A European randomised Phase 3 study to assess the efficacy and safety of TOOKAD® Soluble for localised prostate cancer compared to Active Surveillance

In the year 2006, 300 000 men were diagnosed with prostate cancer in the
European community, where prostate cancer was the most commonly diagnosed
cancer in men, and the third commonest cause of cancer related death. Prostate
cancer is the second most common cause of cancer related death in the US, where
it accounts for 3% of all male deaths and is currently the leading type of
cancer in men, representing one third of incident cancer cases. In 2009, an
estimated 192 000 new cases were diagnosed and 27 000 men died of prostate
cancer in the US. Among patients diagnosed with prostate cancer, 46%- are
reported as being at low risk, 30% at moderate risk and 24%% at high risk
according to the D*Amico classification.3,4 The widespread use of PSA screening
in the clinical practice, including primary care, led to an increased
proportion of disease being diagnosed at early, low risk stages, resulting in a
very high societal burden.

Conventional radical therapies comprise radical surgery and radiation therapies
(brachytherapy, external beam radiation). Cryotherapy is also offered in
certain centres, as well as high intensity focused ultrasound (HIFU). The
efficiency of radical therapy in low risk prostate cancer is not documented.
Evidence of the efficacy of radical treatments may be inferred from randomised
controlled trials assessing the role of PSA screening (where men with prostate
cancer were most commonly treated with radical therapies). The US trial has
shown no difference in prostate cancer related mortality between PSA screening
and the control group over a period of 7 years. This study has been criticised
for having a high degree of contamination in the control group (many entered
the trial already having had a PSA test). The European Screening trial has
shown that screening does reduce the cancer-specific mortality over a period of
10 years. According to the European trial, 1410 men would need to be screened,
48 diagnosed and treated (with radical therapy mainly) for cancer in order so
one man*s life could be saved. However, it has been suggested that these
studies may have underestimated the baseline risk of mortality. Significant
rates of positive margins may be found after either surgery or positive
biopsies after radiation therapy.
The main problem with radical therapies is safety. Despite technological
refinements in radiation therapy (brachytherapy, intensity modulated radiation
therapy -IMRT-, and proton therapy as alternatives to external beam radiation)
and surgery (laparoscopic and robotic surgery as alternatives to radical
prostatectomies), radical whole-gland therapies cause erectile dysfunction in
30-70%, incontinence (requiring pad usage) in 5-10%, and rectal symptoms
(diarrhoea, bleeding, proctitis) in 5-20% of treated patients. This occurs
because all radical therapies treat the whole prostate regardless of the cancer
volume within the prostate and thus, structures that are in close proximity to
the prostate (neurovascular bundles, urinary sphincter, bladder neck and
rectum) get damaged.

The currently accepted alternative to radical therapies is active surveillance.
This primary management strategy involves 2 to 3 monthly PSA testing, clinical
examination, and 1 to 2 yearly repetition of transrectal ultrasound (TRUS)
guided biopsies to ensure that were progression was to occur, it would be
detected early and curative therapy instituted if appropriate.

Although prostate cancer is one of the rare cancers to benefit from the
existence of an easily applicable tool for early diagnosis, i.e. PSA testing,
most countries avoid recommending general or systematic screening fearing the
consequences of more radical therapies that may follow, notably side effects.
This represents a loss of opportunity for patients who are not tested and may
benefit from earlier diagnosis (a significant fraction of cancers are diagnosed
at actual moderate to high risk, and prostate cancer is still one of the
leading causes of death).

Focal therapy may offer a middle ground between radical therapy and active
surveillance, the two available extremes of care. Focal therapy proposes to
treat prostate cancer with a similar approach as other solid organ
malignancies. That is, treatment is directed to the area of cancer and nearby
normal tissue in order to preserve tissue and, as a consequence, organ
function. By avoiding damage to the whole prostate, damage to the nerves,
muscle, urinary sphincter, bladder and rectum can be avoided.

Primary Objective:
To assess the impact of TOOKAD® Soluble VTP on the rate of absence of definite
cancer using patients on
active surveillance as a comparison (co-primary objective A).

To determine the difference in risk of treatment failure associated with
observed histological progression of
disease in men with low risk prostate cancer who undergo TOOKAD® Soluble VTP
compared to men on active
surveillance (co-primary objective B).


Secondary endpoints:
To determine the differences between men who undergo TOOKAD® Soluble VTP and
men on active
surveillance with regard to:
• the rate of additional prostate cancer radical therapy
• the total cancer burden in the prostate
• the rate of adverse events
• the rate of incontinence, erectile dysfunction, urinary symptoms
• the rate of severe prostate cancer related events: cancer extension to T3,
metastasis and prostate cancer related
death.
The overall quality of life will be recorded for potential utility and
descriptive studies.

The study is designed as a phase III randomised controlled open label trial.
Men with low risk prostate cancer will be randomised to active surveillance or
TOOKAD® Soluble VTP. Men in the VTP arm will then undergo multiparametric MRI
for morphometric description of prostate followed by transrectal
ultrasound-guided biopsy (from 10 to 24 cores), to allow accurate treatment
planning prior to the VTP procedure. Each group will be followed-up with PSA
testing, clinical evaluation and patient reported questionnaires on a 3 monthly
basis. In addition, each group will have multiparametric MRI followed by
transrectal ultrasound-guided prostate biopsy at 12 and 24 months after
randomisation to active surveillance or TOOKAD® Soluble VTP.

In order to activate the treatment, patients must undergo Vascular Targeted
Photodynamic therapy (VTP). Subjects will be placed in the lithotomy position
and will remain in this position throughout the procedure. A Foley catheter is
placed in the bladder prior to the procedure, and removed at least 6 hours
after the procedure. Transrectal ultrasound is used to view the prostate and
the implant catheters. A transperineal template is used to guide the placement
of the flexible hollow implant catheters into the prostate. These have a metal
trocar to aid insertion. This procedure is similar to that used routinely for
high dose rate (HDR) brachytherapy of prostate cancer.

Following satisfactory positioning of the implant catheter the metal trocar is
removed and replaced with a cylindrically diffusing optical fibre.

WST11 will be delivered in glass vials which must be reconstituted in a 5%
glucose solution for injection prior to being injected. This will be injected
intravenously during the VTP procedure. The dosing will be 4mg/kg body weight
and treatment will consist of one injection.

For those patients randomised to VTP:
The risks related to the general anaesthetic are the same as with any such
procedure. These may include nausea on waking up, transient soreness in the
throat (from the tube used to maintain your breathing) and some loss of
concentration for the first few hours after waking up. Serious complications of
anaesthesia for this sort of procedure are extremely rare.

There are some other risks related to the drug itself, which are outlined
below. You must be aware that both the study drug and the device that is used
to activate it (laser) are experimental. Therefore possibility of unknown risks
exists in this study as in all other research studies. This procedure may have
effects that no one knows about.

For those patients randomised to Active Surveillance:
As the tumour will remain untreated, it can progress in size and
aggressiveness. This risk is considered as low and you will be closely
followed-up (every three month) to ensure that, should such a progression
occur, it would be detected early and curative therapy could be instituted if
appropriate.

For all patients:
There is a small risk of infection or bleeding when needles are inserted into
the prostate to take a small piece of tissue for examination under the
microscope (biopsy).
Some patients find magnetic resonance imaging (MRI) claustrophobic as it is
necessary to slide your pelvis into a large machine and the machine can be
rather noisy during the imaging. Making it possible to listen to pleasant music
during the procedure helps the latter.

The research may involve unforseeable risks to unborn children.

The risk profile attributed to WST11 is favourable compared with alternative
therapies.