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

NCT01987102 | Completed Phase 1 Results DMC

• 1 other identifier: ISO-MTX-003
• Study Type: interventional
• Target: 18
• Locations: 4 countries
• Sites: 5

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

Conditions

Osteosarcoma

Keywords

Methotrexate; Rescue treatment

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (10)

• 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

• 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

• 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

• Time to Successful MTX Elimination (Definition C)

  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

Study Arms (2)

Cohort 1

EXPERIMENTAL

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; Drug: [6R] 5,10-methylenetetrahydrofolate (arfolitixorin)

Cohort 2

EXPERIMENTAL

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; Drug: [6R] 5,10-methylenetetrahydrofolate (arfolitixorin)

Interventions

Calcium Folinate DRUG

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.

Also known as: Leucovorin

Cohort 1; Cohort 2

[6R] 5,10-methylenetetrahydrofolate (arfolitixorin) DRUG

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.

Also known as: Modufolin, arfolitixorin

Cohort 1; Cohort 2

Eligibility Criteria

• Age: 6 Years - 40 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

• Isofol Medical AB: lead

Study Sites (5)

Fakultní nemocnice Brno Klinika detske onkologie

Brno, 62500, Czechia

Location

Fakultní nemocnice v Motole

Prague, 15006, Czechia

Location

Semmelweis Egyetem II. Sz. Gyermekgyógyászati Klinika

Budapest, 1094, Hungary

Location

Instytut Matki i Dziecka

Warsaw, 01-211, Poland

Location

Department of Oncology, Skåne University Hospital

Lund, 22185, Sweden

Location

MeSH Terms

Conditions

Osteosarcoma

Interventions

Leucovorin; 5,10-methylenetetrahydrofolic acid

Condition Hierarchy (Ancestors)

Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma

Intervention Hierarchy (Ancestors)

Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes

Results Point of Contact

• Title: Chief Medical Officer
• Organization: Isofol Medical AB

karin.ganlov@isofolmedical.com

+46 (0)702433750

Study Officials

• Mikael Eriksson, MD PhD

  Department of Oncology, Skåne University Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 5, 2013
• First Posted: November 19, 2013
• Study Start: December 1, 2013
• Primary Completion: January 3, 2017
• Study Completion: January 3, 2017
• Last Updated: September 25, 2020
• Results First Posted: June 26, 2019

Record last verified: 2020-09

Data Sharing

• IPD Sharing: Will not share

Locations

SE (1); HU (1); PL (1); CZ (2)