A Phase 3, Randomized, Double-blind Study of Adjuvant Nivolumab versus Placebo for
Participants with Hepatocellular Carcinoma Who Are at High Risk of Recurrence after Curative
Hepatic Resection or Ablation

Hepatocellular carcinoma is the sixth most common cancer worldwide and the
second leading cause of cancer-related death. The global incidence has
continuously increased, with roughly 700,000 new cases diagnosed worldwide
annually. The incidence varies geographically largely due to variations in
hepatitis B and C virus infection. Most cases arise in eastern Asia and
sub-Saharan Africa, where the dominant risk factor is chronic infection with
hepatitis B virus (HBV), while in North America, Europe, and Japan, infection
with hepatitis C virus (HCV), together with alcohol use are the main risk
factors for HCC.
HCC is a highly lethal cancer with a mortality-to-incidence rate ratio of 0.98
and 5-year survival rates of approximately 5%-6%. Factors such as late
diagnosis, underlying liver dysfunction, and an aggressive and heterogeneous
tumor biology have been identified as reasons for poor outcomes.
Moreover, the prognosis is further compromised because of the low effectiveness
of available treatments, which emphasizes the need for early diagnosis and more
effective therapies in HCC.

Treatment of HCC is challenging because the disease is highly heterogeneous
with different etiologies, varying approaches to diagnosis and treatment, and
variations in responses to therapy. The patient*s underlying liver function has
an important influence on HCC treatment decisions. A total of 90% of HCC
patients have an underlying cirrhosis requiring management of both the
malignancy and the cirrhosis. Additionally, many patients require ongoing
support for concomitant underlying disease such as HBV or HCV or non-viral
related liver disease (eg, non-alcoholic
steatohepatitis), making HCC treatment strategies and management even more
complex.

Surveillance programs for early detection of HCC in high-risk populations and
improvement of therapeutic modalities have increased the likelihood of
potentially curative treatments contributing to significant improvements of
survival rates in this population. Unfortunately, despite remarkable
improvements, the long-term prognosis, even after curative treatment, remains
unsatisfactory. The 5-year risk of recurrence exceeds 70% after resection or
local ablation, and most of the recurrences (especially those that appear early
during follow-up) are due to tumor dissemination
and have a more aggressive biological pattern as compared to primary tumors,
jeopardizing the survival of this population. In this context, preventing
recurrence with effective neoadjuvant or adjuvant therapies, particularly in
those patients at higher risk of recurrence, represents a
significant high unmet medical need in HCC. Up until now, attempts to address
this need have proven largely unsuccessful, with no treatments showing benefits
in randomized studies, which results in a lack of current standard of care
(SOC) in the adjuvant setting.

At this time, curative therapies for primary tumors remains the best chance to
cure patients with localized HCC. However, survival rates particularly in those
patients with high risk of recurrence remain poor, and novel therapeutic
approaches are needed to improve prognosis in
this population.

This study has been transitioned to CTIS with ID 2023-508726-10-00 check the CTIS register for the current data.

Objectives of the study
Primary Objective
To compare recurrence-free survival (RFS)(based on BICR assessment) of
nivolumab versus placebo in all randomized participants.

Secondary Objectives
• To compare overall survival (OS) of nivolumab versus placebo in all
randomized participants.
• To evaluate time to recurrence (TTR) (based on BICR assessment) of nivolumab
versus placebo in all randomized participants.

Phase 3, randomized, double-blind study of nivolumab monotherapy versus placebo
in participants who have undergone curative liver resection or ablation,
following a first diagnosis of hepatocellular carcinoma (HCC), and who are at
high risk for recurrence.
About 883 patients, will be enrolled in this study, for 530 being treated.
Randomized patients will receive nivolumab 480 mg or placebo every 4 weeks.
Patients will have 50% chance to receive nivolumab and 50% chance to receive
the placebo.
Patients will undergo screening procedures prior to first treatment to assess
if they are eligible to take part in the study. A pre-treatment tumor sample to
determine biomarkers is required to be submitted prior to randomization for
patients who undergo a resection and is optional for patients who undergo local
ablation.
Nivolumab and placebo will be given by a 30 min infusion.
Throughout the study, patients will have the following procedures: up to 2
biopsies, CT/MRI scans, physical exams, ECGs, vital signs, blood sampling and
pregnancy testing. They will also have to complete questionnaires regularly.
On-study tumor assessments will be done every 12 weeks from randomization for
the first 2 years and will continue every 24 weeks thereafter until disease
recurrence.
All patients will receive their treatment until their cancer returns (as
evaluated by CT scan or MRI), unacceptable toxicity, or if they withdraw their
consent to continue the treatment, whichever comes first.
Patients will be expected to receive their treatment for a maximum of 1 year
and be in follow-up for 5 years.
Follow-up: after stopping their treatments, patients will be asked to come back
to the hospital for 2 follow-up visits, at 30 and 100 days after their last
dose of study treatment, respectively.
Additional visits (approximately every 3 months) after follow-up visits
(survival visits).

The medical interventions include treatment with nivolumab or placebo.
Nivolumab will be supplied by the sponsor.

Patients will be randomised 1:1 to:
• Arm A: nivolumab 480 mg as a 30 minute infusion every 4 weeks (Q4W)
• Arm B: placebo as a 30 minute infusion every 4 weeks (Q4W)

Treatment, in the absence of recurrence (confirmed by BICR), unacceptable
toxicity, or
withdrawal of consent, will be continued for a maximum of 1 year total
duration.

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 & serious adverse events.
Patients will be asked to complete questionnaires (FACT-Hep & EQ-5Q-3L) about
their quality of life. Blood will also be collected at certain visits for
research purposes (PK, immunogenicity and biomarker studies). If ablation and a
tumor biopsy occurred no longer than 3 months ago, archival tumor tissue will
be sent to a central laboratory for analysis of biomarkers. Otherwise the tumor
biopsy obtained during the resection or ablation procedure will be obtained and
sent to central laboratory. A tumour biopsy will be performed at disease
recurrence. Patients will undergo radiographic assessment by CT or MRI at
screening, every 12 weeks for the first 2 years, then every 24 weeks for up to
a maximum of 5 years until disease recurrence (confirmed by Blinded Independent
Review Committee). The frequency of visits and number of procedures carried out
during this trial would be typically 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
patients 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 patients enrolled in the study.
BMS will conduct rigorous safety monitoring to ensure patients safety by
regularly & systematically reviewing safety data; the reported safety events
will be closely followed-up; sites and study investigators will receive
training on the implementation of 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.