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Development of a new promising rescue agent for high dose methotrexate (HDMTX) treatment in osteosarcoma - a safety and dose finding study

Date

11 Sep 2017

Session

Poster display session

Presenters

Mikael Eriksson

Citation

Annals of Oncology (2017) 28 (suppl_5): v521-v538. 10.1093/annonc/mdx387

Authors

M. Eriksson1, M. Rychłowska-Pruszyńska2, M. Csoka3, E. Kabickova4, P. Mudry5

Author affiliations

  • 1 Skåne University Hospital, Department of Oncology, 221 85 - Lund/SE
  • 2 Paediatric Surgical Oncology Clinic Warsaw, Institution of Mother and Child, 01-211 - Warsaw/PL
  • 3 2nd Department Of Paediatrics, Semmelweis University, 1085 - Budapest/HU
  • 4 Department Of Paediatric Haematology And Oncology, Motol University Hospital, 150 06 - Prague/CZ
  • 5 University Hospital Brno And School Of Medicine, Masaryk University, Department of Pediatric Oncology, 662 63 - Brno/CZ
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Background

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.

Methods

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.

Results

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.

Conclusions

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

Funding

Isofol Medical AB

Disclosure

All authors have declared no conflicts of interest.

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