OsteosarcomaPhase 2NCT02022358
Will Glucarpidase After Methotrexate Treatment for Bone Sarcoma Lead to Fewer Side Effects and Reduce Chemotherapy Delays?
A Phase 2 study testing Glucarpidase, Methotrexate and Folinic Acid in people with Osteosarcoma and Spindle Cell Sarcoma of Bone, run by University College, London at 1 site in United Kingdom.
Trial summary
Methotrexate is one of the most effective chemotherapy drugs in the treatment of osteosarcoma and some other types of bone sarcoma which are treated the same way as osteosarcoma. However, it frequently leads to sore mouth, tummy pain and increased risk of developing infections. Read more about this study
- Who is it for?
- Ages 5 to 50 years
- Conditions the study is for
- Osteosarcoma, Spindle Cell Sarcoma of Bone
- What is being tested?
- Glucarpidase, Methotrexate and Folinic Acid
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 34 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Jul 2007to Jun 2015
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 5 to 50 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Written informed consent from patient or parent/guardian Diagnosis of high grade osteosarcoma, localised or metastatic or high grade osteosarcoma as a second malignancy or spindle cell sarcoma of bone or relapsed high grade osteosarcoma Ability to comply with study and follow up procedures (WHO performance scale 0-2) No concomitant anti-cancer or investigational drugs during the study and complete resolution of toxicity related to previous treatment Life expectancy of at least 3 months Haematopoietic function: Absolute neutrophil count ≥1 x109/L, Platelets ≥75 x109/L Hepatic function: Bilirubin ≤1.5 x ULN Renal function: Glomerular Filtration Rate (radioisotope) ≥ 70 ml/min/1.73m2
Who cannot join
- Previous treatment with glucarpidase Pregnant or breast feeding women (patients with reproductive potential of either gender must use contraception) Concomitant treatment with agents which interact with methotrexate metabolism or excretion Serous effusions, including ascites and pleural effusions
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Randomised, Cross-over Phase II Study to Investigate the Efficacy and Safety of Glucarpidase for Routine Use After High Dose Methotrexate in Patients With Bone Sarcoma
Methotrexate is one of the most effective chemotherapy drugs in the treatment of osteosarcoma and some other types of bone sarcoma which are treated the same way as osteosarcoma. However, it frequently leads to sore mouth, tummy pain and increased risk of developing infections.
The investigators try to save or "rescue" normal cells from the side effects of methotrexate by giving a drug called folinic acid. Folinic acid is started 24 hours after methotrexate and given regularly until methotrexate levels are really low and not dangerous to normal cells anymore. Despite this rescue, side effects are still a problem and many patients are not well enough to receive subsequent chemotherapy on time. Almost half of the planned chemotherapy cycles are not given on time due to methotrexate side effects.
In this study the investigators will examine if adding a drug called glucarpidase to folinic acid is helpful. Glucarpidase is an enzyme that inactivates methotrexate in the blood stream. Lower methotrexate concentration in the blood stream leads to fewer side effects. The investigators would like to see if glucarpidase helps patients to have their chemotherapy on time, by reducing the side effects of methotrexate.
Read the detailed description
In this study the patient will receive 4 courses of high-dose methotrexate. High-dose methotrexate is normally given at weekly intervals, in blocks of two.The first two courses will be given on weeks 1 \& 2; the second two courses on weeks 4 \& 5. Two courses will be given with folinic acid rescue (standard high-dose methotrexate), and the other two will be given with glucarpidase rescue as well as folinic acid. This will enable us to compare whether there is any difference in side effects with and without glucarpidase and also how quickly patients recover from them.
Half of the patients will receive standard high-dose methotrexate on weeks 1 \& 2 and high-dose methotrexate with glucarpidase on weeks 4 \& 5 (arm A) and half of the patients will first have high-dose methotrexate with glucarpidase on weeks 1 \& 2 and then standard high-dose methotrexate on weeks 4 \& 5 (arm B).
All patients receiving methotrexate have daily blood tests to monitor the levels of methotrexate in their body, and monitor their kidney function. However, patients on this study will have extra blood tests for chemotherapy drug levels and glucarpidase antibody levels. During each hospital admission for chemotherapy, blood samples will be taken as follows:
Day 1: Just before starting methotrexate (extra blood test) and at the end of methotrexate infusion (extra blood test) Day 2: 24 hours after starting methotrexate (routine blood test) and 20 minutes after the 24-hour blood test (i.e. just after the glucarpidase/placebo infusion) (extra blood test) Day 3+: Routine daily blood tests until the body has got rid of the methotrexate Extra blood samples will also be taken 15 days after starting each cycle and 1 month, 3 and 6 months, after starting the second cycle.
Patients will also be asked to complete mucositis assessment and quality of life questionnaires.
- Conditions
- Osteosarcoma, Spindle Cell Sarcoma of Bone
- Being tested
- Glucarpidase, Methotrexate, Folinic Acid
- Keywords
- Osteosarcoma, Methotrexate, Glucarpidase, Mucositis
- Medical subject headings
- Osteosarcoma, Mucositis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GlucarpidaseDrug
Also called Voraxaze
Glucarpidase rescue (50 units/kg x 1, intravenously)
MethotrexateDrug
Methotrexate (12 g/m2 x 1, intravenously)
Folinic AcidDrug
Folinic acid rescue 15mg/m2 four times daily adjusted according to methotrexate levels
| Study group | Role | What they receive |
|---|---|---|
| M | Active comparator | Methotrexate (12 g/m2 x 1, intravenously) with standard folinic acid rescue
In arm A patients will receive cycle M first followed by cycle GluM. Cycle M starts with course M1 on day 1 followed by course M2 planned for day 8. Cycle GluM starts with course GluM1 on day 1 followed by GluM2 planned for day 8. Cycle GluM will not start for a minimum of 14 days from the beginning of course M2, or until bone marrow, renal and hepatic functions have completely recovered and the patient is clinically ready to receive further chemotherapy . Receives: Drug: Methotrexate; Drug: Folinic Acid |
| GluM | Experimental | Methotrexate (12 g/m2 x 1, intravenously) with folinic acid and glucarpidase rescue (50 units/kg x 1, intravenously).
In arm B, patients will receive cycle GluM first followed by cycle M. Cycle GluM starts with course GluM1 on day 1 followed by GluM2 planned for day 8.Cycle M starts with course M1 on day 1 followed by course M2 planned for day 8. Cycle M will not start for a minimum of 14 days from the beginning of course GluM2, or until bone marrow, renal and hepatic function have completely recovered and the patient is clinically ready to receive further chemotherapy Receives: Drug: Glucarpidase; Drug: Methotrexate; Drug: Folinic Acid |
What is being measured
The primary outcome is the main question the study is designed to answer.
Estimate of the difference in proportions of patients ready to receive chemotherapy on Day 15 of each chemotherapy cycle comparing standard rescue and glucarpidase+standard rescue
The first day of each cycle is denoted Day 1. Therefore, the primary outcome will be the proportion of patients who are clinically fit to start cycle 2 of chemotherapy 14 days later.
Measured: Day 15 of each cycle
Secondary outcomes (10)
To investigate whether glucarpidase rescue after high-dose methotrexate reduces the incidence of methotrexate associated adverse effects
Incidence and grading of mucositis, renal toxicity, liver toxicity, neutropaenia, thrombocytopaenia and infections
Measured: Day 8 and 15
Plasma methotrexate concentration
Plasma methotrexate concentration
Measured: Every 24 hours from Time +24 until clearance of methotrexate
Incidence of glucarpidase related adverse effects
Each cycle lasts 3 weeks and patients receive two treatment cycles. The time frame will therefore be 6 weeks
Measured: 6 weeks
Number of days required in hospital per cycle
Each cycle lasts 3 weeks and patients receive two treatment cycles. The time frame will therefore be 6 weeks
Measured: 6 weeks
Assessment of quality of life
Completion of quality of life questionnaires at Day 1, 8, 15 each cycle
Measured: 6 weeks
Serum anti-glucarpidase IgG levels following glucarpidase administration
Day 1, 8, 15 each cycle. Day 30 cycle 2, 3 and 6 months from entry
Measured: 6 months
To investigate whether glucarpidase rescue after high-dose methotrexate reduces the severity of methotrexate associated adverse effects
Grading of mucositis, renal toxicity, liver toxicity, neutropaenia, thrombocytopaenia and infections
Measured: Day 8 and 15
To investigate whether glucarpidase rescue after high-dose methotrexate reduces the duration of methotrexate associated adverse effects
Duration in days of mucositis, renal toxicity, liver toxicity, neutropaenia, thrombocytopaenia and infections
Measured: Day 8 and 15
Plasma DAMPA concentration
Plasma DAMPA concentration
Measured: Every 24 hours from Time +24 until clearance of methotrexate
Total dose of folinic acid rescue required per cycle
Each cycle lasts 3 weeks and patients receive two treatment cycles. The time frame will therefore be 6 weeks
Measured: 6 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Dec 2013 (estimated)
- Study startJul 2007
- Primary completionJun 2015
- Study completionJun 2015
Why it stopped: Recruitment almost complete, has been slow and challenging
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for OsteosarcomaStudies of the same condition, open and under way.
- More trials run by University College, LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 34 participants (actual)
Sponsor and investigators
- Lead sponsor
- University College, London
- Sponsor type
- University, hospital or other
- Collaborators
- Richard Scowcroft Foundation
- Responsible party
- Sponsor
- Investigators
- Jeremy Whelan, Professor, Principal investigator, University College London Hospitals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02022358
- Sponsor's protocol ID
- 06/085
- Status last verified
- Jun 2015
- First submitted
- 26 Nov 2013
- Last updated
- 4 Jun 2015
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 4 Jun 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomised, Cross-over Phase II Study to Investigate the Efficacy and Safety of Glucarpidase for Routine Use After High Dose Methotrexate in Patients With Bone Sarcoma
- ClinicalTrials.gov ID
- NCT02022358
- Acronym / sponsor ID
- 06/085
- Conditions
- Osteosarcoma, Spindle Cell Sarcoma of Bone
- Keywords
- Osteosarcoma, Methotrexate, Glucarpidase, Mucositis
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Recruitment almost complete, has been slow and challenging
- Enrolment
- 34 participants (actual)
- Lead sponsor
- University College, LondonUniversity, hospital or other
- Collaborators
- Richard Scowcroft Foundation
- Study start
- Jul 2007
- Primary completion
- Jun 2015 (actual)
- Study completion
- Jun 2015 (actual)
- First posted
- 27 Dec 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Methotrexate is one of the most effective chemotherapy drugs in the treatment of osteosarcoma and some other types of bone sarcoma which are treated the same way as osteosarcoma. However, it frequently leads to sore mouth, tummy pain and increased risk of developing infections.
The investigators try to save or "rescue" normal cells from the side effects of methotrexate by giving a drug called folinic acid. Folinic acid is started 24 hours after methotrexate and given regularly until methotrexate levels are really low and not dangerous to normal cells anymore. Despite this rescue, side effects are still a problem and many patients are not well enough to receive subsequent chemotherapy on time. Almost half of the planned chemotherapy cycles are not given on time due to methotrexate side effects.
In this study the investigators will examine if adding a drug called glucarpidase to folinic acid is helpful. Glucarpidase is an enzyme that inactivates methotrexate in the blood stream. Lower methotrexate concentration in the blood stream leads to fewer side effects. The investigators would like to see if glucarpidase helps patients to have their chemotherapy on time, by reducing the side effects of methotrexate.
Detailed description
In this study the patient will receive 4 courses of high-dose methotrexate. High-dose methotrexate is normally given at weekly intervals, in blocks of two.The first two courses will be given on weeks 1 \& 2; the second two courses on weeks 4 \& 5. Two courses will be given with folinic acid rescue (standard high-dose methotrexate), and the other two will be given with glucarpidase rescue as well as folinic acid. This will enable us to compare whether there is any difference in side effects with and without glucarpidase and also how quickly patients recover from them.
Half of the patients will receive standard high-dose methotrexate on weeks 1 \& 2 and high-dose methotrexate with glucarpidase on weeks 4 \& 5 (arm A) and half of the patients will first have high-dose methotrexate with glucarpidase on weeks 1 \& 2 and then standard high-dose methotrexate on weeks 4 \& 5 (arm B).
All patients receiving methotrexate have daily blood tests to monitor the levels of methotrexate in their body, and monitor their kidney function. However, patients on this study will have extra blood tests for chemotherapy drug levels and glucarpidase antibody levels. During each hospital admission for chemotherapy, blood samples will be taken as follows:
Day 1: Just before starting methotrexate (extra blood test) and at the end of methotrexate infusion (extra blood test) Day 2: 24 hours after starting methotrexate (routine blood test) and 20 minutes after the 24-hour blood test (i.e. just after the glucarpidase/placebo infusion) (extra blood test) Day 3+: Routine daily blood tests until the body has got rid of the methotrexate Extra blood samples will also be taken 15 days after starting each cycle and 1 month, 3 and 6 months, after starting the second cycle.
Patients will also be asked to complete mucositis assessment and quality of life questionnaires.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| M | Active comparator | Drug: Methotrexate, Drug: Folinic AcidMethotrexate (12 g/m2 x 1, intravenously) with standard folinic acid rescue In arm A patients will receive cycle M first followed by cycle GluM. Cycle M starts with course M1 on day 1 followed by course M2 planned for day 8. Cycle GluM starts with course GluM1 on day 1 followed by GluM2 planned for day 8. Cycle GluM will not start for a minimum of 14 days from the beginning of course M2, or until bone marrow, renal and hepatic functions have completely recovered and the patient is clinically ready to receive further chemotherapy . |
| GluM | Experimental | Drug: Glucarpidase, Drug: Methotrexate, Drug: Folinic AcidMethotrexate (12 g/m2 x 1, intravenously) with folinic acid and glucarpidase rescue (50 units/kg x 1, intravenously). In arm B, patients will receive cycle GluM first followed by cycle M. Cycle GluM starts with course GluM1 on day 1 followed by GluM2 planned for day 8.Cycle M starts with course M1 on day 1 followed by course M2 planned for day 8. Cycle M will not start for a minimum of 14 days from the beginning of course GluM2, or until bone marrow, renal and hepatic function have completely recovered and the patient is clinically ready to receive further chemotherapy |
Who may qualify
- Ages
- 5 to 50 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (1 listed)
- Written informed consent from patient or parent/guardian Diagnosis of high grade osteosarcoma, localised or metastatic or high grade osteosarcoma as a second malignancy or spindle cell sarcoma of bone or relapsed high grade osteosarcoma Ability to comply with study and follow up procedures (WHO performance scale 0-2) No concomitant anti-cancer or investigational drugs during the study and complete resolution of toxicity related to previous treatment Life expectancy of at least 3 months Haematopoietic function: Absolute neutrophil count ≥1 x109/L, Platelets ≥75 x109/L Hepatic function: Bilirubin ≤1.5 x ULN Renal function: Glomerular Filtration Rate (radioisotope) ≥ 70 ml/min/1.73m2
Key exclusion criteria (1 listed)
- Previous treatment with glucarpidase Pregnant or breast feeding women (patients with reproductive potential of either gender must use contraception) Concomitant treatment with agents which interact with methotrexate metabolism or excretion Serous effusions, including ascites and pleural effusions
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| GlucarpidaseAlso: VoraxazeGlucarpidase rescue (50 units/kg x 1, intravenously) | Drug | GluM |
| MethotrexateMethotrexate (12 g/m2 x 1, intravenously) | Drug | GluM, M |
| Folinic AcidFolinic acid rescue 15mg/m2 four times daily adjusted according to methotrexate levels | Drug | GluM, M |
Primary outcome
Estimate of the difference in proportions of patients ready to receive chemotherapy on Day 15 of each chemotherapy cycle comparing standard rescue and glucarpidase+standard rescue
Time frame: Day 15 of each cycle
The first day of each cycle is denoted Day 1. Therefore, the primary outcome will be the proportion of patients who are clinically fit to start cycle 2 of chemotherapy 14 days later.
10 secondary outcomes
To investigate whether glucarpidase rescue after high-dose methotrexate reduces the incidence of methotrexate associated adverse effects
Time frame: Day 8 and 15
Plasma methotrexate concentration
Time frame: Every 24 hours from Time +24 until clearance of methotrexate
Incidence of glucarpidase related adverse effects
Time frame: 6 weeks
Number of days required in hospital per cycle
Time frame: 6 weeks
Assessment of quality of life
Time frame: 6 weeks
Serum anti-glucarpidase IgG levels following glucarpidase administration
Time frame: 6 months
To investigate whether glucarpidase rescue after high-dose methotrexate reduces the severity of methotrexate associated adverse effects
Time frame: Day 8 and 15
To investigate whether glucarpidase rescue after high-dose methotrexate reduces the duration of methotrexate associated adverse effects
Time frame: Day 8 and 15
Plasma DAMPA concentration
Time frame: Every 24 hours from Time +24 until clearance of methotrexate
Total dose of folinic acid rescue required per cycle
Time frame: 6 weeks
Results and safety
The study was stopped early (reason given: Recruitment almost complete, has been slow and challenging). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Jun 2015.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jeremy Whelan, Professor principal investigator
University College London Hospitals
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Glucarpidase, Methotrexate and Folinic Acid in people with Osteosarcoma and Spindle Cell Sarcoma of Bone, run by University College, London at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 4 Jun 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Recruitment almost complete, has been slow and challenging). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Estimate of the difference in proportions of patients ready to receive chemotherapy on Day 15 of each chemotherapy cycle comparing standard rescue and glucarpidase+standard rescue (time frame: Day 15 of each cycle). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Jun 2015.