A Randomized, Multicenter, Double-Blind, Phase 3 Study of Nivolumab, Nivolumab in Combination with Ipilimumab, or Placebo as Maintenance Therapy in Subjects with Extensive-Stage Disease Small Cell Lung Cancer (ED-SCLC) after Completion of Platinum-based First Line Chemotherapy

CA209-451 is a multi-centre, phase 3 study involving adult patients with
Extensive-Stage Disease Small Cell Lung Cancer (ED-SCLC) that have been treated
with prior platinum-based chemotherapy.

The study will involve an investigational drug called Nivolumab given alone or
in combination with Ipilumimab as maintenance therapy to patients who have
completed a first line platinum-based chemotherapy regimen and achieved an
ongoing Complete Response (CR), Partial Response (PR) or Stable Disease (SD).

Small-cell lung cancer (SCLC) accounts for approximately 12% of all lung cancer
deaths. Despite treatment with platinum-based chemotherapy, approximately 80%
of all patients experience disease progression and currently the median
survival rate of these patients is approximately 7 months. Patients whose
disease is diagnosed in an advanced stage (so called extensive stage) undergo a
platinum-based chemotherapy until the tumor size has been reduced or at least a
disease stabilization has been reached. At this point the chemotherapy
treatment will be stopped and patients are closely monitored to detect a
recurrence or relapse of the tumor. Unfortunately, in almost all patients who
were diagnosed in an advanced stage a recurrence of the tumor will occur.
Therefore there is a clear need for further therapeutic options for patients
who have reached at least a disease stabilization after the initial
chemotherapy. In a previous clinical trial patients with advanced SCLC and
recurrence of their disease after one or more chemotherapy treatments underwent
treatment with Nivolumab monotherapy or Nivolumab and Ipilimumab combination
therapy and tumor shrinkages were observed in these patients justifying the
proposed study CA209-451.

Considering the short median overall survival for patients who have completed
first line platinum based treatment, as well as the even shorter
progression-free survival experienced in this disease, new treatments
complementary to SCLC standard first-line platinum-base treatment are required.

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.

The aim of this study is to determine if Nivolumab or Nivolumab in combination
with Ipilimumab will improve the survival time and/or prolong the time until
the tumor starts to show growth again (so called Progression-Free Survival
(PFS)) compared to a placebo. There is no established treatment with proven
efficacy for patients who have completed the first chemotherapy, therefore
treatment is not being withheld from those in the placebo group as they would
not usually receive further treatment anyway.

Approximately 810 patients will take part in this study, approximately 17 of
those will be from the Netherlands.

The aim of the study is to compare overall survival (OS) and Blinded
Independent Central Review (BICR)-assessed progression free survival (PFS), of
nivolumab, and nivolumab in combination with ipilimumab, versus placebo in
subjects with ED-SCLC after completion of platinum-based first line
chemotherapy.

This is a randomized, double-blind, three arm, multicenter, Phase 3 study in
adult subjects with ED-SDLC, who achieve Stable Disease, Partial Response or
Complete Response after completion of platinum based first line chemotherapy.
The study will aim to treat 810 eligible male or female subjects across 30
countries, with the expected duration of treatment being up to 18 months
(depending on the response to treatment).
Subjects will undergo screening tests to determine eligibility and, those
eligible for the study, will be randomized to a 1:1:1 ratio across the 3
treatment arms until Progressive Disease or unacceptable toxicity:
* Arm A: Nivolumab (240mg) administered every 2 weeks.
* Arm B: Nivolumab (1mg/kg) and Ipilimumab 3mg/kg administered every 3 weeks
for 4 doses, followed by Nivolumab (240mg) every 2 weeks.
* Arm C: Placebo administered according to above treatment Arms A/B to maintain
a blinded study.
In order to maintain a blinded study, the schedule of investigational and
placebo treatments is divided into 6 week-cycles at the start of the therapy,
followed by ongoing 2-Week cycles until discontinuation criteria are met.
Randomization will be done by an automated sorting process through IVRS (a
telephone based computer system) which will assign subjects to a treatment Arm
based on their ECOG status, gender and whether they had prior Prophylactic
Cranial Irradiation (PCI). This ensures that all 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. Treatment
will continue until disease progression, discontinuation due to toxicity,
withdrawal of consent, or the study ends. If the investigator feels it is
appropriate, subjects will be permitted to continue treatment beyond initial
progression per RECIST 1:1.
After treatment all subjects will be asked to continue with follow-up visits
for 100 days after their last dose of study treatment. Adverse events will be
collected and monitored continuously during the follow-up period. Beyond 100
days, subjects will be followed up by telephone for long term survival and
subsequent anti-cancer medication information every 3 months for 5 years. For
any subjects whose disease has not yet progressed, radiographic assessment
(CT/MRI) will continue to be performed during the follow up period.

Subjects will receive open-label treatment with nivolumab (Arm A); or a
specific regimen of nivolumab & ipilimumab in combination (Arms B ); or
placebo. Nivolumab and Ipilimumab 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. Subjects will be evaluated for presence or continued lack of
tumor until distant recurrence beginning 6 weeks relative to the first dose of
study treatment, and will continue to have surveillance assessment every 6
weeks for the first 36 week then every 12 weeks until disease progression.

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. 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.