Clinical trial NCT00223665: Effects of IAS in Men With Localized Biochemical Relapsed Prostate Cancer
Official title: A Prospective Study of Intermittent Androgen Suppression (IAS) in Men With Localized Prostate Cancer Who Have Biochemical Relapse After Radiation Therapy or Radical Prostatectomy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Prostate Cancer
Keywords: Intermittent Hormone Therapy
Intermittent Androgen Suppression
Biochemical Relapsed Prostate Cancer
Androgen Deprivation Therapy
Localized Prostate Cancer
Lead sponsor: University of Washington
Sponsor class: OTHER
Collaborators: name: Sanofi
First posted: 2005-09-22
Enrollment: 102
Sex: MALE
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: All subjects underwent androgen suppression with a two-week lead-in of Flutamide, followed by 9 monthly injections of Leuprolide Acetate. If PSA reached the appropriate nadir at by month 9, the androgen suppression was interrupted. Once the PSA reached the appropriate threshold, the subjects resumed treatment for another 9 months. These cycle continued until the patient withdrew from the study, was taken off the study due to toxicities or the decision of the investigator, or until the treatment with IAS was no longer effective in controlling the prostate cancer.
Primary purpose: TREATMENT

Brief summary: This study was a prospective analysis in men with localized prostate cancer who had rising Prostate Specific Antigen (PSA) levels after definitive treatment with surgery or radiation. Patients received Intermittent Androgen Suppression (IAS) in 9 month cycles until they became metastatic, became castrate resistant, or withdrew from the study. Subjects were monitored for time to development of Castration Resistant Prostate Cancer (CRPC) and overall survival. They were also monitored for the impact of IAS on a variety of neuro-psychiatric assessments and on bone density.

Detailed description: The standard first line treatment for men with early stage newly diagnosed localized prostate cancer is a surgical removal of the prostate, localized external beam radiation, brachytherapy, or a combination of surgery and radiation. In most patients Prostate Specific Antigen (PSA) levels will decline after these localized treatments, demonstrating a response to these therapies. However despite an initial response to localized treatment, some men will go on to later develop a rise in PSA levels, an indicator of Biochemical Relapsed Prostate Cancer (BRPC). For BRPC patients who have not yet developed metastasis, the standard treatment is Androgen Deprivation Therapy (ADT) to decrease levels of Testosterone, subsequently decreasing PSA levels. A low value for the PSA is more desirable as it may indicate no tumor growth.

ADT may be administered as a continuous treatment (Continuous Androgen Suppression, or CAS) or as intermittent treatment (Intermittent Androgen Suppression, or IAS). This treatment is continued until the development of Castration Resistant Prostate Cancer (CRPC), indicated by a rise in PSA despite ADT. Giving the hormone therapy intermittently (in cycles of treatment and off treatment periods) appears to delay the change of prostate cancer to a type of prostate cancer that resists hormone therapy, prolonging efficacy of ADT monotherapy. IAS may also decrease the impact of ADT on mental status.

This study evaluated the effect of intermittent androgen suppression on time to androgen independent progression (the development of castration resistant disease) and overall survival in men with localized prostate cancer. Subjects were also evaluated for the effects of intermittent androgen suppression on a variety of neuro-psychiatric assessments and on bone density.

The subjects in this study had a rising PSA value after definitive therapy either with radical prostatectomy or external beam irradiation for the treatment of prostate cancer. All subjects were males at or over the age of 21 years.

New subjects were introduced to this study protocol (along with other non-study treatment options) during a clinic visit with Dr. Higano or another sub-investigator. After informed consent was obtained, subjects underwent the following screening procedures before starting treatment: Bone density scan (DEXA), Technetium-99 bone scan, CT scan of the chest, abdomen, and pelvis, blood draw, and neuro-psychiatric assessments. Subjects then began androgen suppression with a two-week lead-in of Flutamide, followed by 9 monthly injections of Leuprolide Acetate. During the treatment, they had quarterly clinic visits and blood draws. Their PSA levels were monitored monthly, and if their PSA reached the appropriate nadir at by month 9, the androgen suppression was interrupted. At the end of each treatment cycle, subjects underwent another bone density test, blood draw, problem solving test, and neuro-psychiatric assessments.

During the "off treatment" phase, the subject will again had quarterly clinic visits, blood draws, and neuro-psychiatric assessments. PSA and testosterone were be monitored monthly. Once the PSA reached the appropriate threshold, the subject performed another set of screening procedures and resumed treatment for another 9 months. This cycle continued until the patient withdrew from the study, was taken off the study due to toxicities or the decision of the investigator, or until the treatment with IAS was no longer effective in controlling the prostate cancer. The neuro-psychiatric assessments were only performed during the subject's first cycle of treatment (consisting of the 9 months on treatment, and at month 3 of the off treatment period afterwards).

Eligibility criteria: Inclusion Criteria:

* Biochemical relapse (rising PSA) after initial treatment (radiation therapy, brachytherapy, or radical prostatectomy) for histologically or cytologically confirmed adenocarcinoma of the prostate
* Clinical stage A2, B, C, D1
* Age: older than 21 years old
* Performance status of 0 or 1
* Pretreatment serum testosterone, normal range (or no clinical evidence of testosterone deficiency).
* If less than 30 months since completion of radiation therapy, biopsy of prostate suggested within 6 months of study entry. If more than or equal to 30 months since completion of radiation therapy, biopsy of prostate suggested within 1 year.
* Written informed consent.

Exclusion Criteria:

* Abnormal bone scan suggestive of metastatic osseous disease.
* Previous hormonal manipulation including orchiectomy or any medication with significant antiandrogenic activity (combined androgen suppression over 9 months, monotherapy antiandrogens, estrogens, ketoconazole). \*Neoadjuvant androgen suppression therapy of less than or equal to 3 months is allowed, if this androgen suppression therapy was completed more than or equal to 1 year prior to study enrollment AND if the Testosterone level is within the normal ranges.
* Any systemic chemotherapy or curative radiotherapy within 6 months.
* Hepatic dysfunction:

  * Total bilirubin greater than 2.0 mg/dl
  * Aspartate transaminase (AST; SGOT) greater than 3 times the upper limit of normal range
  * Lactate dehydrogenase (LDH) greater than 3 times the upper limit of normal range).
* Renal dysfunction:

  * Blood urea nitrogen (BUN) greater than 40 mg/dl
  * Serum Creatinine greater than 2.0 mg/dl.
* History or presence of other malignancy within the last 5 years (except treated squamous/basal cell carcinoma of the skin or superficial bladder carcinoma).
* Hypersensitivity to flutamide or leuprolide.

Primary outcomes:
measure: Time to Androgen Independence of Serum Prostate-Specific Antigen (PSA)
timeFrame: From date of first treatment until the date of development of CR, metastatic progression, or study withdrawal, whichever came first, assessed up to 16 years.
measure: Effect of IAS on Overall Survival.
timeFrame: From date of first treatment until the date of death or study withdrawal, whichever came first, assessed up to 16 years.
Secondary outcomes:
measure: Change in Standardized Bone Mineral Density (BMD) of the Spine During IAS
timeFrame: From screening prior to first dose of ADT through the start of the second cycle of ADT.
measure: Change in Standardized Bone Mineral Density (BMD) of the Left Hip During IAS
timeFrame: From screening prior to first dose of ADT through the start of the second cycle of ADT.
measure: Development of Osteopenia (Bone Loss) During IAS
timeFrame: From screening prior to first dose of ADT through the start of the second cycle of ADT.
measure: Testosterone Levels During IAS
timeFrame: Baseline, Month 3, Month 9, and Month 12
measure: Estradiol Levels During First Cycle of IAS
timeFrame: Baseline, Month 3, Month 9, and Month 12
measure: Score on Spatial Ability Test (Block Design) During First Cycle of IAS
timeFrame: Baseline, Month 3, Month 9, and Month 12
measure: Score on Spatial Ability Test (Mental Rotation) During First Cycle of IAS
timeFrame: Baseline, Month 3, Month 9, and Month 12
measure: Score on Executive Function Testing (Stroop Task) During First Cycle of IAS
timeFrame: Baseline, Month 3, Month 9, and Month 12
measure: Score on Verbal Memory Testing (Proactive Interference) During First Cycle of IAS
timeFrame: Baseline, Month 3, Month 9, and Month 12
measure: Score on Visual Working Memory Test During First Cycle of IAS
timeFrame: Baseline, Month 3, Month 9, and Month 12
measure: Score on Verbal Memory Testing (Story Recall) During First Cycle of IAS
timeFrame: Baseline, Month 3, Month 9, and Month 12
measure: Score on Spatial Memory Testing During First Cycle of IAS
timeFrame: Baseline, Month 3, Month 9, and Month 12
measure: Score on Verbal Ability/Fluency Testing During First Cycle of IAS
timeFrame: Baseline, Month 3, Month 9, and Month 12
Other outcomes:
Locations:
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
Study officials:
affiliation: University of Washington
name: Celestia Higano, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kuo KF, Hunter-Merrill R, Gulati R, Hall SP, Gambol TE, Higano CS, Yu EY. Relationships between times to testosterone and prostate-specific antigen rises during the first off-treatment interval of intermittent androgen deprivation are prognostic for castration resistance in men with nonmetastatic prostate cancer. Clin Genitourin Cancer. 2015 Feb;13(1):10-6. doi: 10.1016/j.clgc.2014.08.003. Epub 2014 Aug 10.