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

Phase 1

Completed

Conditions: Osteosarcoma

Interventions: Drug: Calcium Folinate
Drug: [6R] 5,10-methylenetetrahydrofolate (arfolitixorin)

Registration Number: NCT01987102

Lead Sponsor: Isofol Medical AB

Brief 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 18

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 2	Calcium Folinate	1 MAP cycle (incl. 2 HDMTX Courses using Calcium Folinate rescue 15mg/m2) 1 MAP cycle (incl. 2 HDMTX Courses using \[6R\] 5,10-methylenetetrahydrofolate rescue 7,5mg/m2 or 30mg/m2\) \Dose will depend on outcome from Cohort 1
Cohort 1	Calcium Folinate	1 MAP cycle (incl. 2 HDMTX Courses using Calcium Folinate rescue 15mg/m2) 1 MAP cycle (incl. 2 HDMTX Courses using \[6R\] 5,10-methylenetetrahydrofolate rescue 15mg/m2)
Cohort 1	[6R] 5,10-methylenetetrahydrofolate (arfolitixorin)	1 MAP cycle (incl. 2 HDMTX Courses using Calcium Folinate rescue 15mg/m2) 1 MAP cycle (incl. 2 HDMTX Courses using \[6R\] 5,10-methylenetetrahydrofolate rescue 15mg/m2)
Cohort 2	[6R] 5,10-methylenetetrahydrofolate (arfolitixorin)	1 MAP cycle (incl. 2 HDMTX Courses using Calcium Folinate rescue 15mg/m2) 1 MAP cycle (incl. 2 HDMTX Courses using \[6R\] 5,10-methylenetetrahydrofolate rescue 7,5mg/m2 or 30mg/m2\) \Dose will depend on outcome from Cohort 1

Primary Outcome Measures

Name	Time	Method
Number of AEs Per Severity (All Courses)	From the start of HDMTX administration through 8 days post dose for each course of HDMTX in total	Characterization (number 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 (Grade refers to the severity of the AE). The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE; Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening, and Grade 5 Death related to AE.
Number of HDMTX Related AEs Per Severity (All Courses)	From the start of HDMTX administration through 8 days post dose for each course of HDMTX in total	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 (Grade refers to the severity of the AE). The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE; Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening, and Grade 5 Death related to AE.
Number of Ongoing AEs Per HDMTX Course	From the start of HDMTX administration through 8 days post dose for each course of HDMTX	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 (Grade refers to the severity of the AE). The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE; Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening, and Grade 5 Death related to AE.
Number of Ongoing HDMTX Related AEs Per HDMTX Course	From the start of HDMTX administration through 8 days post dose for each course of HDMTX	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 (Grade refers to the severity of the AE). The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE; Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening, and Grade 5 Death related to AE.

Secondary Outcome Measures

Name	Time	Method
Number of HDMTX Courses in Which the Initial Hydration Was Increased	Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L
Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B	8 days after start of first and/or second HDMTX course in a MAP cycle	Definition A: Successful advancement from 1st to 2nd HDMTX course within the same MAP cycle. Fulfilling all of the following criteria 8 days after start of first HDMTX course within the same MAP cycle: 1. Serum MTX: ≤0.1μmol/L 2. Neutrophils: ≥0.25x109/L 3. Platelets: ≥50x109/L 4. Serum bilirubin: ≤1.25 x upper limit of normal (ULN) 5. Glomerular filtration rate (GFR) ≥70 mL/min/1.73m2 6. No AE Grade 2 or more related to HDMTX hindering a potential HDMTX administration, at the discretion of the investigator Definition B: Successful advancement to next MAP cycle Fulfilling all of the following criteria 8 days after start of the second HDMTX course in previous MAP cycle: 1. Serum MTX: ≤0.1μmol/L 2. Neutrophils: ≥ 0.75 x 109/L 3. Platelets: ≥75x109/L 4. Serum bilirubin: ≤1.25xULN 5. GFR ≥70 mL/min/1.73m2 6. No AE Grade 2 or more related to HDMTX hindering a potential Adriamycin/Doxorubicin and Cisplatin (AP) administration, at the discretion of the investigator
Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement From First to Second HDMTX Course Within the Same MAP Cycle According to Definition A.	8 days after start of first HDMTX course in a MAP cycle	Definition A: Successful advancement from first to second HDMTX course within the same MAP cycle Fulfilling all of the following criteria 8 days after start of first HDMTX course within the same MAP cycle: 1. Serum MTX: ≤ 0.1 μmol/L 2. Neutrophils: ≥ 0.25 x 109/L 3. Platelets: ≥ 50 x 109/L 4. Serum bilirubin: ≤ 1.25 x ULN 5. GFR ≥ 70 mL/min/1.73 m2 6. No AE Grade 2 or more (NCI CTCAE v4.0) related to HDMTX hindering a potential HDMTX administration, at the discretion of the investigator
Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement to Next MAP Cycle According to Definition B.	8 days after start of second HDMTX course in a MAP cycle	Definition B: Successful advancement to next MAP cycle Fulfilling all of the following criteria 8 days after start of the second HDMTX course in previous MAP cycle: 1. Serum MTX: ≤ 0.1 μmol/L 2. Neutrophils: ≥ 0.75 x 109/L 3. Platelets: ≥ 75 x 109/L 4. Serum bilirubin: ≤ 1.25 x ULN 5. GFR ≥ 70 mL/min/1.73 m2 6. No AE Grade 2 or more (NCI CTCAE v4.0) related to HDMTX hindering a potential Adriamycin/Doxorubicin and Cisplatin (AP) administration, at the discretion of the investigator
Time to Successful MTX Elimination (Definition C)	Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L	Definition C: Time to successful MTX elimination = Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L
Number of HDMTX Courses With Delayed MTX Elimination (Definition D).	Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L	Definition D: Delayed MTX elimination (according to COGs excretion toxicity management instructions) S-MTX levels of: \> 10 μmol/L at 24 h after start of MTX administration, OR \> 1 μmol/L at 48 h after start of MTX administration, OR \> 0.1 μmol/L at 72 h after start of MTX administration or later
Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E).	Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L	Definition E: Delayed early MTX elimination (according to US label for Calcium Folinate) S-MTX levels of: * 50 μmol/L at 24 hours after start of MTX administration, OR * 5 μmol/L at 48 hours after start of MTX administration OR An increase in S-Creatinine level of 100% or greater at 24 hours after start of MTX administration.
Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F).	Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L	Definition F: Delayed late MTX elimination (according to US label for Calcium Folinate) S-MTX level: \> 0.2 μmol/L at 72 hours AND \> 0.1 μmol/L at 96 hours after start of MTX administration.
Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions	Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L	The MTX-toxicity management instructions provided in the protocol are based on the Children's Oncology Group (COG) treatment management recommendations used in study protocol AOST0331, EURAMOS 1. The COG recommend changes in the hydration and the rescue frequency and/or dose to be done if pre-specified toxicities of different severity grades occur.
Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD.	From the start of HDMTX administration through 8 days post dose for all 4 courses of HDMTX in total	The severity of AEs have been done using NCI CTCAE v4.0. Total number of AEs per severity grade are presented for all AEs and for AEs related to MTX. For AEs related to MTX the number of AEs occurring per preferred term and severity grade are detailed.The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE; Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening, and Grade 5 Death related to AE.

Trial Locations

Locations (5): Fakultní nemocnice v Motole
🇨🇿
Prague, Czechia
Semmelweis Egyetem II. Sz. Gyermekgyógyászati Klinika
🇭🇺
Budapest, Hungary
Fakultní nemocnice Brno Klinika detske onkologie
🇨🇿
Brno, Czechia
Department of Oncology, Skåne University Hospital
🇸🇪
Lund, Sweden
Instytut Matki i Dziecka
🇵🇱
Warszawa, Poland