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

Study Overview
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Brief Summary
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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
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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.

Official Title
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An Open-Label, Multicenter, Phase I/II Clinical Trial to Identify the Modufolin® Dose With Most Favorable Safety Prospect and Confirmed Ability to Mitigate High-Dose Methotrexate Induced Toxicity During Treatment of Osteosarcoma Patients

Conditions
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Osteosarcoma

Intervention / Treatment
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* Drug: Calcium Folinate
* Drug: [6R] 5,10-methylenetetrahydrofolate (arfolitixorin)


Participation Criteria
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Eligibility Criteria
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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. Serum MTX: ≤0.1μmol/L Neutrophils: ≥0.25x109/L Platelets: ≥50x109/L Serum bilirubin: ≤1.25x upper limit of normal (ULN) Glomerular filtration rate (GFR) ≥70 mL/min/1.73m2 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.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>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) | Drug: Calcium Folinate<br>* 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.<br>* Other names: Leucovorin;Drug: [6R] 5,10-methylenetetrahydrofolate (arfolitixorin)<br>* 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.<br>* Other names: arfolitixorin;|
| Experimental: Cohort 2<br>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 | Drug: Calcium Folinate<br>* 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.<br>* Other names: Leucovorin;Drug: [6R] 5,10-methylenetetrahydrofolate (arfolitixorin)<br>* 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.<br>* Other names: arfolitixorin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of AEs Per Severity (All Courses) | 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. | From the start of HDMTX administration through 8 days post dose for each course of HDMTX in total | 
| Number of HDMTX Related AEs Per Severity (All Courses) | 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. | From the start of HDMTX administration through 8 days post dose for each course of HDMTX in total | 
| Number of Ongoing AEs Per HDMTX Course | 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. | From the start of HDMTX administration through 8 days post dose for each course of HDMTX | 
| Number of Ongoing HDMTX Related AEs Per HDMTX Course | 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. | From the start of HDMTX administration through 8 days post dose for each course of HDMTX | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B | 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: Serum MTX: ≤0.1μmol/L Neutrophils: ≥0.25x109/L Platelets: ≥50x109/L Serum bilirubin: ≤1.25 x upper limit of normal (ULN) Glomerular filtration rate (GFR) ≥70 mL/min/1.73m2 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: Serum MTX: ≤0.1μmol/L Neutrophils: ≥ 0.75 x 109/L Platelets: ≥75x109/L Serum bilirubin: ≤1.25xULN GFR ≥70 mL/min/1.73m2 No AE Grade 2 or more related to HDMTX hindering a potential Adriamycin/Doxorubicin and Cisplatin (AP) administration, at the discretion of the investigator | 8 days after start of first and/or second HDMTX course in a MAP cycle | 
| 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. | 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: Serum MTX: ≤ 0.1 μmol/L Neutrophils: ≥ 0.25 x 109/L Platelets: ≥ 50 x 109/L Serum bilirubin: ≤ 1.25 x ULN GFR ≥ 70 mL/min/1.73 m2 No AE Grade 2 or more (NCI CTCAE v4.0) related to HDMTX hindering a potential HDMTX administration, at the discretion of the investigator | 8 days after start of first HDMTX course in a MAP cycle | 
| Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement to Next MAP Cycle According to Definition B. | 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: Serum MTX: ≤ 0.1 μmol/L Neutrophils: ≥ 0.75 x 109/L Platelets: ≥ 75 x 109/L Serum bilirubin: ≤ 1.25 x ULN GFR ≥ 70 mL/min/1.73 m2 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 | 8 days after start of second HDMTX course in a MAP cycle | 
| Time to Successful MTX Elimination (Definition C) | Definition C: Time to successful MTX elimination = Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L | Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L | 
| 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 HDMTX Courses With Delayed MTX Elimination (Definition D). | 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 | Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L | 
| Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E). | 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. | Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L | 
| Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F). | 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. | Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L | 
| Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | 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. | Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L | 
| Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | 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. | From the start of HDMTX administration through 8 days post dose for all 4 courses of HDMTX in total | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Methotrexate, Rescue treatment