An Open-Label, Randomized Phase 3 Trial of Nivolumab, or Nivolumab plus Ipilimumab, or Nivolumab plus platinum doublet chemotherapy versus platinum doublet chemotherapy in Subjects with Chemotherapy-Naïve Stage IV or Recurrent Non-Small Cell Lung Cancer (NSCLC)

This is a clinical trial of nivolumab OR nivolumab with ipilimumab OR nivolumab
with platinum doublet chemotherapy, versus standard of care chemotherapy in
patients with chemotherapy-naive Stage IV or recurrent Non-Small Cell Lung
Cancer (NSCLC). Lung cancer is the second most common cancer in the UK and the
most common cause of cancer related deaths in men and women. A significant
number of patients have advanced lung cancer at diagnosis. Unfortunately with
current standard of care chemotherapy, the survival rate remains poor, with
less than 5% of advanced lung cancer patients alive five years on from
diagnosis. There is a clear unmet medical need for patients with advanced
NSCLC. Nivolumab, is a new type of immunotherapy drug which stimulates the
body*s own immune system to help attack cancer cells. It works by blocking a
protein on the body*s immune cells, called PD1, so that tumours can be
recognised as foreign and attacked by the immune system. Ipilimumab is already
on the market in the UK for the treatment of melanoma, a type of skin cancer.
Following a screening period, eligible patients will be randomised to 1 of 6
treatment arms depending on their PD-L1 status and their type of NSCLC.
Patients will receive either nivolumab; nivolumab and ipilimumab in
combination; nivolumab and chemotherapy in combination OR chemotherapy alone.
Patients will receive study drugs until their cancer progresses or their doctor
decides they should come out of the study (except for the chemotherapy arm).
Patients will undergo the following procedures during the study: tumour tissue
biopsy (possible), CT/MRI scans, physical exams, vital signs and blood sampling
for routine safety testing and study specific testing. 1980 patients will be
treated in the study with approximately 30 being treated in the Netherlands.

The study will look at patients with chemotherapy-naive Stage IV or recurrent
Non-Small Cell Lung Cancer (NSCLC). The research aims to compare a new drug
called nivolumab OR nivolumab with ipilimumab (another cancer drug) OR
nivolumab combined with chemotherapy against standard of care chemotherapy to
see which treatment helps patients live longer without their cancer getting
worse, which is known as Progression Free Survival (PFS). The study will also
measure Overall Survival (OS) i.e. the length of time from the start of
treatment that patients are still alive.

This is a randomised, open label six-arm study in patients with
chemotherapy-naive stage IV or recurrent Non-Small Cell Lung Cancer (NSCLC).
All patients will be randomly assigned to active treatment, either nivolumab
alone OR nivolumab combined with Ipilimumab OR nivolumab combined with
chemotherapy OR standard of care chemotherapy.
Nivolumab and ipilimumab are both immunotherapy drugs - but nivolumab works in
a different way to ipilimumab. Nivolumab works by blocking a body substance
called PD-L1. PD-L1 (programmed death) is a type of protein found on the
surface of some cancer cells. However, as not all patients produce this
protein, their PD-L1 status will be determined by immunohistochemical (IHC)
staining of PD-L1 protein. This will be performed on the submitted tumour
sample prior to randomisation. Subjects will be randomised into equal ratios
into one of the six treatment arms. Subjects will be stratified by PD-L1
expression level and histology (squamous vs non-squamous).
Subjects will receive open-label treatment with nivolumab (Arm A); a specific
regimen of nivolumab & ipilimumab in combination (Arms B and D); a regimen of
nivolumab combined with chemotherapy (Arm G) or standard of care chemotherapy
(Arms C and F).
Chemotherapy (Arms C and F) is administered in 3-week cycles for up to a
maximum of 4 cycles of IV chemotherapy. Chemotherapy treatment will continue
until disease progression, unacceptable toxicity or completion of the 4 cycles,
whichever comes first. Subjects with squamous histology may receive either
gemcitabine (1250 mg/m2) with cisplatin (75 mg/m2) or gemcitabine (1000 mg/m2)
with carboplatin (AUC 5); subjects with non-squamous histology may receive
pemetrexed (500 mg/m2) with either cisplatin (75 mg/m2) or carboplatin (AUC 6);
subjects with non-squamous histology may also receive optional continuation
maintenance therapy with pemetrexed alone until disease progression or
unacceptable toxicity.
Nivolumab in combination with chemotherapy (arms G) is administered in 3-week
cycles for up to a maximum of 4 cycles of IV chemotherapy, followed by
nivolumab monotherapy or nivolumab in combination with maintenance chemotherapy
every 3 weeks until disease progression or unacceptable toxicity.
Treatment with nivolumab +/-ipilimumab will be for a maximum of 24 months
After treatment, all subjects will enter the follow-up phase of the study.
Subjects will have 2 visits within the first 4 months after stopping treatment.
The remaining follow-up visits can be conducted over the phone and will occur
every 3 months. The duration of the study from start of enrolment to analysis
of the primary OS and PFS endpoint is expected to be 47 months. The study will
end once additional survival follow-up has concluded.

Subjects will receive open-label treatment with nivolumab (Arm A); a specific
regimen of nivolumab & ipilimumab in combination (Arms B and D); a regimen of
nivolumab combined with chemotherapy (Arm G) or standard of care chemotherapy
(Arms C and F).
All of these compounds are provided by the sponsor.

As part of the trial, patients will be expected to attend multiple clinic
visits, where they will undergo physical examinations, vital sign measurements
(including oxygen saturation levels), blood tests for safety assessment,
pregnancy testing (for females of child bearing potential), and monitoring for
adverse events. In addition, every 6 weeks (from week 6 until week 48) and then
every 12 weeks, patients will undergo radiographic assessment of their tumours
(by CT or MRI) until disease progression or treatment discontinuation whichever
occurs later. Blood will also be collected at certain visits for research
purposes (PK, immunogenicity and biomarker studies). The frequency of visits
and number of procedures carried out during this trial would typically be
considered over and above standard of care. These procedures are conducted by
medically trained 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 will be utilised in this trial.