A Phase 3, Open-label, Randomized Study of Nivolumab Combined with Ipilimumab, or with Standard of Care Chemotherapy, versus Standard of Care Chemotherapy in participants with Previously Untreated Unresectable or Metastatic Urothelial Cancer

CA209-901 is a multi-centre, phase 3 study involving adult patients with
previously untreated unresectable or metastatic urothelial carcinoma. The study
will compare nivolumab combined with ipilimumab or with standard of care
chemotherapy followed by nivolumab alone versus standard of care platinum
doublet therapy. Approximately 1792 patients will take part in this study,
approximately 70 of those will be from the Netherlands.

Urothelial carcinoma (UC) of the bladder is the ninth most common cancer in the
world. Approximately 20% to 25% of all patients with UC of the bladder develop
metastatic disease, for which median survival is approximately 14 months.

Cisplatin is among the most active agents in UC and the gemcitabine/cisplatin
doublet has become a standard regimen for patients with metastatic UC. However,
in clinical practice, more than 50% of all patients with unresectable or
metastatic UC have contraindications for treatment with cisplatin. While no
standard treatment has been defined for cisplatin-unfit patients,
carboplatin-containing regimens are considered appropriate alternatives.
Despite this, combination regimens that do not include cisplatin have never
been shown to improve survival, and patients who are not candidates for
cisplatin-containing chemotherapy regimens have significantly worse outcomes
with regard to response to treatment and overall survival (OS).
There is thus a clear need to improve upon the established standard of care in
for all patients with metastatic UC, but especially for those who are not fit
to receive a cisplatin based therapy.

Cancer immunotherapy is based on the knowledge that tumours can be recognized
as foreign rather than as self and can be effectively attacked by an activated
immune system. Nivolumab and ipilimumab are types of immunotherapy drugs called
monoclonal antibodies that work by blocking inhibitory signalling pathways in
the immune response. This results in stimulation of the body*s own immune
system to help attack the cancer cells. Nivolumab has demonstrated clinical
activity and been approved for the treatment of several tumour types, including
melanoma, advanced renal cell cancer and advanced NSCLC. Ipilimumab is approved
for the treatment of melanoma (alone or in combination with nivolumab). There
is a sound biological rationale for the combination of nivolumab and
ipilimumab, with existing pre-clinical data suggestive of a synergistic effect.
Additionally, studies in first line metastatic NSCLC provided impressive
overall survival for the combination regimen, with an acceptable safety profile.

The aim of this study is to determine if the combinations of nivolumab and
ipilimumab and nivolumab and standard of care chemotherapy represents an
improvement in survival (progression free and overall) compared to standard of
care platinum doublet chemotherapy (gemcitabine/carboplatin) in participants
with previously untreated, unresectable or metastatic urothelial carcinoma that
are not eligible for treatment with cisplatin. The study will also investigate
the same effect in all patients randomised, i.e. in patients both eligible and
ineligible for cisplatin. Changes in Health related Quality of Life from
baseline will also be compared between the immunotherapy and standard of care
chemotherapy groups.

This study has been transitioned to CTIS with ID 2022-501784-40-00 check the CTIS register for the current data.

The study aims to demonstrate that treatment with nivolumab combined with
ipilimumab will improve efficacy in cisplatin-ineligible participants with
previously untreated unresectable or metastatic UC and also treatment with
nivolumab combined with SOC chemotherapy will improve efficacy in
cisplatin-eligible participants with previously untreated unresectable or
metastatic UC.

This is an open-label, randomized Phase 3 clinical trial of combination
immunotherapy compared to standard of care platinum doublet therapy for first
line treatment in adult participants with previously untreated unresectable or
metastatic urothelial carcinoma.

Participants will undergo screening test and assessments to determine
eligibility and, those eligible for the study will be randomized to a treatment
arm. Randomization will be done by an automated sorting process through IVRS (a
telephone based computer system) which will assign participants to a treatment
based on their PD-L1 status, cisplatin eligibility and presence of liver
metastasis. This ensures that both all Arms are equally balanced with subject
numbers for comparison at time of analysis, while maintaining the integrity of
the randomization itself.

Treated participants will be evaluated for recurrence beginning on Week 9 and
then every 8 weeks (± 1 week) for 48 weeks, followed by evaluations every 12
weeks thereafter, until progression, unacceptable toxicity, withdrawal of
consent, or end of treatment, whichever comes first.

A Data Monitoring Committee (DMC) will be established and meet regularly during
the study to ensure that subject safety is carefully monitored and to provide
oversight regarding safety and efficacy considerations.

This study will include two final analyses for the co-primary endpoints
(Progression Free Survival (PFS) and Overall Survival (OS)), with each to take
place once the required number of events has taken place:
• The PFS final analysis will occur when there are at least 278 events among
345 cisplatin-ineligible randomized participants. This is expected
approximately 41 months after the first participant*s randomization. At this
time an OS interim analysis will occur (approximately 208 deaths among the same
population).
• The OS final analysis is projected to occur when there are at least 348
deaths among approximately 445 cisplatin-ineligible randomized participants,
approximately 55 months after the first participant*s randomization date.

Survival follow-up may continue until end of study, which is defined as the
final date on which data for the primary endpoint was or is expected to be
collected.

Participants will be randomly assigned to one of the below treatment arms. They
and their study doctors will be told to which group they were allocated.

Arm A:
Part 1: nivolumab 1 mg/kg plus ipilimumab 3 mg/kg given on same day every 3
weeks for 4 cycles.
Part 2: nivolumab 480 mg every 4 weeks starting 6 weeks following the last dose
of combination therapy, and continuing until confirmed disease progression,
unacceptable toxicity, or participant withdrawal of consent, or 24 months -
whichever comes first.

Arm B:
Up to 6 cycles of Standard of care platinum chemotherapy doublet: cisplatin &
gemcitabine or carboplatin & gemcitabine (only for cisplatin-ineligible
participants) given at 3-weekly cycles.
Participants assigned to receive cisplatin-gemcitabine may be eligible to
switch to carboplatin-gemcitabine following a minimum of 1 cycle of
cisplatin-gemcitabine, and after consultation with the medical monitor.

Arm C:
Part 1: Nivolumab (360 mg + Gemcitabine-cisplatin) every 3 weeks for up to 6
cycles.
Part 2: Nivolumab monotherapy (480 mg) every 4 weeks starting 3 weeks following
the last dose of combination therapy and continuing until confirmed disease
progression, unacceptable toxicity, or participant withdrawal of consent, or 24
months, whichever comes first.

• Arm D: Gemcitabine - cisplatin for 6 3-weekly cycles.

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 2 years), patients will be required to have a biopsy in order to
participate.

Patients will undergo radiographic assessment of their tumours by CT or MRI at
screening and then every 8 weeks for the first year and every 12 weeks
thereafter until disease progression or treatment discontinuation. 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.

New Immune system targeted therapy (immunotherapies) such as Nivolumab and
Ipilimumab could potentially provide clinical benefit and improvements in the
outcomes for patients with this disease (improvement in progression free and
overall survival). 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.