A Double-Blind, Randomized, Two Arm Phase 2 Study of Nivolumab in Combination with Ipilimumab versus Nivolumab in combination with Ipilimumab placebo in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)

CA209-714 is a multi-centre, phase 2 study involving adult patients with
untreated metastatic or recurrent Squamous Cell Carcinoma of the Head and Neck
(SCCHN). The study will compare nivolumab combined with ipilimumab vs.
nivolumab alone as first line treatment in this population. Approximately 396
patients will take part in this study, approximately 15 of those will be from
the Netherlands.

Metastatic and recurrent SCCHN causes substantial morbidity and high mortality
and has a median overall survival of less than 12 months with the current
available treatments. In a sub-set of patients that progress after platinum
based therapy (referred to as platinum refractory), the median overall survival
is about 6 months and there are no well-defined treatment options. As such,
there is high unmet medical need in improving upon the established standard of
care in recurrent and metastatic SCCHN, in both the platinum eligible and
platinum refractory populations.

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, renal cell cancer and
NSCLC. Furthermore, it has demonstrated a survival benefit in second line
platinum refractory recurrent and metastatic SCCHN (when compared to
investigators choice single agent chemotherapy). 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.

The aim of this study is to determine if the combination of nivolumab and
ipilimumab represents an improvement in response compared to current treatment
options for platinum refractory recurrent or metastatic SCCHN patients, a group
in which there is currently a high level of unmet need. The study will also
investigate the combination therapy compared to nivolumab alone in a smaller
sub-group of platinum eligible patients, and these results will complement a
concurrent study (CA209-651) which is assessing the efficacy of the combination
compared to current standard of care in platinum eligible patients.

The aim of the study is to compare the Overall Response Rate (ORR) and assess
Duration of Response (DoR) of the treatment of nivolumab in combination with
ipilumumab vs. nivolumab in combination with ipilimumab placebo, as determined
by a blinded independent central review (BICR) using Response Evaluation
Criteria In Solid Tumors (RECIST 1.1) criteria, for first line treatment of
recurrent or metastatic SCCHN in the platinum refractory setting.

This is a randomized, double blinded, two-arm Phase 2 trial in adult subjects
with untreated metastatic SCCHN or recurrent SCCHN that is not amenable to
curative therapy.

Subjects will undergo screening tests to determine eligibility and, those
eligible for the study will be randomized to a treatment arm in a 2:1 ratio:
Arm A: Nivolumab and Ipilimumab
Arm B: Nivolumab and Ipilimumab-Placebo

Randomization will be done by an automated sorting process through IVRS (a
telephone based computer system) which will assign subjects to a treatment
based on platinum sub-group and their PD-L1 and HPV p16 status. This ensures
that both Arms are equally balanced with subject numbers for comparison at time
of analysis, but also ensures the integrity of the randomization itself.

Subjects must receive their treatment within 3 days of randomization. Dose
reductions will be not be allowed for nivolumab, ipilumumab or
ipilumumab-placebo. Treatment will continue until disease progression,
discontinuation due to toxicity, withdrawal of consent, or the study ends.
Continuation of treatment beyond initial investigator-assessed progression
(either clinical or radiographical) will be permitted if the subject has an
investigator-assessed clinical benefit and is tolerating study drug.

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.

The total duration of the study from start of randomization to final analysis
of ORR is expected to be approximately 19 months, assuming 13 months accrual
duration. Survival follow-up may continue for up to 5 years from the time of
this analysis. The study will end once survival follow-up has concluded.

Subjects will be randomly assigned to a treatment arm in a 2:1 ratio,
allocation will be double-blinded.

Arm A:
* Nivolumab 3 mg/kg IV will be administered every 2 weeks
* Ipilimumab 1 mg/kg IV will be administered every 6 weeks

Arm B:
* Nivolumab 3 mg/kg IV will be administered every 2 weeks
* Ipilimumab-Placebo IV will be administered every 6 weeks

Both nivolumab and ipilimumab will be provided by the sponsor.

Treatment with nivolumab and ipilimumab will be given for up to 24 months in
the absence of disease progression or unacceptable toxicity. Subjects who
complete 24 months of nivolumab with ipilimumab and have subsequent disease
progression may reinitiate nivolumab with ipilimumab at the same dose and
schedule given previously on study and continue such treatment for up to 1
additional year.

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. Blood will also be
collected at certain visits for research purposes (PK, immunogenicity and
biomarker studies).
If there is no archive tumour tissue available or the sample was taken too long
ago (more than 6 months), patients will be required to have a biopsy in order
to participate. A biopsy of tumour tissue will also be collected at the time of
disease progression.
In addition, every 6 weeks, patients will undergo radiographic assessment of
their tumours (by CT or MRI) for the first 48 weeks, and then every 12 weeks
thereafter. These assessments will continue until disease progression or
initiation of subsequent therapy. 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. An independent Data Monitoring Committee (DMC) will be utilized in
this trial to ensure that the safety data is reviewed during the study. New
Immune system targeted therapy (immunotherapies) such as Nivolumab and
Ipilimumab could potentially provide clinical benefit and improvement in the
outcome for patients with this disease (disease improvement and improvement in
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.