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

H. Kim Lyerly

Status and phase

Completed

Phase 1

Conditions

Breast Cancer

Unspecified Adult Solid Tumor, Protocol Specific

Lung Cancer

Pancreatic Cancer

Colorectal Cancer

Treatments

Biological: therapeutic autologous dendritic cells

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

Biological: denileukin diftitox

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00128622

NCI-7042

DUMC-NCI-7042

CDR0000437795

Details and patient eligibility

About

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.

Full description

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.

Enrollment

24 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

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

PATIENT CHARACTERISTICS:

Age

18 and over

Sex

Male or female

Menopausal status

Not specified

Performance status

Karnofsky 70-100%

Life expectancy

More than 6 months

Hematopoietic

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

Hepatic

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

Renal

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

Cardiovascular

No New York Heart Association class III-IV cardiac disease

Immunologic

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

Other

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

PRIOR CONCURRENT THERAPY:

Biologic therapy

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

Chemotherapy

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

Endocrine therapy

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

Radiotherapy

At least 4 weeks since prior and no concurrent radiotherapy

Surgery

See Disease Characteristics

Other

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)