Expert Says Olutasidenib Appears Safe as Monotherapy in Relapsed/Refractory IDH1-Mutant Gliomas

July 10, 2020

In an interview with Targeted Oncology, Macarena de la Fuente, MD, discussed the findings from a phase 1b/2 study of olutasidenib as treatment of patients with relapsed/refractory IDH1-mutated gliomas, either alone or in combination with azacitidine.

During the 2020 American Society of Clinical Oncology Virtual Scientific Program, data from a phase 1b/2 study of olutasidenib demonstrated that the agent was safe and well tolerated as a single agent in patients with relapsed/refractory IDH1-mutated gliomas. The agent was also evaluated in combination with azacitidine (Vidaza).

The IDH1 mutation is present in more than 70% of patients with gliomas of grades II/III; olutasidenib is a potent oral inhibitor of the IDH1 protein, which led to the rationale for evaluating this agent in gliomas, as well as other solid tumors.

According to the safety findings from this study, the median duration of treatment was 4.2 months (range, 0.03 to 15.9) for the single agent. Overall, 11 patients continue on treatment. The most common treatment-emergent adverse events (AEs) in the single-agent arm occurring in more than 25% of patients included fatigue (50%), nausea (54%), diarrhea (31%), alanine aminotransferase (ALT) increase (31%) and headache (31%), compared with the combination arm where treatment-emergent AEs that occurred in ≥ 2 pts included nausea (n=4), fatigue (n=2), ALT increase (n=5) & aspartate transaminase increase (n=4).

This trial remains ongoing, and more data will be provided in the future as the agent continues to be evaluated in this patient population. The second portion of the study will evaluate the efficacy of the drug.

In an interview with Targeted Oncology, Macarena de la Fuente, MD, assistant professor, Neurology, Sylvester Comprehensive Cancer Center/University of Miami, discussed the findings from a phase 1b/2 study of olutasidenib as treatment of patients with relapsed/refractory IDH1-mutated gliomas, either alone or in combination with azacitidine.

TARGETED ONCOLOGY: Could you provide the rationale for this study?

De La Fuente: IDH1 mutations are present in about 75% of lower-grade gliomas and about 5% of glioblastoma, as well in other solid tumors. These mutations result in the production of 2-hydroxyglutarate (2-HG). That is an oncometabolite that leads to epigenetics alterations and promote tumorigenesis in glioma cells. Olutasidenib, the drug that we are talking about, is an oral CNS penetrant, selective inhibitor of IDH1mutations. The drug has been tested in hematologic malignancies, and now we are running this trial in a variety of solid tumors, including gliomas.

TARGETED ONCOLOGY: What is the rationale for potentially combining this agent with azacitidine?

De La Fuente: As the accumulation of 2-HG causes DNA hypermethylation and other epigenetic dysregulations, we thought the combination of olutasidenib with a demethylating agent as azacitidine as compelling.

TARGETED ONCOLOGY: What was what was the design of the study, and what methods were used to test this agent?

De La Fuente: This was a basket study with multiple cohorts including different tumor types. Here we present the glioma cohort. The glioma cohort included a safety lead-in with two arms, the single agent arm with olutasidenib and the combination arm with olutasidenib plus standard dose azacitidine. After that, the plan was to move both arms to an expansion cohort for clinical activity, but because of safety reasons, it was decided that only the single-agent arm was continued to the clinical activity phase 2 study.

TARGETED ONCOLOGY: What was what was found with this agent?

De La Fuente: Overall, the drug was well tolerated as a single agent, and the most common grade 3/4 AEs that we observed were ALT elevation in 3 patients on the monotherapy cohort and in 3 patients in the combination cohort. There were 2 dose-limiting toxicities related to the drug in the combination cohort, which met the criteria for stopping that cohort. Besides that, the drug was well tolerated. Many AEs were asymptomatic and reversible.

TARGETED ONCOLOGY: What would you say are the clinical implications of these findings going forward?

De La Fuente: With this trial, we demonstrated that this drug can penetrate the CNS, and that it's safe and well tolerated as a single agent in this population that include heavily pretreated, enhancing gliomas. Although this trial was not powered to evaluating efficacy, we saw 1 patient that has a partial response, and 4 patients that achieved more than 50% tumor reduction by independent central volumetric assessment.

I think the next step for this drug probably would be to move forward with phase 2 and phase 3 studies as single agent and in combinations with other agents, either demethylating agents or other compounds.

TARGETED ONCOLOGY: Beyond glioblastoma, what other tumor types do you think that this may have potential efficacy in?

De La Fuente: There are trials ongoing in hematologic malignancies and solid tumors, as chondrosarcoma, cholangiocarcinoma, and other tumor types.