CA-4948 Yields Promising Clinical Activity in R/R AML/MDS; Initial Findings Read Out for CI-8993 in R/R Solid Tumors

Updated results from a phase 1/2 dose escalation study (NCT03328078) assessing CA-4948 in patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) highlighted positive responses to treatment, according to a press release from developer Curis. Additionally, a phase 1 study (NCT04475523) examining CI-8993 highlighted promising safety data in a population of patients with relapsed/refractory solid tumors.

Investigators assessed preliminary findings from the CA-4948 study that included patients with relapsed/refractory AML/MDS who had enrolled as of September 20, 2021. Patients with AML who had a U2AF1 or SF3B1spliceosome mutation treated with the agent experienced a 40% (n = 2/5) rate of complete remission (CR) or CR with partial hematologic recovery. Within 6 months or more, both patients achieved minimal residual disease negativity. Additionally, 3 patients experienced a significant and consistent reduction in tumor burden, with 50% or higher reduction in blast counts. Patients with MDS who had the same mutations achieved a 57% (n = 4/7) overall response rate. One patient required a stem cell transplant after a cycle of treatment. Investigators also observed a reduction in tumor burden within this population, with 4 patients achieving 50% or higher reduction in blast counts.

Additionally, the study of CI-8993 for patients with relapsed or refractory solid tumors treated a total of 13 patients in 2 dose cohorts: 0.15 mg/kg and 0.3 mg/kg. The results have shown promising efficacy and no dose-limiting toxicities. Investigators reported that the safety data spotlights the effectiveness of the procedures to manage the expected development of cytokine release syndrome. Moreover, pharmacodynamic findings could yield early indication that using CI-8993 to target VISTA could activate a number of anti-cancer mechanisms. The study is currently enrolling patients to be treated at a dose level of 0.6 mg/kg.

Curis hopes to speak with the FDA in the first half of 2022 to potentially put CA-4948 monotherapy on a rapid registrational path.

“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 at Curis, said in a press release.

CA-4948 is a IRAK4 kinase inhibitor that plays a necessary role in toll-like receptor and IL-1R signaling pathways that are ordinarily dysregulated in those with AML and MDS. Moreover, the treatment was designed to inhibit FLT3, which could help to provide additional benefit within this patient population. Additionally, monoclonal antibody with active Fc, CI-8993 was designed to antagonize the VISTA signaling pathway, which is a novel checkpoint ligand that is frequently expressed on myeloid and T cells. The treatment relieves negative regulation of hematopoietic cells and boosts anti-tumor immunity.

As of December 2021, 49 patients with relapsed/refractory AML or MDS have been treated with CA-4948 in the 200 mg, 300 mg, 400 mg, or 500 mg dose cohorts. The treatment had a tolerable safety profile across all dose levels, including the recommended phase 2 dose of 300 mg. Treatment-related adverse effects (TRAEs) were found to be both reversible and manageable with no dose-limited myelosuppression or cumulative toxicities. No grade 4/5 TRAEs were reported.

Additional findings from the study indicated that 2 of 3 patients with relapsed/refractory AML with a FLT3 mutation had their mutation eliminated. following treatment, meaning that CA-4948 may work to modify the disease. One patient achieved complete remission ,and 2 patients had 50% or higher reduction in blast counts.

Reference

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. January 6, 2022. Accessed January 6, 2022. https://yhoo.it/3nnvGB9