Effects of IAS in Men With Localized Biochemical Relapsed Prostate Cancer

NCT ID: NCT00223665

Last Updated: 2018-08-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 102 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 1997-01-08
• Study Completion Date: 2012-09-06

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).

Conditions

Prostate Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Intermittent Androgen Suppression (IAS)

Intermittent Androgen Suppression in 9 month cycles with a combination of a two-week lead-in of Flutamide, followed by 9 monthly injections of Leuprolide Acetate.

Flutamide dosed as 250mg orally three times a day for 14 days prior to the initiation of Leuprolide Acetate.

Leuprolide Acetate dosed as 7.5mg intramuscular (IM) injections once per month for a total of 9 months.

Group Type: EXPERIMENTAL

Flutamide

Intervention Type: DRUG

Flutamide dosed at 250mg orally three times a day for 14 days prior to the initiation of Leuprolide Acetate.

Leuprolide Acetate

Intervention Type: DRUG

Leuprolide Acetate dosed at 7.5mg intramuscular (IM) injections once per month for a total of 9 months.

Interventions

Flutamide

Flutamide dosed at 250mg orally three times a day for 14 days prior to the initiation of Leuprolide Acetate.

Intervention Type: DRUG

Leuprolide Acetate

Leuprolide Acetate dosed at 7.5mg intramuscular (IM) injections once per month for a total of 9 months.

Intervention Type: DRUG

Other Intervention Names

Eulexin; Lupron Depot; Eligard; Lupron

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.

• Minimum Eligible Age: 21 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Sanofi

INDUSTRY

Sponsor Role: collaborator

University of Washington

OTHER

Sponsor Role: lead

Responsible Party

Celestia Higano

Professor, Medicine, Division of Oncology & Urology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Celestia Higano, MD

Role: PRINCIPAL_INVESTIGATOR

University of Washington

Locations

Seattle Cancer Care Alliance

Seattle, Washington, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 25242417 (View on PubMed)

Other Identifiers

973730AC06

Identifier Type: OTHER

Identifier Source: secondary_id

HSD 30296

Identifier Type: OTHER

Identifier Source: secondary_id

30296

Identifier Type: -

Identifier Source: org_study_id