FDA Lifts Partial Clinical Hold on TakeAim Leukemia Trial of Emavusertib in AML/MDS

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The FDA has lifted a partial clinical hold on the phase 1/2 TakeAim Leukemia trial evaluating emavusertib monotherapy and in combination with azacitidine and venetoclax in patients with relapsed/refractory acute myeloid leukemia or high-risk myelodysplastic syndrome.

FDA

The FDA has lifted a partial clinical hold on the phase 1/2 TakeAim Leukemia trial (NCT04278768) evaluating emavusertib (previously CA-4948) monotherapy and in combination with azacitidine and venetoclax (Venclexta) in patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS).¹

Additionally, the recommended phase 2 dose (RP2D) of emavusertib monotherapy has been established as 300 mg twice per day.

“We are pleased to announce that FDA has removed the partial clinical hold on the TakeAim Leukemia study, and that we are proceeding with 300 mg BID as our RP2D,” James Dentzer, president and chief executive officer of Curis, stated in a news release. “We are working with our clinical sites to enroll targeted patients with AML [patients with a FLT3 or spliceosome mutation who have received (at most) 2 prior lines of treatment]. We also plan to initiate a front-line combination study of emavusertib with azacitidine and venetoclax.”

In April 2022, the FDA placed a partial clinical hold on the study and requested additional information regarding findings associated with the death of a patient who had relapsed/refractory AML and experienced rhabdomyolysis, among other conditions, which had previously been disclosed as a dose-limiting toxicity of emavusertib. The regulatory agency requested safety, efficacy, and other data related to this toxicity, and the determination of a RP2D.²

Enrollment for the monotherapy phase 1a portion of the study was allowed to resume in August 2022, and the trial needed to enroll an additional 9 patients to be treated with 200 mg of emavusertib.³

Notably, the phase 1/2 TakeAim Lymphoma study (NCT03328078) investigating the safety and efficacy of emavusertib in patients with relapsed or refractory B-cell malignancies also went under a partial clinical hold in April 2022.⁴ However, this hold was lifted in August 2022.⁵

Data from TakeAim Leukemia showed that as of the data cutoff date of March 17, 2023, 84 patients received emavusertib monotherapy at doses ranging from 200 mg to 500 mg twice per day, and investigators reported significant blast count reductions, irrespective of dose level, mutation status, or number of prior lines of treatment.¹

Additionally, responses to monotherapy were experienced by patients with AML harboring FLT3 mutations and those with AML harboring U2AF1 or SF3B1 spliceosome mutations who had received no more than 2 prior lines of treatment.

Two of 3 patients with a FLT3 mutation treated at 300 mg twice per day achieved a complete response (CR), and 2 of 3 patients with a spliceosome mutation treated at this dose level achieved a CR or CR with partial hematologic recovery. The duration of response (DOR) in these patients ranged from 5.6 months to 7.0 months.

The open-label, dose-escalation, dose-expansion TakeAim Leukemia trial is enrolling patients at least 18 years of age with a life expectancy of at least 3 months and an ECOG performance status of 0 or 1. The phase 2a monotherapy dose-expansion portion of the study is including those with AML harboring FLT3 mutations who are relapsed/refractory after a FLT3 inhibitor; those with relapsed/refractory AML harboring SF3B1 or U2AF1 spliceosome mutations; and those with relapsed/refractory high-risk MDS with SF3B1 or U2AF1 spliceosome mutations and a bone marrow blast count of at least 8% who are ineligible for chemotherapy.⁶

Key exclusion criteria include patients with acute promyelocytic leukemia, known central nervous system leukemia, chronic myeloid leukemia, and any prior systemic anticancer treatment within 14 days of starting treatment with emavusertib.

In the monotherapy dose-expansion portion of the trial, patients will be divided into 4 separate cohorts based on baseline disease, and they will receive emavusertib at the RP2D of 300 mg twice per day.

The primary end points of phase 2a portion of the research are CR rate in patients with AML and overall response rate in patients with MDS. Secondary end points include safety, DOR, time to response, transfusion independence, and overall survival.

“We believe emavusertib has the potential to be the cornerstone agent in the treatment of hematological malignancies,” Dentzer added in the news release. “In 2024, we expect to have updated data from the TakeAim Leukemia monotherapy study, clarification of a monotherapy registrational study design, and initial data from an azacitidine and venetoclax combination study.”