A Study to Evaluate the Safety, Pharmacokinetics, and Anti-Tumor Activity of RO7589831 as Monotherapy and in Combination With Pembrolizumab in Participants With Advanced Solid Tumors
- Registration Number
- NCT06004245
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
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, and in combination with pembrolizumab, 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 295
- Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
- Have a microsatellite instability (MSI) and/or deficient mismatch repair (dMMR), histologically or cytologically documented advanced (unresectable and/or metastatic) solid tumor; for the combination with pembrolizumab only: Histologically confirmed locally advanced, or metastatic colorectal adenocarcinoma (CRC) with no prior systemic treatment for metastatic disease and not amenable to surgery
- Have received and then progressed following, or are intolerant to, standard therapy 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
- 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)
- Significant cardiovascular/cerebrovascular disease within 6 months prior to Day 1 of study drug administration
- Alcohol or drug dependence or abuse
- Patients with known Werner (WRN) syndrome
- Prior treatment with any WRN helicase inhibitor
- Treatment with moderate or strong CYP3A4 inducers within 14 days prior to initiation of study treatment
- Treatment with moderate or strong CYP3A4 or P-glycoprotein inhibitors within 14 days prior to initiation of study treatment
- Pregnancy, breastfeeding, or intention of becoming pregnant during the study
Additional Exclusion Criteria for the Combination with Pembrolizumab Only:
- Active or history of autoimmune disease or immune deficiency with some exceptions
- History of interstitial lung disease or pneumonitis
- Treatment with systemic immunosuppressive medication (such as corticosteroids) within 2 weeks prior to initiation of study treatment with some exceptions
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description RO7589831 Dose Escalation RO7589831 - RO7589831 Monotherapy Expansion RO7589831 - RO7589831 + Pembrolizumab Expansion RO7589831 - RO7589831 + Pembrolizumab Expansion Pembrolizumab -
- Primary Outcome Measures
Name Time Method Incidence of Dose-Limiting Toxicities Cycle 1 (1 cycle is 3 weeks) 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)
- Secondary Outcome Measures
Name Time Method 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) 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) 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) 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) 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) 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) Overall Survival From start of study treatment to the time of death from any cause (up to approximately 36 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)
Trial Locations
- Locations (25)
UZ Leuven Gasthuisberg
🇧🇪Leuven, Belgium
City of Hope Cancer Center
🇺🇸Duarte, California, United States
SCRI Oncology Partners
🇺🇸Nashville, Tennessee, United States
Royal Marsden Hospital (Sutton)
🇬🇧Sutton, United Kingdom
City of Hope at Irvine Lennar
🇺🇸Irvine, California, United States
Norton Cancer Institute - MDC
🇺🇸Louisville, Kentucky, United States
Duke University
🇺🇸Durham, North Carolina, United States
Oklahoma University Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Alfred Hospital
🇦🇺Melbourne, Victoria, Australia
BCCA-Vancouver Cancer Centre
🇨🇦Vancouver, British Columbia, Canada
Princess Margaret Cancer Center
🇨🇦Toronto, Ontario, Canada
Rigshospitalet
🇩🇰København Ø, Denmark
CLCC Leon Berard Lyon
🇫🇷Lyon, France
Gustave Roussy
🇫🇷Villejuif, France
Seoul National University Bundang Hospital
🇰🇷Seongnam-si, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Clinica Universitaria de Navarra
🇪🇸Pamplona, Navarra, Spain
Vall d?Hebron Institute of Oncology (VHIO), Barcelona
🇪🇸Barcelona, Spain
Clinica Universidad de Navarra Madrid
🇪🇸Madrid, Spain
START Madrid. Centro Integral Oncologico Clara Campal
🇪🇸Madrid, Spain
Hospital Clinico Universitario de Valencia
🇪🇸Valencia, Spain
Sarah Cannon Research Institute
🇬🇧London, United Kingdom
The Christie
🇬🇧Manchester, United Kingdom