A Randomized Phase I/II Trial of ICM (Irinotecan, Cisplatin, Mitomycin C) with or without AZD2281 (OLAPARIB) in Patients with Advanced Pancreatic Cancer
In the laboratory pancreatic cancers with defects in the BRCA/Fanconi DNA repair pathway are exquisitely sensitive to Parp inhibitors (Olaparib) and to intercalating agents such as Mitomycin C and cisplatin. Early clinical trials indicate that patients with BRCA deficient cancers respond to Parp inhibitors. Patients with familial pancreatic cancer and Jewish patients with pancreatic cancer are more likely than sporadic pancreatic cancer patients to have defects in the BRCA/Fanconi pathway. Combining Olaparib with ICM is expected to prevent resistance to the Parp inhibitor, which has been shown to occur in vitro. Given the modest efficacy of gemcitabine based chemotherapy, patients with previously untreated advanced pancreatic cancer can participate in this study. Primary: 1.Phase I - Assess the safety and toxicities of IC with Olaparib escalating to ICM with Olaparib in patients with locally advanced and metastatic pancreatic cancer and determine the phase 2 dose. 2. Phase II - Assessment of the objective response rates (ORR) of patients with locally advanced and/or metastatic pancreatic cancer treated with IC/ICM with placebo vs. IC/ICM with Olaparib. Secondary: 1. To further assess the safety and toxicities of IC/ICM with Olaparib in patients with locally advanced and metastatic pancreatic cancer in the patients enrolled in the phase 2 study. 2.Determine the progression free survival and overall survival of patients with locally advanced and/or metastatic pancreatic cancer treated with ICM with placebo vs. ICM with Olaparib in the phase 2 study. Correlate mutations found in patients PBLâ??s and tumor tissue to response rates â?? OS and PFS to ICM with Olaparib or placebo Exploratory Aims: 1.Compare clinical vs. patient- cancer cell line responses to Olaparib /ICM. 2.Measure circulating, mutant KRAS levels as a marker of disease burden in patients undergoing Olaparib/ICM therapy.
INCLUSION: 1. Provision of fully informed consent prior to any study specific procedures Histologic or cytologic confirmation of exocrine pancreatic adenocarcinoma Locally advanced and/or metastatic disease by imaging (CT or MRI or EUS) confirmed by biopsy if possible. Acquisition of tissue is encouraged if the patient gives informed consent 2. Measurable disease according to RECIST criteria 3. Willingness to undergo a thin needle core biopsy for tumor tissue if it is easily accessible if the initial tissue for diagnosis is not sufficient for additional research marker analysis (not required for patients with known germline mutations in BRCA2 or PALB2) 4. Prior neoadjuvant or adjuvant therapy is acceptable, as long as no more than one drug of the ICM regimen was used 5. No prior chemotherapy for advanced pancreatic cancer with Olaparib, Irinotecan, cisplatin or Mitomycin C: (Gemzar, Tarceva, and 5-FU or xeloda oxaliplatin and taxotere permitted) 6. 3 or more weeks since last surgery, radiation, chemotherapy mentioned in #6 above or investigational therapies 7. No prior PARP inhibitors 8. Negative HCG pregnancy test for females or current breastfeeding 9. ECOG status less than 3 (0, 1, 2 acceptable) 10. Life expectancy greater than 3 months 11. Patients must have normal organ and bone marrow function measured within 7 days prior to administration of study treatment 12. Age greater than 18 13. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and 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 EXCLUSION: 1. Patients with 2nd primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for â?¥ 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 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 6 months for their advanced pancreatic cancer (not including adjuvant/neoadjuvant) 5. Patients receiving the certain classes of inhibitors of CYP3A4 6. Unresolved toxicities ( greater than CTCAE grade 2) caused by previous cancer therapy 7. Patients with known brain metastases. A scan to confirm the absence of brain metastases is not required 8. Major surgery less than 3weeks of starting study treatment and patients must have recovered from any effects of any major surgery 9. Patients considered a poor medical risk due to serious, uncontrolled medical disorders, non-malignant systemic disease or active, uncontrolled infection 10. Patients unable to swallow oral medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication 11. Breast feeding women 12. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) 13. Patients with known active hepatic disease (i.e., Hepatitis B or C) 14. 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. Patients with uncontrolled seizures 16. Grade 2 neuropathy at entry from any etiology, including diabetes (in view of Irinotecan) 17. Prior episodes of recurrent deep vein thrombosis or Trousseauâ??s Syndrome unless the patient is anticoagulated
PHASE 1 This clinical trial is taking place at two hospitals where up to 30 people are expected to take part with 15 participants expected at Johns Hopkins and 15 at the University of Columbia, NY. The patients enrolled into the phase I component will not be blinded. Healthy Volunteers We expect about 130 people to take part in this multicenter study. About 65 people at Johns Hopkins will take part and 65 at Columbia. Phase I subjects will receive a combination of irinotecan, cisplatin, and olaparib. For specific study drug treatment information, please contact Regina Norton, email@example.com
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