Clinical trial NCT06004245: 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
Official title: A Phase I, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Anti-Tumor Activity of RO7589831 as Monotherapy and in Combination With Pembrolizumab in Participants With Advanced Solid Tumors Harboring Microsatellite Instability (MSI) and/or Deficient Mismatch Repair (dMMR)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Advanced Solid Tumors
Keywords: Deficient mismatch repair
dMMR
Microsatellite instability
MSI
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2023-08-22
Enrollment: 295
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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

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)
* 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

Primary outcomes:
measure: 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)
timeFrame: From first dose of study drug until 30 days after last dose of study drug (up to approximately 15 months)
measure: Incidence of Dose-Limiting Toxicities
timeFrame: Cycle 1 (1 cycle is 3 weeks)
Secondary outcomes:
measure: Maximum Plasma Concentration Observed (Cmax) of RO7589831
timeFrame: 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)
measure: Time of Maximum Plasma Concentration Observed (Tmax) of RO7589831
timeFrame: 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)
measure: Area Under the Plasma Concentration-Time Curve (AUC) of RO7589831
timeFrame: 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)
measure: Apparent Oral Clearance (CL/F) of RO7589831
timeFrame: 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)
measure: Volume of Distribution (V/F) of RO7589831
timeFrame: 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)
measure: Terminal Half-Life (T1/2) of RO7589831
timeFrame: 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)
measure: Objective Response Rate
timeFrame: From start of study treatment until end of follow-up (up to approximately 36 months)
measure: Disease Control Rate
timeFrame: From start of study treatment until end of follow-up (up to approximately 36 months)
measure: Duration of Response
timeFrame: 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)
measure: Progression-Free Survival, as Assessed by the Investigator
timeFrame: 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)
measure: Overall Survival
timeFrame: From start of study treatment to the time of death from any cause (up to approximately 36 months)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope Cancer Center
state: California
city: Irvine
country: United States
facility: City of Hope at Irvine Lennar
state: California
city: Louisville
country: United States
facility: Norton Cancer Institute - MDC
state: Kentucky
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Oklahoma City
country: United States
facility: Oklahoma University Health Sciences Center
state: Oklahoma
city: Nashville
country: United States
facility: SCRI Oncology Partners
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Melbourne
country: Australia
facility: Alfred Hospital
state: Victoria
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Vancouver
country: Canada
facility: BCCA-Vancouver Cancer Centre
state: British Columbia
city: Toronto
country: Canada
facility: Princess Margaret Cancer Center
state: Ontario
city: København Ø
country: Denmark
facility: Rigshospitalet
city: Lyon
country: France
facility: CLCC Leon Berard Lyon
city: Villejuif
country: France
facility: Gustave Roussy
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Vall d?Hebron Institute of Oncology (VHIO), Barcelona
city: Madrid
country: Spain
facility: Clinica Universidad de Navarra Madrid
city: Madrid
country: Spain
facility: START Madrid. Centro Integral Oncologico Clara Campal
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute
city: Manchester
country: United Kingdom
facility: The Christie
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital (Sutton)
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: