Denileukin Diftitox Followed By Vaccine Therapy In Treating Patients With Metastatic Cancer

Study Overview

Denileukin Diftitox Followed by Vaccine Therapy in Treating Patients With Metastatic Cancer

RATIONALE: Combinations of biological substances in denileukin diftitox may be able to carry cancer-killing substances directly to the cancer cells. Vaccines made from a gene-modified virus and a person's white blood cells may help the body build an effective immune response to kill cancer cells. Giving denileukin diftitox together with vaccine therapy may kill more cancer cells. PURPOSE: This phase I trial is studying the side effects of giving denileukin diftitox together with vaccine therapy in treating patients with metastatic cancer that expresses carcinoembryonic antigen.

OBJECTIVES: Primary * Determine the safety and feasibility of two different schedules of denileukin diftitox followed by active immunotherapy comprising autologous dendritic cells infected with recombinant fowlpox-CEA(6D)-TRICOM vaccine in patients with metastatic CEA-expressing malignancies. Secondary * Determine the immune response to this regimen in these patients. * Determine, preliminarily, clinical response rate and/or time to progression in patients with assessable disease treated with this regimen. OUTLINE: Patients undergo leukapheresis for collection of peripheral blood mononuclear cells (PBMCs). PBMCs are cultured with sargramostim (GM-CSF) and interleukin-4 for the production of dendritic cells( DC). DC are mixed with recombinant fowlpox-TRICOM to produce the vaccine. Patients are assigned to 1 of 2 cohorts according to timing of study enrollment. * Cohort 1: Patients receive denileukin diftitox IV over at least 15 minutes once in week 0 and vaccine therapy comprising autologous DC infected with recombinant fowlpox-CEA (6D)-TRICOM vaccine intradermally and subcutaneously once in weeks 0 (beginning 4 days after the denileukin diftitox infusion), 3, 6, and 9. If < 2 of 6 patients experience dose-limiting toxicity, a second cohort of patients is enrolled. * Cohort 2: Patients receive denileukin diftitox as in cohort 1 once in weeks 0, 3, 6, and 9 and vaccine as in cohort 1. In both cohorts, treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed annually for up to 15 years. PROJECTED ACCRUAL: A total of 6-12 patients (6 per cohort) will be accrued for this study.

Breast Cancer
Colorectal Cancer
Lung Cancer
Pancreatic Cancer
Unspecified Adult Solid Tumor, Protocol Specific

BIOLOGICAL: denileukin diftitox
BIOLOGICAL: recombinant fowlpox-CEA(6D)/TRICOM vaccine
BIOLOGICAL: therapeutic autologous dendritic cells

CDR0000437795
DUMC-NCI-7042
NCI-7042

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 2005-08-08	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2012-11-08
First Submitted that Met QC Criteria 2005-08-08	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ESTIMATED) 2012-11-12
First Posted (ESTIMATED) 2005-08-10	Results First Posted N/A	Last Verified 2012-11

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: Denileukin Diftitox plus vaccine This is a single arm Phase I safety study.	BIOLOGICAL: denileukin diftitox BIOLOGICAL: recombinant fowlpox-CEA(6D)/TRICOM vaccine BIOLOGICAL: therapeutic autologous dendritic cells

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Denileukin Diftitox plus vaccine

This is a single arm Phase I safety study.

BIOLOGICAL: denileukin diftitox

BIOLOGICAL: recombinant fowlpox-CEA(6D)/TRICOM vaccine

BIOLOGICAL: therapeutic autologous dendritic cells

Primary Outcome Measures	Measure Description	Time Frame
Safety as measured by rate of adverse events during study drug treatment		3 months

Secondary Outcome Measures	Measure Description	Time Frame
Rate of immune response as measured by ELISPot at week 10		3 months

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:
18 Years

Accepts Healthy Volunteers:

Histologically confirmed malignancy

Metastatic disease
Tumor expresses carcinoembryonic antigen (CEA), as evidenced by any of the following:

At least 50% of tumor expresses CEA by immunohistochemistry (IHC) with ≥ a moderate intensity of staining
Peripheral blood CEA level > 5.0 ng/mL
Tumor known to be universally CEA-positive (e.g., colon or rectal cancer)
Measurable or evaluable disease
Received or refused prior therapy with a possible survival or palliative benefit AND meets the following disease-specific criteria:

Patients with colorectal cancer must have experienced disease progression during ≥ 1 prior palliative chemotherapy regimen for metastatic disease comprising 1 of the following regimens:

Fluorouracil or capecitabine AND oxaliplatin
Fluorouracil or capecitabine AND irinotecan
Chemotherapy in combination with bevacizumab
Patients with breast cancer must have experienced disease progression during ≥ 1 prior palliative chemotherapy regimen for metastatic disease comprising 1 of the following regimens:

Anthracycline- or taxane-based chemotherapy
Chemotherapy AND trastuzumab (Herceptin®) (required for patients with tumors overexpressing HER2/neu (i.e., 3+ by IHC or positive by fluorescence in situ hybridization [FISH])
Patients with lung cancer must have experienced disease progression during ≥ 1 prior palliative chemotherapy regimen for metastatic disease comprising 1 of the following regimens:

Platinum-based (e.g., cisplatin or carboplatin) chemotherapy (for chemotherapy-naive patients only)
Taxane-based (e.g., docetaxel or paclitaxel) chemotherapy OR vinorelbine (for patients who received prior chemotherapy)
Patients with pancreatic cancer must have experienced disease progression during prior chemotherapy, including gemcitabine
Patients with other malignancies must have experienced disease progression after prior first-line therapy that would confer a survival or palliative benefit, if such a therapy exists

Patients who experienced disease progression during prior first-line palliative chemotherapy must be advised regarding second-line therapy before study enrollment
Previously resected brain metastases allowed provided there is no evidence of brain metastasis within the past month by MRI or CT scan
No requirement for further systemic chemotherapy for ≥ 3 months
Hormone receptor status:

Not specified

18 and over

Male or female

Not specified

Karnofsky 70-100%

More than 6 months

WBC ≥ 3,000/mm^3
Hemoglobin ≥ 9 g/dL (transfusion or epoetin alfa allowed)
Platelet count ≥ 100,000/mm^3

Bilirubin < 1.5 mg/dL (≤ 2.0 mg/dL for patients with Gilbert's syndrome)
SGOT and SGPT < 1.5 times upper limit of normal
Albumin ≥ 3.0 g/dL
No active acute or chronic viral hepatitis

Hepatitis B surface antigen negative
Hepatitis C negative
No other hepatic disease that would preclude study treatment

Creatinine < 1.5 mg/dL
No active acute or chronic urinary tract infection

No New York Heart Association class III-IV cardiac disease

HIV negative
No history of autoimmune disease*, including, but not limited to, the following:

Inflammatory bowel disease
Systemic lupus erythematosus
Ankylosing spondylitis
Scleroderma
Multiple sclerosis
No active cytomegalovirus (CMV) disease

Patients with CMV-seropositivity are eligible
No other active acute or chronic infection
No history of allergies to eggs or any component of the study vaccine, denileukin diftitox, or diphtheria toxin NOTE: *Patients with a positive anti-nuclear antibody (ANA) ≤ 1:256 with no other evidence of autoimmune disease are eligible

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 4 months after completion of study treatment
No acute or chronic skin disorder that would preclude study treatment
No other malignancy within the past 5 years except nonmelanoma skin cancer, controlled carcinoma in situ of the cervix, or controlled superficial bladder cancer
No psychological or medical impediment that would preclude study compliance
No other serious acute or chronic illness that would preclude study treatment

See Disease Characteristics
Prior vaccine, dendritic cell, or CEA-targeted immunotherapy allowed
At least 4 weeks since prior and no other concurrent immunotherapy
Concurrent palliative single-agent trastuzumab for breast cancer allowed provided patient has been on therapy for ≥ 3 months before study entry

See Disease Characteristics
At least 4 weeks since prior and no concurrent chemotherapy

At least 4 weeks since prior hormonal therapy
At least 6 weeks since prior steroid therapy except steroids used as premedication for chemotherapy or contrast-enhanced studies
No concurrent steroids, including corticosteroids administered to manage toxic effects from dendritic cell or denileukin diftitox administration
Concurrent palliative endocrine therapy for breast cancer allowed provided patient has been on therapy for ≥ 3 months before study entry

At least 4 weeks since prior and no concurrent radiotherapy

See Disease Characteristics

Recovered from all prior therapy
At least 4 weeks since prior investigational drugs or procedures
At least 4 weeks since other prior therapy
No other concurrent immunosuppressive therapy (e.g., azathioprine or cyclosporine)

Collaborators and Investigators

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

National Cancer Institute (NCI)

Investigators

STUDY_CHAIR: Michael A. Morse, MD, Duke Cancer Institute

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

Schonfeld K, Mahnke K, Schallenberg S, et al.: Treatment of melanoma bearing individuals with ONTAK® depletes regulatory T cells resulting in an augmented immune response following vaccination. [Abstract] J Invest Dermatol 126 (Suppl S3): A-594, s101, 2006.
Morse MA, Hobeika AC, Osada T, Serra D, Niedzwiecki D, Lyerly HK, Clay TM. Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines. Blood. 2008 Aug 1;112(3):610-8. doi: 10.1182/blood-2008-01-135319. Epub 2008 Jun 2.

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