A phase 3, randomized, double-blind trial of nivolumab in combination with intravesical BCG versus standard of care BCG alone in participants with high-risk non-muscle invasive bladder cancer that is persistent or recurrent after treatment with BCG

Bladder cancer is the ninth most common cancer worldwide.
Approximately 75% to 80% of all bladder cancers present as superficial,
non-muscle-invasive disease, while the remaining 20% to 25% are muscle-invasive
or metastatic at the time of presentation. Initial treatment for patients with
non-muscle invasive bladder cancer (NMIBC) includes transurethral resection of
the bladder tumour (TURBT). During this procedure the surgeon removes the
tumour in the bladder through the urethra. The urethra is the tube that carries
urine from the bladder to the outside of the body.
Intravesical BCG has become the standard of care (SOC) as adjuvant treatment
for patients with high-risk NMIBC after TURBT. With intravesical therapy, the
doctor puts the liquid drug (in this case, BCG) right into the bladder rather
than giving it by mouth or injecting it into the blood. Despite the recognized
benefit of BCG treatment in this patient population, tumour recurrence (when
the cancer comes back) and progression (when the cancer gets worse) within 5
years following BCG induction and maintenance is not uncommon. While some
patients will respond to a second induction course, treatment with BCG beyond 2
induction courses does not have any additional clinical benefit.

There is significant unmet need in patients who have persistence or recurrence
of high-risk NMIBC that is not BCG unresponsive. New therapies are required to
reduce the rate of recurrence,cystectomy (removal of the bladder entirely), and
progression to metastatic disease.

There is evidence for the efficacy of nivolumab in UC and proof of concept for
PD-1 inhibition in NMIBC:
• In metastatic UC, nivolumab as monotherapy has received accelerated approval
in the US for the treatment of patients with locally advanced or metastatic UC
who have had disease progression during or following platinum-containing
chemotherapy or who have had disease
progression within 12 months of neoadjuvant or adjuvant treatment with
platinum-containing chemotherapy. It has received approval in the EU for the
treatment of locally advanced unresectable or metastatic UC in adults after
failure of prior platinum-containing therapy. See the current prescribing
information for nivolumab (Opdivo*) for more information.
• In NMIBC, preliminary evidence of clinical activity of PD-1 inhibition comes
from study Keynote-057, a single-arm study of pembrolizumab in BCG-unresponsive
NMIBC. In the interim analysis of this study, the response rate of CIS
(carcinoma in situ) participants treated with pembrolizumab monotherapy was 39%
at Month 3, with 80.2% of participants having a complete duration of > 6
month.3. The safety profile was consistent with the profile of pembrolizumab
across tumour types. These data are clinically significant in a group of
participants for whom there are no effective intravesical or systemic treatment
options, and cystectomy is the SOC.

Intravesical BCG results in tumour inflammation and nivolumab enhances T-cell
activity within the tumour; combining BCG with nivolumab therefore offers the
potential for improved response of the tumour to immunotherapy. This study aims
to demonstrate that treatment with nivolumab in combination with intravesical
BCG will improve event-free survival (EFS) vs intravesical BCG alone.

Primary objective
To compare the event free survival per pathological review committee (PRC) of
nivolumab plus BCG vs BCG alone in all randomized Participants
EFS, defined as the time from randomization until any of the following events:
recurrence (TaHG, T1 or CIS) or progression of disease, or death from any
cause. For participants with carcinoma in situ (+/- papillary disease) at study
entry, a lack of complete response of the CIS component at the 13-week
assessment will be considered an event.

Additional clinical endpoints include worsening-free survival (WFS), complete
response rate (CRR) in patients with carcinoma in situ (CIS), and overall
survival (OS). Additional objectives of the study include characterization of
safety and tolerability, pharmacokinetics,
potential predictive biomarkers, and changes in patient-reported outcomes for
quality of life assessment.

This is a Phase 3, randomized, double-blind, international, multicentre study
of nivolumab in combination with BCG vs nivolumab-placebo with BCG in adult
participants with high-riskNMIBC that is persistent or recurrent after
treatment with BCG and does not qualify as BCG
unresponsive.
Participants are assigned to 1 of 2 treatment groups (Arm A and Arm B).
Treatment assignment is based on 3 stratification factors used in randomization:
1. Disease status per PRC:
2. Time from last dose of BCG until NMIBC high risk recurrence per
investigator.:
3. Intended BCG strain:
It is expected that approximately 700 participants will be randomized in a 1:1
ratio to 1 of 2 treatment arms. Assuming a 20% screen failure rate, it is
estimated that approximately 875 participants with persistent or recurrent
high-risk NMIBC after prior BCG treatment will be enrolled.
Participants will receive:
• Arm A: Nivolumab at a flat dose of 480 mg intravenous (IV) every 4 weeks for
up to 24
months (104 weeks) and intravesical BCG (induction) weekly for 6 weeks followed
by maintenance intravesical BCG weekly for 3 weeks at 3, 6, 12, 18, 24, 30, and
36 months
• Arm B: Nivolumab-placebo IV Q4W for up to 24 months (104 weeks) and
intravesical BCG (induction) weekly for 6 weeks followed by maintenance
intravesical BCG weekly for 3 weeks at 3, 6, 12, 18, 24, 30, and 36 months

The dose of BCG used for each weekly intravesical treatment will be based on
current prescribing information for the particular BCG strain and preparation
administered. This may vary as BCG strain and/or preparation administered may
vary based on geographic region. BCG will be given at full dose.

The treatment period will end when the participant is discontinued from the
last dose of study treatment (nivolumab/nivolumab-placebo or BCG) or completes
3 years of study treatment.

The medical interventions include treatment with nivolumab, nivolumab-placebo
and BCG. Nivolumab will be supplied by the sponsor but not placebo nor BCG.
Patients will be randomly assigned to one of the following treatments:
• Treatment A: Nivolumab at a flat dose of 480 mg intravenous (IV) every 4
weeks for up to 24
months (104 weeks)
• Treatment B: Matching-placebo every 4 weeks for up to 24 months (104 weeks)

BCG will be given weekly for the first 6 weeks of treatment (induction) and
then weekly for 3 weeks at 3, 6, 12, 18, 24, 30, and 36 months from the first
treatment (maintenance).

The dose of BCG used for each weekly intravesical treatment will be based on
current prescribing information for the particular BCG strain and preparation
administered. This may vary as BCG strain and/or preparation administered may
vary based on geographic region. BCG will be given at full dose.

The treatment period will end when the participant is discontinued from the
last dose of study treatment (nivolumab/nivolumab-placebo or BCG) or completes
3 years of study treatment.

As part of the trial, patients will be expected to attend multiple clinic
visits where they will undergo physical examinations, vital sign measurements,
blood tests for safety assessment, pregnancy testing (for females of child
bearing potential) and monitoring for adverse events. Patients will be asked to
complete questionnaires about their quality of life. Blood will also be
collected at certain visits for research purposes (PK and biomarker studies).
If there is no archive tumour tissue available or the sample was taken too long
ago (more than 3 months ago), patients will be required to have a biopsy in
order to participate. Cystoscopy of the bladder will be done at screening and
every 13 weeks (~ 3 months) for 5 years. Thereafter they will be performed
every year. Bladder biopsies are also performed during treatment at week 26 and
again at disease progression or recurrence. Patients will undergo radiographic
assessment of their tumors by CT or MRI at screening and thereafter on a yearly
basis.
The frequency of visits and number of procedures carried out during this trial
would typically be considered over and above standard of care. The procedures
are carried out by trained medical professionals and every effort will be made
to minimise any risks or discomfort to the patient. Treatment for cancer often
has side effects, including some that are life threatening. To assure an
ongoing favourable risk/benefit assessment for participants enrolled onto the
study, an independent Data Monitoring Committee (DMC) will be established to
provide oversight of safety and efficacy considerations. Additionally, the DMC
will provide advice to the sponsor regarding actions the committee deems
necessary for the continuing protection of participants enrolled in the study.
BMS will conduct a rigorous safety monitoring to ensure participants* safety by
regularly and systematically reviewing safety data; the reported safety events
will be closely followed-up; sites and study investigators will receive an
intensive training on the implementation of the BMS-986205 and nivolumab
toxicity management strategies.
New immune system targeted therapy (immunotherapies) such as nivolumab could
potentially provide clinical benefit and improvements in the outcomes for
patients with this disease. However, with all experimental drugs and clinical
trials, there are known and unknown risks. Study medication and procedure
related risks are outlined in the patient information sheet in detail to ensure
the patients are fully informed before agreeing to take part in the study.