A Randomized Phase 3 Open Label Study of Nivolumab vs Temozolomide Each in Combination
with Radiation Therapy in Newly Diagnosed Adult Subjects with Unmethylated MGMT (tumor O-6-methylguanine DNA methyltransferase) Glioblastoma.

Glioblastoma is a particularly invasive and aggressive brain tumour with high
mortality and morbibity despite the current treatments. The adverse events
associated with 2nd-line treatment such as repeated brain tissue resection,
radiation therapy and other chemotherapy agents in these subjects can be highly
toxic to the patient and can involve long term complications.

There is an urgent need for novel treatment interventions to improve clinical
outcomes and quality of life for subjects suffering from GBM. Nivolumab
monotherapy has shown clinical activity across several tumour types, including
advanced melanoma, Non Small Cell Lung Cancer and Renal Cell Cancer. Nivolumab
has demonstated a manageable safety profile in greater than 700 patients in
clinical trials.

Given the recent benefits in overall survival achieved with immunotherapeutics
in melanoma and prostate cancer, researchers believe that treatment with
immunotherapy agents (medications that use the body's immune system to attack
cancer cells) may offer promise in other difficult to treat cancers such as GBM.

The rationale for selecting unmethylated MGMT subjects is that they represent
the GBM population with the highest unmet medical need. Subjects with
unmethylated MGMT tumors are less responsive to temozolomide and have a worse
prognosis compared to methylated MGMT tumors.

This study will investigate whether treatment with Nivolumab in combination
with radiation therapy, is comparable to Temozolomide in combination with
radiation therapy in patients with Unmethylated MGMT Glioblastoma. We will
measure this by comparing how many patients are still alive after a certain
period of time once they have started treatment (also called Overall Survival
(OS)), in each group of patients.

DESIGN
This is a randomised (an automatic system allocates the treatment the patient
will be given depending on their date of birth, date of consent and gender)
open label Phase 3 study in adults (>=18 years old) male and female subjects
with a Newly diagnosed histologically confirmed supratentorial glioblastoma
(Grade 4 malignant glioma by World Health Organization including gliosarcoma).

Following surgical resection subjects will be randomized 1:1 to receive
radiotherapy plus nivolumab or radiotherapy plus temozolomide. Stratification
will be based on complete or partial resection. Patients in both arms will
start therapy upon recovery from the surgical procedure.

Subjects will undergo a screening period to determine eligibility within 42
days prior to start of radiation therapy. Subjects will be assigned to one of
the two treatment arms.

GROUP TREATED WITH NIVOLUMAMB AND RADIATION

The proposed dosing regimen for Nivolumab in this study is based upon safety
and tolerability data from the use of this medication in other tumour types.
The proposed dosing regimen is expected to be tolerable in subjects with GBM.

WHAT WILL HAPPEN TO THE PARTICIPANTS

Subjects randomized to the radiation + nivolumab arm will receive nivolumab
therapy for 16 weeks. Nivolumab will be administered at the dose of 240 mg
every two weeks. Patients that remain on nivolumab therapy for 16 weeks will
transition at Week 17 to nivolumab 480 mg administered every 4 weeks beginning
at Week 17.
Nivolumab will be administered as an IV infusion over 30 minutes on Treatment
Day 1.
A Treatment will continue until documented disease progression, there is
discontinuation due to toxicity, withdrawal of consent, or the study ends.

Subjects will receive Radiation Therapy over a 6 weeks period. A total dose of
60 Gy will be administered in daily doses of 2 Gy, typically on a 5 days on and
2 days off schedule as appropriate for scheduling, over 6 weeks.
Upon the completion of Radiation Therapy, Nivolumab subjects will continue with
nivolumab 240 mg maintenance dosing until week 17 when they transition to
Nivolumab 480 mg.

Subjects randomised to the radiation + temozolomide will receive the same
Radiation Therapy; a total dose of 60 Gy will be administered in daily doses of
2 Gy, typically on a 5 days on and 2 days off schedule as appropriate for
scheduling, over 6 weeks. The therapy will be combined with temozolomide
treatment. Patients will receive temozolomide (TMZ, Temodar®) daily for 6
weeks. Temozolomide will be dosed at 75 mg/m2 once per day continuously
throughout Radiation Therapy. After completion of RT, there will be a 4 week
break. Subjects will then receive 6 cycles of temozolomide daily x 5 days every
28 days.

10-20% Patients treated with Radiation Therapy have been shown to experience
pseudo-progression. Pseudoprogression is well-recognized in neuro-oncology,
namely the radiographic enlargement of tumor lesions that would be interpreted
as disease progression by conventional response criteria, but upon histologic
examination reveal necrosis and/or inflammation, not disease progression.
Treatment is permitted with RT-related pseudo progression based on RANO
guidelines. Immuno-oncology subjects have been shown to have treatment-related
changes, and subjects can continue on treatment if changes are observed, but
must be confirmed within 12 weeks of the scan.

At the conclusion of the study, subjects who continue to demonstrate clinical
benefit will be eligible to receive BMS supplied study drug. Study drug will be
supplied via an extension of the study, a rollover study requiring approval by
responsible health authority and ethics committee or through another mechanism
at the discretion of BMS.

A total of 550 patients will be randomised to treatment with the maximum length
of the study being 35 months long.

STUDY PROCEDURES
Patients will be asked to sign an informed consent form before any study
related procedures are performed.

Study assessments will take place as described below (please refer to the Flow
Chart 5.1 on pages 53-57 in the protocol for ease of use).

SCREENING PERIOD: (may take up to 42 days to complete)
The screening tests/procedures include:
• Review of medical history
• Review of medications a patient is currently taking and has taken in the past
including herbal supplements, over the counter medications, and steroid
medications
• A physical examination including measurement of height, weight and vital
signs (temperature, blood pressure, respirations and heart rate) and neurologic
status.
• The amount of oxygen in blood as measured by a non-invasive finger tip pulse
oximeter
• Performance status check (Karnofsky scale): patients will be asked about the
symptoms they are having from their cancer
• Collection of blood (approximately 4 teaspoons/20 mLs) for laboratory tests
to measure blood chemistry, including kidney and liver function, count red and
white blood cells and platelets, measure thyroid function, and check for
hepatitis B or C infection. Patients must not have HIV, hepatitis B, or
hepatitis C in order to be able to participate in the study.
• A urine test (with dipstick) to check for any abnormalities
• Tumour tissue sample: If a patient has had cancer surgery in the past, study
doctor will request the original samples from the medical facility where it was
done. The patient will be asked to give permission for this sample to be sent
to an additional laboratory for research testing.
• Contrast enhanced magnetic resonance imaging (MRI) of the brain within 24-48
hours of your surgery.
• A urine or blood pregnancy test for women of childbearing potential must be
performed within 24 hours before the first dose of study medication is given.
Results of the pregnancy test must be negative for you to participate in this
study. Patients will be asked to complete a series of computer-based mental
response and activity tests using a laptop. The testing will be completed at
the clinic.

BASELINE VISIT
If based on the results of the screening visit tests and procedures, patient
qualifies to participate in the study they will come for Baseline Visit. This
may be done up to 3 days before first day of study treatment or the day patient
receive study treatment
At the Baseline Visit the following tests and procedures will be performed:
* Review of any changes in patient*s health and medications since the last visit
* Measurement of weight and vital signs (including performance status)
* Collection of a urine or blood sample for a pregnancy test for women of
childbearing potential. A pregnancy test must be performed within 24 hours
before the first dose of study medication is given. Results of the pregnancy
test must be negative for patients to participate in this study

TREATMENT PERIOD
Patients will be randomised in a 1:1 fashion to receive either Nivolumab and
Radiation Therapy or Temozolomide and Radiation Therapy.

Chemotherapy is typically administered as a course of several cycles of
treatment.

As described previously, patients in Nivolumab arm will receive nivolumab as a
30 minute intravenous infusion on Day 1 and every 2 weeks for 16 weeks after
that day. Patients will then be given nivolumab every 4 weeks for the remainder
of the treatment period. Patients will also receive radiation therapy 5 days a
week for 6-7 weeks starting at the beginning of treatment. At each visit,
patients will also receive a brief physical exam, blood tests and assessment of
side effects they may be having.

Patients in Temolozomide arm will return to the clinic for visits every 2
weeks. They will be given Temozolomide daily for 6-7 weeks. Then, after a 4
week break from taking Temozolomide.
Patients will take capsules on Days 1 through 5 of a 28 day cycle for up to 6
cycles and you will continue to return to the clinic for visits every 2 weeks.
At each visit, patients will also receive a brief physical exam, blood tests
and assessment of side effects they may be having. Patients will also receive
radiation therapy 5 days a week for 6-7 weeks starting at the beginning of
treatment. Patients will also have blood tests on Day 21 or Week 3 of the cycle.

During the Treatment period, patients will be asked questions about the state of
their health including but not limited to the following questions:
• How their cancer is affecting their daily activities.
• What medications they took or are currently taking including herbal
supplements and over-the-counter medicines.
• What side effects they experienced.
• Patients will be asked to report the development of any new or worsening
medical problems (since their last visit) to the study doctor/sire personnel

The following procedures/samples will be performed and/or collected at 1 or
more treatment visits:
• A brief physical examination, including body weight and examination of
performance status.
• Vital sign measurements (blood pressure, heart rate, breathing rate, and
oxygen levels measured by a non-invasive finger tip pulse oximeter) will be
assessed. If patients assigned to nivolumab develop a reaction during the
infusion, they will continue to have their vital signs measured until the study
doctor determines it is no longer necessary.
• Urine or blood pregnancy test for women of childbearing potential (result
must be negative to receive study drug). During treatment, pregnancy test
(urine or blood) will be done every 4 weeks.
• Blood samples will be drawn to assess 1 or more of the following:
* blood chemistry, including kidney and liver function, count your red and
white blood cells and platelets and measure your thyroid function (about 2 1/2
teaspoons or 13 mLs)
* biomarker tests (about 8 to 12 teaspoons/40 to 59 mLs). These may be drawn at
the following time points: Day 1 of Week 1, Week 3, Week 7 and Week 13. An
optional sample may be taken if your disease worsens.
* For subjects receiving nivolumab, additional blood samples will also be drawn
before some infusions to assess their immune response to nivolumab and to
measure the levels of nivolumab in their blood. Patients will have from 1 1/2
teaspoons/8 mLs to 3 teaspoons/16 mLs of blood drawn at the following time
points: Predose on Day 1 of Week 1, Week 5, Week 13, Week 17 (and at the end of
the infusion), Week 21 and Week 33. Thereafter, every 16 weeks at predose until
discontinuation or withdrawal of consent and first follow-up visit

Patients should not have more than about one third cup/88 mLs of blood drawn on
any one single day for the purposes of this study.

• A contrast enhanced MRI of brain will be completed 4 weeks after completing
concurrent radiation therapy and then every 8 weeks (± 1 week) thereafter,
until disease has worsened or study treatment stopped c(whichever occurs
later).
• At about the same visit as the MRI, study doctor will perform a neurologic
assessment using the neurologic assessment in neuro-oncology (NANO) scale.
• Study doctor will document any radiation therapy patient has received.

Patients will be discontinued from receiving study treatment based on their
disease assessments or if they are having side effects that make them unable to
tolerate study therapy.

Radiation therapy
All patients participating in this trial will receive radiation therapy in
combination with either nivolumab or temozolomide. Radiation therapy is given
daily (usually Monday through Friday) for a total of 30 treatments and may last
up to 7 weeks if doses are skipped. Treatments must be done at the same
treatment center throughout the course of the study.

Health Related Questionnaires:
Patient will be expected to complete a serious of questions to assess their
signs and symptoms and how the disease is affecting your daily activities.
These questionnaires are called the EORTC QLQ-C30, BN20, and EQ-5D and will be
completed prior to dosing Day 1 Week 1 and then with each MRI prior to tumor
assessment discussion.

END OF TREATMENT AND FOLLOW UP:
After stopping study treatment, patients will be asked to come back to the
clinic after a month after they stop treatment and then about 2 1/2 months
after the first follow-up visit.

Patients will be asked the same questions regarding the medical condition, side
effects, medications etc. Also, the procedures/samples performed and /or
collected while they were taking study treatment may be repeated at one or more
of the visits.

Patients receiving nivolumab, will have more blood collected to measure immune
response and the levels of nivolumab in blood (about 1 1/2 teaspoons = 8 mLs
will be drawn)

Additional Follow Up/Survival Visits (after follow up visit 2)
The remaining follow up visits may be conducted over the telephone or at
doctor*s clinic. These visits will occur approximately every 3 months and
potentially more frequently. Patients will be asked the same questions
regarding their medical condition as described previously. During this period
study doctor will continue to assess patients* health condition It may be
necessary to have another MRI scan.

During the additional follow up visits you will be asked to complete health
related questionnaires (EORTC QLQ-C30, BN20, and EQ-5D), either via phone or a
clinic visit

BROAD TIMETABLE OF RESEARCH AND REPORTING:
The anticipated global first patient first visit is projected for the beginning
of January 2016. End of Recruitment is planned for October 2016 but it will
close when the recruitment target is met.
The subjects* safety will be monitored on an ongoing basis by a Data Monitoring
Committee. The DMC will meet at least every 6 months or more frequently as
needed on an adhoc basis.

The medical interventions include Nivolumab and Temozolomide. All of these
compounds will be supplied by the Sponsor. Due to significant issues with the
provisioning of Temozolomide (TMZ), the site will be allowed to purchase and
use TMZ (140 mg, 100 mg and 20 mg capsules) from the local markets until this
shortage problem is resolved. It would be reimbursed by BMS.

Nivolumab is given intravenously every 2 and 4 weeks, continuing will depend on
the subjects* response to the medicine. Temozolomide is taken daily for 6 weeks
and on Days 1 through 5 of a 28 day cycle for up to 6 cycles

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 childbearing potential) and monitoring for
adverse events. In addition, every 8 weeks patients will undergo radiographic
assessment of their tumour(s) MRI until disease progression or treatment
discontinuation whichever occurs later.
Blood samples will be collected at certain visits for research purposes (PK and
immunogenicity) including Biomarker samples.
The frequency of visits and number of procedures carried out during this trial
would typically be considered over and above standard over care. These
procedures are carried out by trained medical professionals and every effort
will be made to minimize any risks or discomfort to the patient.
Treatment for cancer often have side effects, including some that are
life-threatening.
Because of the potential for clinically meaningful nivolumab related AEs
requiring early recognition and prompt intervention, management algorithms have
been developed to assist investigators in assessing and managing the following
groups of Adverse Events: Gastrointestinal, Renal, Pulmonary, Hepatic,
Endocrinopathy, Skin and Neurological