CONNECT TarGeT A: Phase 2 Study of Ribociclib-Containing Post-Radiotherapy Combinations in Pediatric and Young Adult Patients Newly Diagnosed with High-Grade Glioma (HGG), including Diffuse Intrinsic Pontine Glioma (DIPG): Ribociclib and Everolimus for HGG/DIPG which Harbor Alterations of the Cell Cycle and/or PI3K/mTOR Pathways And Ribociclib and Temozolomide for Diffuse Hemispheric Glioma (DHG), H3G34-mutant
CONNECT TarGeT A
What is the goal of the study?
In this phase 2 study (Figure 1), pediatric, adolescent, and young adult patients newly-diagnosed with HGG and DIPG will be offered molecularly-guided post-radiotherapy (RT) treatment following a ribociclib-containing approach: Patients with HGG and DIPG harboring alterations of the cell cycle and/or PI3K/mTOR pathways will be treated with the combination of ribociclib and everolimus to assess efficacy of this molecularly-targeted treatment, defined by progression-free survival (PFS; HGG [stratum A]) and OS (DIPG [stratum B]), respectively, with key longitudinal biomarker correlatives as above. Given incorporation of the new ribociclib powder for oral solution (PfOS) formulation, enrollment of the first 6 patients will be limited to those with localized HGG or DIPG, who will comprise a feasibility cohort identifying the dose of ribociclib PfOS formulation that is safe and tolerable in combination with everolimus, with pharmacokinetic comparisons to the previously studied ribociclib capsule formulation (Part 1 Initial Feasibility Cohort); this dose will be used for subsequent patients on all phase 2 (Part 2) strata of ribociclib and everolimus. Outcomes among patients with primary thalamic, spinal cord, and/or secondary (radiation-related) HGG (stratum C) will be descriptively analyzed. Objective radiographic response rates and agent-specific toxicities will also be assessed, with a feasibility cohort to determine the recommended phase 2 dose of the combination of ribociclib and everolimus in patients with metastatic disease who received upfront craniospinal irradiation (stratum D). Patients with localized DHG, H3G34-mutant will be treated with the combination of ribociclib and temozolomide (stratum E). As most DHG, H3G34-mutant tumors are MGMT promoter methylated and receive temozolomide (alkylating chemotherapy) as part of standard of care, we are studying the adjuvant combination of ribociclib and temozolomide following upfront RT. Stratum E will open with a Phase 1 Run-In to determine the recommended phase 2 dose (RP2D) of ribociclib PfOS formulation in combination with temozolomide in patients newly-diagnosed with DHG, H3G34-mutant post-RT, with pharmacokinetic testing. Once the RP2D is determined, patients with localized DHG, H3G34-mutant will be enrolled on the Stratum E efficacy expansion cohort to descriptively assess survival outcomes, with similar longitudinal biomarker correlatives as above.
Who can participate in the study?
Please contact the study team listed below to learn more.