Investigation of [6R] 5,10-methylenetetrahydrofolate (Arfolitixorin) as Rescue Therapy for Osteosarcoma Patients Treated With HDMTX.

Main Inclusion Criteria (HDMTX with SOC rescue):

* Patients must have histological evidence of osteosarcoma (metastatic disease accepted).
* Patients must be eligible for HDMTX according to the MAP treatment schedule described in the study protocol and fulfill all of the criteria below prior to first course of HDMTX in the study.

  1. Serum MTX: ≤0.1μmol/L
  2. Neutrophils: ≥0.25x109/L
  3. Platelets: ≥50x109/L
  4. Serum bilirubin: ≤1.25x upper limit of normal (ULN)
  5. Glomerular filtration rate (GFR) ≥70 mL/min/1.73m2
  6. No adverse event (AE) Grade 2 or more (NCI CTCAE v4.0) related to HDMTX hindering a potential HDMTX administration, at the discretion of the investigator.
* Patients must be 12-40 years of age. This age range may be extended with younger patients for enrolment in Cohort 2 if collected data from Cohort 1 support this and it is recommended by the DSMB.

Exclusion criteria for enrolment:

* Involvement in another clinical trial within 30 days before enrolment in the study.
* Hypersensitivity to Calcium Folinate.
* Previous treatment with glucarpidase.
* Known serious concomitant systemic disorders (e.g., active infection including HIV, liver dysfunction, cardiac disease) that, in the opinion of the investigator, would compromise the patient's ability to complete the study

Main Inclusion criteria for continuation (HDMTX treatment with Modufolin rescue):

* Patients, who were included in the study in accordance with the inclusion criteria above, must have received 2 adjacent courses of HDMTX with SOC rescue according to the MAP treatment schedule in accordance with this study protocol.
* Patients eligible for continued HDMTX according to the MAP treatment schedule and with a history of successful advancement from first to second HDMTX course within the previous MAP cycle
* Patients eligible for continued HDMTX according to the MAP treatment schedule and with a history of successful advancement to next MAP cycle after end of previous MAP cycle
* No significant changes to the patient's medical condition from the start of the study that in the opinion of the investigator would compromise the patient's ability to complete the study.
* Patients who have undergone surgical resection of their tumor must have recovered from their surgery and be eligible to continue on the MAP regimen; any post-operative complications should be resolved to NCI CTCAE v4.0 Grade 1 or better.