CA-4948 Garners Positive Early Results in Relapsed/Refractory AML and MDS

The updated results of an ongoing phase 1/2 study indicated that CA-4948 achieved promising responses and a tolerable safety profile in patients with relapsed/refractory acute myeloid leukemia and myelodysplastic syndromes.

Single agent CA-4948 yielded a notable reduction in bone marrow blasts and promising early responses in patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to positive, updated data from an ongoing phase 1/2 study (NCT04278768) presented at the 2021 European Hematology Association Virtual Congress.1

Following a cut off of April 30, 2021, findings from the study indicated that a reduction in bone marrow blasts had been observed in 10 of 12 patients who were evaluable for bone marrow response. This was defined as patients who had an elevated blast count at baseline and at least 1 malignancy assessment after the first cycle. Of the 17 evaluable patients (MDS, n = 9; AML, n = 8), 5 experienced an objective response, which consisted of 1 full hematologic recovery complete response (CR), a CR with incomplete recovery (CRi) and negative minimal residual disease (MRD), 1 partial response, and 2 bone marrow CRs. All patients who experienced any objective response showed signs of hematologic recovery.

“As we have observed increasingly mature sets of data, we continue to be pleased by the steady progression of clinical activity demonstrated by CA-4948 monotherapy in this historically difficult-to-treat late-line population,” James Dentzer, president and chief executive officer of Curis, said in a press release. “We believe these updated data further support the growing body of evidence that CA-4948's anti-cancer activity continues to deepen the longer patients remain on drug, which is enabled by its safety and durability profile to date. Further, after backfilling patient cohorts and evaluating additional data after the April 30, 2021, cut-off date for today's presentation, we have concluded 300mg BID is the optimal dose to take into phase 2 studies.”

The open label, single arm, dose escalation trial utilized a 3+3 design to assess the safety and activity of the oral small molecule IRAK4 kinase inhibitor. The study enrolled 22 patients who had high-risk MDS (n = 11) and AML (n = 11) who received 1 of several doses of CA-4948 twice daily, including 200 mg, 300 mg, 400 mg, and 500 mg.

The primary objective of the study was to determine both the maximum tolerated dose and recommended phase 2 dose based on the agent's safety and tolerability, dose-limiting toxicities (DLTs), as well as biologic activity and pharmacokinetic and pharmacodynamic activity.

Additional data from the study indicated that all patients who had an SF3B1 or U2AF1 spliceosome mutation (n = 3), all were able to achieve a marrow CR or better. One of the patients, who had been on the study for over 8 months, reportedly experienced a marrow CR and went on to achieve a CRi with negative MRD. Another patient with FLT3-mutant AML who had relapsed following previous treatment with decitabine and venetoclax (Venclexta) and was refractory to gilteritinib (Xospata), achieved a PR and elimination of detectable FLT3 following treatment with CA-4948. One patient with AML who had been on study for over 7 months and received 4 prior lines of chemotherapy experienced a reduction in long-term IRAK4 expression, as well as a full hematologic recovery.

“We are especially pleased with the outcomes seen to date for patients with spliceosome or FLT3 mutations,” Dentzer explained. “All 3 patients with a spliceosome mutation achieved an objective response. The FLT3 patient also achieved an objective response and, after 2 cycles of CA-4948, the patient's FLT3 mutation was found to be completely eradicated. While these are early days, and we have a limited set of patient data, we are very encouraged about the potential CA-4948 may have to become a disease-modifying alternative for these late-line patients, where no approved therapies currently exist.”

Additionally, genomic analyses were performed across multiple patients. DNA sequencing identified disease modification with the reduction of cancer-associated variant allele frequency following treatment with CA-4948. Similarly, RNA sequencing revealed that disease modifications occurred with the reduction of long and short ratio of IRAK4 following treatment with the experimental agent.

In terms of safety, no significant myeloid suppressive adverse effects were reported by investigators. Although the 300 mg recommended phase 2 dose did not yield any DLTs, 13% of those who were treated with the 400 mg dose experienced DLTs such as grade 3 rhabdomyolysis (n = 2) and 66% of those in the 500 mg cohort experienced grade 3 rhabdomyolysis (n = 1) and grade 3 syncope (n = 1).

In addition to demonstrating efficacy as a monotherapy, CA-4948 has recently been found to boost the antitumor efficacy of other therapies including azacitidine, venetoclax, and the combination of azacitidine and venetoclax.

“We believe synergistic activity observed in leukemia cells provides a rationale for clinical testing of CA-4948/azacitidine, CA-4948/venetoclax, and the triplet combination of all three agents together in patients with AML,” the lead investigator Guillermo Garcia-Manero, chief of the Section of Myelodysplastic Syndromes within the Department of Leukemia at The University of Texas MD Anderson Cancer Center concluded.


  1. 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. July 12, 2021.
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