A phase 1/2a, first-in-human clinical study demonstrated that the highly selective, irreversible pan-FGFR inhibitor gunagratinib was safe and well-tolerated in patients with advanced solid tumors, including CCA.
Gunagratinib (ICP-192) is a novel, irreversible pan-FGFR inhibitor that showed activity against the acquired resistance to first-generation reversible FGFR inhibitors. The phase 1/2a, first-in-human clinical study ICP-CL-00301 (ClinicalTrials.gov Identifier: NCT03758664) evaluated the safety, tolerability, pharmacokinetics/pharmacodynamics, and preliminary antitumor activity of gunagratinib in patients with advanced solid tumors.
The study design includes a dose escalation (modified 3+3 design) followed by dose expansion. Eligible patients with advanced solid tumors with or without FGF/FGFR alterations were enrolled in the study. In the dose-escalation phase, patients were treated with escalating doses (2 mg, 4 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, and so forth) of gunagratinib once daily in 21-day cycles until disease progression or unacceptable toxicity. In the dose-expansion phase, patients with cholangiocarcinoma (CCA) who harbor FGFR2 gene fusions/translocations and who had received ≥1 first-line chemotherapy treatments were administered gunagratinib daily at 12 mg continuously. The data cutoff was February 2021.
At data cutoff, a total of 30 patients were enrolled in the study, with 23 participants in the dose-escalation phase and 7 patients in the dose-expansion phase. The median age of the study population was 55.0 years (range, 28.0-75.0 years), 56.7% were male, and the Eastern Cooperative Oncology Group performance status was between 0 and 1.
The maximum tolerated dose had not been reached, and no dose-limiting toxicities were reported. In both cohorts, the most common treatment-related adverse events, occurring in >20% of the patients, included hyperphosphatemia (73.33%), hypercalcemia (33.33%), hypertriglyceridemia (23.33%), increased alanine aminotransferase (23.33%), increased aspartate aminotransferase (26.67%), and diarrhea (26.67%). Hyperphosphatemia was observed at all dose levels and at doses of ≥8 mg once daily; it was managed with oral phosphate binders, as needed.
Pharmacokinetic/pharmacodynamic analysis found dose-dependent increases in plasma exposure (maximum concentration [Cmax], area under the concentration time-curve to the last measured concentration [AUClast]) with oral dosage levels of gunagratinib. Increases in serum phosphorus were reported with gunagratinib doses of ≥8 mg once daily.
Among patients with FGF/FGFR gene aberrations (n = 12), the overall response rate was 33.3%, including 1 (8.3%) patient with CCA who experienced a complete response and 3 (25%) patients with partial responses. The disease control rate was 91.7% (11 of 12 patients).
Based on these results, the researchers concluded that gunagratinib is safe and well-tolerated in patients with advanced solid tumors, including CCA.
Source: Guo Y, Yuan C, Ying J, et al. Phase I result of ICP-192 (gunagratinib), a highly selective irreversible FGFR inhibitor, in patients with advanced solid tumors harboring FGFR pathway alterations. J Clin Oncol. 2021;39(suppl_15):4092-4092.
To sign up for our newsletter or print publications, please enter your contact information below.
