AN OPEN-LABEL, MULTICENTER, DOSE ESCALATION PHASE I STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS, AND THERAPEUTIC ACTIVITY OF RO6958688, A NOVEL T CELL BISPECIFIC ANTIBODY THAT TARGETS THE HUMAN CARCINOEMBRYONIC ANTIGEN (CEA) ON TUMOR CELLS AND CD3 ON T CELLS, ADMINISTERED INTRAVENOUSLY IN PATIENTS WITH LOCALLY ADVANCED AND/OR METASTATIC CEA(+) SOLID TUMORS

Binding of RO6958688 to CEA and CD3 leads to T-cell activation and tumor cell
lysis. The RO6958688-mediated tumor cell lysis is CEA-specific and does not
occur in the absence of CEA expression or in the absence of simultaneous
binding (cross-linking) of T cells to CEA-expressing tumor cells (RO6958688
Investigator*s Brochure). In addition to killing, T cells undergo activation
followed by tumor lysis as
detected by increase of late and early T-cell activation markers (CD25 and
CD69, respectively), cytokine release (interferon * [IFN*], tumor necrosis
factor * [TNF*], granzyme B, interleukin [IL]-2, IL-6, IL-10), and
proliferation of T cells (RO6958688 Investigator*s Brochure).

See for more background information page 38-46 in the protocol.

Study BP29541 is a first in-human, open-label, multicenter, dose-escalation
Phase I clinical study of single-agent RO6958688. The study will be conducted
in two parts. Part I of the study is single ascending dose in single patient
cohorts to evaluate the safety of RO6958688 at the doses that are expected to
be below relevant biological effects (starting from a receptor occupancy of
0.11% for the CD3 epsilon chain receptors), and Part II is multiple ascending
dose with a dose finding part where RO6958688 is given QW to define the MTD
and/or the recommended dose for further development. Sponsor will open, in Part
II, parallel multiple ascending dose escalation cohorts of patients receiving
obinutuzumab pre-treatment. QW dosing of RO6958688 (± 1 day) will be
implemented initially to generate data that can be analyzed to assess whether
different dosing schedules are more effective. Sponsor will also open, in Part
II, cohorts of patients pretreated with obinutuzumab either with QW flat dose,
Q3W flat dose or step up dosing scheme will also be enrolled, in order to
assess if obinutuzumab pretreatment would decrease the incidence and/or delay
the onset of ADA directed against RO6958688

This is an open-label, multicenter, dose-escalation Phase I clinical study of
single-agent RO6958688. The study will be conducted in two parts. Part I of
the study is single ascending dose in single patient cohorts to evaluate the
safety of RO6958688 at the doses that are expected to be below relevant
biological effects (starting from a receptor occupancy of 0.11% for the CD3
epsilon chain receptors), and Part II is multiple ascending dose with a dose
finding part where RO6958688 is given QW to define the MTD and/or the
recommended dose for further development. Sponsor will also open, in Part II,
cohorts of patients pretreated with obinutuzumab either with QW flat dose, Q3W
flat dose or step up dosing scheme, in order to assess if obinutuzumab
pretreatment would decrease the incidence and/or delay the onset of ADA
directed against RO6958688. Refer to figure 6, page 62 of the protocol with the
study scheme/cohorts.


RO6958688 will be administered via intravenous infusion. At the discretion of
the investigator and in agreement with the Sponsor, all patients can receive
further doses QW at the same dose level or the next available tolerated dose
level that has been cleared for dose escalation after they have completed 2
months of treatment at the current dose level. The treatment period for this
protocol is 24 months for RO6958688 and may be modified if supported by
emerging data. Because of the potential for progression prior to response with
immune therapies, patients who exhibit clinical benefit will continue treatment
beyond radiographic progression after discussion and agreement with the Sponsor.
The study will be conducted in two parts. Part I and Part II of the trial will
enroll patients with locally advanced and/or metastatic carcinoembryonic
antigen (CEA) positive solid tumors who have progressed on standard treatment,
are intolerant to standard of care (SOC), and/or are non amenable to SOC.

For more information see also page 58-66 in the protocol (page 14-15 in the
synopsis)

Patients eligible for participation in this study are treated with RO6958688,
see for administration details, page 89-99 of the protocol.

The following problems may be caused by RO6958688 in this study:

Swelling (inflammation) of non-healthy lymph nodes induced by RO6958688
causing obstruction of the airways leading to acute respiratory failure
(breathing difficulties) resulting in death, occurred in a patient treated with
a dose of 600mg RO6958688 in the dose-escalation part of the single agent
BP29541 study. The patient had received the full planned dose and the event
started within 24 hours after administration of the first RO6958688
dose.Patients will receive a preventive treatment with corticosteroids for up
to 4 days after the first administration of RO6958688 (QW and Q3W regimen). The
use of corticosteroids before the infusion of RO6958688 may be considered if
indicated.

Infusion related reaction, allergic and hypersensitivity reactions:
Based on experience with monoclonal therapeutic antibodies, reactions to
RO6958688 during and/or after the administration of the study drug (so-called
infusion-related reactions, allergic or anaphylactic reaction, hypersensitivity
reaction) may be experienced.

Infusion-related reactions (IRR): IRRs could occur at the time of, shortly
after or within 24 hours after study drug administration (IV infusion). They
are more likely to occur at the first infusion with the severity and chance of
them occurring decreasing at future administrations. Symptoms of an IRR
include fever, shivering or chills, nausea, vomiting, high blood pressure,
disturbed heart rhythm, breathing difficulties, headache, low blood pressure,
(tumor) pain, restlessness, diarrhoea, dizziness, sweating, flushing, rapid
breathing.When experiencing an infusion related reaction, it may be necessary
to give medications to prevent the worsening of this reaction and prevent
future reactions.

Allergic reaction: allergic reaction to the study drug may also occur.
Allergic reactions can be mild, such as a skin rash or pimples, but can also be
severe, such as difficulty breathing or shock. Allergic and IRR appearance can
be difficult to tell apart. A severe allergic reaction must be treated, and
the patient may have to be admitted to the emergency unit for this. In very
rare cases, such a reaction can be fatal.

Development of antibodies to the study drug: When receiving RO6958688, there
is a possibility that the immune system might develop antibodies against the
drug, so-called anti-drug antibodies (ADA), which may occur after the
administration of monoclonal therapeutic antibodies. Therefore, if these
special antibodies are developed, it may affect the body*s ability to respond
to other drugs of a similar type. At times side effects can occur due to the
development of ADA which worsen over time. Usually these side effects are skin
rash, joint and muscle pain, fever and tiredness. It is possible to have a
transient changed sense of taste or to develop transient peeling of the skin at
the palms and soles of their feet. Medicines can be prescibed to decrease the
effect of these symptoms. If these side effects are severe or persist for a
very long time, it may be necessary to permanently discontinue administration
of RO6958688.

If certain side-effects occur due to the drug RO6958688, the doctor will always
discuss the options to tolerate the treatment better. If any of the symptoms
that are experienced are related to infusion during RO6958688 administration,
the infusion may slow down, or temporarily or permanently be stopped. Once the
symptoms have responded to any treatment and resolved, the infusion may be
continued. To help prevent or reduce the intensity of any reaction related to
the infusion, orally or intravenously (in the vein) a drug against fever, such
as paracetamol and an antihistamine about 30 minutes before the infusion of
RO6958688 can be given. If a severe IRR (infusion-related reaction) is
experienced at the time of an infusion, corticosteroid treatment may also be
received intravenously. If severe reaction related to the infusion during the
previous treatment cycle is experienced, medication against the reaction will
be received, such as paracetamol or an antihistamine, or a corticosteroid to
prevent the occurrence of similar signs and symptoms at the next cycle of
treatment, 30 minutes before infusion. The doctor / study research staff will
carefully monitor the patient while given RO6958688 and for a time afterwards.
If a severe reaction develops, especially severe breathing difficulties,
additional tests on the blood or an x-ray of the chest might be needed. The
infusion will not resume unless the doctor is sure that the patient recovered
completely from the reaction. In the event of a severe reaction, the patient
may be withdrawn from the study.
Most of these side effects will disappear when appropriately treated or when
the treatment with the study drug is delayed and/or stopped.
It is possible that new side effects of RO6958688, unknown at this time, may
occur during the study.
Study procedure related risk

Tumor biopsy (Part II)

The most common risks of a biopsy are discomfort during the biopsy procedure,
bleeding and infection. With lung biopsies there is also a risk of
pneumothorax (lung collapse); often a chest X-ray is done immediately after the
biopsy to check if this has happened and if necessary a chest tube may be
inserted to re-expand the lung. If you have trouble breathing or your heart
rate increases after being discharged from the hospital, it is important to
call your study doctor or emergency services immediately. Other risks may
exist depending on the location of the tumor being biopsied including puncture
of a nearby organ. Your study doctor will discuss these with you. If your
study doctor feels you would be at an additional risk from the biopsy after
start of treatment then this biopsy would either be postponed or cancelled
without affecting your treatment or your participation in the study.

What are the risks of the tumor assessment?

There is a potential risk of radiation exposure from CT scans; however, this
risk is considered small. An intravenous (in the vein) contrast dye is usually
given with a CT scan. If allergies are experienced already it is more likely
to have an allergic reaction to the dye. This reaction may be mild (such as
skin rash or hives) to severe (such as breathing difficulties or shock). A
severe allergic reaction would require immediate medical treatment and could
result in permanent disability or death. YMRI: Implanted medical devices that
contain metal may malfunction or cause problems during an MRI exam. There is a
very slight risk of an allergic reaction if contrast material is injected.
Such reactions usually are mild and easily controlled by medication. If
allergic symptoms are experienced, a radiologist or other physician will be
available for immediate assistance.

Blood sampling
The risks of blood sampling include slight pain from the needle prick,
bruising, discomfort where the blood was taken, and, in rare cases, fainting or
infection may occur or anemia may worsen.