Stereotactic Radiation, Nelfinavir Mesylate & Neoadjuvant Chemotherapy In Locally Advanced Pancreatic Cancer

Study Overview

Stereotactic Radiation, Nelfinavir Mesylate & Neoadjuvant Chemotherapy in Locally Advanced Pancreatic Cancer

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.

PRIMARY OBJECTIVES: 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. SECONDARY OBJECTIVES: 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. TERTIARY OBJECTIVES: 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.

Adenocarcinoma of the Pancreas
Stage III Pancreatic Cancer

DRUG: gemcitabine hydrochloride
DRUG: leucovorin calcium
DRUG: fluorouracil
DRUG: nelfinavir mesylate
RADIATION: stereotactic body radiation therapy
RADIATION: hypofractionated radiation therapy
PROCEDURE: therapeutic conventional surgery

0441-07-FB
NCI-2009-01443 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))
P30CA036727 (U.S. NIH Grant/Contract)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2010-01-25	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2023-10-04
First Submitted that Met QC Criteria 2010-02-11	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2023-10-10
First Posted (ACTUAL) 2010-02-12	Results First Posted N/A	Last Verified 2023-10

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Na

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Treatment (SRT, radiosensitizer, and chemotherapy) See Detailed Description	DRUG: gemcitabine hydrochloride Given IV DRUG: leucovorin calcium Given IV DRUG: fluorouracil Given IV DRUG: nelfinavir mesylate Given PO RADIATION: stereotactic body radiation therapy Undergo radiotherapy RADIATION: hypofractionated radiation therapy Undergo radiotherapy PROCEDURE: therapeutic conventional surgery Undergo surgery

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Treatment (SRT, radiosensitizer, and chemotherapy)

See Detailed Description

DRUG: gemcitabine hydrochloride

Given IV

DRUG: leucovorin calcium

Given IV

DRUG: fluorouracil

Given IV

DRUG: nelfinavir mesylate

Given PO

RADIATION: stereotactic body radiation therapy

Undergo radiotherapy

RADIATION: hypofractionated radiation therapy

Undergo radiotherapy

PROCEDURE: therapeutic conventional surgery

Undergo surgery

Primary Outcome Measures	Measure Description	Time Frame
Dose-limiting toxicity as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0	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.	Within 1 month of surgery
Maximally tolerated dose (MTD) of stereotactic radiotherapy and concurrent nelfinavir mesylate	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.	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

Secondary Outcome Measures	Measure Description	Time Frame
Rate of complete surgical resection	At the MTD, the rate of surgical complete resection with 90% exact binomial confidence intervals will be calculated.	At the time of surgery (2-3 weeks after completion of SRT)
Pathological response	At the MTD, the rate of pathologic response with 90% exact binomial confidence intervals will be calculated.	Pre- to post-treatment
Tumor response on CT/MRI	Pre- to post-treatment changes in tumor size on CT or MRI scan (if CT is not sufficient).	Change from pre- to post-treatment
Radiologic response and pathologic response	Correlation between the radiologic response and pathologic response	Pre- to post-treatment
Phospho-AKT expression in pancreatic tumor tissue (correlative)	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.	Pre- to post-nelfinavir mesylate
Pharmacokinetics of nelfinavir mesylate (correlative)	The data will be modeled using WinNonLin Pro version 4.1. The pharmacokinetic parameters will be presented as the mean and standard deviation.	After at least 1 week of NFV: 0 h (trough); After NFV dosing: 1, 2, 3, 4, 5, 6, 8, and 12 h
Pharmacogenomic status of CYP2C19*2 (G681A) (correlative)	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.	Enrollment, at the time of planned tumor tissue procurement, and at the time that re-staging studies are done

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
19 Years

Accepts Healthy Volunteers:

The time between other investigational agents and enrollment on this study is at least 30 days
Pathologically confirmed adenocarcinoma of the pancreas
Patients have localized or locally advanced disease with no evidence of distant metastases
The maximum dimension of the tumor must be =< 8 cm
Karnofsky Performance Status of 60% or better
Patients with biliary or gastroduodenal obstruction must have drainage or surgical bypass prior to starting chemoradiation
Patients who received chemotherapy > 5 years ago for malignancies other than pancreatic cancer are eligible, provided that chemotherapy was completed > 5 years ago and that there is no evidence of the second malignancy at the time of study entry
Patients who received radiation therapy > 5 years ago for malignancies other than pancreatic cancer and whose radiation therapy field is not overlapping with the 20% isodose line of current radiation field are eligible, provided that radiation therapy was completed > 5 years ago and that there is no evidence of the second malignancy at the time of study entry
All malignant disease must be able to be encompassed within a single irradiation field
All patients must have radiographically assessable disease
Patients must have a absolute granulocyte count (AGC) greater than or equal to 1500/uL and platelet count greater than or equal to 100,000/uL
Patients must have a serum creatinine less than or equal to 2 mg/dL and total bilirubin less than or equal to 2.0 mg/dL in the absence of biliary obstruction
If the patient has biliary obstruction, biliary decompression will be required; either endoscopic placement of biliary stent (7 French or greater) or percutaneous transhepatic drainage are acceptable; once biliary drainage has been established, institution of gemcitabine therapy may proceed when the total bilirubin falls to below 4.0 mg/dL
The patient must be aware of the neoplastic nature of his/her disease and willingly provide written, informed consent after being informed of the procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts
Patients may have had prior chemotherapy for pancreatic cancer
Any prior therapy is acceptable except radiation to the abdomen

Patients receiving the following drugs will be clinically evaluated as to whether dosage/medication can be changed to permit patient on study: carbamazepine; phenobarbital; phenytoin; rifabutin; sildenafil; atorvastatin; cyclosporine; tacrolimus; sirolimus; methadone; ethinyl estradiol; azithromycin
Patients who can not undergo staging laparoscopy and marker implantation; this may include patients with a prior history of multiple abdominal operations in which laparoscopy may not be technically feasible or potentially harmful
The patient is eligible if they have a common bile duct stent adjacent to the tumor that may be used as an internal marker, or if the patient has already had a staging laparoscopy without marker implantation and the markers can be implanted (by interventional radiology) prior to the beginning of radiation therapy
History of allergy to chemotherapy agents or to antiemetics appropriate for administration in conjunction with protocol-directed chemotherapy
Uncontrolled inter-current illness including, but not limited to ongoing or active infection requiring intravenous antibiotics, symptomatic congestive heart failure, unstable angina pectoris, or serious, uncontrolled cardiac arrhythmia, that might jeopardize the ability of the patient to receive the chemotherapy program outlined in this protocol with reasonable safety
Patients with human immunodeficiency virus (HIV) infection, or hepatic insufficiency
Patients may not be receiving or have received any other investigational agents during/or within 1 month prior to treatment with NFV (nelfinavir mesylate)
Patients who can not take oral medications
Patients with active duodenal ulcer or bleeding or history of a gastrointestinal fistula or perforation or other significant bowel problems (severe nausea, vomiting, inflammatory bowel disease and significant bowel resection)
Patients with prior malignancy will be excluded EXCEPT for adequately treated basal cell or squamous cell skin cancer, adequately treated noninvasive carcinomas, or other cancers from which the patient has been disease-free for at least 5 years
Patients receiving the following drugs that are contraindicated with NFV will be excluded: amiodarone; quinidine; rifampin; dihydroergotamine; ergonovine; ergotamine; methylergonovine; St. John's wort (hypericum perforatum); lovastatin; simvastatin; pimozide; midazolam; triazolam
Pregnant and nursing women are excluded from this study

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

National Cancer Institute (NCI)

Investigators

PRINCIPAL_INVESTIGATOR: Chi Lin, University of Nebraska

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Lin C, Verma V, Ly QP, Lazenby A, Sasson A, Schwarz JK, Meza JL, Are C, Li S, Wang S, Hahn SM, Grem JL. Phase I trial of concurrent stereotactic body radiotherapy and nelfinavir for locally advanced borderline or unresectable pancreatic adenocarcinoma. Radiother Oncol. 2019 Mar;132:55-62. doi: 10.1016/j.radonc.2018.11.002. Epub 2018 Dec 20.

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