Vaccine and Antibody Treatment of Prostate Cancer

This study will evaluate the side effects of a fixed dose of vaccine and GM-CSF with increasing doses of anti-CTLA-4 antibody in patients with advanced prostate cancer. The vaccine consists of a "priming vaccine" called PROSTVAC/TRICOM, made from vaccinia virus, and a "boosting vaccine" called PROSTVAC-F/TRICOM, made from fowlpox virus. GM-CSF is a chemical that boosts the immune system, and anti-CTLA-4 antibody is a protein that may improve anti-tumor activity and the response to the vaccines. DNA is inserted into the priming and boosting vaccine viruses to cause production of proteins that enhance immune activity and also to produce prostate specific antigen (PSA)-a protein that is normally produced by the patient's tumor cells.

Patients 18 years of age and older with androgen-insensitive prostate cancer that has spread beyond the original site may be eligible for this 7-month study. Candidates must have disease that has worsened despite treatments with hormones and up to one chemotherapy regimen. Their tumor must produce PSA, and they must have no history of allergy to eggs or egg products Candidates are screened with a medical history and physical examination, blood and urine tests, electrocardiogram, pathological confirmation of the diagnosis and presence of the PSA marker, chest x-rays, imaging studies to assess the extent of tumor, and, if clinically indicated, a cardiologic evaluation.

Participants receive the priming vaccination on study day 1. After 2 weeks and then again every 4 weeks while on the study, they receive a boosting vaccine. All vaccines are injected under the skin. On the day of each vaccination and daily for the next 3 days, patients receive an injection of GM-CSF to increase the number of immune cells at the vaccination site. On the day of the first six boosting vaccinations, they receive anti-CTLA-4 antibody as an infusion through a vein over 90 minutes.

Patients are monitored for safety and treatment response with the following tests and procedures:

-Blood and urine tests monthly, or more often if needed, to monitor liver, kidney, and other organ function.

-Imaging studies to assess the tumor before starting treatment, again around study days 99 and 183, and then every 3 months after that while on study.

-Apheresis (a procedure for collecting immune cells called lymphocytes) to measure the immune response to treatment. Apheresis is done three times: before starting the study and again around study days 99 and 183. For this procedure, blood is collected through a needle in an arm vein. The blood circulates through a machine that separates it into its components by spinning, and the lymphocytes are extracted. The rest of the blood is returned to the patient through the same needle. This will only be done in participants who have the tissue marker HLA-A2 (about 50% of patients).

Patients whose disease responds to treatment and who do not develop severe side effects may continue treatment beyond the initial 7-month study period on vaccine alone (without the antibody). After treatment is completed, patients are monitored for up to 15 years. This includes a medical history and physical examination for 5 years following the last vaccination. Information beyond 5 years is collected once a year by telephone.

Condition	Intervention	Phase
Prostatic Neoplasms	Drug: PROSTVAC-V/TRICOM  Drug: PROSTVAC-F/TRICOM  Drug: MDX-010	Phase I

Further study details as provided by National Institutes of Health Clinical Center (CC):

Expected Total Enrollment:  24

Initial studies with vaccines for prostate cancer have shown early evidence of clinical activity; however, this has only been seen in a minority of patients with advanced disease. It is possible that by inhibiting the normal down regulation of the specific immune response generated to vaccine, we could sustain and potentiate immune responses that may lead to augmented anti-tumor responses as suggested by preclinical and clinical studies.

This is an open label, phase I trial of vaccine and MDX-010 (human anti-CTLA-4 mAb) in patients with metastatic androgen insensitive prostate cancer who have received no more than one prior regimen of chemotherapy. All patients will receive a fixed dose of vaccine vectors containing PSA and three human costimulatory molecules (ICAM, LFA-3 and B7.1; designated TRICOM) and sargramostim, and sequential cohorts will get dose escalation of MDX-010 (human anti-CTLA-4 mAb). The vaccine vector used for the priming vaccination is vaccinia with the above 3 genes, while all follow-up booster vaccines are given with fowlpox vectors containing the identical transgenes. The primary endpoint is to characterize the toxicity of the regimen.

It is anticipated that a maximum of 24 patients may be enrolled onto this protocol.

Dose levels with dose escalation of MDX-010 (human anti-CTLA-4 mAb)

Genders Eligible for Study:  Male

Criteria

INCLUSION CRITERIA:

A. Histopathological documentation of prostate cancer confirmed in the Laboratory of Pathology at the: NIH Clinical Center, National Institutes of Health (NIH), the National Naval Medical Center, or Walter Reed Army Medical Center prior to starting this study. If no pathologic specimen is available, patients may enroll with a pathologist's report showing a histologic diagnosis of prostate cancer and a clinical course consistent with the disease.

B. Must have metastatic androgen insensitive prostate cancer with no bone pain requiring narcotics and have had no more than 1 regimen of chemotherapy. Patients who are chemotherapy naive either must have refused docetaxel based chemotherapy or not be a candidate for docetaxel based chemotherapy.

C. Life expectancy greater than or equal to 6 months.

D. ECOG performance status of 0-1.

E. No systemic steroid or steroid eye drop use within 2 weeks prior to initiation of experimental therapy.

F. Hematological eligibility parameters

-Granulocyte count greater than or equal to1,500/mm(3)

-Platelet count greater than or equal to100,000/mm(3)

-Hgb greater than or equal to 9 Gm/dL

-Lymphocyte count greater than or equal to 500/mm(3).

G. Biochemical eligibility parameters (within 16 days of starting therapy)

-Hepatic function: Bilirubin less than 1.5 mg/dl, AST and ALT less than 2.5 times upper limit of normal

-PT/PTT within the institution limits of normal

H. No other active malignancies within the past 12 months (with the exception of non-melanoma skin cancers or carcinoma in situ of the bladder) or life threatening illnesses.

I. Willing to travel to the NIH for follow-up visits.

J. 18 years of age or greater.

K. Vaccinia-naive or vaccinia immune.

L. Able to understand and sign informed consent.

M. Agree to use adequate contraception prior to study entry and for at least 4 months following the last vaccine injection.

N. Patients must remain on medical castration therapy, unless they have had surgical castration

O. Patients must have recovered from acute toxicities related to prior therapy or surgery. For chemotherapy typically this is 3-4 weeks.

P. Parameters for assessment of baseline renal function:

-24-hour urine collection for baseline to measure creatinine clearance, protein and electrolytes. Allowing CrCl greater than or equal to 60 (In patients who are not able to obtain an accurate collection, a calculated creatinine clearance and urine analysis will be done)

-Patients must have less than grade 2 proteinuria (unless the cause is determined not to be renal.)

EXCLUSION CRITERIA:

A. Patients should have no evidence of being immunocompromised as listed below.

-Human immunodeficiency virus positivity due to the potential for decreased tolerance and may be at risk for severe side effects.

-Hepatitis B or C positivity

-Concurrent use of topical steroids (including steroid eye drops) or systemic steroids. Nasal or inhaled steroid use is permitted

B. Patients should have no autoimmune diseases that have required treatment such as, Addison's disease, Hashimoto's thyroiditis, or systemic lupus erythematous, Sjogren syndrome, scleroderma, myasthenia gravis, Goodpasture syndrome, and active Grave's disease. Patients with a history of autoimmunity that has not required systemic immunosuppressive therapy or does not threaten vital organ function including CNS, heart, lungs, kidneys, skin, and GI tract will be allowed.

C. History of allergy or untoward reaction to prior vaccination with vaccinia virus or to any component of the vaccinia vaccine regimen.

D. Do not administer the recombinant vaccinia vaccine if the recipient, or for at least three weeks after vaccination, their close household contacts (close household contacts are those who share housing or have close physical contact) are: persons with active or a history of eczema or other eczematoid skin disorders; those with other acute, chronic or exfoliative skin conditions (e.g., atopic dermatitis, burns, impetigo, varicella zoster, severe acne, or other open rashes or wounds) until condition resolves; pregnant or nursing women; children 3 years of age and under; and immunodeficient or immunosuppressed persons (by disease or therapy), including HIV infection.

E. Serious intercurrent medical illness (e.g., one that requires treatment) which would interfere with the ability of the patient to carry out the treatment program, including, but not limited to, inflammatory bowel disease, Crohn's disease, ulcerative colitis, or active diverticulitis.

F. Patients with cardiac disease that have fatigue, palpitation, dyspnea or angina with ordinary physical activity (New York Heart Association class 2 or greater) are not eligible.

G. Patients with a history of congestive heart failure or who have objective evidence of congestive heart failure by physical exam or imaging are not eligible.

H. Patients with pulmonary disease that have fatigue or dyspnea with ordinary physical activity are not eligible.

I. Concurrent chemotherapy.

J. No brain metastasis, or with a history of seizures, encephalitis, or multiple sclerosis.

K. Serious hypersensitivity reaction to egg products.

L. Prior splenectomy.

M. Patients who have received prior MDX-01.

Please refer to this study by ClinicalTrials.gov identifier  NCT00113984

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  050167; 05-C-0167
Last Updated:  February 15, 2006
Record first received:  June 11, 2005
ClinicalTrials.gov Identifier:  NCT00113984

 

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