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

Early Phase 1

Completed

• Conditions: Acute Lymphoblastic Leukemia (ALL)
• Interventions: Drug: Allopurinol

• Registration Number: NCT02046694
• Lead Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary

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.

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 Timeline

• Study Start: 2014-01-06
• Study First Submitted: 2014-01-23
• Study First Submitted QC: 2014-01-23
• Study First Posted: 2014-01-28
• Primary Completion: 2020-04-06
• Study Completion: 2020-04-06
• Status Verified: 2022-06
• Last Update Submitted: 2022-06-17
• Last Update Posted: 2022-06-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 34

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Allopurinol	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.

Primary Outcome Measures

Name	Time	Method
Absolute neutrophil count	8 weeks	Absolute neutrophil count (ANC) measured 8 weeks after the addition of allopurinol (study week 9).

Secondary Outcome Measures

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

Trial Locations

Locations (3)

Johns Hopkins Hospital; 🇺🇸 Baltimore, Maryland, United States

Texas Children's Cancer and Hematology Centers; 🇺🇸 Houston, Texas, United States

Seattle Children's Hospital; 🇺🇸 Seattle, Washington, United States