A Study Evaluating the Safety, Pharmacokinetic and Anti-tumor Activity of RO7428731 in Participants With Glioblastoma

Study Overview
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Brief Summary
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This is an open-label, multicenter study to assess safety, tolerability, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and preliminary efficacy of RO7428731 administered as a monotherapy in participants with newly diagnosed or recurrent epidermal growth factor receptor variant III (EGFRvIII)-positive glioblastoma (GBM).

Official Title
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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

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: RO7428731


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion criteria for all participants: Life expectancy of greater than or equal to 12 weeks, in the opinion of the Investigator Diagnosis of GBM based on World Health Organization (WHO) classification of central nervous system (CNS) tumors, 5th edition Participants must have confirmed EGFRvIII-expression Karnofsky Performance Status (KPS) Score of >=70% Adequate organ functions prior to start of study treatment Willingness to abide by contraceptive measures for the duration of the study. 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 therapy with surgical resection and adjuvant radiotherapy with or without concomitant temozolomide. Participants are allowed to have received any number of cycles of temozolomide maintenance. Adult participants with newly diagnosed EGFRvIII-positive GBM with methylated MGMT promotor status who have completed standard of care with surgical resection and adjuvant radiotherapy with concomitant and maintenance temozolomide or discontinued temozolomide 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 standard of care therapy with surgical resection and adjuvant radiotherapy with or without concomitant temozolomide. Inclusion criteria for Part III and Part IV A only: Documented first or second recurrence of GBM At least one measurable GBM lesion as per Response Assessment in Neuro-Oncology (RANO) criteria prior to initiation of study treatment. Exclusion Criteria: Exclusion criteria for all participants: Participants with infratentorial tumors and tumors primarily located in or close to critical structures (e.g., brain stem) Presence of extracranial metastatic or leptomeningeal disease Known hypersensitivity to immunoglobulins or to any other component of the investigational medicinal product formulation Active bleeding or pathological condition that carries a high risk of bleeding, including inherited and acquired coagulopathies Participants unable to undergo an MRI with contrast. Exclusion criteria for Part I and Part II only: Recurrent malignant gliomas Any prior anti-tumor treatment for GBM: tumor resection, adjuvant radiotherapy with or without concomitant temozolomide and temozolomide maintenance (Part I only) must be the only tumor-directed treatment that the participant has received for GBM. Exclusion criteria for Part III and Part IV A only: More than two recurrences of GBM Prior anti-EGFRvIII-targeting agents (including vaccines), anti-angiogenic therapy, and/or gene therapy for the treatment of GBM and gliomas.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I: Dose Escalation<br>Participants with newly diagnosed GBM will receive RO7428731, intravenously (IV), up to one year or until disease progression, withdrawal of consent, unacceptable toxicity, or death, whichever occurs first. | Drug: RO7428731<br>* Participants will receive RO7428731 as described.<br>|
| Experimental: Part II: Dose-Expansion(s)<br>Participants with newly diagnosed GBM will receive RO7428731, IV, in maximum of two dose expansion cohorts at a dose(s) not exceeding the maximum tolerated dose (MTD) established in Part I. | Drug: RO7428731<br>* Participants will receive RO7428731 as described.<br>|
| Experimental: Part III: Safety Run-in<br>Participants with recurrent GBM will receive RO7428731, IV in a dosing schedule determined in Part I. At the end of the Safety Run-in period, a decision will be made as to whether to open the Dose-Expansion Cohort Part IVA or open a second Safety Run-in Cohort at a lower dose. | Drug: RO7428731<br>* Participants will receive RO7428731 as described.<br>|
| Experimental: Part IV A: Dose-Expansions Cohort<br>Participants with recurrent GBM will receive RO7428731, IV at specified doses and dosing schedules. | Drug: RO7428731<br>* Participants will receive RO7428731 as described.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Adverse Events (AEs) |  | Up to the safety follow-up visit 60 days after the last treatment (up to approximately 15 months) | 
| Percentage of Participants with Dose Limiting Toxicities (DLTs) |  | Cycle 1 (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Concentration of RO7428731 |  | Up to the safety follow-up visit 60 days after the last treatment (up to approximately 15 months) | 
| Percentage of Participants With RO7428731 Anti-drug Antibodies (ADAs) |  | From baseline up to the safety follow-up visit 60 days after the last treatment (up to approximately 15 months) | 
| Objective Response Rate (ORR) |  | From start of study treatment up to approximately 3 years | 
| Disease Control Rate (DCR) |  | From start of study treatment up to approximately 3 years | 
| Duration of Response (DOR) |  | From the time of first occurrence of a documented response until the time of documented disease progression or death (death within 30 days from last study treatment) from any cause, whichever occurs first (up to approximately 3 years) | 
| Progression-free Survival (PFS) |  | From start of study treatment to the first occurrence of documented disease progression or death from any cause, whichever occurs first (up to approximately 3 years) | 
| Overall Survival (OS) |  | From start of study treatment to the time of death from any cause (up to approximately 3 years) |