A randomized phase 2 single blind study of Temozolomide plus Radiation Therapy combined with Nivolumab or Placebo in newly diagnosed adult subjects with MGMT-Methylated (tumour 06-methylguanine DNA methyltransferase) Glioblastoma.

Glioblastoma is a particularly invasive and aggressive brain tumour with high
mortality and morbidity 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.
This study will include subjects with newly diagnosed glioblastoma whose tumour
has a certain biomarker profile that is referred to as methylated
O6-methylguanine-DNA methyltransferase (MGMT). This MGMT gene type has been
shown to be important in predicting the response of GBM tumours to chemotherapy
treatment.

Patients with MGMT-unmethylated GBM are being studied in CA209-498, but
patients with MGMT-methylated GBM may also benefit from addition of
immunotherapy to chemoradiation. In this companion phase 2 trial we will
estimate the added benefit of nivolumab in subjects receiving RT+TMZ. Depending
on test conditions, MGMT status is anticipated to be reported as
partially-methylated or indeterminate in approx. 5-10% of the overall
population.

To compare PFS of subjects with newly-diagnosed MGMT methylated or
indeterminate GBM subtypes treated with RT plus TMZ combined with nivolumab or
placebo. PFS will be determined by BICR based on RANO criteria.
To compare OS of subjects with newly-diagnosed MGMT methylated or indeterminate
GBM subtypes without baseline corticosteroids and regardless of baseline
corticosteroids (ie, all-comers) treated with RT plus TMZ combined with
nivolumab or placebo.

STUDY 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)
single blind phase 2 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, temozolomide plus nivolumab or radiotherapy, temozolomide plus
placebo. 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.
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,
discontinuation due to toxicity, withdrawal of consent, or the study ends.
All subjects will receive Radiation Therapy and temozolomide 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. 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 320 patients will be randomised to treatment. Enrolment and
randomization of the targeted number of patients is expected to require approx.
12 months.
STUDY PROCEDURES
Patients will be asked to sign an informed consent form before any study
related procedures are performed.

There are three periods to the study: screening, treatment and follow-up.

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 plus
Radiation Therapy and Temozolomide or Placebo plus Radiation Therapy and
Temozolomide.
Chemotherapy is typically administered as a course of several cycles of
treatment.

As described previously, 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,
discontinuation due to toxicity, withdrawal of consent, or the study ends.
All subjects will receive Radiation Therapy and Temozolomide 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. 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.

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) for up to 24
months and then every 12 weeks thereafter, until disease has worsened or study
treatment stopped (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 and
temozolomide in combination with either nivolumab or placebo. 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.

Cogstate Assessment
Patients will also be asked to complete Cogstate assessment. This series of
computer-based mental response and activity tests completed using a laptop
which the study personnel will show how to use. These will be obtained at
screening and prior to dosing Day 1 Week 1, then at Months 6, 12, 18, 24 and 36.

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 patients will be asked to complete
health related questionnaires EQ-5D, either via phone or at clinic visit.

BROAD TIMETABLE OF RESEARCH AND REPORTING:
The anticipated global first patient first visit is projected for Mid March
2016. End of recruitment is planned for March 2017 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.

Investigational Product(s), Dose and Mode of Administration, Duration of
Treatment with Investigational Product(s): Nivolumab (BMS-936558) 240 mg IV or
placebo as a 30 minute infusion every 2 weeks for 8 doses followed by nivolumab
480 mg as a 30 minute infusion every 4 weeks beginning after 8 doses until
progression, unacceptable toxicity (or other reasons), and temozolomide 75
mg/m2 orally daily during radiation therapy followed by 4 week break then 6
(28-day) cycles temozolomide on Days 1-5 at 150 mg/m2 in cycle 1 increasing to
200 mg/m2 as tolerated up to 6 cycles.

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.

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 up to 24
months and then every 12 weeks 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.