Trial of ICM With or Without AZD2281 (Olaparib) in Patients With Advanced Pancreatic Cancer
Drug: Olaparib (for levels 1 and 5)
Drug: Olaparib (for dose level 2)
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||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|
- Number of Participants Who Experienced a Dose Limiting Toxicity to Determine the Maximum Tolerated Dose (MTD) [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
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. The number of subjects who experienced a dose limiting toxicity was assessed.Dose-limiting toxicity (DLT) is defined as any of the following study drug-related events experienced during Cycle 1:
Thrombocytopenia with platelets <25,000 x106/l > 7 days. Grade 4 neutropenia lasting ≥7 days. Grade 3 or 4 febrile neutropenia. Grade 3 or greater non-haematological toxicities; excluding grade 3 diarrhoea, nausea or vomiting despite adequate treatment and grade 3 fatigue, lethargy and GGT elevation.
Delay of >2 weeks for next scheduled IC/ICM for reasons of toxicity.
- Number of Years From Cycle 1, Day 1 On-Study to Date of Death [ Time Frame: 5 years ] [ Designated as safety issue: No ]The overall survival of subjects with locally advanced and/or metastatic pancreatic cancer treated with Irinotecan, Cisplatin, Olaparib, with escalation to the addition of Mitomycin-C. Survival from cycle 1, day 1 on-study to date of death was assessed.
|Study Start Date:||January 2011|
|Study Completion Date:||February 2016|
|Primary Completion Date:||January 2014 (Final data collection date for primary outcome measure)|
Experimental: Irinotecan, Cisplatin, Olaparib, then add Mitomycin-C
A 3+3 dose escalation design will be used starting with dose 1. The maximally tolerated dose is defined as the highest dose for which at most 1 out of 6 patients experiences a DLT. We will use 3 patients per dose cohort. If 0 of 3 patients have a DLT (see section 5a) then the escalation will be continued at the next dose level. If 1 of 3 patients have a DLT then three more patients will be enrolled at this dose. If 1 of 6 patients has a DLT then the dose escalation will continue. If 2 or more of the first 3 patients, or >2 of 6 patients treated have a DLT at the dose level, we will reduce the dose to the previous dose level of Olaparib for the phase 2 and then test Mitomycin C (phase 1 dose 5). If DLTs are observed at our dose 1 regimen, we will reduce the duration of Olaparib from day 1 and day 8 to just day 1 (dose level -1) and we will not test Mitomycin C in the trial.
Irinotecan 70 mg/m2 IV, Days 1 and 8Drug: Cisplatin
Cisplatin 25 mg/m2 IV, Days 1 and 8Drug: Olaparib (for levels 1 and 5)
Olaparib 100 mg bid oral, Days 1 and 8Drug: Olaparib (for dose level 2)
Olaparib 100mg bid oral, Day 1-3, Day 8-10Drug: Mitomycin-C
Mitomycin 5 mg/m2 IV, Day 1
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01296763
|United States, Maryland|
|The Johns Hopkins University School of Medicine|
|Baltimore, Maryland, United States, 21231|
|United States, New York|
|Columbia University Medical Center|
|New York, New York, United States, 10032|
|Principal Investigator:||Michael Goggins, MD||Sol Goldman Pancreatic Cancer Research Center, JHMI|