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Clinical Trial
. 2020 Sep;149(3):511-522.
doi: 10.1007/s11060-020-03641-2. Epub 2020 Oct 9.

A phase I/II study of ribociclib following radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG)

Mariko DeWire  1 , Christine Fuller  2 , Trent R Hummel  3 , Lionel M L Chow  4 , Ralph Salloum  3 , Peter de Blank  3 , Luke Pater  5 , Sarah Lawson  6 , Xiaoting Zhu  7 , Phil Dexheimer  7 , Adam C Carle  8 , Shiva Senthil Kumar  3 , Rachid Drissi  3 , Charles B Stevenson  9 , Adam Lane  10 , John Breneman  5 , David Witte  2 , Blaise V Jones  11 , James L Leach  11 , Maryam Fouladi  3
Affiliations
Clinical Trial

A phase I/II study of ribociclib following radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG)

Mariko DeWire et al. J Neurooncol. 2020 Sep.

Abstract

Purpose: Cyclin-dependent kinase-retinoblastoma (CDK-RB) pathway is dysregulated in some diffuse intrinsic pontine gliomas (DIPG). We evaluated safety, feasibility, and early efficacy of the CDK4/6-inhibitor ribociclib, administered following radiotherapy in newly-diagnosed DIPG patients.

Methods: Following radiotherapy, eligible patients received ribociclib in 28-day cycles (350 mg/m2; 21 days on/7 days off). Feasibility endpoints included tolerability for at least 6 courses, and a less than 2-week delay in restarting therapy after 1 dose reduction. Early efficacy was measured by 1-year and median overall survival (OS). Patient/parent-by-proxy reported outcomes measurement information system (PROMIS) assessments were completed prospectively.

Results: The study included 10 evaluable patients, 9 DIPG and 1 diffuse midline glioma (DMG)-all 3.7 to 19.8 years of age. The median number of courses was 8 (range 3-14). Three patients required dose reduction for grade-4 neutropenia, and 1 discontinued therapy for hematological toxicity following course 4. The most common grade-3/4 toxicity was myelosuppression. After 2 courses, MRI evaluations in 4 patients revealed increased necrotic volume, associated with new neurological symptoms in 3 patients. The 1-year and median OS for DIPG was 89% and 16.1 months (range 10-30), respectively; the DMG patient died at 6 months post-diagnosis. Five patients donated brain tissue and tumor; 3 were RB+ .

Conclusions: Ribociclib administered following radiotherapy is feasible in DIPG and DMG. Increased tumor necrosis may represent a treatment effect. These data warrant further prospective volumetric analyses of tumors with necrosis. Feasibility and stabilization findings support further investigation of ribociclib in combination therapies.

Trial registration: NCT02607124.

Keywords: Pediatric diffuse intrinsic pontine glioma (DIPG); Pediatric diffuse midline glioma (DMG); Ribociclib.

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