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Methotrexate

Voraxaze administered 50 units/kg intravenously (IV) repeated a maximum of 2 times in a given cycle of chemotherapy.

Placebo administered IV following Voraxaze arm.

50 units/kg IV within 12 hours of study eligibility being confirmed.

Voraxaze (Glucarpidase)

Administered by IV within 12 hours of study eligibility being confirmed.

Placebo

Saroj Vadhan-Raj, MD

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.

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.

Voraxaze for Delayed Methotrexate Clearance

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

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.

BTG International Inc.

M.D. Anderson Cancer Center

Voraxaze

Total

Age Continuous

Female

Male

Gender

United States

Region of Enrollment

Saroj Vadhan, MD

Analysis was to be per protocol, low accrual and early termination led too few responses for evaluation.

Patient Response Rate (Percentage)

Overall Study

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Immune System Diseases

Rare Diseases

Leukemia

Renal Insufficiency

Osteosarcoma

Lymphoma

Lymphosarcoma

50 Units/kg in a bolus intravenous injection over 5 minutes

Voraxaze (glucarpidase)

Paul Litka, MD

This protocol is for the treatment of toxic plasma methotrexate concentrations (\>1 micromole per liter) in patients with delayed methotrexate clearance due to impaired renal function

This treatment protocol will be available on a cost recovery basis to IRB-approved Investigators treating an eligible patient at any site in the US. In order to continue to make Voraxaze™ available following FDA approval and prior to being commercially available. Protherics needs to charge for the product, so there will be a cost to obtain Voraxaze™ under the Open-Label Treatment Protocol. Protherics is permitted under the FDA regulations (21 CFR 312.8) to charge for Voraxaze, to recover those costs associated with its manufacture, research and development, and handling, but do not include other commercial costs (profit).

Patient eligibility is based on MTX concentrations and laboratory values obtained per standard of care. Once an Investigator identifies a potential patient, he/she will contact the Voraxaze central call center (1-877-398-9829) to receive information regarding drug shipment. Eligible patients will have routine demographic, MTX, and Voraxaze therapy information collected.

Each patient will receive a single dose of Voraxaze 50 Units/kg in a bolus intravenous injection over 5 minutes. In addition to Voraxaze, patients will continue to receive standard of care treatment including leucovorin therapy, and supportive care such as hydration, alkalinization of urine and, if necessary, hemoperfusion/dialysis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Voraxaze for Delayed Methotrexate Clearance	NCT00424645	Hematologic Mal... Solid Tumor	Voraxaze (Gluca... Placebo	-	M.D. Anderson Cancer Center
Treatment Protocol of Voraxaze for Patients Experiencing or at Risk of Methotrexate Toxicity	NCT00481559	Neoplasms	Voraxaze (gluca...	-	BTG International Inc.
Voraxaze for Delayed Methotrexate Clearance	NCT00424645	Hematologic Mal... Solid Tumor	Voraxaze (Gluca... Placebo	-	M.D. Anderson Cancer Center

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