An open-label, multicenter, dose escalation and expansion Phase Ib study to evaluate the safety, pharmacokinetics and therapeutic activity of RO6958688 in combination with atezolizumab in patients with locally advanced and/or metastatic CEA-positive solid tumors

Cancer is the leading cause of death worldwide.
Despite the advances in chemotherapy and targeted therapies, the prognosis of
patients with advanced cancer remains poor in general. Consequently, there is a
persisting and urgent medical need to develop new therapies that can be added
to existing treatments to increase survival without causing unacceptable
toxicity.

RO6958688 is a new T-cell bispecific antibody (TCB), which focuses on the
carcinoantigeen (CEA) which is expressed on tumor cells for T cells. Upon
binding of RO6958688, this leads to T cell activation and tumor cell lysis.

Atezolizumab is a humanized immunoglobulin (IgG1) monoclonal antibody that
increases the tumor-specific T cell response by interference in the PDL1 (PD-1)
and PDL1 B7.1(CD80, B7-1) interactions.

Clinical benefit from atezolizumab given as monotherapy or combined therapy was
observed in a broad range of malignancies including non-small cell lung cancer
(NSCLC), renal cell carcinoma (RCC), melanoma, urothelial bladder cancer (UBC),
colorectal cancer (CRC), head and neck cancer, gastric cancer, breast cancer
and sarcoma.

For more background infromation see protocol section 1.1-1.4

The primary objectives of this study are:
* To establish the preliminary safety and tolerability profile of RO6958688 in
combination with atezolizumab
* To determine the maximum-tolerated dose (MTD) in cycle 1 and in later cycles,
if achieved, of RO6958688 in combination with atezolizumab
* To identify a recommended phase II dose and schedule (RP2D) of RO6958688 in
combination with atezolizumab.

Secundary objectives
The secondary objectives for this study are:
* To describe the preliminary pharmacodynamic (PD) effects and duration of PD
response for RO6958688 in combination with atezolizumab in mandatory paired
tumor biopsies and paired blood samples on the basis of alterations in the
quantity and quality of intratumoral T cells and peripheral blood cells
(including but not limited to CD3+, CD4+, CD8+ T cells, and other immune cells
that might act as potential predictors of anti-tumor activity of RO6958688 in
combination with atezolizumab)
* To describe the pharmacokinetics (PK) of RO6958688 and atezolizumab when
administered in combination
* To obtain preliminary anti-tumor activity data of RO6958688 in combination
with atezolizumab on objective overall response rate (ORR), duration of
response (DOR) and derived measures, disease control rate (DCR; defined as
response rate [RR] + stable disease rate [SDR]), preliminary progression-free
survival (PFS)on treatment and overall survival (OS) data according to Response
Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 criteria and modified
RECIST criteria by investigator assessment for the whole study and by central
assessment for prospective and retrospective analysis.
* To estimate the overall response rate (ORR) and disease control rate (DCR)
and PFS on treatment rate at relevant landmark timepoints (24 weeks) for
RO6958688 in combination with atezolizumab.

The exploratory objectives for this study are:
* To explore the relationship between exposure, pharmacodynamics, metabolic
activity of the tumor and clinical effects of RO6958688 when administered in
combination with atezolizumab
* To explore the immunogenicity of RO6958688 when administered in combination
with atezolizumab
* To explore the relationship of host and tumor genetic factors with PD or
clinical response to therapy
* To investigate tumor mutations, gene expression and other biomarkers related
to RO6958688+atezo combination therapy.
* To characterize the natural growth of the tumor using tumor growth kinetics
modeling.
* To explore preliminary safety and efficacy in low/moderate and very low CEA
expressing tumors

This is an open-label, multi-center, dose escalation and expansion Phase Ib
clinical study of RO6958688 in combination with atezolizumab. Each treatment
cycle will be 21 days in duration and consists of IV infusions of RO6958688
given weekly (QW) (+/-1 day) or every 3 weeks (Q3W) (+/-2 days) in combination
with atezolizumab given every 3 weeks (Q3W) (+/-2 days).
Patients will receive atezolizumab (1200 mg fixed dose) IV on Day 1 of each
cycle, followed by RO6958688 at least half an hour later, given IV on Day 1,
Day 8 and Day 15 of each cycle for the QW regimen and on Day 1 of each cycle
for the Q3W regimen. A weekly (QW) step up dosing approach may be considered.
The study will be conducted in two parts (figure 5 protocol, page 65). Part 1
is divided in parts 1A and 1B, and Part II.
Part 1A is a dose escalation part: patients will receive atezo weekly (1200 mg
fixed dose) IV on Day 1 of each cycle, followed by RO6958688 3-weekly at least
30 minutes later, given IV on Day 1, Day 8 and Day 15 of each cycle.
Deel 1B is a dose/schedule finding part:
Gedurende de 6 cycli wordt 6 x atezo 1200 mg toegediend middels 250 mL IV
infusie (3-wekelijks) in combinatie met RO6958688 waarvan er 4 verschillende
doseringsschema's RO6958688 mogelijk zijn:
1.1 Weekly (QW) with a dose of 100 mg RO6958688, or 1.2 every 3 weeks (Q3W)
with a dose of 100 mg RO6958688
2. Weekly (QW) with a starting dose of 40 mg RO6958688 and then the RO6958688
dose will be increased each week up to 150 mg after which RO6958688 will be
administered every 3 weeks (Q3W).
3. Weekly (QW) with a starting dose of 40 mg RO6958688, and then the RO6958688
dose will be increased each week up to 600 or 1200 g after which RO6958688 will
be administered every 3 weeks (Q3W).
4. Weekly (QW) with a starting dose of 100 mg RO6958688, and then the RO6958688
dose will be increased each week up to either 600 mg after which RO6958688 will
be administered every 3 weeks (Q3W). The decision to open this dose regimen
will be related to the data generated in the previous dose regimens (1 to 3).

Part II is an expansion part to confirm the safety and tolerability of the MTD
dose (or OBD) as determined in Part I in order to define an RP2D and schedule
of RO6958688 in combination with atezolizumab, and to explore preliminary
antitumor activity, pharmacokinetic and pharmacodynamic effects.

Patients will be treated until loss of clinical benefit, unacceptable
toxicities, or withdrawal of consent. The treatment period for this protocol
is 24 months for both RO6958688 and atezolizumab and may be modified if
emerging data supports an alternative duration of therapy. In case one of the
treatments is permanently discontinued, treatment with the other drug alone may
be continued as long as the patient experiences clinical benefit in the opinion
of the investigator or until unacceptable toxicity or symptomatic deterioration
develops, which is attributed to
disease progression as determined by the investigator and the Sponsor after an
integrated assessment of radiographic data, biopsy results (if available), and
clinical status, or withdrawal of consent.

For more information regarding the study design, see protocol section3.

Patients eligible for participation in the study will be treated with RO6958688
and atezolizumab. Patients will receive RO6958688 every week (QW) or every 3
weeks (Q3W) and atezolizumab every 3 weeks.
For more details concerning IMP administration see protocol section 4.3

Sections E2, E3 and E4 describe the assessments and impact the study has on
subjects.
In brief:
During 6 cycles the subjects come for 27 visits (weekly schedule) or 23 visits
(every 3 weeks schedule). In the Schedule of Assessments (refer to Appendix 1)
all assessments are described. Among others: Physical examination, blood
withdrawal, IMP infusion, vital functions, lung function, ECG, Biopsies, Scans.


At E9 the possible risk and, side effects and described. For completeness of
the possible side effects, please refer to the ICF.