Combination Chemotherapy and Losartan Potassium Followed by Radiation Therapy and Capecitabine in Treating Patients with Locally Advanced Pancreatic Cancer That Cannot Be Removed by Surgery
- Cytologic or histologic proof pancreatic ductal carcinoma is required prior to study entry; diagnosis must be confirmed by a Dana-Farber Harvard Cancer Center (DFHCC) institution pathology department prior to registration
- No evidence of metastatic disease as determined by chest computed tomography (CT) scan, abdomen/pelvis CT scan (or magnetic resonance imaging [MRI] with gadolinium and/or manganese); all patients must be staged with a physical exam, chest CT, abdominal CT with intravenous contrast (or abdominal MRI with gadolinium and/or manganese)
- Patients with locally advanced, unresectable disease will be included; locally advanced unresectable disease is defined by the National Comprehensive Cancer Network (NCCN) as: * Tumors of the head that have greater than 180 degrees of superior mesenteric artery (SMA) encasement or any celiac abutment, unreconstructable superior mesenteric vein (SMV) or portal occlusion, or aortic invasion or encasement * Tumors of the body with SMA or celiac encasement of greater than 180 degrees, unreconstructable SMV or portal occlusion, or aortic invasion * Tumors of the tail with SMA or celiac encasement of greater than 180 degrees * Irrespective of location, all tumors with evidence of nodal metastasis outside of the resection field are deemed unresectable
- Eastern Cooperative Oncology Group (ECOG)-performance status of 0 or 1 are eligible
- Life expectancy of greater than 3 months
- Baseline systolic blood pressure (SBP) > 100 mm Hg; this is based on the average of two values-separate seated, resting measurements taken five minutes apart; blood pressure (BP) does not need to be checked in both arms unless a reading is below 110 mm Hg, in which case the other arm can be checked as well; if BP is checked in both arms, the higher value is deemed accurate for calculating the average
- Absolute neutrophil count (ANC) >= 1500 cells/mm^3
- Platelet count >= 100,000 cell/mm^3
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal OR two downtrending values
- Total bilirubin =< 1.5 x upper limit of normal if no biliary stenting has been done; OR 2.0 x upper limit of normal if patient is status post (s/p) biliary stenting; OR two downtrending values
- Serum creatinine =< 1.5 mg/dl
- Creatinine clearance >= 30 ml/min (as estimated by Cockcroft Gault equation)
- 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 treatment plus 30 days from the last date of study drug administration; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
- Ability to understand and the willingness to sign a written informed consent document
- Serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator), such as significant cardiac or pulmonary morbidity e.g. congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmias not well controlled with medication) or myocardial infarction within the last 12 months, ongoing infection as manifested by fever
- Patients cannot be already treated on angiotensin-converting enzyme inhibitor (ACE) or angiotensin II receptor blocker (ARB) therapy for hypertension or renal protection (with diabetes) at the time of enrollment
- Patients cannot have baseline hypotension, defined as systolic BP lower than 100 mm Hg on two readings obtained on two separate days prior to study enrollment
- Pregnant or lactating women; women of childbearing potential with either a positive or no pregnancy test (serum or urine) at baseline; (postmenopausal woman must have been amenorrheic for at least 12 months to be considered of non-childbearing potential)
- Any prior chemotherapy, radiation therapy, or biologic therapy (“targeted therapy”) for treatment of the patient’s pancreatic tumor
- Treatment for other invasive carcinomas within the last five years who are at greater than 5% risk of recurrence at time of eligibility screening; carcinoma in-situ and basal cell carcinoma/squamous cell carcinoma of the skin are allowed
- Other serious uncontrolled medical conditions that the investigator feels might compromise study participation
- Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome
- Known, existing uncontrolled coagulopathy
- Unwillingness to participate or inability to comply with the protocol for the duration of the study
- Prior systemic fluoropyrimidine therapy; prior topical fluoropyrimidine use is allowed; prior unanticipated severe reaction to fluoropyrimidine therapy, or known hypersensitivity to 5-fluorouracil or known dihydropyrimidine dehydrogenase deficiency (DPD) deficiency
- Participation in any investigational drug study within 4 weeks preceding the start of study treatment
- History of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance or oral drug intake
- Major surgery, excluding laparoscopy, within 4 weeks of the start of study treatment, without complete recovery
- Patients should not be on cimetidine; another histamine-2 (H2)-blocker or proton pump inhibitor may be substituted before study entry
- Participants may not be receiving any other study agents
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to 5-fluorouricil, irinotecan, oxaliplatin, or losartan
I. To determine the rate of R01 resection in patients with locally advanced unresectable pancreas cancer treated with the combination of fluorouracil, leucovorin calcium, irinotecan hydrochloride, oxaliplatin (FOLFIRINOX)-losartan (losartan potassium) followed by restaging and radiation therapy with capecitabine.
I. To determine the progression-free survival of patients with locally advanced disease who receive FOLFIRINOX-losartan and radiation therapy.
II. To determine overall survival in patients treated with FOLFIRINOX-losartan and radiation therapy.
III. To determine the overall survival of patients with locally advanced disease who receive FOLFIRINOX-losartan without radiation (i.e. patients who demonstrate progression at restaging).
IV. To determine the toxicity of FOLFIRINOX-losartan in patients with locally advanced pancreatic cancer.
V. To determine the toxicity of FOLFIRINOX-losartan and radiation in patients with locally advanced pancreatic cancer.
VI. To determine the rate of downstaging to surgical resection of FOLFIRINOX-losartan followed by radiation in patients with locally advanced pancreatic cancer.
VII. To determine the correlation between a panel of somatic genetic mutations (SNaPSHOT) and outcome in locally advanced pancreatic cancer treated with FOLFIRINOX-losartan with or without (+/-) radiation/capecitabine.
VIII. To determine the correlation between circulating biomarkers of transforming growth factor-beta 1 (TGF-B1) downregulation, including circulating collagen I levels, and outcome in locally advanced pancreatic cancer treated with FOLFIRINOX-losartan +/- radiation/capecitabine.
IX. To describe quality of life, symptom burden and mood in the study population.
X. To measure utilization of health services (emergency room, hospital and intensive care unit, palliative care) in the study population.
INDUCTION THERAPY: Patients receive fluorouracil intravenously (IV) over 2-4 minutes on day 1 and then continuously over 46-48 hours on days 1 and 2, and oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and irinotecan hydrochloride IV over 90 minutes on day 1. Patients also receive losartan potassium orally (PO) once daily (QD) on days 1-14. Treatment repeats every 14 days for 8 courses in the absence of disease progression or unacceptable toxicity.
Beginning in week 18, patients undergo proton beam or photon beam radiation therapy (RT) on days 1-5 and receive capecitabine PO twice daily (BID) 5 days a week for 2 weeks.
After completion of study treatment, patients are followed up every 3-6 months for 2 years and annually for 3 years.
Trial Phase Phase II
Trial Type Treatment
Dana-Farber Harvard Cancer Center
Theodore Sunki Hong
- Primary ID 13-051
- Secondary IDs NCI-2013-01816
- Clinicaltrials.gov ID NCT01821729