Preliminary evidence suggests that combination treatment with silmitasertib plus gemcitabine/cisplatin as first-line therapy has promising efficacy and a favorable safety profile in patients with locally advanced or metastatic CCA.
The multicenter, open-label, phase 1b/2 study S4-13-001 (ClinicalTrials.gov Identifier: NCT02128282) evaluated the safety and efficacy of the oral casein kinase 2 inhibitor silmitasertib (CX-4945) in combination with gemcitabine/cisplatin in patients with unresectable cholangiocarcinoma (CCA). Efficacy and safety results of the pooled analysis of the combined population (phases 1b and 2) were presented at the 2021 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.
This study included 2 phases. The phase 1b portion included dose-escalation, dose-expansion, and exploratory cohorts of silmitasertib with doses ranging from 200 to 1000 mg twice daily (6 days for the escalation/expansion cohorts; 10 and 21 days for the exploratory cohorts). Patients in the phase 2 portion of the study were treated with silmitasertib 1000 mg twice daily for 10 days in combination with gemcitabine/cisplatin (on days 1 and 8 of a 21-day cycle). The primary efficacy end point was progression-free survival (PFS).
The intent-to-treat (ITT) cohort included 88 patients; 87 participants received silmitasertib in the phase 1b (n = 50) and phase 2 (n = 37) portions of the study. The modified ITT (mITT) population included 55 evaluable patients who completed ≥1 full cycles of therapy without dosing interruption or dose reductions. In the combined population (n = 87), the median participant age was 60 years. The majority of patients were male (55%), had metastatic disease (82%), and had intrahepatic CCA (85%).
In the mITT population, the median PFS was 11.2 months, the median overall survival was 17.4 months, the overall response rate was 32.1%, and the disease control rate was 79.3%. At 10 months, PFS was 56.1%. In the safety population (n = 87), 91% of patients experienced ≥1 treatment-emergent adverse events (TEAEs) related to silmitasertib, with the most common (all grades) including diarrhea (66%), nausea (51%), vomiting (33%), fatigue (31%), and anemia (22%). The most common grade ≥3 TEAEs occurring in >10% of patients included anemia (8%), neutropenia (12%), diarrhea (14%), nausea (9%), and thrombocytopenia (8.0%). Treatment discontinuation due to TEAEs was reported in 11 patients (12.6%).
Preliminary evidence from the S4-13-001 study suggests that combination treatment with silmitasertib plus gemcitabine/cisplatin as first-line therapy showed promising efficacy and a favorable safety profile in patients with locally advanced or metastatic CCA. A randomized phase 3 trial is planned to further define the role played by silmitasertib in the treatment of locally advanced or metastatic CCA.
Source: Borad MJ, Bai LY, Chen MH, et al. Silmitasertib (CX-4945) in combination with gemcitabine and cisplatin as first-line treatment for patients with locally advanced or metastatic cholangiocarcinoma: a phase Ib/II study. J Clin Oncol. 2021;39(suppl_3):312-312.
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