A Study to Evaluate the Safety, Pharmacokinetics, and Anti-Tumor Activity of RO7589831 in Participants With Advanced Solid Tumors

Study Overview
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Brief Summary
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This is a first-in-human, Phase I, open-label, multicenter, dose-escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of RO7589831 monotherapy in participants with microsatellite instability (MSI) and/or deficient mismatch repair (dMMR) advanced solid tumors. RO7589831 is an oral drug that acts on a protein called Werner (WRN), which may promote the growth of cancers that are MSI and/or dMMR. By acting on WRN, RO7589831 may be able to block the growth of these types of cancer.

Official Title
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A Phase I, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Anti-Tumor Activity of RO7589831 in Participants With Advanced Solid Tumors Harboring Microsatellite Instability (MSI) and/or Deficient Mismatch Repair (dMMR)

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: RO7589831


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 Have a locally confirmed microsatellite instability (MSI) and/or deficient mismatch repair (dMMR), histologically or cytologically documented advanced (unresectable and/or metastatic) solid tumor Have received and then progressed following or are intolerant to at least 1 standard treatment regimen in the advanced setting Presence of measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Life expectancy of at least (≥)12 weeks Availability of formaldehyde-fixed paraffin-embedded (FFPE) archival tumor tissue for submission to Sponsor/central laboratory for retrospective central testing; for participants without archival tissue, a biopsy from either primary or metastatic tumor lesion, deemed medically feasible, must be taken Adequate hematologic, end-organ, and cardiovascular function, as defined in the protocol Exclusion Criteria: Inability or unwillingness to swallow pills Malabsorption syndrome or other condition that would interfere with enteral absorption Known hypersensitivity or intolerance to ingredients from the study drug formulation including patients with rare genetic disorders such as galactosaemia, glucose-galactose intolerance or congenital lactase deficiency Known uncontrolled central nervous system (CNS) metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control) and/or carcinomatous meningitis Known active or uncontrolled bacterial, viral, fungal, mycobacterial (including but not limited to tuberculosis and atypical mycobacterial disease), parasitic, or other infection (excluding fungal infections of nail beds), or any major episode of infection requiring treatment with intravenous antibiotics or hospitalization within 2 weeks prior to the start of drug administration (related to the completion of the course of antibiotics, except if for tumor fever) or 6 months for any intracranial abscess Has a positive test at screening for hepatitis B virus, hepatitis C virus, or for human immodeficiency virus (HIV), per local diagnostic standard and in accordance with local laws and regulations Uncontrolled diabetes or symptomatic hyperglycemia (i.e., well controlled defined as a screening hemoglobin A1c <8% and no urinary ketoacidosis) Alcohol or drug dependence or abuse Patients with known Werner (WRN) syndrome Prior treatment with any WRN helicase inhibitor Pregnancy, breastfeeding, or intention of becoming pregnant during the study

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
Interventional Model Description: This is an open label study. Participants will be assigned to dose cohorts in the order in which they are enrolled. However, if two or more cohorts in the same part of the study are open for enrollment at the same time, participants will be randomized into these cohorts.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I: RO7589831 Dose Escalation<br> | Drug: RO7589831<br>* RO7589831 will be administered orally and once daily (QD) in 3-week cycles.<br>|
| Experimental: Part II: RO7589831 Dose Expansion<br> | Drug: RO7589831<br>* RO7589831 will be administered orally and once daily (QD) in 3-week cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events, with Severity Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0) |  | From first dose of study drug until 30 days after last dose of study drug (up to approximately 15 months) | 
| Incidence of Dose-Limiting Toxicities |  | Cycle 1 (1 cycle is 3 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration Observed (Cmax) of RO7589831 |  | At prespecified timepoints in Cycles 1, 2, and 3, and every 2 cycles thereafter (1 cycle is 3 weeks) until last dose of study drug (up to approximately 15 months) | 
| Time of Maximum Plasma Concentration Observed (Tmax) of RO7589831 |  | At prespecified timepoints in Cycles 1, 2, and 3, and every 2 cycles thereafter (1 cycle is 3 weeks) until last dose of study drug (up to approximately 15 months) | 
| Area Under the Plasma Concentration-Time Curve (AUC) of RO7589831 |  | At prespecified timepoints in Cycles 1, 2, and 3, and every 2 cycles thereafter (1 cycle is 3 weeks) until last dose of study drug (up to approximately 15 months) | 
| Apparent Oral Clearance (CL/F) of RO7589831 |  | At prespecified timepoints in Cycles 1, 2, and 3, and every 2 cycles thereafter (1 cycle is 3 weeks) until last dose of study drug (up to approximately 15 months) | 
| Volume of Distribution (V/F) of RO7589831 |  | At prespecified timepoints in Cycles 1, 2, and 3, and every 2 cycles thereafter (1 cycle is 3 weeks) until last dose of study drug (up to approximately 15 months) | 
| Terminal Half-Life (T1/2) of RO7589831 |  | At prespecified timepoints in Cycles 1, 2, and 3, and every 2 cycles thereafter (1 cycle is 3 weeks) until last dose of study drug (up to approximately 15 months) | 
| Objective Response Rate |  | From start of study treatment until end of follow-up (up to approximately 36 months) | 
| Disease Control Rate |  | From start of study treatment until end of follow-up (up to approximately 36 months) | 
| Duration of Response |  | From the time of first occurrence of a documented response until the time of documented disease progression or death from any cause, whichever occurs first (up to approximately 36 months) | 
| Progression-Free Survival, as Assessed by the Investigator |  | From start of study treatment to the first occurrence of documented disease progression or death from any cause, whichever occurs first (up to approximately 36 months) | 
| Overall Survival |  | From start of study treatment to the time of death from any cause (up to approximately 36 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Deficient mismatch repair, dMMR, Microsatellite instability, MSI