- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01068327
Stereotactic Radiation, Nelfinavir Mesylate & Neoadjuvant Chemotherapy in Locally Advanced Pancreatic Cancer
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
Study Overview
Status
Detailed Description
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.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Nebraska
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Omaha, Nebraska, United States, 68198
- University of Nebraska Medical Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment (SRT, radiosensitizer, and chemotherapy)
See Detailed Description
|
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Undergo surgery
Given PO
Other Names:
Undergo radiotherapy
Other Names:
Undergo radiotherapy
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
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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.
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Within 1 month of surgery
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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
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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.
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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
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Rate of complete surgical resection
Time Frame: At the time of surgery (2-3 weeks after completion of SRT)
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At the MTD, the rate of surgical complete resection with 90% exact binomial confidence intervals will be calculated.
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At the time of surgery (2-3 weeks after completion of SRT)
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Pathological response
Time Frame: Pre- to post-treatment
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At the MTD, the rate of pathologic response with 90% exact binomial confidence intervals will be calculated.
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Pre- to post-treatment
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Tumor response on CT/MRI
Time Frame: Change from pre- to post-treatment
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Pre- to post-treatment changes in tumor size on CT or MRI scan (if CT is not sufficient).
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Change from pre- to post-treatment
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Phospho-AKT expression in pancreatic tumor tissue (correlative)
Time Frame: Pre- to post-nelfinavir mesylate
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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.
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Pre- to post-nelfinavir mesylate
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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
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The data will be modeled using WinNonLin Pro version 4.1.
The pharmacokinetic parameters will be presented as the mean and standard deviation.
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After at least 1 week of NFV: *0 h (trough); *After NFV dosing: 1, 2, 3, 4, 5, 6, 8, and 12 h
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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
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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.
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Enrollment, at the time of planned tumor tissue procurement, and at the time that re-staging studies are done
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Radiologic response and pathologic response
Time Frame: Pre- to post-treatment
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Correlation between the radiologic response and pathologic response
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Pre- to post-treatment
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Chi Lin, University of Nebraska
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Digestive System Diseases
- Neoplasms
- Neoplasms by Site
- Endocrine System Diseases
- Digestive System Neoplasms
- Endocrine Gland Neoplasms
- Pancreatic Diseases
- Pancreatic Neoplasms
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antiviral Agents
- Enzyme Inhibitors
- Anti-HIV Agents
- Anti-Retroviral Agents
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Protease Inhibitors
- Protective Agents
- Micronutrients
- Vitamins
- Calcium-Regulating Hormones and Agents
- HIV Protease Inhibitors
- Viral Protease Inhibitors
- Antidotes
- Vitamin B Complex
- Fluorouracil
- Leucovorin
- Calcium
- Levoleucovorin
- Nelfinavir
- Gemcitabine
Other Study ID Numbers
- 0441-07-FB
- P30CA036727 (U.S. NIH Grant/Contract)
- NCI-2009-01443 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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