AN OPEN-LABEL, MULTICENTRE, DOSE-ESCALATION, PHASE I STUDY WITH AN EXPANSION PHASE, TO EVALUATE SAFETY, PHARMACOKINETICS AND THERAPEUTIC ACTIVITY OF RO6895882, AN IMMUNOCYTOKINE, CONSISTING OF A VARIANT OF INTERLEUKIN-2 (IL-2v) TARGETING CARCINOEMBRYONIC ANTIGEN (CEA) ADMINISTERED INTRAVENOUSLY, IN PATIENTS WITH ADVANCED AND/OR METASTATIC SOLID TUMORS.

It is increasingly recognized that a low density of infiltrating immune cells
in the tumor is associated with a poor prognosis [2] and that the immune cells
infiltrating the tumor are not fully functional [3]. Activating the immune
system by therapy with cytokines such as IL-2 has therefore been used
successfully for the treatment of cancer [4]. IL-2 was consequently approved
as a treatment for melanoma and renal cell cancer. The utility of IL-2 is
however severely restricted by the widespread occurrence of side effects
requiring specialized care and knowledge [5].
RO6895882 was designed to improve on existing cytokine therapy by including the
following features and modifications: (i) it is a targeted cytokine that binds
to the tumor specific protein CEA (carcinoembryonic antigen). Thereby, it
accumulates in the tumor as shown by non-clinical experiments and will have an
increased local effect compared to untargeted cytokines. (ii) The IL-2 variant
(IL-2v) moiety was modified such that it does not bind to CD25 any longer
resulting in (a) reduced pulmumary endothelial activation, (pulmonary
endothelial activation was associated with vascular side effects, [6]), and
(iii) does not exhibit the preferential activating effect on regulatory
T-cells, which have immunosuppressive properties. In conclusion, RO6895882 is a
targeted immunocytokine with the potential to enhance antitumor immune
responses more efficiently and safely than existing cytokine therapy.

Substudy BP28920/IMG
At the 2 participating Dutch sites, an imaging substudy will be executed with
the title: "AN OPEN-LABEL PHASE I IMAGING STUDY OF RO6895882 USING 89Zr-LABELED
RO6895882 AS A TRACER, ADMINISTERED INTRAVENOUSLY, IN PATIENTS WITH ADVANCED
AND/OR METASTATIC SOLID TUMORS", in which monotherapy RO6895882 will be
combined with zirconium-89-labeled RO6895882.

Substudy BP28920/ obinutuzumab:
In all participating centra an obinutuzumab substudy will be performed wit the
titel:A MULTI-CENTER, RANDOMIZED, OPEN-LABEL
PHASE 1 STUDY TO EVALUATE FEASIBILITY, SAFETY AND PHARMACODYNAMIC EFFECT OF
PRETREATMENT WITH OBINUTUZUMAB PRIOR TO THERAPY WITH RO6895882, AN
IMMUNOCYTOKINE, CONSISTING OF A VARIANT OF INTERLEUKINE-2 (IL-2V) TARGETING
CARCINOEMBRYONIC ANTIGEN (CEA), ADMINISTERED INTRAVENOUSLY, IN PATIENTS WITH
LOCALLY ADVANCED AND/OR METASTATIC SOLID TUMORS, which will combine a
monotherpay with RO6895882 pretreated with RO507259

* to describe the safety profile for qW, q2W and q3W regimens.
* to determine the Maximum Tolerated Dose (MTD), if achieved (all regimens)
* to describe the pharmacokinetics (PK) of single-agent RO6895882.


Substudy BP28920/IMG
The study is designed to evaluate descriptively the tumor targeting and the
differences between CEA-positive and CEA-negative tumors, as well as to
describe qualitatively the relationship between targeting and PD effects. No
formal inferential analysis is foreseen given the limited sample size and the
expected variability in study endpoints. The main objective of the study is
exploratory.

89Zr- RO6895882 is the radioactively labeled form of RO6895882 for which the
radioactive substance zirconium-89 has been linked to RO6895882. 89Zr-
RO6895882 will be administered only once during this imaging sub-study. The
radioactive dose will be a low dose, making it possible to follow the
distribution of RO6895882 throughout the body by imaging (Positron Emission
Tomography [PET] scan). Otherwise 89Zr- RO6895882 has the same type of activity
as the unlabeled compound (RO6895882).

Substudy BP28920/ Obinutuzumab:
* To assess the the effect of pre-treatment with obinutuzumab on decreasing the
proportion of patients with ADA titer at cycle 4
* To evaluate the safety and tolerability of administration of obinutuzumab
given prior
to treatment with RO6895882

This is a first-in-human, open-label, multicenter, dose-escalation phase I
clinical study of single-agent RO6895882 with an expansion phase. The study
will be conducted in three parts. Part I is a single ascending dose study in
single patient cohorts to evaluate safety of RO6895882 at low doses (* 6 mg).
Part II is a dose-escalation part with RO6895882 monotherapy given qW, q2W and
q3W. Part III is an expansion phase of the qW, q2W and q3W MTD (as determined
in Part II). Part III of the trial will also include at least five patients
with CEA-negative tumors of either skin or kidney.
All parts of the trial will enroll patients with CEA-positive solid tumors for
whom no standard therapy is available. Part III is an expansion phase of the
qW, q2W and q3W MTD (as determined in Part II). Part III of the trial will also
include at least five patients with CEA-negative tumors of either skin or
kidney.

See protocol section 3 p. 34-36.

Substudy BP28920/IMG
Patients will be recruited in 5 different groups:
the tolerability of an IV bolus will be tested with the standard supply in a
pre-imaging (pre-IMG) dose group with two patients.
Group A (CEA positive) and B (CEA negative) will receive low dose
89Zr-RO6895882.
Group C (CEA positive) and D (CEA negative) will receive high dose of
89Zr-RO6895882.
Group E (CEA positive) and F (CEA positive) will receive a 2nd dose of
89Zr-RO6895882 on C4D1 and C3D1 respectively (if tumor targetting is
demonstrated by the 89Zr-RO6895882 PET scan at Cycle 1.

The low dose groups (pre-IMG, A, and B) will be recruited once Part I of the
main protocol is completed. The high dose groups (C and D) will start enrolment
after completion of the q2W MAD in Part II of the main study. In group A-D, per
group a minimum of 3 patients will be recruited. New patients will be enrolled
into groups E and F only if there is evidence of tumor targetting in patients
from group C.

See also protocol section 3 p. 33-35

Add. An 89Zr-PET scan will be included on C1D1 for the first 3 imaging patients
to enable more precise radiation dosimetry for the novel 89Zr-RO6895882. The
C1D1 scan will replace the C1D9 scan in order not to increase radiation load on
these patients. This is a de-risking strategy in the event of unexpected
bio-distribution due to the novel format of the antibody-conjugate. The
expected dosimetry has now been calculated but must also be measured in vivo to
ensure patient safety.

Substudy BP28920/ Obinutuzumab:
In this substudy 20 patients will be treated. Fifteen patients will be
randomized into the obinutuzumab pretreatment arm and five
patients to the control arm without obinutuzumab pretreatment. The patients in
the obinutuzumab pretreatment arm will receive 1g of obinutuzumab intravenously
on two consecutive days, Day -13 and Day -12 (+/- 2 days) before the Cycle 1
Day 1 (C1D1) RO6895882 administration
See also protocol section 3.1 P 53-55

The patients in the obinutuzumab pretreatment arm will receive 1g of
obinutuzumab intravenously on two
consecutive days, Day -13 and Day -12 (+/- 2 days) before the Cycle 1 Day 1
(C1D1)
RO6895882 administration.

Patients who are eligible will be treated with RO6895882 according the study
specific schedule as shown in appendix 1 of the protocol p. 106-118.

Substudy BP28920/IMG
Patients who are eligible will be treated with RO6895882 and 89Zr-RO6895882
according the study specific schedule as shown in appendix 1 of protocol
BP28920/IMG on p. 95-98.

Substudy BP28920/ obinutuzumab:
Patients who are eligible will be treated with RO6895882 and RO5072759
according the study specific schedule as shown in appendix 1 of Protocol
BP28920/ obinituzumab P126-133

Targeting CEA overexpressing tumor with IL-2v has the potential to provide
substantial anti-tumor immune response with lower associated toxicity compared
to untargeted, or unmodified IL-2 therapy and may also enable in the future, a
multitude of combinations with other immunotherapies or with established
anti-cancer agents. The existing non-clinical data set with RO6895882, in
conjunction with the extensive clinical experience with IL-2 provide an
acceptable risk-benefit balance for the clinical investigation of RO6895882 in
advanced cancer patients for whom no effective standard therapy exists.

See protocol section 1.2, p. 31-33.

Substudy BP28920/IMG
See also protocol BP28920/IMG, page 30-32.

The side effects of the tracer 89Zr-RO6895882 are not yet known, as it has not
been administered to humans before. Side effects could occur during or shortly
after the injection of the tracer. The amount of radioactivity that the patient
recieved does not have any therapteuric effect. Nonetheless, the patient will
be exposed to ionized radioation. The total amount of radiation that the
patient will receive as a result of this tracer is 60 mSv, this quantity is
accepted as under the current legislation.

SubstudY BP28920/ obinutuzumab:
Side effects of RO6895882 are similuar as in the main study. Possible risks of
obinutuzumab are infusion related reaction, alergic reactions and infections.
For more side effects see patient informationsheet.