E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Rescue after High Dose Methotrexate therapy in Osteosarcoma patients. |
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E.1.1.1 | Medical condition in easily understood language |
Rescue after High Dose Methotrexate therapy in Osteosarcoma patients. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061814 |
E.1.2 | Term | Detoxification |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• 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.
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E.2.2 | Secondary objectives of the trial |
• 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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 (only) 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.
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E.4 | Principal 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
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E.5 End points |
E.5.1 | Primary end point(s) |
• Characterization (frequency and severity grade) of toxicity reported for each course of HDMTX treatment with folate rescue therapy and continuing until eight (8) days after start of HDMTX administration, per NCI CTCAE v4.0.
• Identification of the recommended Modufolin® dose selected for further assessment. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Safety - Continously during the study
• Recommended dose - At Follow-up visit |
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E.5.2 | 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, λz, MRT, CL, Vz and Vss calculated for [6R] 5,10-methylene-THF, 5-formyl-THF, 5-methyl-THF and THF, if data permits.
• Study PK parameters from serum such as AUC, AUClast, C5min, t1/2, λz, MRT, CL, Vz and Vss calculated for MTX. |
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E.5.2.1 | 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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last visit of the last subject |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 40 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 42 |
E.8.9.2 | In all countries concerned by the trial days | 0 |