A Phase 2, Open-Label, Multi-Center, Randomized Study of TAR-200 in Combination with Cetrelimab and Cetrelimab Alone in Participants with Muscle-Invasive Urothelial Carcinoma of the Bladder who are Scheduled for Radical Cystectomy and are Ineligible for or Refusing Platinum-Based Neoadjuvant Chemotherapy

1. Background of the study (in English):
Gemcitabine, an anti-metabolite routinely used in the systemic treatment of
various forms of cancer, has demonstrated activity across all stages of
urothelial cancer, from organ-confined recurrent low-grade tumors to metastatic
disease. TAR-200 is a passive, non-resorbable investigational drug-device
combination product whose primary mode of action is the controlled release of
gemcitabine into bladder urine. Cetrelimab (JNJ-63723283)is a fully human
immunoglobulin G4 (IgG4) kappa monoclonal antibody (mAb) that binds
programmed-cell death protein (PD)-1. In this clinical study, we hypothesize
that metronomic gemcitabine dosing via TAR-200, in combination with cetrelimab,
a PD-1 inhibitor, will not only have marked local cytotoxic effects on bladder
tumors, but will have a systemic priming effect, increasing tumor antigen
presentation
as well as tumor antigen specific T-cell activation and maintenance. When these
T cells are activated by co-treatment with cetrelimab, this systemic anti-tumor
activity will result in material benefits in patients with MIBC, including
those groups that are not suitable for platinum-based chemotherapy.

This study has been transitioned to CTIS with ID 2023-507189-17-00 check the CTIS register for the current data.

2. Objective of the study (in English):
The main purpose of this study is to determine the anti-tumor effects of
TAR-200 + IV cetrelimab (cohort 1) and IV cetrelimab alone (cohort 2).
The secondary objectives are to evaluate the safety and tolerability of up to 4
dosing cycles of TAR-
200 + IV cetrelimab (cohort 1) and IV cetrelimab (cohort 2) alone prior to RC
and to determine the recurrence-free survival (RFS) in participants receiving
TAR-200 + IV cetrelimab (cohort 1) and IV cetrelimab alone (cohort 2).

3. Study design (in English):
This study is a phase 2, open-label, multi-center, parallel group assignment,
randomized study of TAR-200 in combination with cetrelimab (cohort 1) and
cetrelimab alone (cohort 2) in participants with MIBC who are scheduled for
Radical Cystectomy and are ineligible for or refuse platinum-based neoadjuvant
chemotherapy.
The study consists of a Screening phase, Treatment phase and Follow-up phase.
The total duration of study will be up to 2 years and 6 months. Efficacy and
safety will be assessed at specific time points during this study.

5. Intervention (if applicable) (in English):
Study Arms:
Cohort 1: TAR-200 + IV Cetrelimab (Participants will receive TAR-200 in
combination with IV cetrelimab.)
Cohort 2: IV Cetrelimab (Participants will receive IV cetrelimab.)

Participants in Cohort 1 will have the TAR-200 drug-device combination product
(225 mg gemcitabine per TAR-200 system) inserted every 3 weeks, until Week 12.
Cetrelimab (360mg) will be administered intravenously (IV) every 3 weeks until
Week 9.

Participants in Cohort 2 will receive 360 mg of IV Cetrelimab every 3 weeks
until Week 9.

2.3. Benefit-Risk Assessment
The standard of care in MIBC includes RC with urinary diversion and is
considered the preferred
treatment option for patients who are considered surgical candidates. Systemic
neoadjuvant
chemotherapy for these patients is associated with increased OS. Specifically,
pathologic partial
and complete responses, as well as negative lymph node status, correlate with
meaningful diseasefree
and OS benefits (Sonpavde 2009). However, systemic chemotherapy is associated
with
significant toxicity, and up to 80% of patients may refuse or be ineligible for
neoadjuvant and/or
adjuvant regimens (Haseebuddin 2015). There is a significant unmet need for
efficacious and more
tolerable neoadjuvant treatments, specifically for patients who are ineligible
for cisplatin-based
chemotherapy. A clinical benefit has been demonstrated in this
platinum-ineligible patient
population utilizing checkpoint inhibitor monotherapy (anti-PD-1/PDL-1) and
provides rationale
for potential efficacy of single-agent cetrelimab. (Necchi 2019, Powles 2019).
In addition, it is
postulated that the sustained antineoplastic local therapy of TAR-200, in
combination with an
efficacious anti-PD1 immunotherapy, could potentially provide comparable CR
rates to neoadjuvant
chemotherapy, without an overlapping toxicity profile.
Intravesical gemcitabine has consistently exhibited activity and a good
toxicity profile in bladder
cancer, albeit in the setting of non-muscle invasive disease (Shelley 2012).
Ongoing clinical
studies in MIBC and NMIBC have demonstrated good tolerability of intravesical
dosing. Prior
clinical trials evaluating the safety of TAR-200 itself have noted an excellent
tolerability ad safety
profile.
For safety details of intravesical gemcitabine and the TAR-200 drug device
combination product, refer to the
most recent version of the IB.
Overall, the safety profile of IV cetrelimab monotherapy is well-tolerated and
generally consistent
across completed and ongoing clinical trials. Most adverse events (AEs) were
low-grade (Grade 1
to 2) with relatively few related high-grade (Grade 3 to 4) AEs. There was no
pattern in the
incidence, severity, or causality of AEs with respect to cetrelimab dose level.

For the recognized pattern of immune-related adverse events (irAEs) that are
defined, management
algorithms have been developed. Treatment plans for diarrhea/colitis, renal
insufficiency,
pneumonitis, transaminitis, asymptomatic thyroid stimulating hormone elevation,
symptomatic
endocrinopathy, retinopathy, suspicion of adrenal crisis, rash, and
neurological toxicity are
provided in Section 10.9, Appendix 9, Guidelines for Management of
Immune-Related Adverse
Events and Adverse Events of Clinical Interest. Most high-grade events were
manageable with the
use of corticosteroids or hormone replacement therapy (endocrinopathies) as
instructed in these
algorithms.
Additional details on the safety profile of cetrelimab, including results from
other clinical studies,
are also available in the cetrelimab IB.
Overall, for participants who are ineligible for cisplatin-based treatment, the
treatment of TAR-200 in
combination with IV cetrelimab (hereafter referred to as "TAR-200 + IV
cetrelimab) or IV cetrelimab alone, has the potential to increase disease-free
and
survival periods relative to patients who are unable to receive neoadjuvant
chemotherapy. Little
systemic toxicity is expected from TAR-200 reducing the risks observed with
systemic
chemotherapy.
Accounting for the measures taken to minimize AEs in participants
of this study, the identified potential risks of TAR-200 in combination with
cetrelimab are justified
by the anticipated benefits that may be afforded to participants with MIBC who
are scheduled for
radical cystectomy and ineligible for platinum chemotherapy.
From a risk-based alternative treatment perspective, chemoradiotherapy has been
proposed
as an alternative to RC. Several organizations, including the AUA and the EAU,
have updated
their guidelines to support chemoradiotherapy as an alternative to RC in
patients with
muscle-invasive disease. However, chemoradiotherapy has been associated with
both acute and latent toxicity,
including local and systemic symptoms. Such acute toxicities include anemia,
fatigue, colitis, and
cystitis, while latent longer-term toxicities and side effects may include
bladder contracture,
hemorrhagic cystitis, secondary malignancy, and urethral or rectal stricture.
Therefore, while
participants in this clinical study should be counseled on all treatment
options, RC
remains a standard of care.
More detailed information about the known and expected benefits and risks of
TAR-200 and
cetrelimab may be found in the respective IBs for these study drugs.