A Phase 1 Trial of Escalating High Dose Methotrexate Supported by Glucarpidase to Treat Patients with Primary Central Nervous System Lymphoma (PCNSL). (CRUK/08/010)

Methotrexate (MTX) remains the most important drug in the treatment of PCNSL but has considerable toxicities and is dose-limited by renal function. Glucarpidase (Voraxaze^®) is an enzyme, which rapidly hydrolyses MTX and is licensed in the United States for the treatment of toxic levels of MTX in patients with delayed excretion due to impaired renal function. We designed this trial to investigate whether pre-emptive administration of glucarpidase after MTX infusion might allow safer therapy and allow higher doses to be given without increased toxicity.

Newly diagnosed PCNSL patients aged ≥18yrs would be entered into 3 successive, dose escalating cohorts. Patients would receive an increasing MTX dosage (3, 5 and 10 grams/m² according to their cohort). They would receive up to 6 cycles of single agent MTX at their cohort dose level with an MRI assessment every 2 cycles. All cycles were pre-emptively supported by the administration of glucarpidase. This was followed by whole brain radiotherapy (WBRT) tailored to age and fitness. MTX was infused over 4 hours and glucarpidase was given 22 hours from the start of the MTX infusion at a dose of 50units/Kg over 15mins. MTX levels were measured pre + post glucarpidase and at 48 and 72 hours post MTX. Further levels were taken if required. Standard fluids, alkalinisation and folinic acid rescue was used in addition. MTX levels were measured locally to guide clinical decisions and centrally by HPLC to assess true clearance as there is cross-reactivity between MTX and the metabolites to which it is cleaved by Glucarpidase, making routine assays inaccurate as they may include metabolites and thus give a falsely high reading. The first cohort consisting of 6 patients would receive 3g/m² MTX per cycle. Using the modified Fibonacci scheme, the intention was to escalate to 6g/m² (2 × starting dose) and then 10 g/m² (3.3 × starting dose) in 2 subsequent cohorts. If 2 patients have dose limited toxicity (DLT), the escalations are stopped. Each cohort would commence after the preceding one has completed at least 2 cycles of MTX.

The trial stopped after recruiting 4 patients in cohort 1 due to 2 patients experiencing DLT. The patients were 2 male and 2 female, aged between 51 and 71yrs, all HIV negative and histologically confirmed as DLBCL by brain biopsy. In total, ten assessable cycles of MTX (3g/m²) with no dose reductions were delivered to these 4 patients. There were toxicity delays in 3 cycles.

There were 38 adverse events (6 > grade 2) and 8 serious adverse events, 2 of which were DLTs in separate patients and led to the closure of the study as per protocol rules. The two DLTs were renal impairment with delayed MTX excretion in one patient following their 1st cycle of MTX and repeated renal pain/urinary retention alongside grade 2 infusion reactions to glucarpidase in the other. The patient with renal impairment had normal baseline renal function but experienced a creatinine rise 48hrs after the start of the MTX infusion and peaking at 269μmoles/l. by day 6. This remained elevated for 21 days before returning to normal. One patient had infusion reactions to glucarpidase of grade 2 severity with each of 3 cycles received despite a dose reduction in cycle 3. The development of antibodies to glucarpidase was demonstrated in 2 patient samples but there was no evidence of neutralising potential.

The central HPLC assays did indeed confirm rapid MTX clearance by the enzyme in all 10 cycles, with levels of MTX 1 hour post glucarpidase at or near the clinical cut-off (0.05μmol/L) and no levels above this at 48 hours from the start of the MTX infusion. As expected, local assays were less reliable - for example the patient with renal injury cleared their MTX (judged by HPLC) rapidly but the local assays continued to show apparent delayed clearance over nearly 2 weeks.

In summary, used pre-emptively, Glucarpidase was well tolerated and achieved the expected rapid reduction in MTX levels, however, HPLC is required to demonstrate this in real time as hospital laboratory monitoring suffers from metabolite interference. It was not possible to escalate MTX doses in this protocol, most likely due to the nature of the patient population. The occurrence of an acute renal injury in this setting suggests that the damage may occur early at the point of high (therapeutic) MTX serum levels, which may not be wholly prevented by subsequent rapid clearance of residual drug by Glucarpidase.

Off Label Use: This study is of an unlicensed use of a licensed product. The product (glucarpidase) is licensed for the prevention of toxicity when there is renal impairment post methotrexate administration but this study investigated its use as pre-emptive therapy for preventing toxicity in a single setting (primary central nervous system lymphoma).