Trial of ICM With or Without AZD2281 (Olaparib) in Patients With Advanced Pancreatic Cancer
Condition: Pancreatic Cancer
MeSH terms: Pancreatic Neoplasms
Intervention: Irinotecan; Cisplatin; Olaparib (for levels 1 and 5); Olaparib (for dose level 2); Mitomycin-C
Intervention description: Irinotecan 70 mg/m2 IV, Days 1 and 8; Cisplatin 25 mg/m2 IV, Days 1 and 8; Olaparib 100 mg bid oral, Days 1 and 8; Olaparib 100mg bid oral, Day 1-3, Day 8-10; Mitomycin 5 mg/m2 IV, Day 1
Intervention MeSH terms: Irinotecan; Olaparib; Mitomycins; Mitomycin
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Irinotecan; Cisplatin; Carboplatin; Mitomycin-C; Olaparib; AZD2281

Summary:

      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).
    

Eligibility criteria:

        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).