Stereotactic Radiation Therapy, Nelfinavir Mesylate, Gemcitabine Hydrochloride, Leucovorin Calcium, and Fluorouracil in Treating Patients With Locally Advanced Pancreatic Cancer
Adenocarcinoma of the Pancreas
Stage III Pancreatic Cancer
Drug: gemcitabine hydrochloride
Drug: leucovorin calcium
Drug: nelfinavir mesylate
Radiation: stereotactic body radiation therapy
Radiation: hypofractionated radiation therapy
Procedure: therapeutic conventional surgery
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase 1 Study of Hypofractionated Stereotactic Radiotherapy and Concurrent HIV Protease Inhibitor Nelfinavir as Part of a Neoadjuvant Regimen in Patients With Locally Advanced Pancreatic Cancer|
- Dose-limiting toxicity as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 [ Time Frame: Within 1 month of surgery ] [ Designated as safety issue: Yes ]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.
- Maximally tolerated dose (MTD) of stereotactic radiotherapy and concurrent nelfinavir mesylate [ Time Frame: 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 escalation ] [ Designated as safety issue: Yes ]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.
- Rate of complete surgical resection [ Time Frame: At the time of surgery (2-3 weeks after completion of SRT) ] [ Designated as safety issue: No ]At the MTD, the rate of surgical complete resection with 90% exact binomial confidence intervals will be calculated.
- Pathological response [ Time Frame: Pre- to post-treatment ] [ Designated as safety issue: No ]At the MTD, the rate of pathologic response with 90% exact binomial confidence intervals will be calculated.
- Tumor response on CT/MRI [ Time Frame: Change from pre- to post-treatment ] [ Designated as safety issue: No ]Pre- to post-treatment changes in tumor size on CT or MRI scan (if CT is not sufficient).
- Correlation between the radiologic response and pathologic response [ Time Frame: Pre- to post-treatment ] [ Designated as safety issue: No ]
- Phospho-AKT expression in pancreatic tumor tissue (correlative) [ Time Frame: Pre- to post-nelfinavir mesylate ] [ Designated as safety issue: No ]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.
- Pharmacokinetics of nelfinavir mesylate (correlative) [ Time Frame: After at least 1 week of NFV: *0 h (trough); *After NFV dosing: 1, 2, 3, 4, 5, 6, 8, and 12 h ] [ Designated as safety issue: No ]The data will be modeled using WinNonLin Pro version 4.1. The pharmacokinetic parameters will be presented as the mean and standard deviation.
- Pharmacogenomic status of CYP2C19*2 (G681A) (correlative) [ Time Frame: Enrollment, at the time of planned tumor tissue procurement, and at the time that re-staging studies are done ] [ Designated as safety issue: No ]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.
|Study Start Date:||November 2007|
|Primary Completion Date:||August 2013 (Final data collection date for primary outcome measure)|
Experimental: Treatment (SRT, radiosensitizer, and chemotherapy)
See Detailed Description
Drug: gemcitabine hydrochloride
Other Names:Drug: leucovorin calcium
Other Names:Drug: fluorouracil
Other Names:Drug: nelfinavir mesylate
Other Name: ViraceptRadiation: stereotactic body radiation therapy
Other Names:Radiation: hypofractionated radiation therapy
Undergo radiotherapyProcedure: therapeutic conventional surgery
I. To establish the safety, dose-limiting toxicities and maximally tolerated dose of hypofractionated stereotactic radiotherapy concurrently with nelfinavir in patients with locally advanced pancreatic cancer given as part of a neoadjuvant chemoradiation therapy regimen.
I. To evaluate the surgical complete resection rate. II. To evaluate the pathological response. III. To evaluate tumor response on computed tomography (CT)/magnetic resonance imaging (MRI).
IV. To evaluate the correlation between the radiologic response and pathologic response.
I. To measure phospho-AKT expression in pancreatic tumor tissue prior to and following the neoadjuvant chemo-radiation program. (Correlative) II. To measure nelfinavir pharmacokinetics at steady-state. (Correlative) III. To measure the pharmacogenomic status of CYP2C19*2 (G681A) in the study population. (Correlative)
OUTLINE: This is a dose-escalation study of stereotactic radiotherapy (SRT) and concurrent nelfinavir mesylate.
NEOADJUVANT THERAPY: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes, leucovorin calcium IV over 30 minutes, and fluorouracil IV continuously over 24 hours on days 1 and 8. Treatment repeats every 3 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive nelfinavir mesylate orally (PO) twice daily (BID) beginning in week 9 and continuing until the completion of SRT or until 14 days after the completion of SRT. Patients undergo concurrent SRT once daily for 5 days in week 11.
SURGERY AND ADJUVANT CHEMOTHERAPY: Approximately 2-3 weeks after completion of SRT, patients undergo restaging to evaluate disease response. Patients with resectable or potentially resectable disease and no metastasis undergo definitive surgery 2-3 weeks later. Approximately 1 month after surgery, these patients receive three additional courses of gemcitabine hydrochloride, leucovorin calcium, and fluorouracil as above. Patients with unresectable disease that is stable or responsive at the time of surgical exploration may resume treatment with gemcitabine hydrochloride, leucovorin calcium, and fluorouracil as above in the absence of disease progression or unacceptable toxicity. Patients with metastatic disease at the time of restaging are removed from the study.
After completion of study treatment, patients are followed every 3 months for 1 year, every 4 months for 1 year, and then every 6 months thereafter.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01068327
|United States, Nebraska|
|University of Nebraska Medical Center|
|Omaha, Nebraska, United States, 68198|
|Principal Investigator:||Chi Lin||University of Nebraska|