FDA Lifts Partial Clinical Hold on the TakeAim Leukemia Study of Emavusertib

The FDA has lifted the partial clinical hold on the monotherapy phase of the TakeAim Leukemia study (NCT04278768) of emavusertib (CA-4948) alone or in combination with azacytidine (Vidaza) and venetoclax (Venclexta) in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), according to Curis, Inc.¹

Previously, the FDA requested additional data from the study due to a death of a patient who experienced rhabdomyolysis in addition to several other conditions, as this death was first reported as a dose-limiting toxicity (DLT) of emavusertib. The FDA requested safety, efficacy, other data related to rhabdomyolysis, and the company's strategy for managing rhabdomyolysis, if it is detected, prior to lifting the restriction on patient enrollment.

The monotherapy phase of the trial has now been given permission to resume enrolling approximately 9 additional patients at the 200mg dose level as part of the monotherapy dose-finding phase (phase 1a) of the study. The partial hold remains in place for phase 1b, the combination therapy phase, and phase 2a, the expansion phase of the study, until phase 1a is complete and the FDA approves proceeding to the next phases of the study.

"We are pleased to announce the results of the FDA's review and to have addressed potential concerns about the identification and management of rhabdomyolysis," said James Dentzer, president and chief executive officer of Curis, in the press release. "We are working with our clinical sites to quickly resume enrollment of additional patients."

The multicenter, open-label, phase 1/2a dose escalation and expansion TakeAim Leukemia study looks to evaluate patients with R/R AML and high-risk myelodysplastic syndrome (MDS). Patients will be split into 1 of 4 cohorts to receive orally administered emavusertib alone and in combination with azacitidine or venetoclax.²

Cohort 1 will include those diagnosed with FLT-ITD-mutant R/R AML who failed 1 to 3 pretreatments, including a FLT3 inhibitor. In cohort 2, patients enrolled will be those with FLT3 wild-type R/R AML after failing 1 to 3 pretreatments.

The first MDS cohort, cohort 3, will include patients with R/R high-risk MDS with spliceosome mutations (SF3B1, U2AF1, SRSF2, ZRSR2), resistant or refractory to hypomethylating agents (HMA), and who are ineligible for intensive chemotherapy and had up to 3 pretreatments. Then, the final cohort will include patients with R/R high-risk MDS without spliceosome mutations, who are resistant or refractory to HMA, ineligible for intensive chemotherapy, and had a maximum of 3 pretreatment.

Phases 1 and 1b of the study will follow a 3 + 3 design. The 3 patients initially enrolled will be evaluated for dose-limiting toxicity during cycle 1 of treatment. If no DLTs are observed, patients can proceed to receive the next higher dose level. If no DLTs are reported in the first 3 patients, the dose level may be expanded.

In the phase 2a dose expansion portion of the study, a Simon-2 stage design will be followed with approximately 9 patients enrolled in each cohort. If a response to treatment is observed, 30 patients will be enrolled in each cohort.

The starting dose of emavusertib in the study is 200 mg twice daily. In the dose-escalation phase of the trial, the agent will be administered for 28 consecutive cycles. The other experimental arm that is part of the dose-escalation phase will receive emavusertib 200 mg twice a day for 21 days of a 28-day cycle, combined with azacytidine 75 mg/m2 administered by intravenous or subcutaneous infusion. In the final dose-escalation cohort, patients will be given emavusertib 200 mg for 21 days of a 28-day cycle in combination with venetoclax 100 mg orally for 21 days of a 28-day cycle.

Within the dose-expansion phase, patients will receive the recommended phase 2 dose (RP2D) determined from the phase 1 dose-escalation phase.

The coprimary end points of phase 1 include determining the maximum-tolerated dose (MTD) of emavusertib monotherapy, the RP2D of emavusertib, and the MTD of emavusertib plus azacytidine.

The phase 2 coprimary end points consist of determining the RP2D of emavusertib plus azacytidine, the MTD of emavusertib plus venetoclax, the RP2D of emavusertib with venetoclax, complete response rate, duration of response, and safety determined by the frequency of adverse events.

Secondary end points of the study include assessing and characterizing pharmacokinetics and overall response rate.

Updated preliminary data from the TakeAim Leukemia study is expected to be released in 2023. In addition, Curis and FDA are working together to proactively discuss clinical plans for emavusertib in leukemia, including creating an optimal dose and development path.

References:

1. FDA allows patient enrollment to resume in monotherapy dose escalation of emavusertib in TakeAim leukemia study. News release. Curis, Inc. August 30, 2022. Accessed August 30, 2022.

2. Dose escalation/ expansion trial of CA-4948 as monotherapy and in combination with azacitidine or venetoclax in patients with AML or MDS. Clinicaltrials.gov. Updated March 31, 2022. Accessed April 4, 2022. https://bit.ly/3DLS3ak