CA-4948 Shows Early Activity, Tolerability in Relapsed/Refractory AML and High-Risk MDS

CA-4948 monotherapy was found to have preliminary activity with acceptable safety and tolerability in patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS), according to updated data from an ongoing phase 1/2 trial (NCT04278768).¹

Among 5 patients with U2AF1 or SF3B1 spliceosome-mutated, relapsed/refractory AML, the agent was found to produce a complete response (CR) or complete response with partial hematologic recovery (CRh) rate of 40%. Notably, both patients who achieved CR/CRh have been on the study for longer than 6 months and achieved minimal residual disease negativity status. Moreover, 3 patients with elevated blast counts experienced a 50% or higher tumor burden reduction in their counts.

In 7 patients with U2AF1 or SF3B1 spliceosome-mutated, relapsed/refractory MDS, CA-4948 was found to elicit an objective response rate of 57%. One of these patients who achieved a marrow CR went on to undergo stem cell transplant following cycle 1 of treatment. Four patients experienced a 50% or greater reduction in their blast counts.

Lastly, in 3 patients with FLT3-mutated, relapsed/refractory AML, the agent elicited a CR rate of 33%, with 2 patients showcasing eradication of the mutation after treatment underscoring the agent’s disease-modifying potential. In this subset, 2 patients with elevated blast counts experienced a 50% or higher reduction in their counts.

“These data continue to build on what we believe to be a compelling profile for CA-4948, showing its activity as a monotherapy in a targeted population of patients living with relapsed/refractory AML/MDS, for whom prior lines of therapy have been unsuccessful,” James Dentzer, president and chief executive officer of Curis, Inc., stated in a press release. “We are especially pleased that these results demonstrate both a favorable safety profile and improved anticancer activity compared with standard-of-care therapies for these patients.”

The open-label, single-arm, dose-escalation trial used a 3+3 design to evaluate the safety and activity of CA-4948. A total of 22 patients had been enrolled; this included 11 patients with high-risk MDS and 11 patients with AML. Participants were administered CA-4948 at 1 of the following dose levels, twice daily: 200 mg, 300 mg, 400 mg, and 500 mg.

The primary objective of the trial was to identify the maximum tolerated dose and the recommended phase 2 dose (RP2D) of the agent based on safety and tolerability, dose-limiting toxicities, biologic activity, and pharmacokinetic and pharmacodynamic activity.

Prior data from the trial were shared during the 2021 EHA Congress and showcased the potential of CA-4948 in these patient populations whose disease is characterized by spliceosome or FLT3 mutation.²

“Today’s clinical data update provides an expanded data set for this genetically-defined patient population and further support the rationale for seeking a discussion with FDA in the first half of 2022 to discuss the potential for a rapid registrational path forward for CA-4948 as a monotherapy in genetically-defined patient populations,” according to Curis, Inc.

As of December 16, 2021, a total of 49 patients with relapsed/refractory AML or MDS had received treatment with CA-4948 at any of the following dose levels: 200 mg, 300 mg, 400 mg, and 500 mg.

Regarding safety, the agent was found to be well tolerated across several dose levels, including the RP2D of 300 mg twice daily. The treatment-related adverse effects reported with CA-4948 were noted to be manageable and reversible. No dose-limiting myelosuppression was reported, nor were any cumulative toxicities observed. Notably, no grade 4 or 5 treatment-related toxicities were experienced.

Enrollment to the phase 1 trial is ongoing. Additional data are anticipated to be shared at a medical conference in 2022.

References

1. Curis announces updated data with additional encouraging clinical activity in phase 1/2 study of CA-4948 monotherapy in targeted patients with relapsed or refractory AML and MDS; and initial clinical data from phase 1 study of CI-8993 in patients with relapsed or refractory solid tumors. News release. Curis, Inc.; January 6, 2022. Accessed January 7, 2022. https://yhoo.it/3FaUBO1
2. Curis announces positive updated data from ongoing phase 1/2 study of CA-4948 monotherapy in patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndromes. News release. Curis, Inc.; June 11, 2021. Accessed January 7, 2022. https://bit.ly/3qXfuax