AN OPEN-LABEL, MULTICENTER, PHASE I STUDY EVALUATING THE SAFETY, TOLERABILITY, PHARMACOKINETICS,
PHARMACODYNAMICS, AND PRELIMINARY CLINICAL ACTIVITY OF RO7428731 IN PARTICIPANTS WITH GLIOBLASTOMA EXPRESSING MUTANT EPIDERMAL GROWTH FACTOR RECEPTOR VARIANT III

- Aged >=18 years
- Life expectancy of >= 12 weeks, in the opinion of the Investigator
- Diagnosis of GBM based on on world health organization (WHO) classification
of central nervous system (CNS) tumors, 5th edition
- Confirmed Epidermal growth factor receptor variant III (EGFRvIII)
- expression by a College of American Pathologists (CAP)/Clinical Laboratory
Improvement Amendments (CLIA) certified central laboratory, in an archival
tumor tissue sample using an investigational EGFRvIII immunohistochemistry
(IHC) assay
- Karnofsky Performance Status (KPS) Score of >=70%
- Adequate organ functions within 7 days prior to start of study treatment
- Coagulation activity: International Normalized Ratio <=1.5
- Willingness to abide by contraceptive measures for the duration of the study

Additional Inclusion Criteria for Part I and Part II only
- Participants whose tumors have an unmethylated (Part I and Part II) or
methylated (Part I only) O6-methylguanine-DNA methyltransferase

(MGMT) promotor status based on local assessment - Participants (in
Part I):
-- Adult participants with newly diagnosed EGFRvIII-positive GBM with
unmethylated MGMT promotor status who have completed standard of care (SoC)
therapy with surgical resection and adjuvant radiotherapy with or without
concomitant TMZ. Participants are allowed to have received any number of cycles
of TMZ
maintenance
-- Adult participants with newly diagnosed EGFRvIII-positive GBM with
methylated MGMT promotor status who have completed SoC with surgical resection
and adjuvant radiotherapy with concomitant and maintenance TMZ or discontinued
TMZ maintenance due to reasons other than progressive disease

- Participants (in Part II):
--- Adult participants with newly diagnosed EGFRvIII-positive GBM with
unmethylated MGMT promotor status who have completed SoC
therapy with surgical resection and adjuvant RT with or without concomitant
temozolomide (TMZ)
- Treatment start date at least 4 weeks after but not more than 9 weeks from
the last dose of RT or TMZ, whichever was administered last (applicable to all
participants in part I/II)
- Baseline MRI within 2 weeks prior to start of study treatment with no
evidence of progressive disease per response assessment in neurooncology (RANO)
criteria from the post-operative MRI to the baseline MRI

Additional Inclusion Criteria for Part III and Part IVA only
- Previous first line treatment with at least radiotherapy (RT) and, for
participants with a methylated MGMT promotor status, TMZ
- Documented first or second recurrence of GBM
- At least one measurable GBM lesion as per RANO criteria prior to initiation
of study treatment that meets the following criteria: I) Contrast enhancing and
clearly defined, bi-dimensionally measurable margins AND ii) At least two
perpendicular diameters measuring >=10 mm X >=10 mm

- Participants with infratentorial tumors and tumors primarily located in or
close to critical structures
- Presence of extracranial metastatic or leptomeningeal disease
- Known hypersensitivity to immunoglobulins or to any other component of the
investigational medicinal product (IMP) formulation
- Therapy with any other investigational drug within 28 days or 5 half-lives of
the drug before the first day of study treatment
- Treatment with systemic immunosuppressive medication within 2 weeks prior to
initiation of study treatment
- Administration of a live, attenuated vaccine within 28 days before first day
of study treatment or anticipation that such a live attenuated vaccine will be
required during the study
- Acute treatment-related toxicities from prior anti-cancer therapy that have
not resolved to Grade <=1 or returned to baseline, except for alopecia (any
grade), Grade 2 peripheral neuropathy, and any laboratory changes that still
meet the inclusion criteria defined above
- Significant cardiovascular disease
- Active bleeding or pathological condition that carries a high risk of
bleeding, including inherited and acquired coagulopathies
- History or evidence upon physical/neurological examination of central nervous
system disease unrelated to cancer and potentially interfering with protocol
treatment unless adequately controlled by medication
- Dementia or altered mental status that would prohibit informed consent
- Alcohol or drug dependency or abuse
- Participants unable to undergo an MRI with contrast
- Any other disease, metabolic dysfunction, physical examination finding, or
clinical laboratory finding that contraindicates the use of an investigational
drug, may affect the interpretation of the results, or may render the
participant at high risk from treatment complications

Exclusion Criteria-applicable for Part I and Part II only
- Recurrent malignant gliomas

Exclusion criteria-applicable for Part III and Part IVA only
- More than two recurrence of GBM
- Prior EGFRvIII targeting agents, anti-angiogenic therapy and/ or gene-therapy
for the treatment of GBM and gliomas

Specific Exclusion Criteria if Pretreatment with Obinutuzumab is Implemented
- History of progressive multifocal leukoencephalopathy
- Active tuberculosis requiring treatment within 3 years prior to initiation of
study treatment or latent tuberculosis that has not been appropriately treated
- Positive test results for human T-cell lymphotropic virus 1 (HTLV-1). This
testing is required in participants from endemic countries (Japan,
countries in the Caribbean basin, South America, Central America, sub- Saharan
Africa, and Melanesia)
- Known hypersensitivity to any of the components of obinutuzumab