Trial Information

Intermittent Hormonal Therapy With Leuproreline (3.75 mg SR) and Flutamide in the Treatment of Stage D2 or Tx Nx M1 Different From M1a

The primary objective of this study is to:Compare median overall survival, compare median
progression-free survival.

Secondary objectives of this study are to: Assess overall quality of life (evaluated through
a questionnaire), Assess subjective clinical efficacy,Assess tolerance to treatment.

These three secondary criteria will be studied separately for each group, and comparisons
will also be made between groups.

This is an open, comparative, randomized (1/1), multicentre European (France, Germany, Czech
Republic, Slovakia and Bulgaria) study on parallel groups of patients presenting with
metastatic prostrate cancer (stage D2 or Tx Nx M1 ≠ M1a), with a PSA level ≥ 5-fold higher
than normal (i.e. PSA ≥ 20 ng/ml, as quantitated by the Hybritech radioimmunoassay) which
return to normal within 6 months after the initiation of total androgen blockade therapy
with Leuprorelin 3,75 mg LP and Flutamide. It will involve 300 preselected patients at
least.

A minimum of 180 eligible patients is required for this study. Selected patients will be
randomized centrally in two parallel groups at study entry.

This phase IIB study will enable evaluation of a high number of patients by direct
comparison with conventional administration. Intermediate analyses will still be carried out
at 3-month intervals to compare the number of hormonal escapes occurring in both groups. The
study will be interrupted if differences of greater than 2 SD are noted. These analysis will
be stopped after 5 years if no significant difference appeared

The study comprises two therapeutic phases:

A 6 month induction phase with complete androgen suppression. This phase involves patients
meeting the preselection criteria.

A data processing run per complete androgen suppression according to two methods, continuous
or intermittent, for the patients satisfying the criteria of selection of the study and
which will thus be randomized

The selected patients will be randomized centrally (randomization balanced by country in
blocks of 2) in two parallel groups at the time of inclusion (60 patients to be included in
each country, 3 per center):

Group A patients will receive a continuous complete androgen suppression therapy by
leuproreline 3.75mg SR (1 subcutaneous injection each 28 days) and flutamide (1 tablet, 3
times per day), until the appearance of signs of disease progression or study end.

Group B patients will receive an intermittent complete androgen suppression therapy by
leuproreline 3.75 mg SR (1 subcutaneous injection each 28 days) and flutamide (1 tablet, 3
times per day), until the study end or the appearance of signs of disease progression under
treatment, according to the following process:

Interruption of treatment at study entry

Reinstitution of treatment as soon as:

PSA ≥ 10ng/ml (normal < 4ng/ml; Hybritech radioimmunoassay) and/or Other signs of
progression

Interruption of treatment when:

PSA < normal (PSA < 4 ng/ml; Hybitech radioimmunoassay); assay performed at consultation
(even if PSA returns to normal between 3-month visits) and There is no other diasease
progression (PSA is quantitated monthly using the Hybitech EIA technique: normal < 4 ng/ml)
Group A patients will be routinely followed-up on a 3-month basis until there are signs of
disease progression. During these visits, patients will be assessed with respect to quality
of life status, ECOG performance status, signs and symptoms, and tolerance to treatment.
Laboratory blood tests will also be performed before each visit to assay red and white blood
cells, platelets, transaminases, γ-GT, bilirubin, PSA, and testosterone.

Group B patients (intermittent therapy) are monitored every 3 months during on-treatment
periods under the same conditions as described for group A.

The 3-month clinical follow-up is the same during off-treatment periods, but if PSA
increases to ≥ 10 ng/ml the patient must be contacted to schedule a prompt special visit in
order to reinstitute hormonal therapy. Subsequent visits will be scheduled on a 3-month
basis from the time of the special visit. Special visits will be the same as routine
consultations, except that the laboratory tests will not be redone.

When on-therapy tumor progression has been documented, every 6 months the investigators will
note all treatments administered to patients until death (while specifying the cause of
death).