AN OPEN LABEL, SINGLE ARM, MULTICENTER, SAFETY STUDY OF ATEZOLIZUMAB IN LOCALLY ADVANCED OR METASTATIC UROTHELIAL OR NON-UROTHELIAL CARCINOMA OF THE URINARY TRACT

Atezolizumab is a humanized immunoglobulin G, subclass 1 (IgG1) monoclonal
antibody consisting of two heavy chains (448 amino acids) and two light chains
(214 amino acids). Atezolizumab was engineered to eliminate the crystallizable
fragment (Fc)-effector function via a single amino acid substitution that
results in a non-glycosylated heavy chain that has minimal binding to Fc
receptors and prevents Fc-effector function at expected concentrations in
humans. Atezolizumab targets human programmed death-ligand 1 (PD-L1) and
inhibits its interaction with its receptor, programmed cell death protein 1
(PD-1). Atezolizumab also blocks the binding of PD-L1 to B7.1, an interaction
that is reported to provide additional inhibitory signals to T cells (Butte et
al. 2007). Therapeutic blockade of PD-L1 by atezolizumab is expected to enhance
the magnitude and quality of tumor-specific T-cell responses, resulting in
improved anti-tumor activity. Consequently, atezolizumab is being investigated
as a potential therapy against solid tumors and hematologic malignancies in
humans.

This study is being conducted to evaluate the safety of atezolizumab as
second-line treatment for locally advanced or metastatic urothelial or
non-urothelial carcinoma of the urinary tract. The study includes evaluation of
the efficacy of atezolizumab and potential tumor biomarkers associated with
atezolizumab.

Study MO29983 is an open label, single-arm, multicenter study of the safety of
atezolizumab as second-line treatment for patients with locally advanced or
metastatic urothelial or non-urothelial carcinoma of the urinary tract.

Atezolizumab 1200 mg, every 3 weeks, intravenously

The subject may experience side effects of the study drug or procedures used in
this study. Side effects can range from mild to severe and can vary from person
to person. Everyone who participates in the survey will be closely monitored
for any side effects. Roche, the study doctor and other doctors, however, do
not know all the side effects that could occur. The research doctors can give
participants medication to help reduce side effects and may need to stop the
subject temporarily or permanently using atezolizumab. Many side effects
disappear soon after the patient stops what causes the side effects. In some
cases, side effects can be severe, long persist or never disappear. There is
also a very small risk of death. The patient should talk to the study doctor
about any side effects that may occur during participation in the study.

Adverse reactions known to be associated with atezolizumab
Of the side effects described in this section is known to be associated with
atezolizumab.

Adverse reactions known to be associated with atezolizumab
Common (occurs in more than 10% of patients)
* Fatigue
* Joint pain (arthralgia)
* Lack of energy (asthenia)
* Back Pain
* Decreased appetite
* Diarrhea
* Shortness of breath (dyspnea)
* Pain in the stomach (abdominal pain)
* Headache
* Itchy skin
* Nausea
* Fever
* Rash
* Vomiting
Uncommon (affects
1% *10% of patients)
* Chills
* Difficulty in swallowing (dysphagia)
* Increase in liver enzymes, which may indicate inflammation of the liver
* A high concentration of sugar in the blood (hyperglycaemia)
* Allergic reaction or intolerance to medication (hypersensitivity)
* Diminished concentration of potassium in the blood (hypokalemia)
* Reduced sodium levels in the blood (hyponatraemia)
* Low blood pressure (hypotension)
* Under active thyroid (hypothyroidism)
* Decreased supply of oxygen in the body, resulting in shortness of breath
(hypoxia)
* Flu-like symptoms
* Infusion-related reactions
* Muscle and bone pain (musculoskeletal pain)
* Nerve damage, possibly resulting in numbness, pain and / or loss of motor
function (peripheral neuropathy)
* Inflammation of the lungs (pneumonitis)
* Low number of platelets in the blood, giving you a greater chance of bruising
or bleeding (thrombocytopenia)

Rare but potentially serious side effects (occurring in less than 1% of
patients)
* Decreased production of hormones by the adrenal gland (adrenal)
* Diabetes
* Overactive thyroid (hyperthyroidism)
* Inflammation of the liver (hepatitis)
* Inflammation of the colon (colitis)
* Nerve damage which can cause muscle weakness and / or paralysis
(Guillain-Barré syndrome)
* Inflammation of the brains and the membrane around the brains and spinal cord
(meningo-encephalitis)
* Nerve damage resulting in muscle weakness (myasthenic syndrome / myasthenia
gravis)
* Inflammation of the pancreas (pancreatitis)
* Increased concentration pancreatic enzymes, which may indicate inflammation
of the pancreas (increased levels of amylase and lipase)
* Severely elevated concentrations of sugar and acids in the blood or urine
(diabetic ketoacidosis)

At the side effects known to be associated with atezolizumab like Roche and
research your doctors you to be extra careful about the following:
* Inflammation of the colon (colitis); possible symptoms include diarrhea,
bloody stools and abdominal pain.
* Inflammation of the thyroid gland (hypothyroidism, hyperthyroidism); possible
symptoms include headache, fatigue, weight loss, weight gain, mood changes,
hair loss and constipation.
* Inflammation of the adrenal gland (adrenal fatigue); possible symptoms
include dizziness, irritability, fainting, low blood pressure, darkening of the
skin, and craving for salty foods.
* Inflammation of the liver (hepatitis); possible symptoms include yellowing of
the skin, pain in the abdomen, nausea, vomiting, itching, fatigue, bleeding or
bruising under the skin, and dark urine.
* Inflammation of the brains and the membrane around the brains and spinal cord
(meningo-encephalitis); possible symptoms include a stiff neck, headache,
fever, chills, vomiting, seizures, irritability and sensitivity of the eyes to
light.
* Nerve damage that results in muscle weakness (myasthenic syndrome /
myasthenia gravis); possible symptoms are weakness in the arm and leg muscles,
double vision and difficulty speaking and chewing.
* Nerve damage which can cause muscle weakness and / or paralysis
(Guillain-Barré syndrome); possible symptoms include tingling in the fingers
and toes, fatigue, and difficulty walking.
* Inflammation of the lungs (pneumonitis); possible symptoms are newly
occurring or worsening cough, shortness of breath and chest pain.
* Reactions associated with infusion (side effects that occur during infusion
or within 1 day of infusion); Symptoms include fever, chills, shortness of
breath, and suddenly red in the face, neck / throat or chest.
* Inflammation of the pancreas (pancreatitis); symptoms may include abdominal
pain, nausea, vomiting and fever.
* disorder with high concentration of sugar in the blood (diabetes mellitus);
possible symptoms include increased thirst, increased hunger, frequent

Allergic reactions

At atezolizumab may experience allergic reactions. These usually occur for
while it is given into your vein or shortly after administration. The symptoms
can include nausea, vomiting, skin reactions (hives or rash), breathing
difficulties or low blood pressure. These reactions can be mild or severe and
may result in death or permanent disability. If you have any of these symptoms,
your study doctor will interrupt the administration of atezolizumab into your
vein or even stop. Your study doctor can also give you medicines to treat these
symptoms.

Adverse reactions possibly related to atezolizumab
The following side effects may be related to atezolizumab:
* There is a chance that your immune system specific antibodies (proteins made
in the body that respond to a foreign substance) develops to this research
tool. If you develop these specific antibodies would may affect the ability of
your body to react in the future atezolizumab.
* Potential to cause harm to the developing fetus
* Eye inflammation; possible symptoms include eye pain and redness, vision
problems or blurry vision (uveitis).
* Inflammation of the kidney; possible symptoms include frequent urination,
pelvic pain, and swelling of the body which can result in failure of the
kidneys (nephritis).
* Inflammation or damage to the muscles; possible symptoms include muscle pain
and weakness, urine with a dark brown or red color, and nausea or vomiting
(myositis, myopathy including rhabdomyolysis).

Systemic immune activation
In rare situations, when atezolizumab is combined with another medicine that
increases the immune response of your body (an immune modulating drug), can
occur more than normal (excessive) immune response. Like other immune-mediated
diseases, can cause excessive immune activation, systemic side effects
associated with severe inflammation and / or generalized infection (sepsis).
Here, various organs in your body (such as your liver, kidneys, lungs and bone
marrow) become involved, causing a serious condition that can lead to
hospitalization, life-threatening conditions or even death. Possible symptoms
of systemic immune activation, are a very low blood pressure that does not
respond to standard treatment * including administration of fluids via the
veins (intravenous fluid administration), a high temperature (a temperature
higher than 38.5 *C), cough, severe shortness of breath (dyspnea), which oxygen
therapy and / or mechanical support (intubation) is required, severe dizziness,
confusion, weakness, reduced urination with loss of kidney function (renal
failure), significantly increased liver enzymes (liver failure), very low
numbers of blood cells and / or bleeding in the organs.

If you warn one or get more of these symptoms you should contact your doctor
immediately as you may need immediate treatment and should be hospitalized.
Your study doctor may give you medicines to treat these symptoms.

Other medications

If you need a live attenuated vaccine, you should get at least 4 weeks before
you are treated with atezolizumab. You must agree to not to live attenuated
vaccines (eg. FluMist®) to be given during treatment or within 5 months after
the last dose atezolizumab. If you know you'll need a vaccination during the
investigation, you should tell your doctor.
Atezolizumab may have a number of side effects, the side effects caused by
other drugs which also stimulate the immune system, may overlap. It can be
dangerous to use atezolizumab together with such other drugs. It is important
to tell your doctor if you have used for the last medication that stimulates
the immune system. It is also important that you not use other medicines in the
10 weeks after your last dose atezolizumab that may affect your immune system
(immunomodulatory drugs).
It is not known how long after discontinuation of study drug will / will
persist side effect (s) of study drug.

Potential risks and inconveniences associated with blood

During this study, small amounts of blood drawn from a vein, and used for
testing on the basis of which your research doctors can see how it goes with
you. Blood collection can cause pain where the needle is inserted, and there is
a small risk of bruising or infection at the puncture site. Some people get
dizzy, get an upset stomach or faint when their blood is collected.
Potential risks and inconveniences associated with CT scans
CT scans are special X-ray tests that are used to examine the internal organs
and bones of the body, and they are required to measure your response to this
treatment. You'd probably get these scans if you would participate in this
scientific research, as your doctor should your illness eye should take.
You will from the start of study treatment for 54 weeks, approximately every 9
weeks to be exposed to radiation from CT scans and then every 12 weeks until
disease progression or termination of the investigation (whichever is first on
the agenda). If you do not participate, you can be scanned with a similar
frequency or less often (this depends on your cancer center and research your
doctor). Through your participation in this study may therefore increase your
exposure to radiation from the scans. One possible effect that could occur at
doses in connection with this study was a slight increase in the risk of
developing cancer later in life. Since the effects of radiation may accumulate
over time, it is important to be aware of your radiation exposure in the past.
If you are exposed to in the past 12 months by CT scans, X-rays or other means
of radiation, inform please the research team. If it is determined that your
previous radiation exposure exceeds the applicable guidelines, it is possible
that you will not participate in this study.
As part of the CT-scan, it may be necessary to include in a contrast agent via
the mouth and / or to have it injected into a vein in order to make visible
certain organs and disease locations on the scan. A contrast agent administered
via the mouth could lead to side effects such as nausea, constipation, diarrhea
and a swollen abdomen. At the place where a needle is inserted to administer
contrast material into your vein you may experience pain, ecchymosis, redness
and swelling or infection. It is normal to have a warm, flushed sensation when
the contrast material is administered. You can get an allergic reaction to the
contrast material rashes, hives, shortness of breath, can cause wheezing and
itching, and in rare cases, result in your heart stops beating (cardiac
arrest). The use of contrast material during these tests would be a normal part
of monitoring your response to therapy, even if you would not participate in
this scientific research.

Possible risks and discomforts associated with MRI scans

MRI scans are special imaging procedures that are needed to measure your
response to this treatment. For most patients, the risks or side effects
associated with undergoing MRI scans minimal. An MRI scan will be used no
ionizing radiation, as in conventional X-rays. Instead, it will continue to
generate images with the aid of a magnetic field and radio signals. Because an
MRI scanner uses strong magnets, you should not undergo MRI if you have any
metal implants in your body. People with an artificial heart valve, metal
sheet, pen, or other metal objects in their bodies (including hail of shrapnel)
are not eligible for MRI scans. The research team will ask questions to make
sure you can safely undergo an MRI scan.
There may be some of anxiety and claustrophobia (fear to be in small spaces) in
connection with the scanner. Staff at the center use imaging techniques to
reduce such feelings in patients. Also can prescribe your research doctor mild
tranquilizers or anti-anxiety medicines to help reduce your symptoms. As part
of the standard MRI scan there is provided a contrast agent comprising
gadolinium is injected into a vein, in order to improve the visibility. The
risks associated with the contrast agent include mild nausea, headache, hives,
temporary low blood pressure, chest pain, back pain, fever, weakness and
seizures. There have been reports of severe and potentially fatal condition
called "nephrogenic systemic fibrosis (NSF, a condition in which fibrosis
occurs and which can result in kidney failure). This condition has been
reported in patients receiving contrast agent based on gadolinium. This
disorder is not seen in patients with normal functioning kidneys or slight
problems with the kidney function. Before being included in the study, will
carry out your research doctor tests to determine if your kidneys are working
properly. This is to check that the contrast agent is safe for you.

Potential risks and discomfort associated with biopsies

The risks associated with biopsies include pain, redness, swelling, excessive
bleeding, bruising or fluid drainage in the slot, abnormal wound healing,
fever, infection, and allergic reaction to the medication used to numb the skin
over the biopsy site.

Risks related to reproduction

If you are pregnant, or if you are currently breastfeeding, you should not
participate in this study because you or your child may be exposed when
participating to an unknown risk.
If you are a woman who may become pregnant, you should have a blood test
showing that you are not pregnant before you can participate in this study.
Also will urge you did a pregnancy test blood or urine regularly during the
investigation. As a result of a blood or urine test is positive, you will not
receive doses atezolizumab more.
If you become pregnant, you must agree to abstain from sexual intercourse or
use of contraceptive methods considered effective by your study doctor. You
must use this during this investigation and atezolizumab after your last dose
for 5 months. Ask your doctor what research methods of contraception should be
used. Also, you should not breastfeed for 5 months after your last dose
atezolizumab.
Tell it directly to your study doctor if you suspect that you have become
pregnant during the study or within 5 months after your last dose atezolizumab.
The study doctor or research staff will inform you about the possible risks to
your unborn child and the options available to you.