o.day 1-3, day 8-10 (if this dose is not tolerated, go to Dose 5: Mitomycin + Olaparib Dose level 2) Dose level 4: Cisplatin/Irinotecan i.v.(day 1, 8) and Olaparib 200 bid p.o. day 1-12 (if this dose is not tolerated, go to Dose 5: Mitomycin + Olaparib Dose level 3)) Dose level 5: Cisplatin/Irinotecan i.v.(day 1, 8), Mitomycin Day 1 (5 mg/m2 IV), along with the established tolerated dose level of Olaparib.

Other intermediate dose schedules of Olaparib may be considered to achieve the most optimal tolerable regimen" If there are DLTs at Dose 1, we will reduce the duration of Olaparib

Note: The Principal Investigator and Astrazeneca decided not to move forward with the Phase II part of the study. Therefore the arms of Irinotecan, Cisplatin, Mitomycin C with Olaparib versus Irinotecan, Cisplatin, Mitomycin C without Olaparib will not be compared.

Inclusion Criteria:

1. Provision of fully informed consent prior to any study specific procedures.

2. Histologic or cytologic confirmation of exocrine pancreatic adenocarcinoma.

3. Locally advanced, inoperable (due to venous or arterial encasement ≥ 180° of the vessel), and/or metastatic disease by imaging (CT, MRI, or EUS). Acquisition of tissue rather than cytology is encouraged if the patient gives informed consent.

4. Measurable disease according to RECIST 1.1 criteria

5. Prior neoadjuvant or adjuvant therapy is acceptable, as long as no more than one drug of the ICM regimen was used.

6. No prior chemotherapy for advanced pancreatic cancer with Olaparib is permitted. Gemzar, Tarceva, and 5-FU or Xeloda, Oxaliplatin Taxotere, and FOLFIRINOX are permitted.

7. Three weeks since last surgery or chemotherapy mentioned in #5 above or investigational therapies. Four weeks since radiation.

8. No prior PARP inhibitors of any type

9. ECOG status < 3

10. Life expectancy > 3 months

11. Patients must have normal organ and bone marrow function

12. Age >=18.

13. Patient is willing and able to comply with the protocol for the duration of the study including treatment, scheduled visits, and examinations.

14. Evidence of non-childbearing status for women of childbearing potential, or postmenopausal status: negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on day 1

    For inclusion in genetic research, patients must fulfill the following criterion:

15. Provision of informed consent for genetic research. If a patient declines to participate in the genetic research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study.

Exclusion Criteria:

1. Patients with second primary cancer, except: adequately treated non-melanoma skin cancer or curatively treated in-situ solid tumors with no evidence of disease for ≥ 5 years.
2. Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), less than 3 weeks from the last dose prior to study treatment (or a longer period depending on the defined characteristics of the agents used). The patient can receive a stable dose of bisphosphonates for bone metastases before and during the study as long as these were started at least 4 weeks prior to treatment.
3. For patients who have locally advanced pancreatic cancer only, if they have received therapeutic doses of radiation therapy to their pancreatic bed (~50 Gy) for treatment of their locally advanced pancreatic cancer
4. Patients having already had prior chemotherapy for more than 12 months for their advanced pancreatic cancer (not including adjuvant/neoadjuvant)
5. Patients receiving the following classes of inhibitors of CYP3A4 (see Section for guidelines and wash out periods).
6. Current use of azole antifungals, macrolide antibiotics, or protease inhibitors
7. Unresolved toxicities (>CTCAE 4.0 grade 2) caused by previous cancer therapy.
8. Patients with known brain metastases. A scan to confirm the absence of brain metastases is not required unless the initial examination reveals CNS signs of disease.
9. Major surgery less than 3 weeks prior to starting study treatment and patients must have recovered from any effects of any major surgery.
10. Patients considered a poor medical risk due to serious, uncontrolled medical disorders, non-malignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent.
11. Patients unable to swallow oral medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
12. Breast feeding and/or pregnant women.
13. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
14. Patients with known active hepatic disease (i.e., Hepatitis B or C). Patients with a known hypersensitivity to Olaparib or any of the excipients of the product or history of severe allergic reactions to platinums or chemotherapy.
15. Grade 2 neuropathy at entry from any etiology, including diabetes (in view of Cisplatin).
16. Prior episodes of recurrent deep vein thrombosis or Trousseau's Syndrome unless the patient is successfully anticoagulated. If a patient has had a history of clotting or is suspected to have Trousseau's syndrome and is not anticoagulated, a D-Dimer level will be checked. If it is > 3 x ULN, patients will be expected to be anticoagulated with low molecular weight heparinoids (i.e. Lovonox).