Phase 1/2a study of the IRAK4 inhibitor CA-4948 as monotherapy or in combination with azacitidine or venetoclax in patients with relapsed/refractory (R/R) acute myeloid leukemia or lyelodysplastic syndrome.

Abstract

7016 Background: CA-4948 is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) and FLT3. IRAK4 is critical in triggering inflammation, oncogenesis, and survival of cancer cells. Genetic mutations in the splicing factors SF3B1 and U2AF1 drive overexpression of a highly active long isoform of IRAK4 and have been associated with disease progression and poor prognosis of high-risk myelodysplastic syndrome (HR-MDS) and acute myeloid leukemia (AML). Methods: This is an open-label, phase 1/2a dose escalation and cohort expansion trial (NCT04278768). In phase 1 Dose Escalation, patients with R/R AML or HR-MDS are treated with CA-4948 monotherapy. Phase 1b includes 2 arms of combination therapy: CA-4948 + azacitidine (AZA) and CA-4948 + venetoclax (VEN). The primary objectives of this study are to assess the safety, clinical activity, and identify the Recommended Phase 2 Dose (RP2D) of CA-4948 as monotherapy or in combination with AZA or VEN in R/R AML or HR-MDS. The Phase 2a Dose Expansion includes patients for CA-4948 monotherapy: R/R AML with FLT3 mutation, or AML and HR-MDS R/R to HMA with U2AF1 or SF3B1 mutations. Results: As of December 16th, 2021, 49 patients have been treated in the phase 1 portion, of whom 43 started by September 30th, allowing 2 on-study disease assessments. The median number of prior therapies was 2 (range 1-5). Four monotherapy dose levels of CA-4948 were tested (200 to 500 mg orally BID). No dose-limiting toxicities were observed at 200 mg and 300 mg BID. No Grade 4 or 5 treatment-related AEs (TRAEs) were reported, and all the TRAEs were manageable. Reversible, manageable Grade 3 rhabdomyolysis occurred in 1/26 (4%) patients at 300 mg BID, 2/17 (12%) at 400 mg BID, and 1/3 (33%) at 500 mg BID. RP2D was determined as 300 mg BID. Of 43 patients starting before Sept 30th, 2021, 14 had SF3B1, U2AF1 or FLT3 mutations and demonstrated more promising efficacy. In the 5 evaluable AML patients with spliceosome mutations, 40% reached CR/CRh (1 CR, 1 CRh), both with study duration >6 months. In the 7 spliceosome-mutated HR-MDS patients, 57% reached marrow CR, including 1 with RBC transfusion independence and 1 proceeding to HSCT. One of the three FLT3-mutated AML reached CR, and 2 became FLT3-negative. Among the 29 patients without SF3B1/U2AF1/FLT3 mutations, 1 reached CR and 2 PR. Phase 1b and Phase 2a are ongoing. RNA-seq on selected samples showed decrease in relative expression of IRAK4-long isoforms with response to CA-4948. Conclusions: CA-4948 is well tolerated and effective in heavily pretreated AML and HR-MDS patients, especially in those with U2AF1/SF3B1/FLT3 mutations. No dose-limiting myelosuppression was reported, suggesting CA-4948 may be a candidate for combination therapy. Accrual of Phases 1b and 2a is ongoing. Clinical trial information: 04278768.

Targeting IRAK4 with Emavusertib in Lymphoma Models with Secondary Resistance to PI3K and BTK Inhibitors

“…In this cell line, nor emavusertib nor ibrutinib alone were able to induce an anti-proliferative response while the combination of the two compounds proved to be beneficial. Our data extend the reported preliminary data combining emavusertib with ibrutinib in ABC-DLBCL and MCL and with venetoclax and azacytidine in AML [ 24 , 25 , 26 , 27 , 28 ] that led to the early combination clinical trials [ 29 , 30 ].…”

“…Considering the early safety data from clinical trials [ 29 , 30 ], our study identifies the IRAK4 inhibitor emavusertib as a novel compound to be explored as single agent in trials for patients with MYD88-mutated indolent B cell lymphomas and as combination partner with BTK or PI3K inhibitors in unselected populations of patients.…”

“…Emavusertib has shown single agent antitumor activity in ABC DLBCL, mantle cell lymphoma (MCL), and acute myeloid leukemia (AML) models [ 23 , 24 , 25 , 26 , 27 ], and in combination with ibrutinib (in ABC DLBCL, MCL), venetoclax and azacytidine (in AML) [ 24 , 25 , 26 , 27 , 28 ]. Early safety and clinical activity have been reported in both lymphoma and AML patients [ 29 , 30 ] and phase 1/2 trials are active for patients with hematologic cancers (NCT05178342, NCT04278768, NCT03328078).…”

Treatment of myelodysplastic syndromes in the era of precision medicine and immunomodulatory drugs: a focus on higher-risk disease

“…In patients without SF3B1/U2AF1/FLT3 mutations, only 1 patient (of 29 total patients) achieved CR. CA-4948 was safe without any dose-limiting toxicity [72,73]. The trial is ongoing (NCT04278768), and further follow-up and larger studies are needed to assess the efficacy of emavusertib in HR-MDS.…”

Molecular Threat of Splicing Factor Mutations to Myeloid Malignancies and Potential Therapeutic Modulations

“…Results from 14 patients with SF3B1 , U2AF1 , or FLT3 mutations were promising. Out of five AML patients, two reached complete remission/complete remission with partial hematologic recovery (CR/CRh) (1 CR, 1 CRh), and out of seven patients with spliceosome-mutated HR-MDS, four reached marrow CR [ 130 ]. The CA-4948 monotherapy was well tolerated and resulted in a reduction in bone marrow blasts in 89% of evaluated patients, and three patients with splicing factor mutations all achieved CR, and patients with objective responses also showed signs of hematologic recovery [ 131 ].…”