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A Randomized Multi-center Phase I/II Trial of ICM (Irinotecan, Cisplatin, Mitomycin C) With or Without AZD2281 (Olaparib) in Patients With Advanced Pancreatic Cancer

Phase 1/Phase 2
18 Years
Open (Enrolling)
Pancreatic Cancer

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Trial Information

A Randomized Multi-center Phase I/II Trial of ICM (Irinotecan, Cisplatin, Mitomycin C) With or Without AZD2281 (Olaparib) in Patients With Advanced Pancreatic Cancer

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 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

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

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

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

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

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).

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The number of Participants with Adverse Events and the severity of these adverse events as a Measure of Safety and Tolerability.

Outcome Description:

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. 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.

Outcome Time Frame:

1 year

Safety Issue:


Principal Investigator

Michael Goggins, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Sol Goldman Pancreatic Cancer Research Center, JHMI


United States: Food and Drug Administration

Study ID:




Start Date:

January 2011

Completion Date:

January 2016

Related Keywords:

  • Pancreatic Cancer
  • Irinotecan
  • Cisplatin
  • Carboplatin
  • Mitomycin-C
  • Olaparib
  • AZD2281
  • Pancreatic Neoplasms



Columbia University Medical Center New York, New York  10032
The Johns Hopkins University School of Medicine Baltimore, Maryland  21231