Combination Chemotherapy With or Without Oregovomab Followed By Stereotactic Body Radiation Therapy and Nelfinavir Mesylate in Treating Patients With Locally Advanced Pancreatic Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by University of Nebraska
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Chi Lin, MD, University of Nebraska
ClinicalTrials.gov Identifier:
NCT01959672
First received: October 8, 2013
Last updated: July 1, 2014
Last verified: July 2014
  Purpose

This phase II trial studies how well combination chemotherapy with or without oregovomab followed by stereotactic body radiation therapy (SBRT) and nelfinavir mesylate works in treating patients with locally advanced pancreatic cancer. 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, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as oregovomab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Stereotactic body 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. Giving combination chemotherapy with or without oregovomab followed by SBRT and nelfinavir mesylate may kill more tumor cells.


Condition Intervention Phase
Acinar Cell Adenocarcinoma of the Pancreas
Duct Cell Adenocarcinoma of the Pancreas
Recurrent Pancreatic Cancer
Stage IA Pancreatic Cancer
Stage IB Pancreatic Cancer
Stage IIA Pancreatic Cancer
Stage IIB Pancreatic Cancer
Stage III Pancreatic Cancer
Drug: gemcitabine hydrochloride
Drug: leucovorin calcium
Biological: oregovomab
Drug: nelfinavir mesylate
Radiation: stereotactic body radiation therapy
Procedure: therapeutic conventional surgery
Other: laboratory biomarker analysis
Drug: fluorouracil
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Neoadjuvant Chemotherapy With and Without Immunotherapy to CA125 (Oregovomab) Followed by Hypofractionated Stereotactic Radiotherapy and Concurrent HIV Protease Inhibitor Nelfinavir in Patients With Locally Advanced Pancreatic Cancer

Resource links provided by NLM:


Further study details as provided by University of Nebraska:

Primary Outcome Measures:
  • Rate of progressive disease, defined as at least a 25% increase in the longest diameter of a lesion, taking as reference the longest diameter recorded since the treatment started [ Time Frame: Up to 4 months ] [ Designated as safety issue: No ]
    An exact one-sided 90% confidence interval will be constructed round the progressive disease rate.


Secondary Outcome Measures:
  • Incidence of toxicity, graded by the National Cancer Institute Common Toxicity Criteria version 4.0, reported by frequency and severity [ Time Frame: Up to 30 days after the final dose of study drug ] [ Designated as safety issue: Yes ]
    Adverse events will be tallied for overall frequency (number and percentage of subjects), worst reported severity, and relationship to study drugs. Serious adverse events will be summarized similarly.

  • Failure-free survival [ Time Frame: Date of administration study drug to the date of first appearance of tumor lesions by imaging, or death, assessed up to 5 years ] [ Designated as safety issue: No ]
    Analyzed using Kaplan-Meier plots, medians and ranges.

  • Overall survival [ Time Frame: Date of first of study drug to the date of death, assessed up to 5 years ] [ Designated as safety issue: No ]
    Analyzed using Kaplan-Meier plots, medians and ranges.

  • Surgical complete resection (negative margin) rate [ Time Frame: Up to week 18 ] [ Designated as safety issue: No ]
  • Tumor response rate, evaluated on the pathology specimen [ Time Frame: Up to week 18 ] [ Designated as safety issue: No ]
    The proportion of patients responding will be summarized using frequencies and percentages.

  • Tumor response rate, evaluated on CT/magnetic resonance imaging (MRI) using Response Evaluation Criteria in Solid Tumors [ Time Frame: Up to week 16 ] [ Designated as safety issue: No ]
    The proportion of patients responding will be summarized using frequencies and percentages.

  • Tumor motion, assessed with 4D CT [ Time Frame: Week 8 ] [ Designated as safety issue: No ]
  • Organ motion, assessed with 4D CT [ Time Frame: Week 8 ] [ Designated as safety issue: No ]
  • Tumor motion, assessed with respiratory gating data [ Time Frame: Week 11 ] [ Designated as safety issue: No ]
  • Organ motion, assessed with respiratory gating data [ Time Frame: Week 11 ] [ Designated as safety issue: No ]
  • Dosimetry [ Time Frame: Week 11 ] [ Designated as safety issue: No ]
    The effect of tumor/organ motion on the dosimetry will be evaluated.

  • Local control [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    The effect of tumor/organ motion on local control will be evaluated.

  • Survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    The effect of tumor/organ motion on survival will be evaluated.


Other Outcome Measures:
  • Change in proportion of patients with cellular immune response, defined as having a significant increase from baseline in CA125 enzyme-linked immunosorbent spot [ Time Frame: Baseline to up to week 12 ] [ Designated as safety issue: No ]
    Defined relative to baseline according to the permutation test The proportion of patients responding will be summarized using frequencies and percentages.

  • Value of 4DCT and respiratory gating in defining tumor, clinical, and planning target volumes for pancreatic cancer SBRT [ Time Frame: Week 11 ] [ Designated as safety issue: No ]

Estimated Enrollment: 66
Study Start Date: September 2013
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (chemotherapy, immunotherapy, SBRT, surgery)
See Detailed Description
Drug: gemcitabine hydrochloride
Given IV
Other Names:
  • dFdC
  • difluorodeoxycytidine hydrochloride
  • gemcitabine
  • Gemzar
Drug: leucovorin calcium
Given IV
Other Names:
  • CF
  • CFR
  • LV
Biological: oregovomab
Given IV
Other Names:
  • B43.13
  • MOAB B43.13
  • monoclonal antibody B43.13
  • OvaRex
Drug: nelfinavir mesylate
Given PO
Other Name: Viracept
Radiation: stereotactic body radiation therapy
Undergo SBRT
Other Names:
  • SBRT
  • stereotactic radiation therapy
  • stereotactic radiotherapy
Procedure: therapeutic conventional surgery
Undergo surgical resection
Other: laboratory biomarker analysis
Correlative studies
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the efficacy of neoadjuvant chemotherapy, (gemcitabine [gemcitabine hydrochloride], leucovorin [leucovorin calcium], fluorouracil [5-FU]) with or without oregovomab, followed by hypofractionated stereotactic radiotherapy (SRT) concurrently with nelfinavir (nelfinavir mesylate) in patients with locally advanced pancreatic cancer that is cancer antigen (CA)125 positive (>= 10) or CA125 negative (< 10).

SECONDARY OBJECTIVES:

I. To assess the safety of neoadjuvant chemotherapy, (gemcitabine, leucovorin, 5-FU) with or without oregovomab, followed by SRT concurrently with nelfinavir in patients with locally advanced pancreatic cancer that is CA125 positive (>= 10) or CA125 negative (< 10).

II. To assess the cellular and humoral immune responses to active immunotherapy with oregovomab/monoclonal antibody in patients with pancreas cancer with CA125 level greater than 10 undergoing chemotherapy and radiation treatments.

TERTIARY OBJECTIVES:

I. To evaluate tumor and organ motion with 4-dimensional (4D) computed tomography (CT) and respiratory gating system and to evaluate the effect of tumor/organ motion on the dosimetry, local control and survival.

OUTLINE:

CHEMOTHERAPY: Patients receive gemcitabine hydrochloride intravenously (IV), leucovorin calcium IV over 30 minutes, and fluorouracil IV over 24 hours on days 1 and 8.

IMMUNOTHERAPY: Patients with CA125 level >= 10 receive oregovomab IV over 15-30 minutes on day 15. Treatment repeats every 3 weeks for 3 courses (weeks 1, 4, 7) and post- radiation therapy for 1 course (week 14). Patients may receive an additional 3 courses concurrently with chemotherapy upon recovery from surgery based on CA125 level. Patients also receive nelfinavir mesylate orally (PO) twice daily (BID) for 5 weeks beginning on day 15 of week 9.

STEREOTACTIC RADIATION THERAPY: Beginning in week 11, patients undergo SBRT in 5 fractions over 5 consecutive days. Upon completion of radiation therapy, patients resume nelfinavir mesylate for 14 days (week 12-13). Patients without metastasis and with resectable disease undergo surgery in week 17-18.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 1 year, and then every 6 months thereafter.

  Eligibility

Ages Eligible for Study:   19 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Pathologically confirmed adenocarcinoma of the pancreas; patients have resectable or borderline resectable disease with no evidence of distant metastases; the maximum dimension of the tumor must be =<10 cm
  • Karnofsky performance status of 60% or better
  • 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
  • Absolute neutrophil count (ANC) greater than or equal to 1500/μL
  • Platelet count greater than or equal to 100,000/μL
  • Serum creatinine less than or equal to 2.0 mg/dL
  • 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 =< 4.0 mg/dL; patients with biliary or gastroduodenal obstruction must have drainage or surgical bypass prior to starting chemoradiation
  • 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
  • No prior therapy with the exception of 1 cycle of chemotherapy based on current diagnosis and clinical condition
  • Patients must have CA125 level >= 10 to participate in the immunotherapy aspect of the trial and receive oregovomab; if the patient has CA125 >= 10 who is not eligible to receive oregovomab (e.g. allergic to the drug) but is eligible for the rest of treatment, this patient should be accrued to the part of protocol without oregovomab

Exclusion Criteria:

  • Patients who cannot undergo staging laparoscopy; for example, 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
  • Patients with a known allergy to murine proteins or have had a documented anaphylactic reaction or allergy to any of chemotherapy agents used in this protocol, oregovomab, or to antiemetics appropriate for administration in conjunction with protocol-directed therapy
  • 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 therapy program outlined in this protocol with reasonable safety
  • Pregnant and nursing women are excluded from this study
  • 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 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 known human immunodeficiency virus (HIV) infection, or hepatic insufficiency
  • Patients who cannot take oral medications
  • Patients may not be receiving or have received any other investigational agents during/or within 1 month prior to treatment with oregovomab or nelfinavir
  • Patients with an active autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus [SLE], ulcerative colitis, Crohn's disease, multiple sclerosis [MS], ankylosing spondylitis)
  • Patients with a recognized acquired, hereditary, or congenital immunodeficiency disease including cellular immunodeficiency's, hypogammaglobulinemia or dysgammaglobulinemia
  • Patients receiving the following drugs that are contraindicated with nelfinavir (NFV) (VIRACEPT) will be excluded if they cannot be change or discontinued; drugs that should not be coadministered with Viracept:

    • Antiarrhythmics: amiodarone, quinidone
    • Antimicrobacterial: rifampin
    • Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine
    • Herbal products: St. John's Wort (hypericum perforatum)
    • 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors: lovastatin, simvastatin
    • Neuroleptic: pimozide
    • Sedative/hypnotics: midazolam, triazolam
  • Patients receiving the following drugs will be clinically evaluated as to whether dosage/medication can be changed to permit patient on study:

    • Anticonvulsants: carbamazepine, phenobarbital
    • Anticonvulsants: phenytoin; phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration
    • Antimicrobacterial: rifabutin, nelfinavir, it is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin
    • Erectile dysfunction agent: sildenafil; sildenafil shall not exceed a maximum single dose of 25 mg in a 48 hour period
    • HMG-CoA reductase inhibitor: atorvastatin; use lowest possible dose of atorvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with VIRACEPT
    • Immunosuppressants: cyclosporine, tacrolimus, sirolimus
    • Narcotic analgesic: methadone; dosage of methadone may need to be increased when coadministered with VIRACEPT
    • Oral contraceptive: ethinyl estradiol; alternative or additional contraceptive measures should be used when oral contraceptives and VIRACEPT are coadministered
    • Macrolide antibiotic: azithromycin; dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01959672

Locations
United States, Nebraska
University of Nebraska Medical Center Recruiting
Omaha, Nebraska, United States, 68198
Contact: Chi Lin    402-552-3844    Clin@unmc.edu   
Principal Investigator: Chi Lin         
Sponsors and Collaborators
University of Nebraska
Investigators
Principal Investigator: Chi Lin University of Nebraska
  More Information

No publications provided

Responsible Party: Chi Lin, MD, Principal Investigator, University of Nebraska
ClinicalTrials.gov Identifier: NCT01959672     History of Changes
Other Study ID Numbers: 441-13, NCI-2013-02273, NCI-2013-02118, NCI-2012-00835, 441-13, P30CA036727
Study First Received: October 8, 2013
Last Updated: July 1, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Adenocarcinoma
Pancreatic Neoplasms
Carcinoma, Acinar Cell
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Antibodies, Monoclonal
Fluorouracil
Gemcitabine
Leucovorin
Levoleucovorin
Protease Inhibitors
Nelfinavir
HIV Protease Inhibitors
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents

ClinicalTrials.gov processed this record on July 31, 2014