Trial of ICM With or Without AZD2281 (Olaparib) in Patients With Advanced Pancreatic Cancer

NCT01296763 | Completed Phase 1 Results DMC

• 3 other identifiers: J1070RC2CA148346-01NA_00032826
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 2

Brief 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).

Conditions

Pancreatic Cancer

Keywords

Irinotecan; Cisplatin; Carboplatin; Mitomycin-C; Olaparib; AZD2281

Outcome Measures

Primary Outcomes (1)

• Number of Participants Who Experienced a Dose Limiting Toxicity to Determine the Maximum Tolerated Dose (MTD)

  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.

  2 years

Secondary Outcomes (1)

• Number of Years From Cycle 1, Day 1 On-Study to Date of Death

  5 years

Study Arms (1)

Irinotecan, Cisplatin, Olaparib, then add Mitomycin-C

EXPERIMENTAL

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.

Drug: Irinotecan; Drug: Cisplatin; Drug: Olaparib (for levels 1 and 5); Drug: Olaparib (for dose level 2); Drug: Mitomycin-C

Interventions

Irinotecan DRUG

Irinotecan 70 mg/m2 IV, Days 1 and 8

Irinotecan, Cisplatin, Olaparib, then add Mitomycin-C

Cisplatin DRUG

Cisplatin 25 mg/m2 IV, Days 1 and 8

Irinotecan, Cisplatin, Olaparib, then add Mitomycin-C

Olaparib (for levels 1 and 5) DRUG

Olaparib 100 mg bid oral, Days 1 and 8

Irinotecan, Cisplatin, Olaparib, then add Mitomycin-C

Olaparib (for dose level 2) DRUG

Olaparib 100mg bid oral, Day 1-3, Day 8-10

Irinotecan, Cisplatin, Olaparib, then add Mitomycin-C

Mitomycin-C DRUG

Mitomycin 5 mg/m2 IV, Day 1

Irinotecan, Cisplatin, Olaparib, then add Mitomycin-C

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of fully informed consent prior to any study specific procedures.
• Histologic or cytologic confirmation of exocrine pancreatic adenocarcinoma.
• 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.
• Measurable disease according to RECIST 1.1 criteria
• Prior neoadjuvant or adjuvant therapy is acceptable, as long as no more than one drug of the ICM regimen was used.
• No prior chemotherapy for advanced pancreatic cancer with Olaparib is permitted. Gemzar, Tarceva, and 5-FU or Xeloda, Oxaliplatin Taxotere, and FOLFIRINOX are permitted.
• Three weeks since last surgery or chemotherapy mentioned in #5 above or investigational therapies. Four weeks since radiation.
• No prior PARP inhibitors of any type
• ECOG status \< 3
• Life expectancy \> 3 months
• Patients must have normal organ and bone marrow function
• Age \>=18.
• Patient is willing and able to comply with the protocol for the duration of the study including treatment, scheduled visits, and examinations.
• 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
• 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.

You may not qualify if:

• 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.
• 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.
• 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
• Patients having already had prior chemotherapy for more than 12 months for their advanced pancreatic cancer (not including adjuvant/neoadjuvant)
• Patients receiving the following classes of inhibitors of CYP3A4 (see Section for guidelines and wash out periods).
• Current use of azole antifungals, macrolide antibiotics, or protease inhibitors
• Unresolved toxicities (\>CTCAE 4.0 grade 2) caused by previous cancer therapy.
• 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.
• Major surgery less than 3 weeks prior to starting study treatment and patients must have recovered from any effects of any major surgery.
• 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.
• Patients unable to swallow oral medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
• Breast feeding and/or pregnant women.
• Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
• 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.
• Grade 2 neuropathy at entry from any etiology, including diabetes (in view of Cisplatin).

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead
• National Cancer Institute (NCI): collaborator

Study Sites (2)

The Johns Hopkins University School of Medicine

Baltimore, Maryland, 21231, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Related Publications (1)

• Yarchoan M, Myzak MC, Johnson BA 3rd, De Jesus-Acosta A, Le DT, Jaffee EM, Azad NS, Donehower RC, Zheng L, Oberstein PE, Fine RL, Laheru DA, Goggins M. Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer. Oncotarget. 2017 Jul 4;8(27):44073-44081. doi: 10.18632/oncotarget.17237.

  PMID: 28454122 DERIVED

MeSH Terms

Conditions

Pancreatic Neoplasms

Interventions

Irinotecan; Cisplatin; olaparib; Mitomycin

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Mitomycins; Indolequinones; Quinones; Organic Chemicals; Azirines; Heterocyclic Compounds, 1-Ring; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

The P.I. 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.

Results Point of Contact

• Title: Thomas Brown
• Organization: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

tbrown55@jhmi.edu

410-502-5328

Study Officials

• Michael Goggins, MD

  Sol Goldman Pancreatic Cancer Research Center, JHMI

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 21, 2011
• First Posted: February 15, 2011
• Study Start: January 1, 2011
• Primary Completion: January 1, 2014
• Study Completion: February 1, 2016
• Last Updated: March 22, 2016
• Results First Posted: March 22, 2016

Record last verified: 2016-02

Locations

US (2)