A phase I dose escalation study of intravesical TMX-101 in subjects with Non-Muscle-Invasive Bladder Cancer

Imiquimod, originally discovered as an *interferon-inducing* molecule, is the
active ingredient of Aldara* a cream approved and marketed since 1996 for the
topical treatment of genital warts (induced by human papilloma virus, HPV),
basal cell carcinoma and actinic keratosis. Imiquimod is a member of the
imidazoquinoline family. The imidazoquinolines are small-molecule immune
response modulators that are agonists for TLRs 7 and/or TLRs 8. Activation of
these TLRs, which are found primarily on cells of the innate immune system
results in dendritic cell maturation, induction of multiple cytokines including
interferon-alpha (IFN-α), and in enhanced antigen presentation. These
immune-stimulating effects are considered to mediate the antiviral and
anti-tumour activities observed with these compounds, including effects on both
innate and acquired immunity. In addition, imiquimod exerts a direct
pro-apoptotic effect on tumour cells resulting in direct antitumor effects.
Treatment of skin lesions with imiquimod 5% cream in phase III randomized
placebo-controlled studies resulted in histological clearance rates between 79%
and 82%. Direct effects of imiquimod have also been reported by groups working
on melanoma, non-melanoma skin cancers and precancerous conditions.

Telormedix has developed TMX-101 as a new formulation of imiquimod for
intravesical delivery. TMX-101 has been tested as intravesical instillation in
several animal models and has been demonstrated to induce a strong
immunological activation limited to the bladder. Its systemic absorption
measured in various species is <10% of the intravesical dose. Based on existing
preclinical and clinical evidence, it is expected that TMX-101 will exert an
immunological activation and will show activity against bladder cancer lesions.

This trial will determine the safety and tolerability of escalating doses of
intravesical TMX-101 in patients with NMIBC. In addition, it will provide
preliminary evidence of activity on a *marker lesion* and thereby indicate
whether TMX-101 may potentially offer a valid alternative for the treatment of
patients with bladder cancer.

The information obtained from this trial will be essential for the future
clinical development of TMX-101 in bladder cancer.

The primary objectives are the following:
- To assess the safety profile and determine the Optimal Biological Dose (OBD)
or Maximum Tolerated Dose (MTD), whichever occurs first, of intravesically
administered TMX-101.

The secondary objectives are the following:
- To assess the pharmacokinetics of TMX-101 and its main metabolites in blood
and urine.
- To assess biological activity of TMX-101 and pharmacodynamic markers in
urine, in blood and in pre/post dosing tumour biopsies.
- To assess the anti-tumour activity of TMX-101 on a marker lesion after 2
cycles (6 intravesical administrations) in a selected group of patients.
- To describe the relations between tumour characteristics (e.g. tumour
immunohistochemistry) and biological activity.
- To assess the disease recurrence and progression to muscle invasive disease
within 1 year.

This is an open-label Phase I dose escalation trial that will follow a standard
escalation design with cohorts of three patients per dose level. TMX-101 will
be given in cycles of once a week for three weeks.
The study will consist of three parts. Part 1: initial safety assessment in
patients with complete TUR, Part 2: assessment of OBD in patients with a marker
lesion and Part 3: follow-up phase.
During Part 1 the doses will be escalated by doubling (100% increments). In
Part 2 doses will be escalated by reduced increments of approximately 50%. If
significant toxicity is observed the escalation will continue at decreasing
rates (Fibonacci - like scheme) from when the first sign of significant
toxicity is observed.
During Part 1 the safety of one cycle of TMX-101 will be tested in patients
with non-muscle-invasive bladder cancer who have undergone a complete
transurethral resection (TUR). These patients will receive a second cycle of
TMX-101 therapy if no toxicity or disease progression is observed. Safety data
of all subjects that have completed the first cycle of a dosing cohort will be
reviewed to determine the next dose level.
During Part 2 the OBD and its safety will be determined in a two-cycle therapy
in patients who have one marker lesion remaining after TUR, starting with the
highest tested dose level that will have been confirmed to be safe in the
patients in Part 1.
During Part 3 all patients (enrolled in Part 1 and Part 2) will be followed to
assess if they experience a recurrence or progression within the first year.
During this study patients will be treated in cohorts of three per dose level
until the Optimal Biological Dose (OBD) or Maximum Tolerated Dose (MTD) is
reached, whichever occurs first. The number of patients will increase to six in
those cohorts where one out of three patients develops Dose Limited Toxicity
(DLT). The safety of the OBD will be confirmed in at least 6 patients who have
received two cycles of TMX-101 therapy.
To ensure safety each dose level will start with one patient receiving a cycle
of TMX-101. The other two patients from the same cohort will start the therapy
not less than one week later as long as no serious toxicity is observed in the
first patient after the first instillation. If none of the three patients
develops DLT the dose will be escalated. If two or more patients experience DLT
further dosing at that dose level will stop and the dose level immediately
below will be considered to be the MTD. Should only one out of three patients
at the same dose level experience DLT, the number of patients treated at this
dose level will be expanded to six. Provided none of the additional three
patients experiences DLT, the dose will be escalated further; otherwise the
escalation will stop and the dose immediately below will be deemed to be the
MTD. Alternatively dose de-escalation will be considered.
• DLT is defined as any of the following toxicities occurred during the first
cycle at any dose level which the investigator and/or the sponsor judge to be
related to the trial medication.
o Any grade 3 or higher toxicity.
o Any treatment delay >= 21 days due to drug-related adverse events.
• The OBD is defined as Complete Response (CR) (total disappearance of a marker
lesion and the absence of new tumours at other sites), as observed in at least
three patients. As these patients can be from the different dose levels, the
OBD will be considered to be at the highest dose level at which these
activities are observed.
• The MTD is defined as the highest dose level at which less than 33% of
patients experience DLT (assessed by CTCAE version 4.02) during the first cycle
of therapy.
There will be no within-patient dose escalation.
It is planned to have more than one centre involved during the escalation
phase. Escalation to a further dose level will occur only after a comprehensive
analysis of safety data of each cohort by all investigators and the sponsor
during a planned teleconference.
During the escalation phase the patients will visit the centre every week for a
clinical examination and adverse events (AEs) and laboratory screens will be
assessed at each visit. Tumour measurements will be made 2-4 weeks after the
end of the two cycles.
Tumour measurements will be made by an endoscopic evaluation (cystoscopy) that
includes complete bladder cavity assessment.
A 6-hour pharmacokinetic profile of TMX-101 will be assessed in all patients
during the dose escalation phase.
Subjects will be monitored carefully for the development of Adverse Events
(AE).
In patients eligible for the OBD assessment, the bladder will be mapped to
assess the marker lesion 2-4 weeks after the end of the treatment (total of 6
instillations) and, if the marker lesion is still present, it will be resected
by TUR.
AEs will be evaluated according to CTCAE, version 4.02.

Each subject will receive a first cycle of TMX-101 comprising of one dose given
once a week for three consecutive weeks. After the end of the first cycle (day
0 to day 21) if no serious toxicity is noted, the subject will receive, without
interruption, one more cycle of the TMX-101 therapy at the same dose level for
a total of 6 weekly instillations (from day 0 to day 35).

TMX-101 will be administered intravesically by gravity through a Foley
Catheter-12 French. The retention time will be 1 hour.
Instillations will be started at earliest 14 days and at the latest 21 days
after the TUR.

There are risks to taking part in any research study and not all of the risks
of TMX-101 are known at this time since to date, no subjects with bladder
cancer have received TMX-101. One risk is that there may be unwanted side
effects. Another risk is that you may obtain a dose of a drug that does not
help to treat your disease.

All drugs currently used for treatment of superficial bladder cancer have side
effects, which can range from mild and reversible to severe. Local side effects
due to the use of TMX-101 might be similar to those reported with other
intravesical treatments and might be:
• Painful urination, irritative bladder symtoms and involuntary contraction of
the bladder (spasm). These side-effects usually occur within 24 hours after
intravesical instillations and they do resolve spontaneously.
• Presence of blood in the urine.
• Urinating more often than usual, an urgent feeling of having to urinate and
general discomfort felt in the bladder.
• Urinary tract infection (bacterial cystitis)

The active molecule contained in this investigational product is imiquimod, the
active ingredient of Aldara®, a cream on the market since 1997. Many subjects
have been treated to date with imiquimod not only applied to the skin as a
cream, but also given by injection under the skin and injected into the blood.
The following side effects that occur with imiquimod may also occur with
TMX-101:
• Flu-like symptoms: fever, chills, fatigue, muscle aches (myalgia).
• Fatigue, weakness.
• Loss of appetite.
• Upset stomach, nausea (feeling sick to your stomach).
• Headache.
• In some individuals that were treated with Aldara® a lowering of blood cells
counts was noted. A lowering of blood counts might make you more susceptible to
infections, make you bruise more easily or cause fatigue.
• In some individuals treated with Aldara® elevated liver enzymes were
observed. Elevated liver enzymes can be a sign of a liver disorder.

Further information can be found in the Aldara® patient information sheet that
can be supplied to you by your doctor or medical staff.

In animal studies with TMX-101, effects on the Central Nervous System (such as
seizures) were observed at doses largely above the doses used in this study. In
the unlikely case of overdose, you will be monitored for any sign and symptoms
on the Central Nervous System.

The main, but rare, risks associated with surgery (transurethral resection)
are: bleeding, bladder infection (cystitis), perforation of the wall of the
bladder, blood in the urine, blockage of the urethra (water pipe) by blood
clots in the bladder. Further information about this surgery will be provided
by your study doctor.

The main risks associated with biopsies may include: pain and discomfort, minor
bleeding, tenderness at the biopsy site, scarring at the biopsy site and rarely
infection.
Biopsies are performed under the guidance of an imaging technique. Further
information about biopsy will be provided by your study doctor.

Another risk might be some trauma related to bladder catheterisation. This is
unlikely to occur, but in such a case TMX-101 will not be administered and
there will be a treatment delay of at least 10 days.

The main risk associated with withdrawal of blood (injection under the skin) is
discomfort and bruising at the site of puncture.