Voraxaze for Delayed Methotrexate Clearance

Randomized, Double-Blind, Placebo Controlled Trial of Voraxaze™ in Patients With a Delayed MTX Clearance

Primary Objectives:

1. To evaluate the efficacy of Glucarpidase (Voraxaze) in increasing the rate of methotrexate (MTX) clearance following high dose MTX treatment in patients with a delayed MTX clearance.
2. To evaluate the pharmacokinetics (PK) of Glucarpidase following high dose MTX treatment in patients with a delayed MTX clearance.
3. To evaluate the safety profile of Glucarpidase following high dose MTX treatment in patients with a delayed MTX clearance.

Secondary Objectives:

1. To evaluate the effect of Glucarpidase on the incidence of neutropenic fever and use of intravenous (IV) antibiotics.
2. To evaluate the effect of Glucarpidase on the length of hospitalization.
3. To evaluate the effect of Glucarpidase on renal function.
4. To evaluate the effect of Glucarpidase on Quality of Life (QOL).
5. To evaluate the anti-glucarpidase antibody response.
6. To evaluate the efficacy of Glucarpidase following its use in repeated cycles of high dose MTX treatment.

Study Overview

• Status: Terminated
• Conditions: Solid Tumor; Hematologic Malignancy
• Intervention / Treatment: Drug: Voraxaze (Glucarpidase); Drug: Placebo

Detailed Description

Researchers want to learn how glucarpidase may impact patients' length of stay in the hospital, kidney function, and quality of life. Also, researchers want to learn if glucarpidase may decrease the incidence of neutropenic fever, which may decrease the use of antibiotics by vein to treat this kind of fever.

MTX is a high-dose chemotherapy drug that reduces the supply of an important vitamin (folate) required for the growth of cancer cells. In patients with delayed clearance of MTX from the body, there is a risk of more frequent or severe side effects from the drug.

Glucarpidase is a drug that breaks down MTX in the blood, causing the drug to be less toxic and decreasing levels of the drug in the blood.

Before you can start treatment on this study, you will have "screening tests." These tests will help the doctor decide if you are eligible to take part in this study. Your complete medical history will be recorded. You will have a physical exam, including measurement of your vital signs (temperature, pulse, breathing rate, and blood pressure). You will have blood drawn (about 3 teaspoons) for routine tests. You will also have blood drawn (about 1 teaspoon), right before treatment starts, 28 days after the first dose of study drug in each cycle, and at the end of the study to see if you have any antibodies (proteins in the body that help fight infections and foreign substances in the body) to the study drug. Women who are able to have children must have a negative blood pregnancy test. The blood used for the pregnancy test will come from the sample taken for routine tests. (There is no additional blood draw for the pregnancy test).

You may be given either glucarpidase or placebo (a drug that looks like glucarpidase but is not active). Neither you nor the study doctor will know if you have been given glucarpidase or placebo. This is called the blinded phase of this study. Before you can begin on this study, if you are already suffering from side effects (because of difficulty with MTX clearance), such as kidney toxicity, severe mucositis (redness and painful ulcers in the mouth), and/or you have extremely high MTX levels, you will not be randomized and will receive glucarpidase, not placebo. If this is the case, your doctor will know that you have been given glucarpidase.

If you are found to be eligible to take part in this study, you will be assigned to 1 of 2 treatment groups, which will be based on the dose of MTX you received. You will then be randomly assigned (as in the toss of a coin) to one of two treatment groups. Participants in one group will receive glucarpidase. Participants in the other group will receive placebo. There is a higher chance that you may receive glucarpidase than placebo because for every patient that receives placebo, 2 patients will receive glucarpidase. The glucarpidase or placebo dose that you may receive will be given by vein within 12 hours after you have been found eligible to participate in this study. Glucarpidase or placebo will be given during the first study cycle (after MTX treatment is completed, if after 72 hours your MTX levels are found to be high). You may receive additional doses of glucarpidase (depending upon the level of MTX in your blood) up to a maximum of 2 doses. If this is the case, the second dose will be given at least 24 hours after the first dose you received.

Regardless of the treatment group that you are assigned to, you will continue to receive standard treatment (fluids by vein with sodium acetate or sodium bicarbonate and leucovorin) for high MTX levels. In future cycles of MTX, you may receive glucarpidase, if you continue to experience a delay of MTX clearing from your body. The glucarpidase dose may be repeated a maximum of 2 times in a given cycle of chemotherapy. The length of a cycle of chemotherapy will vary, depending on the dose of MTX and the regimen the patient is receiving. One cycle of treatment with glucarpidase is at least 24 hours apart.

You will be asked to fill out several questionnaires regarding your quality of life. These questionnaires will ask about your level of pain, fatigue, nausea, sleep disturbances, etc. They will be given during the first study cycle only (before the study drug is given and daily during the first study cycle). They will take about 5 minutes to complete each time.

You will also have blood drawn (about 3 teaspoons each), at different times, so that study doctors can monitor your kidney function and liver function, depending on your clinical condition. These blood samples will be drawn at least twice a week while you are on this study. You will again have blood drawn for the presence of antibodies 14 days after treatment with glucarpidase, before every cycle of MTX treatment, and at the end of this study.

You will be taken off this study if your disease gets worse, you experience intolerable side effects, or you completed planned therapy (a maximum of 6 cycles of study drug). At the end of this study, your complete medical history will again be recorded. You will have a physical exam, including measurement of your vital signs. You will also have blood drawn (about 1 teaspoon) for routine tests.

This is an investigational study. Glucarpidase is not FDA approved or commercially available. The M. D. Anderson Institutional Review Board (IRB) has authorized the use of glucarpidase for research only. The IRB is a committee made up of doctors, researchers, and members of the community. The IRB is responsible for protecting the participants involved in research studies and making sure all research is done in a safe and ethical manner. Glucarpidase and placebo will be provided free of charge during this study. Up to 46 patients will take part in this study. All patients will be enrolled at M. D. Anderson.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • U.T. M.D. Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients with solid tumors and hematologic malignancies, receiving high dose methotrexate (MTX) (> / = 1 g/m^2 up to 14 g/m^2), who have delayed MTX clearance. Delayed MTX clearance is defined as: a) Serum MTX level at 72 +/- 2 hrs from initiation of infusion > / = 0.1 µmol/L for MTX doses 1-3.5 g/m^2 OR b) Serum MTX level at 72 +/- 2 hrs from initiation of infusion > / = 0.3 µmol/L for MTX doses > 3.5 g/m^2
2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
3. IRB-approved signed informed consent

Exclusion Criteria:

1. Any medical or psychiatric illness that is deemed by the investigator to be likely to interfere with patient's ability to sign informed consent, cooperate and participate in the study
2. Patients receiving medications which may interfere with MTX excretion or enhance MTX toxicity (e.g. Penicillins, Cephalosporins, Tetracyclines, Non-Steroidal Anti-inflammatory Agents, Salicylates, Thiazide Diuretics, Bactrim, and Probenecid)
3. Patients with uncontrolled cardiac disease such as uncontrolled angina, cardiac arrhythmia, or Congestive Heart Failure (CHF) (New York Heart Association (NYHA) 4)
4. Patients with known hypersensitivity to any of the components of the study drug

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Voraxaze; Voraxaze administered 50 units/kg intravenously (IV) repeated a maximum of 2 times in a given cycle of chemotherapy.	Drug: Voraxaze (Glucarpidase); 50 units/kg IV within 12 hours of study eligibility being confirmed.; Other Names: Carboxypeptidease
Placebo Comparator: Placebo; Placebo administered IV following Voraxaze arm.	Drug: Placebo; Administered by IV within 12 hours of study eligibility being confirmed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient Response Rate (Percentage)	Response rate defined as proportion of patients that clear methotrexate (MTX) at 15 min and 24-hour post infusion of study drug, Glucarpidase (Voraxaze) to total patient number. Serum MTX levels (standard methods and mass spectrometry) at 15 minutes, 24 hours, or daily until MTX clearance defined as serum MTX level <0.1 µmol/L.	Study period 2 years

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: BTG International Inc.

Publications and helpful links

Helpful Links

• The University of Texas M.D.Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (Actual): January 1, 2008
• Study Completion (Actual): January 1, 2008

Study Registration Dates

• First Submitted: January 17, 2007
• First Submitted That Met QC Criteria: January 17, 2007
• First Posted (Estimate): January 19, 2007

Study Record Updates

• Last Update Posted (Estimate): December 6, 2012
• Last Update Submitted That Met QC Criteria: December 4, 2012
• Last Verified: December 1, 2012

More Information

Terms related to this study

• Keywords: Solid Tumor; Hematologic Malignancy; Placebo; Voraxaze; Glucarpidase; Delayed Methotrexate Clearance
• Additional Relevant MeSH Terms: Neoplasms by Site; Hematologic Diseases; Neoplasms; Hematologic Neoplasms
• Other Study ID Numbers: 2006-0119