A phase 0 pharmacokinetic trigger trial of infigratinib in patients with recurrent high-grade glioma.

Nader Sanai Ivy Brain Tumor Center, Phoenix, AZ info_outline Nader Sanai, Tigran Margaryan, Jennifer Molloy, Anita DeSantis, Jocelyn Harmon, Amy Hong, Kelly Braun, John Wanebo, Wonsuk Yoo, An-Chi Tien, Artak Tovmasyan, Shwetal Mehta

Authors Nader Sanai Ivy Brain Tumor Center, Phoenix, AZ info_outline Nader Sanai, Tigran Margaryan, Jennifer Molloy, Anita DeSantis, Jocelyn Harmon, Amy Hong, Kelly Braun, John Wanebo, Wonsuk Yoo, An-Chi Tien, Artak Tovmasyan, Shwetal Mehta Organizations Ivy Brain Tumor Center, Phoenix, AZ, Barrow Neurological Institute (Phoenix, AZ), Phoenix, AZ Abstract Disclosures Research Funding Institutional Funding The Ben and Catherine Ivy Foundation and Barrow Neurological Foundation Background: This Phase 0 trial evaluates tumor pharmacokinetic (PK) and pharmacodynamic (PD) responses of fibroblast growth factor receptor (FGFR) inhibitor, infigratinib, in participants with recurrent high-grade glioma carrying FGFR1 K656E or FGFR3 K650E mutation or FGFR3-TACC3 translocation. Patients with high unbound drug concentrations in the gadolinium-nonenhancing tumor region were graduated to a therapeutic regimen of infigratinib. Methods: Recurrent high-grade glioma patients received 7 days of infigratinib (125 mg QD) prior to planned resection at 7-9 hours following the last dose. Tumor tissue (enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound infigratinib concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase and was defined as unbound [infigratinib] > 5-fold biochemical IC50 (i.e., 5 nM) in non-enhancing tumor. PD response was assessed by quantification of percentage of positive pERK, MIB-1, and Cleaved Caspase 3 cells in the surgical tissue compared to baseline archival/biopsy tissue. Patients with tumors exceeding the PK threshold for unbound drug concentration were eligible for expansion phase therapeutic dosing of infigratinib. Results: Seven patients were enrolled into the Phase 0 study with 3 patients who met the PK threshold continued to the expansion phase. In non-enhancing tumor region, the mean unbound concentration of infigratinib was 3.5 nM (n=7). The mean non-enhancing tumor-to-plasma coefficient for unbound drug (Kp,uu) was calculated to be 1.4. The suppression of pERK levels and MIB-1 levels was observed in 17% (1/6) and 67% (4/6) of the patients, respectively. At a median follow-up of 16.3 months [range: 2.8-18.7 months], the median progression-free survival (PFS) was 2.8 months (n=3). One patient remains on treatment. No grade 3+ toxicities were observed, and no adverse events resulted in discontinuation of therapy. Conclusions: Despite relatively high unbound tumor-to-plasma (Kp,uu) value, infigratinib achieves sub-optimal unbound drug concentration in the non-enhancing brain tumor tissue. Pharmacodynamic response with archival tissue as comparator did not reveal inhibition of pERK. Clinical trial information: NCT04424966.

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