Will Glucarpidase After Methotrexate Treatment for Bone Sarcoma Lead to Fewer Side Effects and Reduce Chemotherapy Delays?

Osteosarcoma Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02022358
• Other study ID #: 06/085
• Status: Terminated
• Phase: Phase 2
• First received: November 26, 2013
• Last updated: June 3, 2015
• Start date: July 2007
• Est. completion date: June 2015

Study information

• Verified date: June 2015
• Source: University College, London
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited Kingdom: Research Ethics CommitteeUnited Kingdom: National Health Service
• Study type: Interventional

Clinical 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.

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 34
• Est. completion date: June 2015
• Est. primary completion date: June 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 5 Years to 50 Years

Eligibility

Inclusion Criteria:

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

Exclusion Criteria:

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Osteosarcoma
• Sarcoma
• Spindle Cell Sarcoma of Bone

Intervention

Drug:
• Glucarpidase
Glucarpidase rescue (50 units/kg x 1, intravenously)
• Methotrexate
Methotrexate (12 g/m2 x 1, intravenously)
• Folinic Acid
Folinic acid rescue 15mg/m2 four times daily adjusted according to methotrexate levels

Locations

Country	Name	City	State
United Kingdom	University College Hospital	London

Sponsors (2)

Lead Sponsor	Collaborator
University College, London	Richard Scowcroft Foundation

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Day 15 of each cycle	No
Secondary	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	Day 8 and 15	No
Secondary	Plasma methotrexate concentration	Plasma methotrexate concentration	Every 24 hours from Time +24 until clearance of methotrexate	Yes
Secondary	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	6 weeks	Yes
Secondary	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	6 weeks	Yes
Secondary	Assessment of quality of life	Completion of quality of life questionnaires at Day 1, 8, 15 each cycle	6 weeks	No
Secondary	Serum anti-glucarpidase IgG levels following glucarpidase administration	Day 1, 8, 15 each cycle. Day 30 cycle 2, 3 and 6 months from entry	6 months	Yes
Secondary	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	Day 8 and 15	No
Secondary	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	Day 8 and 15	No
Secondary	Plasma DAMPA concentration	Plasma DAMPA concentration	Every 24 hours from Time +24 until clearance of methotrexate	No
Secondary	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	6 weeks	Yes