CTNI-54 - A phase 0/1 trigger trial of Ribociclib plus Everolimus in recurrent high-grade glioma

Friday, November 18, 2022

7:55 PM – 8:00 PM ET

Location: West/Central Hall

Rapid Report Presenter(s)

Nader Sanai, MD

Barrow Neurological Institute
Phoenix, United States

Author(s)

An-Chi Tien, PhD

Ivy Brain Tumor Center
Phoenix, United States
JJ

Jun Jiang, Ph.D.

Karmanos Cancer Institute
Detroit, United States
YC

Yu-Wei Chang

Ivy Brain Tumor Center
Phoenix, United States
CM

Chelsea Montgomery

Ivy Brain Tumor Center
Phoenix, United States
Anita DeSantis, B.S.

Ivy Brain Tumor Center
Phoenix, United States
YF

Yoko Fujita, Ph.D.

Ivy Brain Tumor Center
Phoenix, United States
SK

Seongho Kim, Ph.D.

Karmanos Cancer Institute
Detroit, United States
Shwetal Mehta, PhD (she/her/hers)

Ivy Brain Tumor Center
Phoenix, United States

Background: The RB-CDK4/6 and mTOR signaling pathways are deregulated in high-grade glioma (HGG) and mTOR activation is a potential mechanism of resistance to CDK4/6 inhibition. This study evaluates the tumor pharmacokinetics (PK) and pharmacodynamics (PD) of combined CDK4/6 and mTOR inhibition in recurrent HGG patients.

Methods: Eligible patients had recurrent HGG with (1) RB+, (2) CDKN2A/B deletion or CDK4/6 amplification, and (3) PTEN loss or PIK3CA mutations. Six patients received five days of ribociclib (400mg QD) plus everolimus (2.5mg QD) and underwent tumor resection at 2, 8 or 24 hours following the last dose. Six dose-escalation cohorts (n = 3 each) reached a dose-level of ribociclib (600mg QD) plus everolimus (70mg QW). Tumor tissue, CSF, and plasma were collected. Total and unbound drug concentrations were determined using validated LC-MS/MS methods. Tumor PD effects were compared to matched archival tissue. A PK ‘trigger’ (i.e., unbound concentration > 5-fold biochemical IC₅₀) and a PD ‘trigger’ ( >30% decrease in both pRB and pS6) in Gd-nonenhancing tissue were set to qualify patients for expansion.

Results: 24 patients with WHO Grade III (n = 2) and Grade IV (n = 22) gliomas were enrolled. No dose-limiting toxicities were observed. Following presurgical drug, all patients demonstrated marked decrease in Gd-enhancement on preoperative MRI. In Gd-nonenhancing tumor regions, the median unbound concentration of ribociclib was 561 nM whereas no unbound everolimus concentrations were detected. Across all dose-levels, 57% (13/23) and 43% (10/23) of tumors demonstrated RB and S6 phosphorylation decrease, respectively.

Conclusion: In adult HGG, ribociclib achieves pharmacologically-relevant concentrations in Gd-nonenhancing tumor. Everolimus exhibits limited penetration into human glioma tissue. Our study supports further development of ribociclib, but not everolimus, for the treatment of glioma patients.