HDMTX followed by calcium folinate (CF) rescue is established as part of MAP chemotherapy to manage toxicity during osteosarcoma treatment. A problem with HDTMX is the variability in plasma exposure of both MTX and CF leading to an unpredictable response. A potentially superior rescue agent methylenetetrahydrofolate (Modufolin®), containing the active metabolite of CF, has been evaluated to identify a safe and effective dose for further development.
This exploratory study performed in Hungary, Poland, Sweden and Czechia involved osteosarcoma patients, 12-40 years, planned for MAP chemotherapy. All patients received one MAP cycle (two HDMTX courses) with standard CF rescue of 15 mg/m2. Those that completed this MAP cycle successfully according to six defined criteria subsequently received Modufolin® in the following cycle (two HDMTX courses). There were two Modufolin® dose cohorts, 15 mg/m2 (1) and 7.5 mg/m2 (2). A Data and Safety Monitoring Board evaluated safety before initiation of the second dose cohort and suggested the dose for further development.
Eight patients 12-17 years were included. Four patients were treated in cohort 1 and four in cohort 2. In cohort 1, no MTX toxicity or delayed elimination with subsequent treatment delay was reported. In cohort 2 one patient reported mucositis grade 3 and failed successful advancement after first course of Modufolin®. In both cohorts and after both types of rescue, there were cases with significantly increased s-creatinine levels.
Modufolin® seems to be a safe and effective rescue agent after HDMTX. The study design however precludes a comparison between Modufolin® and CF, since only patients with successful CF rescue received Modufolin®. The higher dose of 15 mg/m2 seemed more effective as rescue and was selected for further development.
Clinical trial identification
EudraCT Nr 2013-001280-23
Legal entity responsible for the study
Isofol Medical AB
Isofol Medical AB
All authors have declared no conflicts of interest.