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

• Safety of PF-04136309 and FOLFIRINOX by grade 3 or 4 toxicity for clinical use. [ Time Frame: 120 days ] [ Designated as safety issue: Yes ]
• Disease response rate: TCR = SD + PR + CR [ Time Frame: 2 days. At baseline and end of treatment ] [ Designated as safety issue: No ]
• Prevalence and function of MDSC in the bone marrow and tumor before and after treatment with PF-04136309 plus FOLFIRINOX or with FOLFIRINOX alone [ Time Frame: 2 days. At baseline and after completion of cycle 2 ] [ Designated as safety issue: No ]
• Prevalence and function of MDSC in peripheral circulation before and after treatment with PF-04136309 plus FOLFIRINOX or with FOLFIRINOX alone [ Time Frame: 4 days. At baseline and beginning of cycles 2, 4, and 6 ] [ Designated as safety issue: No ]

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.

• Drug: oxaliplatin
  Given IV
  Other Names:

  • 1-OHP
  • Dacotin
  • Dacplat
  • Eloxatin
  • L-OHP
• Drug: irinotecan hydrochloride
  Given IV
  Other Names:

  • Campto
  • Camptosar
  • CPT-11
  • irinotecan
  • U-101440E
• Drug: leucovorin calcium
  Given IV
  Other Names:

  • CF
  • CFR
  • LV
• Drug: fluorouracil
  Given IV
  Other Names:

  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
• Other: laboratory biomarker analysis
  Correlative studies
• Other: flow cytometry
  Correlative studies
• Other: immunohistochemistry staining method
  Correlative studies
  Other Name: immunohistochemistry
• Other: pharmacological study
  Correlative studies
  Other Name: pharmacological studies
• Drug: PF-04136309
  Given PO
  Other Name: PF-4136309

• Experimental: Group A (FOLFIRINOX chemotherapy)
  Patients receive FOLFIRINOX chemotherapy comprising oxaliplatin IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and leucovorin calcium IV over 120 minutes on day 1 and fluorouracil IV, bolus followed by continuous infusion over 46 hours beginning on day 1. Treatment is repeated every 14 days for 6 cycles.
  Interventions:

  • Drug: oxaliplatin
  • Drug: irinotecan hydrochloride
  • Drug: leucovorin calcium
  • Drug: fluorouracil
  • Other: laboratory biomarker analysis
  • Other: flow cytometry
  • Other: immunohistochemistry staining method
  • Other: pharmacological study
• Experimental: Group B (FOLFIRINOX and PF-04136309)
  Patients receive PF-04136309 PO BID on days 1-14. Patients also receive FOLFIRINOX chemotherapy as in Group A.
  Interventions:

  • Drug: oxaliplatin
  • Drug: irinotecan hydrochloride
  • Drug: leucovorin calcium
  • Drug: fluorouracil
  • Other: laboratory biomarker analysis
  • Other: flow cytometry
  • Other: immunohistochemistry staining method
  • Other: pharmacological study
  • Drug: PF-04136309

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 within normal institutional limits 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 with biliary obstruction will need to have stent placed
• 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 hydrochloride
• Patient must not be on any cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors as they may have interaction with PF-04136309
• 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, 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