A Pilot Study of Allopurinol As A Modifier of 6-MP Metabolism in Pediatric ALL

June 17, 2022 updated by: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
This research is being done to determine if allopurinol can change the metabolism of the oral chemotherapeutic medication 6-mercaptopurine (6-MP) in children with acute lymphoblastic leukemia (ALL). 6-MP is originally started at a standard dose in children with ALL, but the dose is adjusted according to the absolute neutrophil count (ANC). Occasionally, 6-MP doses need to be increased in order to get the ANC into a specific target range. Also, increasing the 6-MP dose can lead to unwanted side effects, such as inflammation of the liver as shown by increases in laboratory values (ALT, aspartate aminotransferase (AST), bilirubin), nausea, and abdominal discomfort. Previous studies in children with inflammatory bowel disease has shown that combining allopurinol with 6-MP can decrease side effects associated with high doses of 6-MP and also increase the efficacy of 6-MP. Allopurinol is approved by the Food and Drug Administration for the treatment of tumor lysis syndrome in ALL. Through this research study, the investigators hope to show that the combination of allopurinol and 6-MP will be safe, tolerable, and effective in children with ALL.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

  • Patients will have several visits to the Pediatric Oncology outpatient clinic. Each visit will consist of a physical examination and laboratory evaluation. Each laboratory evaluation will consist of taking approximately 10-15 milliliters of blood (or approximately three teaspoons). These clinic visits may actually coincide with clinic visits that were previously scheduled according to the patient's treatment protocol.
  • At the first study visit, patients will have a physical examination and laboratory evaluation. At that visit, patients will be asked to stop taking 6-MP and methotrexate.
  • At the second study visit, which is one week later, patients will again have a physical examination and laboratory evaluation. The investigators will prescribe allopurinol and restart 6-MP and methotrexate at half of the patient's previous doses.
  • Clinic visits for physical examination and laboratory evaluation will be scheduled every 1-2 weeks for a total of 5 more visits. Doses of allopurinol, 6-MP, and methotrexate may be adjusted at these visits based on laboratory values or clinical symptoms.

Study Type

Interventional

Enrollment (Actual)

34

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Johns Hopkins Hospital
    • Texas
      • Houston, Texas, United States, 77030
        • Texas Children's Cancer and Hematology Centers
    • Washington
      • Seattle, Washington, United States, 98105
        • Seattle Children's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 30 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Currently being treated in the maintenance phase of therapy for pediatric ALL
  • Age ≤30 years
  • 6-MMP:6-TGN ratio ≥40 within 21 days prior to enrollment
  • 6-MMP ≥12,000/8x108 red blood cells (RBC) within 21 days prior to enrollment

  • One of the following within 21 days prior to enrollment:

    1. ANC persistently ≥1500/mm3 (as measured by 3 CBCs done over 6 weeks or 2 successive monthly complete blood counts (CBCs) despite 6-MP ≥150% of Children's oncology group (COG) dosing OR

    2. Evidence of ≥ Grade 3 hepatotoxicity with one of the following:

      ALT ≥5x upper limit of normal (based on institutional standards) AST ≥5x upper limit of normal (based on institutional standards) Direct bilirubin ≥5x upper limit of normal (based on institutional standards) OR

    3. Evidence of ≥ Grade 2 gastrointestinal toxicity (including, but not limited to: nausea, vomiting, anorexia, gastrointestinal pain)

Exclusion Criteria:

  • Allergy to allopurinol
  • Active relapse of ALL or lymphoblastic lymphoma
  • Currently enrolled on any therapeutic research study for the treatment of ALL or lymphoblastic lymphoma
  • Known history of chronic liver disease (other than Gilbert's syndrome)
  • Pregnant or breastfeeding females

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Allopurinol
Patients will stop taking their 6-MP and methotrexate at week 0. One week later (week 1), patients will begin allopurinol daily (100 mg for weight >30 kg, 50 mg for weight ≤30 kg) and will restart 6-MP and methotrexate at 50 percent of the most recent dose. Patients will continue taking allopurinol in combination with 6-MP and methotrexate for the duration of the study (total of 8 weeks). Dose adjustments of 6-MP and methotrexate will be directed by the guidelines outlined in the study protocol.
Drug: Allopurinol
At week 1, patients will begin allopurinol daily (100 mg for weight >30 kg, 50 mg for weight ≤30 kg) and will restart 6-MP and methotrexate at 50 percent of the most recent dose. Patients will continue taking allopurinol in combination with 6-MP and methotrexate for the duration of the study (total of 8 weeks).
Other Names:
  • Zyloprim

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Absolute neutrophil count
Time Frame: 8 weeks
Absolute neutrophil count (ANC) measured 8 weeks after the addition of allopurinol (study week 9).
8 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Feasibility of the addition of allopurinol to ALL maintenance therapy
Time Frame: 8 weeks
Allopurinol compliance rate during ALL maintenance therapy.
8 weeks
Safety of the addition of allopurinol to ALL maintenance therapy
Time Frame: 8 weeks
Occurence of grade 4 adverse events that are possibly, probably, or definitely attributable to allopurinol.
8 weeks
Effects of allopurinol on liver function tests
Time Frame: 8 weeks
Measurement of ALT, AST, and direct bilirubin before and after adding allopurinol.
8 weeks
Alteration of 6-MP metabolism through the addition of allopurinol
Time Frame: 8 weeks
Measurement of 6-thioguanine (6-TGN) and 6-methylmercaptopurine (6-MMP) before and after adding allopurinol.
8 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Investigators

  • Principal Investigator: Stacy Cooper, MD, Johns Hopkins University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 6, 2014

Primary Completion (Actual)

April 6, 2020

Study Completion (Actual)

April 6, 2020

Study Registration Dates

First Submitted

January 23, 2014

First Submitted That Met QC Criteria

January 23, 2014

First Posted (Estimate)

January 28, 2014

Study Record Updates

Last Update Posted (Actual)

June 21, 2022

Last Update Submitted That Met QC Criteria

June 17, 2022

Last Verified

June 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • J1357 (Other Identifier: SKCCC at Johns Hopkins)
  • NA_00084984 (Other Identifier: JHMIRB)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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