A phase I/II trial of high-dose methotrexate (HDMTX) followed by prophylactic glucarpidase in patients with impaired renal function and central nervous system lymphoma (CNSL).

7081 Background: HDMTX is a key component of treatment protocols for CNSL patients (pts), but impaired renal function in elderly or comorbid pts limits its use. The recombinant enzyme glucarpidase rapidly hydrolyzes MTX into non-toxic metabolites and is approved for therapeutic use in pts with delayed MTX elimination following HDMTX. We conducted a phase I/II study (NCT04841434) to assess the efficacy of prophylactic glucarpidase in HDMTX-treated pts with renal impairment or a history of delayed MTX elimination. Methods: A total of 18 pts with CNSL and pre-existing renal insufficiency (glomerular filtration rate [GFR] 40–80 mL/min) or a history of renal failure post-HDMTX were treated with up to six HDMTX cycles. HDMTX was given as a 4-hour infusion at three dose-escalation levels (3.0, 3.5, and 4.0 g/m²; 6 pts each). Glucarpidase (2000 U IV) was administered in each cycle 24 hours after start of HDMTX. The coprimary endpoints were safety and pharmacological efficacy of glucarpidase. Plasma concentrations of MTX and its metabolites were monitored using combined liquid chromatography-tandem mass spectrometry. Results: Overall, 18 pts (63-86 years, median 78) were enrolled with a median baseline GFR of 69.5 mL/min. A median of 3.5 HDMTX treatment cycles was given, with 6 pts completing the maximum allowed 6 cycles. Reasons for protocol-predefined early termination included clinical non-response or radiological disease progression (n=8), investigator decision due to adverse event (AE; n=2), and termination criteria (n=2). Administration of glucarpidase resulted in a median reduction of MTX plasma levels within 15 minutes by 99.2% (95% CI: 98.4-99.1%). Results from serum samples analyses for anti-glucarpidase antibodies were performed and will be available by the meeting, but in pts with more than two HDMTX cycles, there was no statistically significant difference in the reduction of MTX plasma levels between the first and last cycles (p=0.47). Glucarpidase treatment reduced MTX plasma levels to a median of 0.05 µmol/L (range 0.00-0.84) within 15 minutes. MTX plasma levels remained consistently below 0.6 µmol/L across all cycles at 42 hours or later after start of the HDMTX infusion. A single grade III AE potentially related to glucarpidase was recorded: a transient facial flushing with a brief loss of consciousness and rapid and spontaneous full recovery. This event prompted implementation of a premedication (prednisolone, antihistaminic) in all subsequent treatment cycles. No further glucarpidase-related AE’s grade >II occurred. Conclusions: The repeated prophylactic application of glucarpidase was feasible and safe and facilitated HDMTX treatment in pts at risk for delayed MTX elimination. This approach may enable adequate HDMTX dosing in pts with renal insufficiency and limiting comorbidities, and should be further evaluated. Clinical trial information: NCT04841434 .