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Hyperplasia

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Neoplasms by Histologic Type

Genital Neoplasms, Male

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Genital Diseases, Male

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Male Urogenital Diseases

Carcinoma in Situ

Martin Schostak, PD Dr.

André Schrattenholz, Prof. Dr.

Emerging from a differential proteomic study of sample pairs of prostate cancer and benign tissue, annexin A3 (ANXA3) was chosen as a potential novel biomarker for the early and non-invasive diagnosis of prostate cancer. We wanted to show or investigate, that:

* ANXA3 can be detected in urine after standard digital rectal examination.
* ANXA3 has better specificities than tPSA, in particular in the grey zone of PSA
* ANXA3 can help avoid unnecessary biopsies
* ANXA3 can in the long run replace PSA as a marker

The aim of this multi centre and double-blinded study was to investigate specificities and sensitivities of early detection of prostate cancer with a new protein biomarker, annexin A3, using urine after digital rectal examination/massage (exprimate urine) in direct comparison to the corresponding measurements of the gold standard, total PSA. The material obtained by this non-invasive procedure was moreover used to determine appropriate cut-off values and optimal fractions (e.g. after centrifugation) and calibrations for quantitative measurements of this novel marker.

Patients (500-750) were (and are) continuously recruited from four clinical centres in Germany (Berlin, Tübingen, Ludwigshafen) and Austria (Innsbruck). The major aspect was:

• Can annexin A3 provide a better specificity than tPSA, in particular in the grey zone of PSA (2-10 ng/ml) and can annexin A3 thus contribute to a significant reduction of invasive transrectal biopsies?

Annexin A3 (ANXA3) as Protein-Based Marker for Non-Invasive Molecular Diagnostics of Prostate Carcinoma

Charite University, Berlin, Germany

University Hospital Tuebingen

Medical Centre, Ludwigshafen, Germany

Medical University Innsbruck

ProteoSys AG

Bone Density Conservation Agents

Antineoplastic Agents

All Drugs and Chemicals

Toremifene

Antineoplastic Agents, Hormonal

Estrogens

Selective Estrogen Receptor Modulators

Estrogen Receptor Modulators

Hormones

Hormone Antagonists

GTX-006 (Acapodene)

If you are a male 30 years of age or older and have a positive diagnosis of high grade (II or III) prostate Intraepithelial Neoplasia (PIN) or have had an abnormal/suspicious prostate biopsy, you may be eligible for this study. This is a study of an investigational medication that may reduce high grade PIN and prevent the occurrence of prostate cancer. This study is currently enrolling up to 500 men at approximately 60 locations in the United States.

High grade PIN is the development of precancerous, abnormal tissue of the prostate gland that puts men at high risk of developing prostate cancer. This study will take one year of participation with clinic visits every three months. There will be two prostate biopsies during the study, at six and twelve months. If qualified to participate, you will be randomly assigned to one of four treatment groups. Three out of four groups are varying doses of the study medication and the other is the placebo group (like a sugar pill).

A Chemoprevention Study of an Investigational Drug in Men With High Grade Prostate Intraepithelial Neoplasia (PIN)

Precancerous Conditions

Anticoagulants

Other Dietary Supplements

Citric Acid

Sodium Citrate

Citrate

The subject takes one dose by mouth of the 20mg Toremifine Citrate tablet once a day for the length of the trial (360 days).

The subject takes a placebo tablet identical in appearance to the toremifene 20mg tablet, administered by mouth daily for 360 days

Toremifene 20 mg

The subject takes a placebo tablet identical in appearance to the toremifene 20mg tablet, administered by mouth daily for 360 days.

Placebo

Samir Taneja, MD

The purpose of this study is to determine if toremifene citrate is effective and safe in the prevention of prostate cancer in men who have been diagnosed with high grade prostatic intraepithelial neoplasia (PIN).

The purpose of this study is to determine if toremifene citrate is effective and safe in the prevention of prostate cancer in men who have been diagnosed with high grade prostatic intraepithelial neoplasia. Men who have ever been diagnosed with high grade PIN will be enrolled into an 36 month trial and will be assigned to either 20 mg of study drug or placebo per day. Subjects will undergo safety evaluations at Month 3, Month 6, Month 12, Month 18, Month 24, Month 30 and Month 36 along with prostate biopsies at Month 12 and Month 24 and Month 36 to determine efficacy.

Prostate Cancer Prevention Study for Men With High Grade PIN (Prostatic Intraepithelial Neoplasia)

A Randomized, Double-Blind, Placebo-Controlled, Multicenter Efficacy and Safety Study of Toremifene Citrate for the Prevention of Prostate Cancer in Men With High Grade Prostatic Intraepithelial Neoplasia (PIN)

To measure the efficacy of toremifene citrate in men with high grade prostatic intraepithelial neoplasia (PIN). Prostate cancer-free survival distributions (Kaplan-Meier)

To measure the occurrence of a positive cancer biopsy

Measure lipid levels including total cholesterol, LDL, HDL and Triglycerides % change from baseline

% Change from baseline hormone levels, including total testosterone, free testosterone, dihydrotestosterone (DHT) and estradiol

To assess the effect of toremifene in the total PSA (prostate specific antigen) levels from baseline

To assess the effect of toremifene on the AUA (American Urological Association) symptom score mean change from baseline. Scores of 0-7=mild severity, 8-9, moderate, and 20-30, severe with possible responses of 0 (not at all) 1 (\<1/5), 2 (\<50% time), 3 (about 50% time), 4 (\> 50% time) \& 5 (Almost Always). There are 7 questions (1)Incomplete emptying (2)Frequency (3)Intermittency (4)Urgency (5)Weak-stream (6)Straining \& (7)Nocturia. Analysis is change from baseline at final evaluation (36 months) for quality of life due to urinary symptoms. The P Value is from a Wilcoxon signed-rank test. Scores can range from 0-35, highest representing worse symptoms

To measure the occurrence of high grade PIN at the 12, 24, 36 Month intervals in the 360 days study.

To assess the effect of toremifene in % free serum PSA (prostate specific antigen) levels, change from baseline

Toremifene 20mg

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Canada

Argentina

Region of Enrollment

Senior Director, Clinical Operations

MITT: Randomized subjects who were given study drug and did not return it unused and had a baseline and on-study prostate biopsy

Efficacy of Toremifene in the Prevention of Prostate Cancer in Men With High Grade Prostatic Intraepithelial Neoplasia (PIN)

Cholesterol

Triglycerides

All randomized subjects who take at least 1 dose of study drug

The Effect of Toremifene on Lipid Levels

Estradiol

Testosterone total

Testosterone free

Any randomized subject taking at least 1 dose of study drug

The Effect of Toremifene on Hormone Levels

The Effect of Toremifene on Total PSA (Prostate Specific Antigen) Levels

Reference to J Urol.1992 Nov;148(5):1549-57; discussion 1564. AUA symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Assocciation.

The Effect of Toremifene on the Mean Change at 36 Months in AUA (American Urological Association) Symptom Score

Determine occurrence of positive cancer biopsy

Determine occurrence of positive cancer biopsy and survival time

20 mg. Toremifene

Modified, intend-to-treat (MITT) all randomized subj. who take at least 1 dose of study drug, and had baseline and on-study prostate biopsies, where the baseline biopsy did not have cancer.

Occurrence of a Positive Cancer Biopsy

12 months

24 months

36 months

All randomized subjects that took 1 dose of study drug

Occurrence of High Grade PIN at the 12, 24, 36 Month Biopsies

The Effect of Toremifene on % Free Serum PSA (Prostate Specific Antigen) Levels, Change From Baseline

Overall Study

Dietary intervention of ITC-enriched broccoli

400g ITC-enriched broccoli per week for 12 months

Broccoli

400g frozen garden peas per week for 12 months

Peas

Richard F Mithen, PhD

This is a parallel human intervention trial to determine to what extent a dietary intervention of broccoli or peas can change the expression (switching on or off) of genes in prostate tissue in men diagnosed with high-grade Prostate Intraepithelial Neoplasia (PIN).

Cancer is one of the main causes of death among humans in the world. Prostate cancer affects 20,000 men in the UK alone each year. Diet is known to be a major factor that influences risk of cancer. Therefore, changes to the diet may alter cancer risk. Cruciferous vegetables, particularly broccoli, provide the diet with a substantial source of plant chemicals called glucosinolates. Previous research has indicated that glucosinolates break down to form isothiocyanates (ITCs) that can be absorbed in the body. Further research has indicated that ITCs may protect the body against the development of prostate cancer. However, the mechanisms behind this effect are not fully understood.

ITCs are thought to be powerful anti cancer agents as they can modulate the expression (switching on or off) of specific genes involved in the removal of toxic substances such as carcinogens from the body. In this study we wish to evaluate the effect of consumption of a conventionally bred cultivar of broccoli containing high levels of ITCs on gene expression in prostate tissue to gain a better understanding of its mechanism of action. Several studies suggest a further protection against cancer amongst individuals who have a deletion of certain genes.

This pilot study comprises a 12-month intervention of either 400g ITC-enriched broccoli per week of 400g garden peas in men at high risk of developing prostate cancer. Changes in gene expression of prostate biopsy tissue will be compared before and after 6 and 12 months of intervention in both dietary groups.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Annexin A3 (ANXA3) as Protein-Based Marker for Non-Invasive Molecular Diagnostics of Prostate Carcinoma	NCT00400894	Prostate Cancer Benign Prostati... Prostatic Intra...		-	ProteoSys AG
A Chemoprevention Study of an Investigational Drug in Men With High Grade Prostate Intraepithelial Neoplasia (PIN)	NCT00028353	Prostatic Intra...	GTX-006 (Acapod...	30 Years -	GTx
Prostate Cancer Prevention Study for Men With High Grade PIN (Prostatic Intraepithelial Neoplasia)	NCT00106691	Preneoplastic C... Prostatic Intra...	Toremifene 20 m... Placebo	30 Years -	GTx
A Chemoprevention Study of an Investigational Drug in Men With High Grade Prostate Intraepithelial Neoplasia (PIN)	NCT00028353	Prostatic Intra...	GTX-006 (Acapod...	30 Years -	GTx
Broccoli, Peas and PIN	NCT00535977	Prostatic Intra...	Broccoli Peas	30 Years - 70 Years	Quadram Institute Bioscience
Prostate Cancer Prevention Study for Men With High Grade PIN (Prostatic Intraepithelial Neoplasia)	NCT00106691	Preneoplastic C... Prostatic Intra...	Toremifene 20 m... Placebo	30 Years -	GTx

Spots Global Cancer Trial Database for prostatic intraepithelial neoplasia