Partial Trial Hold Is Lifted For Take Aim Leukemia Study

On August 30, 2022, Curis Inc. announced that the FDA has cleared the company to resume enrollment of patients in their Take Aim Leukemia study. This is “a Phase 1/2 open-label dose escalation, dose expansion clinical trial investigating emavusertib (previously CA-4948) as a monotherapy and in combination with azacitidine or venetoclax in patients with relapsed or refractory (R/R) AML or high risk MDS”. If the partial hold on the Phase 1b portion of the trial is lifted, these areas will be targeted:

• Monotherapy in AML patients with spliceosome and FLT3 mutations
• Monotherapy in patients with MDS and spliceosome mutations
• Emavusertib combination therapy with azacitidine or venetoclax in patients without spliceosome or FLT3 mutations

The goals of the study are to determine safety, maximum tolerated dose (MTD), recommended Phase II dose and signals of activity. Updated preliminary clinical data should be available in 2023.

Emavusertib is an IRAK4 kinase inhibitor (a protein kinase that signals immune responses from Toll-like receptors and T-cell receptors). These receptors are often unacceptable responses in patients with cancer. Third parties have recently discovered that the long form of IRAK4 (IRAK4-L) is expressed in over half the patients with AML. Emavusertib was designed to inhibit FLT3, a known driver of IRAK4.

A partial clinical hold was placed on the Take Aim Leukemia trial in April 2022 due to the risk of rhabdomyolysis (a serious medical condition that can be fatal or result in permanent disability. Rhabdomyolysis occurs when damaged muscle tissue releases its proteins and electrolytes into the blood. These substances can damage the heart and kidneys and cause permanent disability or even death). A hold is still in effect for the Phase 1b portion of the trial where emavusertib in combination with azacitidine (Vidaza) or venetoclax (Venclexta) will be studied.

After reviewing the company’s strategy to detect and treat rhabdomyolysis, the FDA lifted the partial hold on the Phase 1a portion of the trial. "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. "We are working with our clinical sites to quickly resume enrollment of additional patients." The company has agreed to enroll nine additional patients into the study at the 200 mg dose level.

The Phase 1/2a TakeAim Leukemia study (when allowed to continue to completion) will divide patients into four cohorts:

• Cohort 1- will include those diagnosed with FLT-ITD-mutant R/R AML who failed 1 to 3 pretreatments, including a FLT3 inhibitor.
• Cohort 2- those with FLT3 wild-type R/R AML after failing 1 to 3 pretreatments.
• Cohort 3- 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.
• Cohort 4- 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.