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

NCT ID: NCT02022358

Last Updated: 2015-06-04

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 34 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-07-31
• Study Completion Date: 2015-06-30

Brief 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.

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

M

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 .

Group Type: ACTIVE_COMPARATOR

Methotrexate

Intervention Type: DRUG

Methotrexate (12 g/m2 x 1, intravenously)

Folinic Acid

Intervention Type: DRUG

Folinic acid rescue 15mg/m2 four times daily adjusted according to methotrexate levels

GluM

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

Group Type: EXPERIMENTAL

Glucarpidase

Intervention Type: DRUG

Glucarpidase rescue (50 units/kg x 1, intravenously)

Methotrexate

Intervention Type: DRUG

Methotrexate (12 g/m2 x 1, intravenously)

Folinic Acid

Intervention Type: DRUG

Folinic acid rescue 15mg/m2 four times daily adjusted according to methotrexate levels

Interventions

Glucarpidase

Glucarpidase rescue (50 units/kg x 1, intravenously)

Intervention Type: DRUG

Methotrexate

Methotrexate (12 g/m2 x 1, intravenously)

Intervention Type: DRUG

Folinic Acid

Folinic acid rescue 15mg/m2 four times daily adjusted according to methotrexate levels

Intervention Type: DRUG

Other Intervention Names

Voraxaze

Eligibility Criteria

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

• Minimum Eligible Age: 5 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Richard Scowcroft Foundation

UNKNOWN

Sponsor Role: collaborator

University College, London

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jeremy Whelan, Professor

Role: PRINCIPAL_INVESTIGATOR

University College London Hospitals

Locations

University College Hospital

London, , United Kingdom

Countries

United Kingdom

Other Identifiers

06/085

Identifier Type: -

Identifier Source: org_study_id