Investigation of [6R] 5,10-methylenetetrahydrofolate (Arfolitixorin) as Rescue Therapy for Osteosarcoma Patients Treated With HDMTX.
Condition: Osteosarcoma
MeSH terms: Osteosarcoma
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      An open-label, multicenter, phase I/II clinical trial to identify the [6R]
      5,10-methylenetetrahydrofolate (arfolitixorin) dose with most favorable safety prospect and
      confirmed ability to mitigate high-dose methotrexate induced toxicity during treatment of
      osteosarcoma patients
    

Detailed description: 
      This is a non-blinded, multicenter, exploratory study in osteosarcoma patients. The study
      focuses on the overall safety of the HDMTX courses given within a Methotrexate, Adriamycin
      (doxorubin) and cisPlatin (MAP) treatment schedule, which is closely related to the efficacy
      of the concomitantly administered folate rescue treatment. Additionally the study aimes to
      collect pharmacokinetic (PK) profiles of metotrexate (MTX) in serum, of folate metabolites in
      plasma and to decide the Modufolin® dose to use in future studies.

      Patients are enrolled in the study at the first, third or the fifth HDMTX course in a MAP
      treatment schedule and receive folate rescue therapy according to a strategy based on the
      Children's Oncology Group (COG) treatment management recommendations used in study protocol
      AOST0331.

      Folate rescue treatment with Calcium Folinate (SOC) or Modufolin® (MOD) commence 24 h after
      start of HDMTX administration and then every 6 h until the serum MTX levels are ≤0.1 μmol/L.
      In case delayed MTX elimination occurs with significant increase in S-creatinine and/or
      occurrence of oral mucositis or signs of hypo cellular bone marrow, the folate rescue dose
      and/or the administered hydration will be adjusted in accordance with the COG based MTX
      toxicity management recommendations.

      All patients receives SOC (15 mg/m2) in the first 2 HDMTX courses and MOD in the following 2
      courses. Patients are enrolled in one of two MOD dose cohorts: Cohort 1 (15 mg/m2) and Cohort
      2 (30 or 7.5 mg/m2 depending on outcome of Cohort 1). Only patients with successful
      advancements from the first 2 HDMTX courses with Calcium Folinate are allowed to continue
      with MOD as rescue in the following MAP cycle.

      Safety data will be reviewed by an independent board, Data and Safety Monitoring Board (DSMB)
      that will assess each patient and made recommendations regarding the enrolment of subsequent
      patients. Furthermore, the DSMB will make a dose level recommendation for Cohort 2 and also a
      recommendation whether younger children may be allowed in this cohort.
    

Intervention name(s): Calcium Folinate; [6R] 5,10-methylenetetrahydrofolate (arfolitixorin)
Intervention type(s): Drug; Drug
Intervention description(s): The enrolled patients will be treated according to the MAP schedule and will receive the study drug Calcium Folinate commencing 24 hours after the administration of HDMTX and then every 6 hours (q6h) thereafter until the S-MTX levels are ≤ 0.1 µmol/L, in accordance with COG management recommendations.
All patients will receive standard o care (SOC) in the two (2) first HDMTX courses and [6R] 5,10-methylenetetrahydrofolate in the two (2) following courses. Patients will be enrolled in two (2) [6R] 5,10-methylenetetrahydrofolate dose cohort groups: with [6R] 5,10-methylenetetrahydrofolate start dose of 15 mg/m2 (i.e. the same as for SOC rescue) the first cohort will be administered, and 7.5 or 30 mg/m2 in the second cohort.; The enrolled patients will be treated according to the MAP schedule and will receive the study drug [6R] 5,10-methylenetetrahydrofolate commencing 24 hours after the administration of HDMTX and then every 6 hours (q6h) thereafter until the S-MTX levels are ≤ 0.1 µmol/L, in accordance with COG management recommendations.
All patients will receive standard o care (SOC) in the two (2) first HDMTX courses and [6R] 5,10-methylenetetrahydrofolate in the two (2) following courses. Patients will be enrolled in two (2) [6R] 5,10-methylenetetrahydrofolate® dose cohort groups: with [6R] 5,10-methylenetetrahydrofolate start dose of 15 mg/m2 (i.e. the same as for SOC rescue) the first cohort will be administered, and 7.5 or 30 mg/m2 in the second cohort.
Other intervention name(s): Leucovorin; Modufolin; arfolitixorin
Intervention MeSH terms: Leucovorin; Calcium; Levoleucovorin
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Methotrexate; Rescue treatment