On February 9, 2021 Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, reported that the first patient has been dosed in its Phase 1 trial evaluating CA-4948, a novel, small molecule IRAK4 kinase inhibitor, in combination with ibrutinib, a BTK inhibitor, in patients with relapsed or refractory (R/R) hematologic malignancies (Press release, Curis, FEB 9, 2021, View Source [SID1234574785]).
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"In dosing the first patient in this Phase 1 study evaluating CA-4948 and ibrutinib, we are taking a highly anticipated step forward in bringing a potent oral therapeutic regimen to patients with relapsed or refractory hematologic malignancies," said James Dentzer, President and Chief Executive Officer of Curis. "BTK inhibitors are an approved category of therapies for patients with various lymphatic cancers yet they only target one of the two main pathways activating NF-κB in B-cell malignancies. CA-4948 targets the other main NF-κB-activating pathway by shutting down signaling through the Myddosome. We have shown highly encouraging increased tumor-reducing activity when combining both covalent and non-covalent BTK inhibitors with CA-4948 in preclinical models."
Mr. Dentzer continued, "We observed single-agent activity in the non-Hodgkin’s lymphoma (NHL) monotherapy study, with the majority of patients treated at 300mg twice daily experiencing at least some reduction in tumor volume. We coordinated with our trial partners to amend the protocol of our existing study to include combination therapy starting at a previously demonstrated therapeutic dose. This will allow us to leverage the clinical sites and staff currently active in our monotherapy study and should save significant time and resources as we advance through the clinic."
"Given the profile CA-4948 has demonstrated in existing studies, it is a promising candidate for combination with a proven BTK inhibitor such as ibrutinib," said Dr. Erel Joffe, M.D., Assistant Attending with the Lymphoma Service at Memorial Sloan Ketting Cancer Center and a lead investigator on the study. "We believe there may be important synergies given that IRAK4 controls the critical TLR pathway that is parallel and complementary to the BTK pathway and that both of these pathways are primary and independent oncogenic activators of NF-κB in lymphoma and leukemia. Effective dual targeting of both independent pathways that drive excessive B-cell proliferation via NF-κB could potentially provide significantly improved outcomes over either treatment in a monotherapy setting."
About the CA-4948+ibrutinib Phase 1 Combination Study
The Phase 1 trial is a two-part, multicenter, open-label, dose escalation and expansion study designed to evaluate the safety, pharmacokinetics, pharmacodynamics, clinical activity, and biomarker correlations of CA-4948 and ibrutinib patients with relapsed or refractory hematologic malignancies. Part 1 of the study is a dose escalation using a 3+3 design. Approximately 18 patients will be enrolled in Part 1 and will receive a starting dose of 200mg CA-4948 BID with subsequent escalation to 300mg BID, both of which have been observed to be safe and effective in the NHL monotherapy study, combined with ibrutinib doses appropriate for their respective NHL subtype. The primary endpoints of Part 1 will be safety and tolerability, maximum tolerated dose, and the recommended Phase 2 dose. Secondary objectives will be pharmacokinetics and preliminary efficacy. Exploratory objectives will include biomarker correlations, such as MYD88-L265P mutations and IRAK4 pathway and NFκB inhibition.
Part 2 of the study will enroll patients across an expansion basket of four cohorts: marginal zone lymphoma (MZL), ABC-DLBCL, primary central nervous system lymphoma (PCNSL), and NHL with adaptive ibrutinib resistance. An interim futility analysis will be conducted after approximately 15-20 patients are enrolled in each cohort. Primary endpoints of Part 2 will be complete response or objective response rate and duration of response compared to historical controls. Secondary objectives will be safety and tolerability, progression-free survival, and population PK sampling for CA-4948. Exploratory objectives will include response correlation with biomarkers including MYD88-L265P or other genetic mutations, gene expressions, cell of origin, IRAK4 signaling, and resistance.