On November 17, 2017 Agios Pharmaceuticals, Inc. (Nasdaq:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported updated data from the dose expansion cohort of the Phase 1 study evaluating single agent ivosidenib in patients with progressive low grade isocitrate dehydrogenase-1 mutant (IDH1m) glioma (Press release, Agios Pharmaceuticals, NOV 17, 2017, View Source [SID1234522137]). The data were presented today in an oral presentation at the Society for Neuro-Oncology (SNO) Annual Meeting in San Francisco.
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"Glioma is a difficult-to-treat disease with many patients diagnosed at a young age and exposed to surgery, radiation and chemotherapy and their associated side effects," said Ingo Mellinghoff, M.D., Memorial Sloan Kettering Cancer Center, an investigator for the study. "The median treatment duration of 16 months and reduction in tumor growth rates compared to a pre-treatment interval is a signal of ivosidenib’s clinical activity in this population. I look forward to working with Agios and the neuro-oncology community to further refine imaging methodology and to assess the biological effects of IDH inhibitors in a perioperative study planned for the first half of 2018."
Ivosidenib is being evaluated in an ongoing Phase 1 dose escalation and expansion trial in advanced IDH1 mutant positive solid tumors, including glioma. Enrollment was completed in January 2016 and data from the glioma dose escalation and expansion cohorts were presented in November 2016. An update on patients with non-enhancing glioma is reported below.
As of the May 12, 2017 data cut off, 35 patients (11 from escalation, 24 from expansion) with non-enhancing disease have been treated with single agent ivosidenib. Eighteen patients (51%) remain on treatment.
Twenty-four patients had World Health Organization (WHO) classified Grade 2 tumors, eight had Grade 3 tumors, one had a Grade 4 tumor and two were unknown.
Patients received daily doses of ivosidenib ranging from 300 mg to 900 mg. Twenty-eight patients received a daily dose of 500 mg, which was selected as the expansion dose.
The median age of these patients is 38 (ranging from 21-71).
The median treatment duration was 16 months (ranging from 1.4 – 27.1 months).
The median number of prior therapies was 2 (ranging from one to five). The median duration of last systemic therapy was 9.6 months.
○ Sixty-three percent of patients had previously received temozolomide and 57% percent had previously received radiotherapy.
A safety analysis conducted for all 35 treated non-enhancing glioma patients as of the data cut-off demonstrated that ivosidenib was well-tolerated with a favorable safety profile in glioma patients.
No dose limiting toxicities were observed.
The majority of adverse events reported by investigators were mild to moderate, with the most common being headache, diarrhea, nausea and vomiting.
There were 5 patients with serious adverse events (SAE) and all were deemed unrelated to study treatment.
Efficacy data from all 35 non-enhancing glioma patients as of the data cut-off showed:
Two patients had a minor response by investigator assessment according to the Response Assessment in Neuro-Oncology for low grade glioma (RANO-LGG).
Twenty-nine (83%) patients had stable disease.
The median progression free survival (PFS) for all non-enhancing patients was 13 months, the median PFS for Grade 2 patients (n=24) has not been reached.
For patients in the expansion arm (n=24), the average six-month tumor growth was 24% prior to treatment and 11% following treatment with ivosidenib.
In addition, preclinical data for ivosidenib and AG-881, a brain-penetrant pan-IDH inhibitor, in an orthotopic mouse xenograft model of human mIDH1-R132H glioma are also being presented as posters.
Preliminary data suggest that both molecules suppress the oncometabolite D-2-hydroxyglutarate (2-HG) in an orthotopic brain tumor model.
○ At the doses explored, treatment with ivosidenib resulted in 85% maximal 2-HG inhibition and treatment with AG-881 resulted in >98% inhibition of 2-HG levels.
○ Neither molecule impeded the therapeutic effect of concomitant or sequenced radiation therapy.
"We are encouraged by both the ivosidenib clinical data demonstrating prolonged stable disease in patients with progressive, low grade glioma and the preclinical data with ivosidenib and AG-881 demonstrating reductions in the oncometabolite 2-HG," said Chris Bowden, M.D., chief medical officer of Agios. "We look forward to quantitatively assessing 2-HG and other biomarker effects with both molecules in our planned perioperative study."
Next Steps in Glioma
On November 1st, 2017, Agios announced plans to initiate a perioperative ‘window’ study in the first half of 2018 with ivosidenib and AG-881 in approximately 45 low grade glioma patients with progressive disease to further investigate their effects on brain tumor tissue. Patients will be randomized to either ivosidenib or AG-881 and treated for four weeks prior to previously scheduled surgery. An additional five patients will serve as a control arm. The study is designed with the following objectives:
To determine the amount of drug penetration in the brain
To confirm the magnitude of IDH target engagement as measured by 2HG levels in brain tumor tissue
To assess the impact of IDH inhibition on differentiation and epigenetic profiles in tumor tissue and
To assess the safety of both molecules.