Rare Disease Report

Phase 1 Trial of Ivosidenib for Patients with AML Boasts Positive Results

JUNE 02, 2018
Kristi Rosa
At the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, researchers have presented positive early phase clinical trial results regarding the use of the isocitrate dehydrogenase 1 (IDH1) inhibitor ivosidenib in patients with IDH1+ acute myeloid leukemia (AML).

The phase 1 trial boasts an overall response rate of 41.9% with a median progression free survival (PFS) of 8.2 months, according to a recent press release. Twenty-four percent of patients enrolled in the study achieved a complete response.

Ivosidenib is a first-in-class, oral targeted inhibitor of mutant IDH1, according to Agios Pharmaceuticals, Inc. In February, the US Food and Drug Administration (FDA) granted the company’s New Drug Application for ivosidenib for the treatment of those with relapsed or refractory acute myeloid leukemia with an IDH1 mutation. The NDA was granted Priority Review and a Prescription Drug User Fee Act (PDUFA) date of August 21, 2018.

IDH1 is a cousin gene to IDH2, which is another AML driver; a drug developed to target IDH2, enasidenib, was just approved by the FDA last year. Previous research has indicated that mutations in either of these genes can potentially stimulate other oncogenes while “muting the action of tumor-suppressor genes.” These inhibitors were developed to inhibit the action of the IDH genes.

For the phase 1 dose escalation and expansion study, researchers assessed the safety and efficacy of 500 mg of ivosidenib administered once-daily in patients with relapsed/refractory AML. The primary efficacy endpoint of the study was the complete remission (CR) per modified IWG 2003 criteria plus CR with partial hematologic recovery.

“CRh was defined as absolute neutrophil count > 0.5 × 109/L and platelet count > 50 × 109/L,” the study authors wrote. “The overall response rate (ORR) comprised CR, CR with incomplete hematologic or platelet recovery, partial response, and morphologic leukemia-free state.”
 
The investigators treated a total of 258 patients with ivosidenib, according to the abstract. Of 179 R/R AML patients treated once-daily with 500 mg of ivosidenib, 17 (9.5%) remained on treatment at the data cutoff date for the analysis, which was November 10, 2017.

“In R/R AML patients, the CR+CRh rate was 31.8% (95% CI: 25.1%, 39.2%), including CR in 24.0% (95% CI: 18.0%, 31.0%),” study authors write. “Median duration of CR+CRh was 8.2 months (95% CI: 5.6, 12.0), and median duration of CR was 10.1 months (95% CI: 6.5, 22.2). The ORR was 41.9% (95% CI: 34.6%, 49.5%).”

The investigators report that the treatment was, overall, well-tolerated. The authors note that the most common adverse event, any grade, regardless the cause, occurred in 25% or more of the 179 R/R AML patients. Of that percentage, 33.5% experienced diarrhea, 31.3% leukocytosis, 31.3% nausea, 29.1% febrile neutropenia, 28.5% fatigue, and 25.7% electrocardiogram QT prolonged. Most of the AEs were not associated with the treatment and were grades 1 or 2.

However, out of the 179 patients, 19 (10.6%) reported IDH differentiation syndrome, including “grade ≥3 IDH-DS in 9 (5.0%); study drug was held owing to IDH-DS in 6 patients (3.4%), and no instances of IDH-DS led to dose reduction, permanent treatment discontinuation, or death,” study authors write.

Authors added that updated mutation clearance results will be provided.

“We know about 50 or so genes that contribute to AML and now researchers are working to design and test drugs that treat the most common and the most powerful of these genes,” Daniel A. Pollyea, MD, MS, investigator at the University of Colorado Cancer Center and clinical director of the Leukemia Services at the CU School of Medicine, said in a recent statement.

The authors concluded that ivosidenib was well-tolerated in R/R AML patients and induced durable remissions.  

"I think ivosidenib is going to be an important weapon in the arsenal," Dr Pollyea said. "It's a very well tolerated oral therapy for patients who have few options and it will be an important new tool for us to use."

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