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A Randomized Phase II Trial Combining Vaccine Therapy With PROSTVAC/TRICOM and Flutamide vs. Flutamide Alone in Men With Androgen Insensitive, Non-Metastatic (D0.5) Prostate Cancer


Phase 2
18 Years
N/A
Open (Enrolling)
Male
Prostate Cancer

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Trial Information

A Randomized Phase II Trial Combining Vaccine Therapy With PROSTVAC/TRICOM and Flutamide vs. Flutamide Alone in Men With Androgen Insensitive, Non-Metastatic (D0.5) Prostate Cancer


Background:

- There is no standard of care for prostate cancer patients progressing on hormone
therapy with a rising serum PSA level without evidence of metastatic disease.

- We have completed a phase II trial in which men with this stage of disease were
randomized to receive a pox vector PSA vaccine vs. the antiandrogen nilutamide.

- The median time to treatment failure on nilutamide was 7.6 months.

- 12 patients on the vaccine arm had nilutamide added at the time of PSA progression.

- The median time for treatment failure after the addition of nilutamide was 13.9 months,
for a total of 25.9 months from initiation of vaccine therapy.

- This suggests that the combination of hormone therapy with vaccine therapy may lead to
an improved clinical benefit compared to hormone therapy alone.

- Due to the increased toxicity of nilutamide compared to other antiandrogens and the
patients prior exposure to bicalutamide therapy, we plan to use flutamide as a second
line hormonal manipulation in the below study.

Objectives:

- To determine if use of a combination of vaccine plus flutamide may be associated with a
trend toward improvement in time to treatment failure compared to flutamide alone.

- To determine preliminary evidence of any patterns of immunologic effects which differ
by treatment including the immunologic effects of flutmaide withdrawal on patients
continuing on vaccine following a rising PSA on flutamide.

Eligibility:

- Must have non metastatic androgen insensitive prostate cancer with a rising PSA with
castrate levels of testosterone and no evidence of metastatic disease on CT scan or
bone scan.

- Hgb greater than or equal to 9 g/dL.

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

- Hepatic function: Bilirubin less than or equal to 1.5 mg/dL, OR patients with Gilbert's
syndrome, a total bilirubin less than or equal to 3.0 mg/dL, AST and ALT less than 2.5
times upper limit of normal

Design:

-Flutamide will be administered at a dose of 250 mg PO tid every day in both arms A and B.

rV-PSATRICOM will be administered s.c. on day 1 in Arm B.

rF-PSATRICOM will be administered s.c. on day 29 & every 4 weeks in Arm B.

- Sargramostim 100 microg s.c. will be given at the vaccine site for 4 consecutive days
starting on day 1 of each vaccine only for patients enrolled at the NCI site.

- For patients with declining PSA no restaging will be done unless they develop symptoms
consistent with metastatic disease.

- For patients with rising PSA, once 2 consecutive PSA rises are seen, a CT will be done
at their next scheduled visit. They will then be re-staged (CT and bone scans) at 3
month intervals as long as PSA continues to rise.

- After 3 months of therapy, patients receiving the flutamide alone (arm A) may cross
over to receive vaccine if they develop a rising PSA and scans are without metastatic
disease. The vaccine may commence 4 weeks after flutamide is stopped if the PSA
continues to rise. If there is an antiandrogen withdrawal response (a decline in PSA
28 days after the discontinuation of flutamide), PSA serum levels will be checked every
28 days and vaccine may commence when the serum PSA levels begin to rise (if scans are
negative for metastatsis). Patients on arm B will have flutamide discontinued and may
continue vaccine therapy. At this point patients may continue to receive treatment on
study until the development of disease on scans or a second occurrence of clinical
progression.

Inclusion Criteria


- INCLUSION CRITERIA:

A. Histopathological documentation of prostate cancer confirmed in the Laboratory of
Pathology at the: NIH Clinical 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 non-metastatic androgen insensitive prostate cancer with a rising PSA with
castrate levels of testosterone and no evidence of metastatic disease on CT scan or bone
scan. A rising PSA is defined as two consecutively rising PSA levels, separated by at
least 1 month apart, with the last measurement that is greater than 1ng/ml. Patients on
nilutamide therapy must undergo nilutamide withdrawal for at least 4 weeks and still show
evidence of a rising PSA. Following treatment with bicalutamide, patients must undergo
withdrawal for at least 6 weeks and still show evidence of a rising PSA.

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 to 1,500/mm(3).

- Platelet count greater than or equal to 100,000/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 or equal to 1.5 mg/dl, OR patients with Gilbert's
syndrome, a total bilirubin less than or equal to 3.0 mg/dL, AST and ALT less than 2.5
times upper limit of normal

H. No other active malignancies within the past 3 years (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. Able to understand and sign informed consent.

L. Must agree to use effective birth control (such as a condom) or abstinence during and
for a period of 4 months after the last vaccination therapy. Patients must be willing to
remain on chemical castration therapy, unless they have had surgical castration.

M. Patients must have recovered from acute toxicities related to prior therapy or surgery.

N. Parameters for assessment of baseline renal function:

Serum creatinine less than or equal to 1.5 times the upper limit of normal OR creatinine
clearance on a 24-h urine collection of greater than or equal to 60 mL/min.

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.

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

- Patients who have undergone allogenic peripheral stem cell transplantation or solid
organ transplantation requiring immunosuppression.

B. Patients who test positive for active Hepatitis B or Hepatitis C infection.

C. 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, active Grave's disease.

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

E. 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.

F. 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.

G. 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.

H. 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.

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

J. Concurrent chemotherapy.

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

L. Patients with a serious hypersensitivity reaction to egg products are not eligible.

M. Prior splenectomy.

N. Patients who have received prior flutamide therapy in the last year. (Patients treated
with flutamide in the neoadjuvant or adjuvant setting or those previously treated with
flutamide who did not have a rising PSA on treatment would be allowed to enroll on the
protocol.)

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Time to treatment failure

Safety Issue:

No

Principal Investigator

Ravi A Madan, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

070107

NCT ID:

NCT00450463

Start Date:

February 2007

Completion Date:

April 2014

Related Keywords:

  • Prostate Cancer
  • Immunotherapy
  • Hormonal Therapy
  • Combination Therapy
  • Prostate Specific Antigen
  • Immunoassay
  • Prostate Cancer
  • Prostatic Neoplasms

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892
Cancer Institute of New JerseyNew Brunswick, New Jersey  08901