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