This phase I trial is studying the side effects and best dose of stereotactic radiation therapy and nelfinavir mesylate when given together with gemcitabine hydrochloride, leucovorin calcium, and fluorouracil in treating patients with locally advanced pancreatic cancer. Stereotactic radiation therapy may be able to send x-rays directly to the tumor and cause less damage to normal tissue. Drugs, such as nelfinavir mesylate, may make tumor cells more sensitive to radiation therapy. Drugs used in chemotherapy, such as gemcitabine hydrochloride, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving stereotactic radiation therapy and nelfinavir mesylate together with combination chemotherapy may kill more tumor cells.
Name: gemcitabine hydrochloride
Description: Given IVType: DrugTreatment (SRT, radiosensitizer, and chemotherapy)
Name: leucovorin calcium
Description: Given IVType: DrugTreatment (SRT, radiosensitizer, and chemotherapy)
Name: fluorouracil
Description: Given IVType: DrugTreatment (SRT, radiosensitizer, and chemotherapy)
Name: nelfinavir mesylate
Description: Given POType: DrugTreatment (SRT, radiosensitizer, and chemotherapy)
Name: stereotactic body radiation therapy
Description: Undergo radiotherapyType: RadiationTreatment (SRT, radiosensitizer, and chemotherapy)
Name: hypofractionated radiation therapy
Description: Undergo radiotherapyType: RadiationTreatment (SRT, radiosensitizer, and chemotherapy)
Name: therapeutic conventional surgery
Description: Undergo surgeryType: ProcedureTreatment (SRT, radiosensitizer, and chemotherapy)
Description: Due to delayed toxicities attributable to radiotherapy, all toxicities observed within 1 month of surgery will be scored. Toxicity will be graded and tabled by dose levels.
Measure: Dose-limiting toxicity as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 Time: Within 1 month of surgeryDescription: The MTD of SRT/nelfinavir mesylate is defined as the highest dose level at which no greater than one dose-limiting toxicity is observed in 6 patients.
Measure: Maximally tolerated dose (MTD) of stereotactic radiotherapy and concurrent nelfinavir mesylate Time: 3 patients will initially be treated at each dose level (4 levels); a minimum of 1 month of observation after surgery is required in all 3 patients before escalationDescription: At the MTD, the rate of surgical complete resection with 90% exact binomial confidence intervals will be calculated.
Measure: Rate of complete surgical resection Time: At the time of surgery (2-3 weeks after completion of SRT)Description: At the MTD, the rate of pathologic response with 90% exact binomial confidence intervals will be calculated.
Measure: Pathological response Time: Pre- to post-treatmentDescription: Pre- to post-treatment changes in tumor size on CT or MRI scan (if CT is not sufficient).
Measure: Tumor response on CT/MRI Time: Change from pre- to post-treatmentDescription: Exploratory analyses will compare pre- to post-nelfinavir mesylate treatment changes in Akt levels between patients who achieve or do not achieve R0 resection by the nonparametric Wilcoxon rank sum test.
Measure: Phospho-AKT expression in pancreatic tumor tissue (correlative) Time: Pre- to post-nelfinavir mesylateDescription: The data will be modeled using WinNonLin Pro version 4.1. The pharmacokinetic parameters will be presented as the mean and standard deviation.
Measure: Pharmacokinetics of nelfinavir mesylate (correlative) Time: After at least 1 week of NFV: *0 h (trough); *After NFV dosing: 1, 2, 3, 4, 5, 6, 8, and 12 hDescription: There is currently insufficient clinical data to indicate whether any of the specific polymorphisms proposed to be studied, particularly those subjects with a heterozygous state, will correlate with meaningful differences in the pharmacokinetic parameters of nelfinavir mesylate. These analyses must therefore be exploratory in nature.
Measure: Pharmacogenomic status of CYP2C19*2 (G681A) (correlative) Time: Enrollment, at the time of planned tumor tissue procurement, and at the time that re-staging studies are doneSingle Group Assignment
There is one SNP
The pharmacokinetic parameters will be presented as the mean and standard deviation.. Pharmacogenomic status of CYP2C19*2 (G681A) (correlative). --- G681A ---
To measure the pharmacogenomic status of CYP2C19*2 (G681A) in the study population. --- G681A ---