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Mutant isocitrate dehydrogenase inhibitors in glioma and cholangiocarcinoma


Several clinical trials studying mutIDH inhibitors in glioma and other solid tumors are ongoing or in planning stages and involve both pan and specific inhibitors.

In 2015, the first phase 1 data on the safety of Ivosidenib ( Tibsovo ) in patients with advanced glioma and other IDH-mutant solid tumors were presented at the annual EORTC-NCI-AAR Molecular Targets and Cancer Therapeutics Symposium and indicated that Ivosidenib treatment was well-tolerated with a positive pharmacokinetic profile.

This multicenter, open-label study was designed as a dose-escalation study with a following dose-expansion cohort.
Ivosidenib was administered daily over 28-days cycles at doses ranging from 100 mg up to 1200 mg. Doses beyond 500 mg did not result in increased plasma 2HG reduction; therefore the 500 mg dose was selected for the dose-expansion arms, which included both enhancing and non-enhancing IDH-mutant gliomas.

Most recent efficacy data reported at the 2016 Society for Neuro-Oncology Annual Meeting indicated a 35% clinical benefit rate ( stable disease or better ) based on imaging at 6-months follow-up.

By 2017, 168 patients were enrolled in the dose-escalation arm and 108 patients in the 500 mg daily dose-expansion arm.
Throughout the study period, Ivosidenib has continued to demonstrate good oral bioavailability, a lengthy half-life ( mean 40–102 h after a single dose ), and a persistent, robust response in 2HG depletion in both plasma and tumor tissue.
No treatment-related serious adverse events have been reported; other adverse events included headache, nausea, fatigue, and gastrointestinal symptoms.

AG-881 ( Vorasidenib ), a pan-inhibitor, is the only other mutIDH inhibitor currently with supporting clinical data in glioma.
In a similarly designed, phase 1, multicenter, open-label, dose-escalation and expansion trial, the safety and pharmacokinetic profiles of AG-881 is being investigated in both mutIDH1 and mutIDH2 gliomas and other solid tumors.

According to the most recent data presented at the 2018 Society for Neuro-Oncology Annual Meeting, 52 glioma patients have received treatment with AG-881 on a 28-days cycle either as part of the dose-escalation arm ( dose range 25–300 mg daily ) or as part of the dose-expansion arm ( 10 or 50 mg daily ).

While preliminary efficacy data has yet to be published, the most frequently observed adverse events included elevation of transaminases ( ALT 44.2 and AST 38.5% ) and headache ( 34.6% ).
Furthermore, at doses more than 100 mg, five subjects experienced dose-limiting toxicity presenting as liver injury.

Forthcoming work with AG-881 includes an additional ongoing phase 1 randomized open-label trial evaluating the ability of pre-treatment with either AG-881 or AG-120 to suppress intra-tumoral 2HG levels in surgical pathology specimens as a measure of pharmacological efficacy.
This trial has used the 10 or 50 mg daily dosing.

Other ongoing clinical trials of mutIDH inhibitor compounds in glioma ( currently without early results ) are also in phase 1 and are mostly in the early recruitment phase.
These studies are evaluating safety and pharmacology of mutIDH-specific inhibitors such as DS-1001b, IDH305, and FT-2012, Enasidenib, and BAY-1436032.

There is a single phase 3, multicenter, randomized, double-blind study in solid tumors comparing Ivosidenib ( 500 mg daily ) to placebo in advanced or metastatic mutIDH1 cholangiocarcinoma, also known as the ClarIDHy trial.
The ClarIDHy protocol was presented at the 2017 ASCO Annual Meeting based on previous phase 1 trial findings of 6% partial improvement and 56% stable tumor response, and a progression-free survival rate of 40% at 6 months in a similar patient population. ( Xagena )

Golub D et al, Front Oncol 2019; 9: 417

XagenaMedicine_2019



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