This study will determine the safety and tolerability of RVU120 as a single agent and in combination with the mTOR inhibitor everolimus in children with recurrent or progressive G3 or G4 medulloblastoma and provide preliminary data regarding the efficacy of this treatment approach.
Diagnosis: Recurrent/progressive Group 3 or Group 4 medulloblastoma confirmed by CLIA-certified methylation testing. Patients ≥4 years at initial diagnosis must have received CSI + systemic chemotherapy; patients <4 years must have received systemic chemotherapy (CSI not required).
Age: 3 to ≤18 years.
Ability to swallow capsules/tablets required.
BSA: 0.4-2.5 m².
Pregnancy/lactation - Pregnant or lactating patients. Negative serum pregnancy test required for patients of childbearing potential.
Clinically significant illness - Serious uncontrolled infections or significant cardiac, pulmonary, hepatic, or other organ dysfunction that may increase risk or interfere with study procedures. Includes prior/concurrent malignancies that may affect safety or efficacy assessment.
Concurrent therapy: any anticancer or investigational therapy; corticosteroids allowed only if stable or decreasing ≥7 days; strong CYP1A2/CYP3A4/3A5 inducers/inhibitors or P-gp inhibitors; prohibited fruits (grapefruit, Seville oranges, starfruit). Must be discontinued ≥7 days or ≥5 half-lives; hypersensitivity to RVU120, everolimus, or rapamycin derivatives; live virus vaccine <21 days before enrollment (everolimus); hereditary galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.
Recent major surgery - Major surgery including tumor biopsy <14 days before enrollment. Minor neurosurgical procedures (VP shunt, cyst fenestration, central line placement) allowed.
Parallel
RVU120
DrugExperimantal - RVU120
Everolimus (Afinitor) tablets
DrugRVU120 + everolimus
Frequency and nature of AEs, SAEs and DLTs according to CTCAE v5.0 in RVU120 monotherapy and combination therapy with everolimus
Assessment of adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicities (DLTs) occurring during treatment with RVU120 monotherapy and RVU120 combined with everolimus. All events will be collected and graded according to CTCAE v5.0.
MTD and/or RP2D of RVU120 as a single agent and in combination with everolimus
Determination of the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of RVU120 administered as a single agent and in combination with everolimus in children with recurrent or progressive Group 3 or Group 4 medulloblastoma. MTD will be defined based on the occurrence of dose-limiting toxicities (DLTs) according to CTCAE v5.0 during the predefined DLT evaluation period. RP2D will be established based on MTD, overall safety profile, and clinical tolerability.
Peak Plasma Concentration (Cmax) of RVU120
Cmax determined from serial blood sampling following administration of RVU120 as monotherapy and in combination with everolimus in children with recurrent or progressive Group 3 or Group 4 medulloblastoma, using non-compartmental analysis
Time to Peak Plasma Concentration (Tmax) of RVU120
Tmax determined from serial blood sampling following administration of RVU120 as monotherapy and in combination with everolimus, based on the time to maximum observed plasma concentration using non-compartmental analysis
Area Under the Plasma Concentration-Time Curve (AUC) of RVU120
AUC determined from serial plasma RVU120 concentrations following administration as monotherapy and in combination with everolimus, using non-compartmental analysis
Terminal Elimination Half-Life (t½) of RVU120
t½ estimated from the terminal phase of the plasma concentration-time profile of RVU120 following administration as monotherapy and in combination with everolimus, using non-compartmental analysis
Change in Tumor Pharmacodynamic (PD) Markers (IHC)
Change in CDK8- and mTOR-dependent phosphorylation events (e.g., pSTAT5, p4EBP-1) measured by immunohistochemistry (IHC) in post-treatment versus pre-study tumor samples in patients treated with RVU120 monotherapy or RVU120 + everolimus. Unit of Measure: H-score or % positive tumor cells
Transcriptomic Changes in Tumor Tissue (RNAseq)
Transcriptomic changes between pre-treatment and post-treatment tumor samples assessed by RNA sequencing (RNAseq) in patients receiving RVU120 monotherapy or RVU120 + everolimus. Unit of Measure: Fold-change in gene expression (log2FC)
CDK8- and mTOR-Dependent Phosphorylation Events (IHC)
Levels of CDK8- and mTOR-dependent phosphorylation events (e.g., pSTAT5, p4EBP-1) measured by IHC in tumor samples from patients treated with RVU120 ± everolimus. Unit of Measure: H-score or % positive tumor cells
Correlation Between PD Marker Changes and Clinical Response
Correlation between changes in PD markers (IHC and RNAseq) and clinical response to RVU120 ± everolimus using correlation coefficients (e.g., Spearman's rho).Unit of Measure: Correlation coefficient (Spearman's rho)
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Bożenna Dembowska Bagińska
Lead sponsor
Children's Memorial Health Institute, Poland
Sponsor institution
Ryvu Therapeutics SA
Collaborator
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