Study of CDK8 Inhibitor RVU120 in Combination With Everolimus in Children With Recurrent or Progressive Group 3 or 4 Medulloblastoma

Browse trials for

• Medulloblastoma 238
• Recurrence 4,279

Keywords

• recurrent or progressive G3 or G4 medulloblastoma

Medulloblastoma

238 studies on the registry are indexed under Medulloblastoma; 51 are open to participants now.

This study's planned enrollment of 48 is above the median of 35 across 198 interventional studies indexed under Medulloblastoma.

Lead sponsor

This is the only study on the registry with Bożenna Dembowska Bagińska as lead sponsor.

Study arms

• Experimental
  Monotherapy - RVU120

  Monotherapy dose finding arm - patient will be treated with single agent RVU120 with interpatient dose escalation to determine MTD and/or RP2D

  Drug: RVU120

• Experimental
  Combination therapy: RVU120+everolimus

  Combination therapy dose finding arm - patient will be treated with RVU120 in combination therapy with everolimus

  Drug: RVU120 · Drug: Everolimus (Afinitor) tablets

• Experimental
  Combination therapy: RVU120+everolimus (expansion)

  Expansion cohort - patient will be treated with RVU120 in combination therapy with everolimus - efficacy cohort

  Drug: RVU120 · Drug: Everolimus (Afinitor) tablets

Interventions

• DrugRVU120

  Experimantal - RVU120

• DrugEverolimus (Afinitor) tablets

  RVU120 + everolimus

Primary outcomes

1. 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.

   Time frame: From Day1 to 30 days after last dose

2. 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.

   Time frame: During Cycle 1 (DLT evaluation period; each cycle is 28 days)

Secondary outcomes

1. 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 frame: Day 1 and Day 14 of Cycle 1 (each cycle is 28 days); Day 1 of subsequent cycles

2. 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

   Time frame: Day 1 and Day 14 of Cycle 1; Cycle 4 Day 1; Cycle 7 Day 1; and every 4 cycles thereafter through study completion (up to 2 years).

3. 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

   Time frame: Day 1 and Day 14 of Cycle 1; Cycle 4 Day 1; Cycle 7 Day 1; and every 4 cycles thereafter through study completion (up to 2 years).

4. 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

   Time frame: Day 1 and Day 14 of Cycle 1; Cycle 4 Day 1; Cycle 7 Day 1; and every 4 cycles thereafter through study completion (up to 2 years).

5. Everolimus Trough Concentration (Ctrough) During Combination Therapy

   Everolimus trough concentrations (Ctrough) measured in patients receiving RVU120 in combination with everolimus. Blood samples are collected immediately prior to dosing (pre-dose) at protocol-specified treatment days to assess steady-state trough levels during combination therapy.

   Time frame: Pre-dose on Cycle 1 Day 1 and Cycle 1 Day 7, and before each subsequent treatment cycle through study completion (up to 2 years).

6. Overall Response Rate (ORR)

   ORR assessed for RVU120 in combination with everolimus in children with recurrent or progressive Group 3 or Group 4 medulloblastoma, following RAPNO guidelines and stratified by molecular subgroup (G3 vs. G4) and MYC/MYCN expression.

   Time frame: From start of treatment until disease progression or death, assessed up to 24 months (per protocol follow-up schedule)

7. Duration of Response

   Duration of Response for patients achieving an objective response to RVU120 + everolimus, evaluated according to RAPNO guidelines and stratified by molecular subgroup (G3 vs. G4) and MYC/MYCN expression

   Time frame: From date of first documented response until disease progression or death, assessed up to 24 months.

8. Progression-Free Survival (PFS)

   PFS assessed for RVU120 + everolimus in children with recurrent or progressive Group 3 or Group 4 medulloblastoma, following RAPNO criteria and stratified by molecular subgroup (G3 vs. G4) and MYC/MYCN expression.

   Time frame: From start of treatment until disease progression or death, whichever occurs first, assessed up to 24 months

9. Overall Survival (OS)

   OS assessed for RVU120 + everolimus in children with recurrent or progressive Group 3 or Group 4 medulloblastoma, stratified by molecular subgroup (G3 vs. G4) and MYC/MYCN expression

   Time frame: From start of treatment until death from any cause, assessed up to 24 months

Other outcomes

1. 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

   Time frame: Baseline (Screening) and Cycle 4 Day 1 (each cycle is 28 days)

2. 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)

   Time frame: Baseline tumor sample (Screening) and post-treatment tumor biopsy at protocol-specified on-treatment time point (e.g., Cycle 4 Day 1).

3. 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

   Time frame: Baseline tumor sample (Screening) and post-treatment tumor biopsy at protocol-specified on-treatment time point (e.g., Cycle 4 Day 1).

4. 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)

   Time frame: Cycle 4 Day 1 (each cycle is 28 days) and clinical response assessed up to 24 months

5. CDK8 Expression in Tumor Tissue (IHC)

   CDK8 expression assessed by immunohistochemistry (IHC) in pre-treatment tumor samples. Unit of Measure: H-score or % positive tumor cells

   Time frame: Pre-treatment tumor assessments (Screening).

6. MYC and MYCN Copy Number Variations (FISH/MLPA)

   MYC and MYCN copy number variations assessed by FISH or MLPA in pre-treatment tumor samples. Unit of Measure: Copy number category (e.g., amplified / non-amplified) * MYC and MYCN copy number variations by FISH * Transcriptomic profiles by RNAseq * Additional diagnostic or molecular biomarkers Associations will be evaluated relative to treatment response.

   Time frame: Pre-treatment tumor assessments (Screening).

7. Baseline Tumor Transcriptomic Profiles (RNAseq)

   Transcriptomic profiles assessed by RNA sequencing (RNAseq) in pre-treatment tumor samples. Unit of Measure: Gene expression profile (normalized counts) * MYC and MYCN copy number variations by FISH * Transcriptomic profiles by RNAseq * Additional diagnostic or molecular biomarkers Associations will be evaluated relative to treatment response.

   Time frame: Pre-treatment tumor assessments (Screening).

8. Correlation Between Baseline Biomarkers and Treatment Response

   Correlation between baseline tumor biomarkers (CDK8 expression, MYC/MYCN copy number, transcriptomic profiles) and treatment response to RVU120 ± everolimus using correlation coefficients (e.g., Spearman's rho). Unit of Measure: Correlation coefficient (Spearman's rho) * MYC and MYCN copy number variations by FISH * Transcriptomic profiles by RNAseq * Additional diagnostic or molecular biomarkers Associations will be evaluated relative to treatment response.

   Time frame: Baseline (Screening) and clinical response assessed up to 24 months

9. Change in Cell-Free Medulloblastoma DNA Levels (NGS)

   Change in cell-free medulloblastoma DNA (cfDNA) levels in cerebrospinal fluid (CSF) and plasma between pre-treatment and post-treatment samples, assessed using next-generation sequencing (NGS), in patients receiving RVU120 monotherapy or RVU120 in combination with everolimus. Unit of Measure: cfDNA concentration (copies/mL or NGS-derived equivalent)

   Time frame: Baseline (Screening) and Cycle 4 Day 1 (each cycle is 28 days)

10. Correlation Between Changes in Cell-Free Medulloblastoma DNA and Clinical Response, PK, and PD

    Correlation between changes in cell-free medulloblastoma DNA (NGS) and clinical response, pharmacokinetics (PK), and pharmacodynamic (PD) markers in patients treated with RVU120 ± everolimus, assessed using correlation coefficients (e.g., Spearman's rho). Unit of Measure: Correlation coefficient (Spearman's rho)

    Time frame: Baseline (Screening) and Cycle 4 Day 1 (each cycle is 28 days)

11. Correlation Between RVU120 Exposure and Clinical Response

    Correlation between RVU120 plasma exposure (AUC, Cmax) and clinical response outcomes (e.g., ORR, DoR, PFS, OS) in patients treated with RVU120 monotherapy or RVU120 + everolimus, assessed using correlation coefficients (e.g., Spearman's rho). Unit of Measure: Correlation coefficient (Spearman's rho)

    Time frame: Cycle 1 PK sampling (Day 1 and Day 14; each cycle is 28 days) and clinical response assessed up to 24 months

12. Correlation Between RVU120 Exposure and PD Markers

    Correlation between RVU120 plasma exposure (AUC, Cmax) and pharmacodynamic markers (e.g., CDK8- and mTOR-dependent phosphorylation events by IHC; transcriptomic changes by RNAseq). Unit of Measure: Correlation coefficient (Spearman's rho)

    Time frame: PK and PD data collected throughout study treatment and assessed through study completion (up to 2 years).

13. Correlation Between Target Engagement and Clinical Activity

    Correlation between target engagement markers (e.g., phosphorylation of pSTAT5, p4EBP-1 by IHC) and clinical activity (e.g., ORR, DoR, PFS, OS) in patients treated with RVU120 ± everolimus. Unit of Measure: Correlation coefficient (Spearman's rho)

    Time frame: Clinical activity and pharmacodynamic data collected throughout study treatment and assessed through study completion (up to 2 years).

14. Correlation Between PK Parameters and PD Markers

    Correlation between PK parameters (AUC, Cmax, Tmax) and PD markers (IHC and RNAseq) in patients receiving RVU120 ± everolimus.

    Time frame: PK, PD, and clinical activity data collected throughout study treatment and assessed through study completion (up to 2 years).

15. Number of Tumor Tissue Samples Collected (FFPE or Fresh-Frozen)

    Number of tumor tissue samples (formalin-fixed paraffin-embedded \[FFPE\] or fresh-frozen) collected from participants for future exploratory research. Unit of Measure: Number of samples

    Time frame: At Screening and Cycle 4 Day 1 (each cycle is 28 days)

16. Number of Plasma Samples Collected

    Number of plasma samples collected and stored for future exploratory research related to medulloblastoma biology and potential therapeutic approaches. Unit of Measure: Number of samples

    Time frame: At Screening and Cycle 4 Day 1 (each cycle is 28 days)

Individual participant data

Plan to share: Undecided