Prostate Cancer Vaccine
Clinical Trial
Phase I Study of Adenovirus/PSA Vaccine in Men with Metastatic Prostate Cancer
Principal Investigator - David M. Lubaroff, Ph.D.
Co-Investigators - Richard D. Williams, MD, Badrinath Konety, MD, Brian
K. Link, MD, Tammy Madsen, PA, Mary Shannon, RN, Dixie Ecklund, RN
Overview
We have developed a vaccine for the treatment of prostate cancer using a replication-defective
adenovirus serotype 5 transformed with the gene for human prostate specific
antigen (PSA). Our hypothesis is that the use of this adenovirus/PSA vaccine
(Ad/PSA) in men with prostate cancer will induce minimum toxicity, induce
antigen-specific anti-PSA immunity, and will reduce tumor size. It is also
our hypothesis that the administration of vaccine in a collagen matrix (Gelfoam)
will augment the immunization potential of the PSA-containing virus, and will
allow the development of anti-PSA immunity in the presence of anti-adenovirus
antibody. We have been carrying out a Phase I Clinical Trial of the Ad/PSA
vaccine in men with metastatic prostate cancer. We are evaluating the vaccine
with respect to the development of toxicity in patients with both biochemical
and clinical evidence of metastatic prostate cancer. As secondary goals of
the study we are assessing the clinical impact vaccination might have on clinical
markers of disease including PSA levels or changes in measurable disease (x-rays,
scans, etc.) and evaluating the vaccine with respect to the development of
anti-PSA immune responses.
Patient Eligibility
Patients in this trial must have histologically confirmed adenocarcinoma of
the prostate with evidence of metastatic disease, either new D2 or D3 disease
stages. The disease must be measurable as evidenced by one or more of the
following positive results: bone scan, abdominal-pelvic CT, chest x-ray, other
standard radiologic techniques, a rise in serum PSA levels. A PSA rise alone
in the absence of other evidence of disease will not be sufficient for inclusion
in this study.
Required laboratory values (obtained within 2 weeks of study entry) - serum
creatinine (< 2.0 mg%), adequate hematologic functions (granulocytes >
1800 per mm3 and platelets > 100,000 per mm3), adequate hepatocellular
function (AST <3x normal and bilirubin <1.5 mg/dl).
Conditions that would exclude a patient include: an active
unresolved infection, parenteral antibiotics <7 days prior to study entry,
known or clinical signs and symptoms of CNS metastasis, other co-morbid medical
conditions which would result in a life expectancy (participation) of less
than 1 year, pre-existing malignancies that required treatment within the
past 5 years except for basal or squamous cell cancers of the skin. Patients
with compromised immune systems, either congenital, acquired, or drug-induced
(immunosuppressive agents) will be excluded from the study.
Treatment
Patients are randomized to either the subcutaneous (sc) aqueous or sc matrix
groups at a single dose of virus to avoid any bias. The initial group of patients
are randomized to receive 1 x 10E6 plaque-forming units (pfu), of the Ad/PSA
vaccine administered either as an aqueous suspension (dose level 1) or in
the Gelfoam matrix (dose level 2). This material is then injected subcutaneously.
The use of the matrix has been shown in collaborative experiments to enhance
infection of host cells by the virus. If no significant toxicities are detected
in the patients receiving this initial dose the next group of patients will
receive the next highest dose of 1 x 10E7 pfu, randomized to sc aqueous or
sc matrix and the dose escalation and randomization continued until we reach
our maximum tolerated dose. The vaccine will be administered sc in the thigh
in volumes of 0.125 ml. Injections will be carried out in the University of
Iowa Clinical Research Center (CRC). Each subject will be housed in the CRC
for 24 hours and observed for early signs of toxicities. Tests, indicated
in the table, will be carried out to determine any toxic effects of the vaccine.
Dose Modifications
The study design is constructed as a dose escalation trial. At each dose level,
patients receive a vaccination and be observed for toxicity and secondary
endpoints. This facilitates the evaluation of biological endpoints and toxicity
as a function of dose. In addition, the design allows for the modification
or termination of the study in the event of dose-limiting toxicity (DLT).
Toxicity will be graded according to the NCI common toxicity criteria (NCI-CTC
version 2.0 can be accessed at website:
http://ctep.info.nih.gov). Non-hematologic dose limiting toxicity (DLT)
will be defined as grade III non-hematologic toxicity. Hematologic DLT will
be declared if patients develop grade IV or grade III and fail to recover
their absolute neutrophil count (ANC) and platelets to Grade I/II levels after
5 weeks, unless such failure is due to progressive tumor.
Maximum Tolerated Dose (MTD): The MTD for the Ad/PSA vaccine will be
the maximum dose which produces dose-limiting toxicity in less than two of
the six patients treated at that dose level.
Optimal Biologic Dose (OBD): The OBD for the vaccine will be that dose
which induces a maximum anti-PSA response, defined by the level of anti-PSA
antibody (ng/ml.) as well as measurements of both CD4 and CD8 T cell responses.
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Evaluation
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Prior to Study Entry
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At Ad/PSA injection
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During first 24 hours
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14 d.
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21 d.
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2 mo.
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4 mo.
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8 mo.
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12 mo.
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| Leukapheresis |
x
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| Physical Examination |
x
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
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| Performance Status |
x
|
x
|
x
|
x
|
x
|
x
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| Vital Signs |
x
|
x
|
x
|
x
|
x
|
x
|
x
|
x
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| Weight |
x
|
x
|
x
|
x
|
x
|
x
|
x
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| Blood for PSA, PAP, anti-PSA Ab, and lymphocytes for cellular immunity |
x
|
x
|
x
|
x
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x
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x
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x
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| Hgb/Hct, WBC, platelets |
x
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
x
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| Differential |
x
|
x
|
x
|
x
|
x
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| AST, ALT, LDH, alkaline phosphatase, bilirubin |
x
|
x
|
x
|
x
|
x
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| Creatinine |
x
|
x
|
x
|
x
|
x
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| Urinalysis |
x
|
x
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x
|
x
|
x
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| Chest X-Ray |
x
|
x
|
x
|
x
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| Bone Scan |
x
|
x
|
x
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| Abdominal CT |
x
|
x
|
x
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| EKG |
x
|
x
|
x
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