- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01987102
Investigation of [6R] 5,10-methylenetetrahydrofolate (Arfolitixorin) as Rescue Therapy for Osteosarcoma Patients Treated With HDMTX.
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
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
-
-
-
Brno, Czechia, 62500
- Fakultní nemocnice Brno Klinika detske onkologie
-
Prague, Czechia, 15006
- Fakultni nemocnice v Motole
-
-
-
-
-
Budapest, Hungary, 1094
- Semmelweis Egyetem II. Sz. Gyermekgyógyászati Klinika
-
-
-
-
-
Warszawa, Poland, 01-211
- Instytut Matki i Dziecka
-
-
-
-
-
Lund, Sweden, 22185
- Department of Oncology, Skåne University Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: NON_RANDOMIZED
- Interventional Model: SEQUENTIAL
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: Cohort 1
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) |
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.
Other Names:
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.
Other Names:
|
EXPERIMENTAL: Cohort 2
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 |
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.
Other Names:
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.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of AEs Per Severity (All Courses)
Time Frame: 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.
|
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)
Time Frame: 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.
|
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
Time Frame: 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.
|
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
Time Frame: 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.
|
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
Time Frame: 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:
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:
|
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.
Time Frame: 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:
|
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.
Time Frame: 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:
|
8 days after start of second HDMTX course in a MAP cycle
|
Time to Successful MTX Elimination (Definition C)
Time Frame: 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
|
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 Frame: 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 With Delayed MTX Elimination (Definition D).
Time Frame: 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 |
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).
Time Frame: 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:
|
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).
Time Frame: 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. |
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
Time Frame: 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.
|
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.
Time Frame: 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.
|
From the start of HDMTX administration through 8 days post dose for all 4 courses of HDMTX in total
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Mikael Eriksson, MD PhD, Department of Oncology, Skåne University Hospital
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Neoplasms, Connective and Soft Tissue
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms, Bone Tissue
- Neoplasms, Connective Tissue
- Sarcoma
- Osteosarcoma
- Physiological Effects of Drugs
- Protective Agents
- Micronutrients
- Vitamins
- Calcium-Regulating Hormones and Agents
- Antidotes
- Vitamin B Complex
- Leucovorin
- Calcium
- Levoleucovorin
Other Study ID Numbers
- ISO-MTX-003
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Osteosarcoma
-
Klinikum StuttgartKlinikum Kassel GmbH (COSS-Biobank)Not yet recruitingOsteosarcoma | High Grade Sarcoma | Recurrent Osteosarcoma | Bone Sarcoma | Undifferentiated Pleomorphic Sarcoma | Bone Tumor | Extraskeletal Osteosarcoma | Osseous Sarcoma | Parosteal Osteosarcoma | Osteoblastic Osteosarcoma | Chondroblastic Osteosarcoma | Fibroblastic Osteosarcoma | Conventional Osteosarcoma | Conventional... and other conditions
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedRecurrent Osteosarcoma | Refractory Osteosarcoma | Stage IV Osteosarcoma AJCC v7 | Stage IVA Osteosarcoma AJCC v7 | Stage IVB Osteosarcoma AJCC v7 | Metastatic OsteosarcomaUnited States, Canada, Puerto Rico
-
M.D. Anderson Cancer CenterSuspendedRecurrent Osteosarcoma | Refractory Osteosarcoma | Metastatic Osteosarcoma | Unresectable Osteosarcoma | Locally Advanced OsteosarcomaUnited States
-
Children's Oncology GroupNational Cancer Institute (NCI)Not yet recruitingMetastatic Osteosarcoma | Localized Osteosarcoma | Unresectable Osteosarcoma | Resectable Osteosarcoma
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedRecurrent Osteosarcoma | Metastatic Osteosarcoma | Localized Osteosarcoma | Osteoblastic OsteosarcomaUnited States
-
National Cancer Institute (NCI)SuspendedMetastatic Osteosarcoma | Localized Osteosarcoma | High Grade Osteosarcoma | Secondary OsteosarcomaUnited States
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedRecurrent Osteosarcoma | Metastatic Osteosarcoma | Localized OsteosarcomaUnited States
-
National Cancer Institute (NCI)Active, not recruitingRecurrent Ewing Sarcoma | Recurrent Osteosarcoma | Stage III Osteosarcoma AJCC v7 | Stage IV Osteosarcoma AJCC v7 | Stage IVA Osteosarcoma AJCC v7 | Stage IVB Osteosarcoma AJCC v7 | Metastatic Osteosarcoma | Metastatic Ewing Sarcoma | Unresectable Ewing Sarcoma | Unresectable OsteosarcomaFrance
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedRecurrent Osteosarcoma | Metastatic Osteosarcoma | Localized OsteosarcomaUnited States
-
Sarcoma Alliance for Research through CollaborationActive, not recruitingOsteosarcoma | Osteosarcoma Recurrent | Osteosarcoma Metastatic | Osteosarcoma in ChildrenUnited States
Clinical Trials on Calcium Folinate
-
Iwate Medical UniversityUnknown
-
Cancer Institute and Hospital, Chinese Academy...UnknownColorectal CancerChina
-
Southwest Autism Research & Resource CenterUnited States Department of Defense; State University of New York - Downstate...RecruitingAutism Spectrum Disorder | Language DisordersUnited States
-
Southwest Autism Research & Resource CenterAutism Speaks; State University of New York - Downstate Medical CenterRecruitingAutism Spectrum Disorder | Language DisordersUnited States
-
Cancer Institute and Hospital, Chinese Academy...Jiangsu HengRui Medicine Co., Ltd.RecruitingBorderline Resectable Pancreatic CancerChina
-
Sun Yat-sen UniversityRecruiting
-
The Affiliated Nanjing Drum Tower Hospital of Nanjing...RecruitingLiver Transplantation | Hepatocellular CarcinomaChina
-
National Cancer Institute (NCI)CompletedHilar Cholangiocarcinoma | Advanced Adult Hepatocellular Carcinoma | Localized Non-Resectable Adult Liver Carcinoma | Recurrent Adult Liver Carcinoma | Recurrent Gallbladder Carcinoma | Stage IV Distal Bile Duct Cancer | Unresectable Extrahepatic Bile Duct Carcinoma | Stage II Gallbladder Cancer | Stage... and other conditionsUnited States
-
TTY BiopharmChang Gung Memorial HospitalCompletedMetastatic Colorectal CancerTaiwan
-
Sixth Affiliated Hospital, Sun Yat-sen UniversityQidong Gaitianli Medicines Co., LtdUnknown