DIPG-27. CLEE011XUS17T (NCT 02607124): A PHASE I/II STUDY OF RIBOCICLIB (LEE011) FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)

AbstractGenomic sequencing studies have uncovered alterations of checkpoint cell cycle regulators (CDK4/6, CDK2NA) in diffuse intrinsic pontine gliomas (DIPG) and high-grade gliomas (HGG). Ribociclib (LEE011) is an orally bioavailable, small molecule inhibitor of CDK4/CyclinD1 and CDK6/CyclinD3 complexes resulting in hypophosphorylation of RB and cell cycle arrest. In a feasibility, phase II study, patients with newly-diagnosed DIPG or HGG received radiation therapy prior to enrollment. All HGG patients and any DIPG patient who had undergone biopsy were screened for total RB protein by immunohistochemistry. Ribociclib was administered daily for 21 of 28 days at 350 mg/m/day. Feasibilty endpoints included toxic death, Grade 3/4 toxicities possibly related to ribociclib resulting in drug discontinuation, > 2 weeks delay in the start of any course or discontinuation of the protocol therapy even after appropriate dose modification. Efficacy was measured by the overall survival distribution for DIPG and HGG. Of the 10 patients enrolled (median 6.5 years; range:4–20), 9 received treatment (8 DIPG, 1 HGG) and one developed leptomeningeal disease prior to therapy. To date, the median number of courses are 4.5 (range: 1–10). Ribociclib was well-tolerated; three patients required dose reduction for grade 4 neutropenia; no patients have come off therapy for toxicity. The most common adverse events were leukopenia, neutropenia, lymphopenia, nausea, vomiting, and fatigue. MRI evaluations in 2 patients revealed increased T2 FLAIR signal with new neurological symptoms within the first 2 cycles of therapy. These patients were responsive to steroids and remain on study. Six patients remain on active therapy at a median of 9 months post diagnosis (range: 3–12). The preliminary analysis demonstrates that ribociclib, administered post radiation therapy is well-tolerated in children and young adults with DIPG and RB+ HGG. Analyses for efficacy and correlative studies will be presented at the meeting.