Phase I study CA-4948 monotherapy in R/R MDS shows positive preliminary results

On December 8, 2020, positive preliminary results of the phase I study (NCT04278768) of CA-4948 monotherapy for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), were released.¹ Results of this study were also presented as a poster at the 62nd American Society of Hematology (ASH) Annual Meeting & Exposition.²

CA-4948 is a first-in-class inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). IRAK4 plays an essential role in the toll-like receptor (TLR) and interleukin-1 receptor signaling pathways, which are frequently dysregulated in non-Hodgkin lymphoma, AML, and MDS. The long form of IRAK4 (IRAK4-L) has also demonstrated oncogenic activity and is preferentially expressed in ~50% of patients with AML and MDS.^1,2

CA-4948^1-3

• First-in-class suppressor of the TLR pathway³
• Orally administered, novel small molecule inhibitor of IRAK4 kinase¹
• Demonstrates inhibition of FLT3 in in vitro and in vivo models²

NCT04278768⁴

• A phase I, single arm, dose escalation study of CA-4948 in adult patients (≥ 18 years) with AML or high-risk MDS
• Primary outcomes: Maximum tolerated dose, recommended phase II dose
• Secondary outcomes: Pharmacodynamics and pharmacokinetics
• Exploratory outcomes: Pharmacodynamics on selected biomarkers in peripheral blood and bone marrow
• Three study cohorts: 200 mg twice daily; 300 mg twice daily; 400 mg twice daily; in 28-day cycles

Results^1,2

• 7 patients have been enrolled in the first two dose cohorts (n = 3, AML patients; n = 4, MDS patients)
• Patients had a median of three prior lines of therapy (range 1–4)
• 6/7 patients remain enrolled in the study
• No dose-limiting toxicities were reported
• All evaluable patients (6/7) had marrow blast reductions
• Marrow complete responses were seen in two patients:
  • blast counts decreased from 23% to 1% in one patient and from 11% to 2% in the other patient

Based on these results, enrollment has begun in the 400 mg dose group. CA-4948 is also being studied in a phase I trial (NCT03328078) for non-Hodgkin lymphoma, which was presented as an oral abstract at the 62nd ASH Annual Meeting & Exposition.⁵ If further clinical trials demonstrate positive results, CA-4948 could provide a new treatment option for the R/R setting, where there is currently an unmet clinical need.