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

Phase IB Study of 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

Study Overview

• Status: Completed
• Conditions: Pancreatic Neoplasms
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: Oxaliplatin; Other: flow cytometry; Drug: Leucovorin; Drug: Fluorouracil; Other: pharmacological study; Other: immunohistochemistry staining method; Drug: Irinotecan; Drug: PF-04136309

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 44
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

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 repeated every 14 days for 6 cycles.	Other: laboratory biomarker analysis; Correlative studies; Drug: Oxaliplatin; Other Names: 1-OHP; Dacotin; Dacplat; Eloxatin; L-OHP; Other: flow cytometry; Correlative studies; Drug: Leucovorin; Other Names: CF; CFR; LV; Drug: Fluorouracil; Other Names: 5-FU; 5-fluorouracil; 5-Fluracil; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Other: immunohistochemistry staining method; Correlative studies; Other Names: immunohistochemistry; Drug: Irinotecan; Other Names: Campto; Camptosar; U-101440E; CPT-11
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 mg PO BID on days 1-14 Treatment is repeated every 14 days for 6 cycles.	Other: laboratory biomarker analysis; Correlative studies; Drug: Oxaliplatin; Other Names: 1-OHP; Dacotin; Dacplat; Eloxatin; L-OHP; Other: flow cytometry; Correlative studies; Drug: Leucovorin; Other Names: CF; CFR; LV; Drug: Fluorouracil; Other Names: 5-FU; 5-fluorouracil; 5-Fluracil; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Other: immunohistochemistry staining method; Correlative studies; Other Names: immunohistochemistry; Drug: Irinotecan; Other Names: Campto; Camptosar; U-101440E; CPT-11; Drug: PF-04136309; Other Names: PF-4136309

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Andrea Wang-Gillam, M.D., PhD, Washington University School of Medicine

Publications and helpful links

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.

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): September 1, 2016

Study Registration Dates

• First Submitted: July 29, 2011
• First Submitted That Met QC Criteria: August 8, 2011
• First Posted (Estimate): August 9, 2011

Study Record Updates

• Last Update Posted (Estimate): September 19, 2016
• Last Update Submitted That Met QC Criteria: September 15, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Adenocarcinoma; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Leucovorin; Irinotecan
• Other Study ID Numbers: 201201124; NCI-2011-01154 (Registry Identifier: CTRP (Clinical Trial Reporting Program))