FOLFIRINOX Plus PF-04136309 In Patients With Borderline Resectable And Locally Advanced Pancreatic Adenocarcinoma

Study Overview

FOLFIRINOX Plus PF-04136309 in Patients With Borderline Resectable and Locally Advanced Pancreatic Adenocarcinoma

This phase I trial studies the side effects and optimal dose of PF-04136309 when given with combination chemotherapy (FOLFIRINOX; 5-fluorouracil, leucovorin, irinotecan, oxaliplatin) in treating patients with locally advanced or borderline resectable pancreatic cancer. These patients are not candidates for surgical resection which is the most effective treatment for pancreatic cancer. Giving PF-04136309 together with FOLFIRINOX may shrink pancreatic tumors in some patients so that surgery becomes an option

PRIMARY OBJECTIVES: To define the optimal dose and toxicity of PF-04136309 in combination with FOLFIRINOX (fluorouracil, leucovorin calcium, irinotecan hydrochloride, and oxaliplatin) in patients with borderline resectable and locally advanced pancreatic cancer. SECONDARY OBJECTIVES: * To evaluate the safety of PF-04136309 and FOLFIRINOX by grade 3 or 4 toxicity for clinical use. * To determine the tumor control rate (TCR) as defined by stable disease (SD), partial response (PR), and complete response (CR): TCR = SD + PR + CR. EXPLORATORY OBJECTIVES: * To determine the prevalence and function of myeloid-derived suppressor cells (MDSC) in the bone marrow, peripheral circulation, and tumor before and after treatment with PF-04136309 and FOLFIRINOX. * To determine the prevalence and function of MDSC in the bone marrow, peripheral circulation, and tumor before and after treatment with FOLFIRINOX.

Pancreatic Neoplasms

DRUG: Oxaliplatin
DRUG: Irinotecan
DRUG: Leucovorin
DRUG: Fluorouracil
OTHER: laboratory biomarker analysis
OTHER: flow cytometry
OTHER: immunohistochemistry staining method
OTHER: pharmacological study
DRUG: PF-04136309

201201124
NCI-2011-01154 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2011-07-29	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2016-09-15
First Submitted that Met QC Criteria 2011-08-08	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ESTIMATED) 2016-09-19
First Posted (ESTIMATED) 2011-08-09	Results First Posted N/A	Last Verified 2016-09

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Parallel

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
ACTIVE_COMPARATOR: Group A (FOLFIRINOX chemotherapy) Patients receive FOLFIRINOX chemotherapy comprising of: * oxaliplatin 85 mg/m2 IV on Day 1 * irinotecan 180 mg/m2 IV on Day 1 * leucovorin 400 mg/m2 IV on Day 1 * 5FU 400 mg/m2 bolus and 2400 mg/m2 CIVI over 46 hours beginning on Day 1 Treatment is repe	DRUG: Oxaliplatin DRUG: Irinotecan DRUG: Leucovorin DRUG: Fluorouracil OTHER: laboratory biomarker analysis Correlative studies OTHER: flow cytometry Correlative studies OTHER: immunohistochemistry staining method Correlative studies OTHER: pharmacological study Correlative studies
EXPERIMENTAL: Group B (FOLFIRINOX and PF-04136309) Patients receive FOLFIRINOX chemotherapy comprising of: * oxaliplatin 85 mg/m2 IV on Day 1 * irinotecan 180 mg/m2 IV on Day 1 * leucovorin 400 mg/m2 IV on Day 1 * 5FU 400 mg/m2 bolus and 2400 mg/m2 CIVI over 46 hours beginning on Day 1 * PF-04136309 500	DRUG: Oxaliplatin DRUG: Irinotecan DRUG: Leucovorin DRUG: Fluorouracil OTHER: laboratory biomarker analysis Correlative studies OTHER: flow cytometry Correlative studies OTHER: immunohistochemistry staining method Correlative studies OTHER: pharmacological study Correlative studies DRUG: PF-04136309

Participant Group/Arm

Intervention/Treatment

ACTIVE_COMPARATOR: Group A (FOLFIRINOX chemotherapy)

Patients receive FOLFIRINOX chemotherapy comprising of: * oxaliplatin 85 mg/m2 IV on Day 1 * irinotecan 180 mg/m2 IV on Day 1 * leucovorin 400 mg/m2 IV on Day 1 * 5FU 400 mg/m2 bolus and 2400 mg/m2 CIVI over 46 hours beginning on Day 1 Treatment is repe

DRUG: Oxaliplatin

DRUG: Irinotecan

DRUG: Leucovorin

DRUG: Fluorouracil

OTHER: laboratory biomarker analysis

Correlative studies

OTHER: flow cytometry

Correlative studies

OTHER: immunohistochemistry staining method

Correlative studies

OTHER: pharmacological study

Correlative studies

EXPERIMENTAL: Group B (FOLFIRINOX and PF-04136309)

DRUG: Oxaliplatin

DRUG: Irinotecan

DRUG: Leucovorin

DRUG: Fluorouracil

OTHER: laboratory biomarker analysis

Correlative studies

OTHER: flow cytometry

Correlative studies

OTHER: immunohistochemistry staining method

Correlative studies

OTHER: pharmacological study

Correlative studies

DRUG: PF-04136309

Primary Outcome Measures	Measure Description	Time Frame
Optimal dose and dose-limiting toxicity of PF-04136309 in combination with FOLFIRINOX	After completion of two cycles. To find the optimal dose, a 3+3 design will be used.	28 days

Secondary Outcome Measures	Measure Description	Time Frame
Safety of PF-04136309 and FOLFIRINOX by grade 3 or 4 toxicity for clinical use.		120 days (30 days after completion of treatment)
Disease response rate: TCR = SD + PR + CR		90 days (completion of cycle 6)
Prevalence and function of MDSC in the bone marrow and tumor before and after treatment with PF-04136309 plus FOLFIRINOX or with FOLFIRINOX alone		Baseline and end of cycle 2
Prevalence and function of MDSC in peripheral circulation before and after treatment with PF-04136309 plus FOLFIRINOX or with FOLFIRINOX alone		Baseline, before cycle 2, before cycle 4, and before cycle 6

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Patient must have histologically or cytologically confirmed pancreatic adenocarcinoma which is borderline resectable or locally advanced; tumors considered borderline include the following: (a) no distant metastases; (b) venous involvement of the superior mesenteric vein/portal vein demonstrating tumor abutment with or without impingement and narrowing of the lumen, encasement of the superior mesenteric vein/portal vein but without encasement of the nearby arteries, or short segment venous occlusion resulting from either tumor thrombus or encasement but with suitable vessel proximal and distal to the area of vessel involvement, allowing for safe resection and reconstruction; (c) gastroduodenal artery encasement up to the hepatic artery with either short segment encasement or direct abutment of the hepatic artery, without extension to the celiac axis; (d) tumor abutment of the superior mesenteric artery not to exceed 180 degrees of the circumference of the vessel wall
Patient must have radiographically measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 10 mm with computed tomography (CT) scan or magnetic resonance imaging (MRI) or >= 10 mm with calipers by clinical exam
Patient myst be >= 18 years of age.
Patient must have life expectancy of > 6 months
Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 1
Patient must have normal bone marrow and organ function as defined below:

Absolute neutrophil count >= 1,500/mcl
Platelets >= 100,000/mcl
Hemoglobin >= 9.0 g/dL
Creatinine should be below the upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal limits
Patient not on anticoagulation must have International Normalized Ratio (INR) and activated partial thromboplastin time (PTT) < 1.5 x ULN
Patients who have had a stent placed for biliary obstruction can be included in the study
Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately
Patient must be able to understand and willing to sign an institutional review board (IRB) approved written informed consent document

Patient must not have evidence of neuroendocrine tumor, duodenal adenocarcinoma, or ampullary adenocarcinoma
Patient must not have a history of other malignancy =< 3 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix
Patient must not have received any chemotherapy or radiation for pancreatic cancer
Patient must not be receiving any other investigational agents
Patient must not have brain metastases; such patients must be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
Patient must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to PF-04136309, 5FU (fluorouracil), oxaliplatin, or irinotecan
Patient must not be on any CYP3A4 inhibitors or inducers as they may have interaction with PF-04136309 and/or irinotecan
Patient must not have an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, any clinically active malabsorption syndrome, inflammatory bowel disease, any condition that increases the risk of severe irinotecan gastrointestinal toxicity, or psychiatric illness/social situations that would limit compliance with study requirements
Patient must not be pregnant and/or breastfeeding
Patient must not be known to be human immunodeficiency virus (HIV)-positive on combination antiretroviral therapy

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

National Cancer Institute (NCI)

Investigators

PRINCIPAL_INVESTIGATOR: Andrea Wang-Gillam, M.D., PhD, Washington University School of Medicine

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Nywening TM, Wang-Gillam A, Sanford DE, Belt BA, Panni RZ, Cusworth BM, Toriola AT, Nieman RK, Worley LA, Yano M, Fowler KJ, Lockhart AC, Suresh R, Tan BR, Lim KH, Fields RC, Strasberg SM, Hawkins WG, DeNardo DG, Goedegebuure SP, Linehan DC. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 2016 May;17(5):651-62. doi: 10.1016/S1470-2045(16)00078-4. Epub 2016 Apr 4.

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