Rescue after High Dose Methotrexate therapy in Osteosarcoma patients. MedDRA version: 18.1 Level: PT Classification code 10061814 Term: Detoxification System Organ Class: 10042613 - Surgical and medical procedures
Conditions
Sponsors
Isofol Medical AB
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patients must have histological evidence of osteosarcoma including metastatic osteosarcoma. 2. Patients must be eligible for high-dose methotrexate treatment (HDMTX) according to the MAP treatment schedule described in the study protocol (see Appendix 1) and fulfill all of the criteria below prior to first course of HDMTX in the study. a. Serum MTX: = 0.1µmol/L b. Neutrophils: = 0.25 x 109/L c. Platelets: = 50 x 109/L d. Serum bilirubin: = 1.25 x ULN e. GFR = 70 mL/min/1.73 m2 f. No AE Grade 2 or more (NCI CTCAE v4.0) related to HDMTX hindering a potential HDMTX administration, at the discretion of the investigator. 3. Patients must be enrolled in HDMTX course 1, 3 or 5 of the MAP treatment schedule (see Appendix 1). 4. Patients enrolled in HDMTX course 3 or 5 must have a history of successful advancement from first to second HDMTX course within the previous MAP cycle, i.e. fulfilling all of the following criteria 8 days after start of first HDMTX course within the same MAP cycle: a. Serum MTX: = 0.1µmol/L b. Neutrophils: = 0.25 x 109/L c. Platelets: = 50 x 109/L d. Serum bilirubin: = 1.25 x ULN e. GFR = 70 mL/min/1.73 m2 f. No AE Grade 2 or more (NCI CTCAE v4.0) related to HDMTX hindering a potential HDMTX administration, at the discretion of the investigator. 5. Patients enrolled in HDMTX course 3 or 5 must have a history of successful advancement to next MAP cycle after end of previous MAP cycle, i.e. fulfilling all of the following criteria 8 days after start of the second HDMTX course in previous MAP cycle: a. Serum MTX: = 0.1µmol/L b. Neutrophils: = 0.75 x 109/L c. Platelets: = 75 x 109/L d. Serum bilirubin: = 1.25 x ULN e. GFR = 70 mL/min/1.73 m2 f. No AE Grade 2 or more (NCI CTCAE v4.0) related to HDMTX hindering a potential HDMTX administration, at the discretion of the investigator. 6. Patients must be 12-40 years of age. The age limit may be lowered to 6-40 years for enrolment in Cohort 2 and for enrolment of additional patients to dose of choice for future development and if recommended by the DSMB. 7. Sexually active females of childbearing potential: Must be surgically sterile, or compliant with a contraceptive regimen during and for six (6) months after last MTX dose in MAP regimen; must have a negative serum or urine pregnancy test (within seven (7) days before study enrolment) and must not be lactating. 8. Sexually active males: Must be surgically sterile or compliant with a contraceptive regimen during and for six (6) months after last MTX dose in MAP regimen. 9. Patient, parent(s), or guardian(s), as appropriate, is/are willing and able to provide signed informed consent. 10. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures specified in the protocol. 11. 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. Are the trial subjects under 18? yes Number of subjects for this age range: 16 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 2 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Involvement in another clinical trial within 30 days before enrolment in the study. 2. Hypersensitivity to Calcium Folinate. 3. Previous treatment with glucarpidase. 4. 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • To characterize safety in terms of toxicity during HDMTX treatment and folate rescue therapy with either Modufolin® or Calcium Folinate. • To identify the recommended dose of Modufolin® for further assessment. ;Secondary Objective: • To examine the feasibility of Modufolin® as folate rescue therapy for HDMTX treatment in osteosarcoma patients previously treated with Calcium Folinate as rescue therapy. • To characterize all AEs and laboratory test result changes regardless of attribution during the entire study period. • To study the pharmacokinetic profiles of [6R] 5,10-MTHF, 5-formyl-THF, 5-methyl-THF, and THF in plasma. • To study the pharmacokinetic profile of S-MTX.;Primary end point(s): • Characterization (frequency and severity grade) of toxicity reported for each course of HDMTX treatment with folate rescue therapy, i.e. from the start of HDMTX administration through eight (8) days post dose, per NCI CTCAE v4.0. • Identification of the recommended Modufolin® dose selected for further assessment.;Timepoint(s) of evaluation of this end point: • Safety - Continously during the study • Recommended dose - At Follow-up visit | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: • Successful advancement - Eight (8) days after start of HDMTX administration of each HDMTX course • Successful MTX elimination - start at HDMTX administration of each HDMTX course • Safety - continously during the entire study period. • PK assessments - Day 2 and Day 3 of each HDMTX course;Secondary end point(s): • Number of administered HDMTX courses with Modufolin rescue classified as having met the criteria for successful advancement at scheduled time according to Definition A and/or Definition B. • Number of administered MAP cycles with Modufolin rescue classified as having met the criteria for successful advancement from first to second HDMTX course within the same MAP cycle at scheduled time according to Definition A. • Number of administered MAP cycles with Modufolin rescue classified as having met the criteria for successful advancement to next MAP cycle at scheduled time according to Definition B. • Time (hours) to successful MTX elimination (Definition C). • Number of HDMTX courses in which the dose of study drug was increased. • Number of HDMTX courses in which the frequency of study drug administration was increased. • Number of HDMTX courses in which the hydration was increased. • Number of HDMTX courses with delayed early MTX elimination (Definition E). • Number of HDMTX courses with delayed late MTX elimination (Definition F). • Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D excretion toxicities as listed in the MTX-toxicity management instructions (see Appendix 2), i.e. delayed elimination of MTX, increased serum creatinine or occurrence of events of mucositis oral or bone marrow hypocellular. • Characterization (frequency and severity) of all reported AEs regardless of attribution per NCI CTCAE v4.0 and laboratory test result changes of clinical relevance during the entire study period. • Study PK parameters from plasma such as AUC, AUClast, C5min, t1/2, ?z, MRT, CL, Vz and Vs | — |
Countries
Czech Republic, Hungary, Poland, Sweden, United States
Contacts
Public ContactPrincipal Investigator
Skåne University Hospital
Outcome results
None listed