Study of Ribociclib and Everolimus in HGG and DIPG or Ribociclib and Temozolomide in DHG, H3G34-mutant

This is a multicenter, international, phase 2 study of post-radiotherapy (RT) combination of ribociclib and everolimus to treat pediatric, adolescent, and young adult patients newly diagnosed with HGG and DIPG that harbor alterations of the cell cycle and/or PI3K/mTOR pathways to assess treatment efficacy (Stratum A-D Part 2). The study will include a feasibility cohort (Strata A-D, Part 1) to identify the dose of ribociclib PfOS (Powder for Oral Suspension) that is safe and tolerable in combination with everolimus. Efficacy for Strata A-D Part 2 study will be defined by progression-free survival (PFS; HGG \[stratum A\]) and Overall Survival (OS; DIPG \[stratum B\]), with key longitudinal biomarker correlatives. Outcomes among patients with primary thalamic, spinal cord, and/or secondary (radiation related) HGG (strata 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 (RP2D) of the combination of ribociclib and everolimus in patients with metastatic disease who received upfront craniospinal irradiation (stratum D).

The study was amended in October 2025 to also include an additional stratum, Stratum E, which will serve patients with localized DHG, H3G34-mutant with the combination of ribociclib and temozolomide. As most DHG, H3G34-mutant tumors are MGMT promoter methylated and receive temozolomide 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 RP2D of ribociclib PfOS formulation in combination with temozolomide in patients newly-diagnosed with DHG, H3G34-mutant post-RT, with PK 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 to the other strata.

Protocol therapy with the maintenance combination of either 1) ribociclib and everolimus or 2) ribociclib and temozolomide must begin no later than 35 calendar days post-completion of RT. The earliest patients can begin protocol treatment is 28 calendar days post-completion of RT. Each cycle will be 28 days in duration and treatment can continue up to a total of 26 cycles. For Strata A-D, Ribociclib will be given orally once daily for 3 weeks (days 1-21), with one week off. Everolimus will be given orally daily continuously (days 1-28). For Stratum E, Ribociclib will be given orally once daily for 3 weeks (days 1-21), and temozolomide will be given days 1-5 for the first 13 cycles (Year 1), and ribociclib alone will be given orally once daily for 3 weeks (days 1-21) for the subsequent 13 cycles (Year 2).