A PHASE III, OPEN-LABEL, MULTICENTER, RANDOMIZED STUDY TO INVESTIGATE THE EFFICACY AND SAFETY OF ATEZOLIZUMAB (ANTI*PD-L1 ANTIBODY) COMPARED WITH CHEMOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC UROTHELIAL BLADDER CANCER AFTER FAILURE WITH PLATINUM-CONTAINING CHEMOTHERAPY

Atezolizumab is a human IgG1 monoclonal antibody consisting of two heavy chains
(448 amino acids) and two light chains (214 amino acids) and is produced in
Chinese hamster ovary cells. Atezolizumab was engineered to eliminate
Fc-effector function via a single amino acid substitution (asparagine to
alanine) at position 298 on the heavy chain, which results in a
non-glycosylated antibody 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
receptors, programmed death-1 (PD-1) and B7.1 (CD80, B7-1). Both of these
interactions are reported to provide inhibitory signals to T cells.
Atezolizumab is being investigated as a potential therapy against solid tumors
and hematologic malignancies in humans.

For more background of the study see page 25-29 in the protocol

This is a phase III, open-label, multicenter, randomized study to investigate
the efficacy and safety of atezolizumab (anti PDL1 antibody) compared with
chemotherapy in patients with locally advanced or metastatic urothelial bladder
cancer after failure with platinum-containing chemotherapy

This is a Phase III, global, multicenter, open-label, two-arm, randomized,
controlled study designed to evaluate the efficacy and safety of atezolizumab
compared with chemotherapy in patients with locally advanced or metastatic UBC
who have progressed during or following a platinum-containing regimen. The
selection of the specific chemotherapy for patients who are randomized to the
chemotherapy arm will be per investigator*s choice.
Male and female patients aged > 18 years with Eastern Cooperative Oncology
Group (ECOG) performance status of 0 or 1 who have histologically or
cytologically proven, locally advanced or metastatic UBC and who have
experienced disease progression during or following treatment for advanced
disease consisting of platinum-based therapy are eligible.
Patients who experience disease progression during or within 12 months
following completion of a platinum-based adjuvant or neoadjuvant regimen will
also be eligible for enrollment into the study.
Patients must have received at least one platinum containing regimen (e.g.,
gemcitabine and cisplatin [GC], methotrexate, vinblastine, doxorubicin, and
cisplatin [MVAC], carboplatin and gemcitabine [CarboGem], etc.) for locally
advanced or metastatic UBC. The maximum number of prior therapies in the
locally advanced or metastatic setting is restricted to two.
Tumor specimens from eligible patients will be prospectively tested for PD-L1
expression by a central laboratory. Both patients and investigators will be
blind to the PD-L1 expression status. The study will enroll all patients whose
tissue is evaluable for expression testing, regardless of PD-L1 expression
status.
This study will enroll approximately 767 patients, including a minimum of 230
patients with PD-L1 immunohistochemistry (IHC) 2/3 (enrollment of all patients
will continue to reach the minimum requirement of patients with PD-L1 IHC 2/3).
Patients will be randomized in a 1:1 ratio to receive either atezolizumab or
chemotherapy (vinflunine, paclitaxel, or docetaxel):
- Arm A (experimental arm): atezolizumab 1200 mg every 3 weeks (q3w)
Arm B (control arm): Vinflunine 320 mg/m2 q3w, paclitaxel 175 mg/m2 q3w, or
docetaxel 75 mg/m2 q3w

Test product

Atezolizumab is administered at a dose of 1200 mg by IV infusion on Day 1 of
each 21-day cycle.

Comparators

Vinflunine is administered at a dose of 320 mg/m2 by IV infusion on Day 1 of
each 21-day cycle.
Paclitaxel is administered at a dose of 175 mg/m2 over 3 hours by continuous IV
infusion on Day 1 of each 21-day cycle.
Docetaxel is administered at a dose of 75 mg/m2 on Day 1 of each 21-day cycle.

Side effects from the drugs or procedures used in this study may be
experienced. Side effects can vary from mild to very serious and may vary from
person to person. Everyone taking part in the study will be watched carefully
for any side effects. However, Roche, the study doctor, and other doctors do
not know all of the side effects that could occur. The study doctors may give
drugs to help lessen side effects. Many side effects go away soon after you
stop what is causing them. In some cases, side effects can be serious and may
be long lasting or may never go away. There also is a rare risk of death. The
doctor will evaluate the subject for any symptoms during your study visits.
One of the drugs the subjects may be randomized to is called docetaxel. This
drug contains alcohol, which may cause the experience of intoxication or feel
drunk during and after treatment. If this is a concern, or if alcohol needs to
be avoided or the exposure to alcohol should be kept to a minimum, this should
be discussed with the doctor prior to participating in the study.


SIDE EFFECTS ASSOCIATED WITH ATEZOLIZUMAB TREATMENT
Some or all of these same side effects can be experienced. It is also possible
that side effects are experienced that are unknown at this time. As is true
for any experimental drug, there may be unknown and potentially serious or life
threatening side effects that could occur with atezolizumab . Once the drug is
stopped it is not known how long the side effect of the drug will last.
The following events are those considered associated with atezolizumab
* Colitis (inflammation of the intestines); symptoms may include diarrhea,
blood in stool, and stomach pain.
* Flu-like illness (symptoms include fever, fatigue, asthenia [lack of energy],
chills, myalgia [muscle pain], arthralgia [joint pain], and headache).
* Inflammation of the thyroid and adrenal glands (hypothyroidism,
hyperthyroidism, or adrenal insufficiency); symptoms may include headaches,
tiredness, weight loss, weight gain, change in mood, hair loss, constipation,
and dizziness.
* Hepatitis (inflammation of the liver); symptoms may include yellowing of
skin, nausea, vomiting, bleeding or bruising, dark urine, and stomach pain.
* Meningitis (inflammation of the membrane around the spinal cord and brain);
symptoms may include neck stiffness, headache, fever, chills, vomiting, and eye
sensitivity to light).
* Neuropathies (damage to the nerves); symptoms may include muscle weakness and
numbness and tingling in hands and feet.
* Pneumonitis (inflammation of the lungs); symptoms may include new or
worsening cough, shortness of breath, and chest pain.
* Reactions associated with infusion (events occurring during or within 1 day
following infusion and include fever, chills, shortness of breath, and flushing)
* Skin reactions (rash, itching, dry skin, redness, and changes in skin
pigmentation)


Immune Related Side Effects
Atezolizumab is designed to increase the number of immune system cells that can
fight cancer. These cells may cause inflammation within the tumor, as well as
with normal tissue. Therefore, by taking atezolizumab you may develop a
condition where there is inflammation against a part of your own body (an
autoimmune disease). These events are rare and are listed in the table above.

Allergic Reactions
Allergic reactions may occur with atezolizumab and typically occur while it is
being given into your vein or shortly after it is given. No events of allergic
reactions to atezolizumab have been reported. Symptoms could include nausea,
vomiting, skin reactions (hives or rash), difficulty breathing, or low blood
pressure. These reactions could be mild or severe and might lead to death or
permanent disability. If you experience these symptoms, your study doctor will
interrupt or even stop the delivery of atezolizumab into your vein. Your
study doctor may also give you some drugs to treat these symptoms.

Other Medications
If a vaccination is required, it is required to receive it at least 4 weeks
before receiving treatment with atezolizumab . The patient must agree not to
receive live, attenuated vaccines during treatment or within 90 days following
the last dose of atezolizumab. Atezolizumab may have some side effects that
may overlap with some of the side effects caused by other medications that also
stimulate the immune system. It may be dangerous to take both of these drugs
at the same time. It is important to tell the doctor the last time any
medication stimulating the immune system has been taken. It is also important
that you do no other drugs that may alter your immune system (immunomodulatory
drugs) are taken for 10 weeks after your last dose of atezolizumab .
Once the drug is stopped, it is not known how long the side effect(s) of the
drug will last.

For risks of chemotherapeutics and other risks, see page 82 to 96 of the
protocol and the informed consent form