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

Primary Purpose

Acute Lymphoblastic Leukemia (ALL)

Status

Completed

Phase

Early Phase 1

Locations

United States

Study Type

Interventional

Intervention

Allopurinol

About this trial

This is an interventional treatment trial for Acute Lymphoblastic Leukemia (ALL) focused on measuring acute lymphoblastic leukemia, ALL, pediatric, maintenance, allopurinol, 6-MP, 6-mercaptopurine

Eligibility Criteria

undefined - 30 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Johns Hopkins Hospital
Texas Children's Cancer and Hematology Centers
Seattle Children's Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Allopurinol

Arm Description

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.

Outcomes

Primary Outcome Measures

Absolute neutrophil count

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

Secondary Outcome Measures

Feasibility of the addition of allopurinol to ALL maintenance therapy

Allopurinol compliance rate during ALL maintenance therapy.

Safety of the addition of allopurinol to ALL maintenance therapy

Occurence of grade 4 adverse events that are possibly, probably, or definitely attributable to allopurinol.

Effects of allopurinol on liver function tests

Measurement of ALT, AST, and direct bilirubin before and after adding allopurinol.

Alteration of 6-MP metabolism through the addition of allopurinol

Measurement of 6-thioguanine (6-TGN) and 6-methylmercaptopurine (6-MMP) before and after adding allopurinol.

Full Information

NCT ID

NCT02046694

First Posted

January 23, 2014

Last Updated

June 17, 2022

Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

1. Study Identification

Unique Protocol Identification Number

NCT02046694

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2022

Overall Recruitment Status

Completed

Study Start Date

January 6, 2014 (Actual)

Primary Completion Date

April 6, 2020 (Actual)

Study Completion Date

April 6, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Lymphoblastic Leukemia (ALL)

Keywords

acute lymphoblastic leukemia, ALL, pediatric, maintenance, allopurinol, 6-MP, 6-mercaptopurine

7. Study Design

Primary Purpose

Treatment

Study Phase

Early Phase 1

Interventional Study Model

Single Group Assignment

Model Description

Pilot Study

Masking

None (Open Label)

Allocation

N/A

Enrollment

34 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Allopurinol

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Allopurinol

Other Intervention Name(s)

Zyloprim

Intervention Description

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).

Primary Outcome Measure Information:

Title

Absolute neutrophil count

Description

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

Time Frame

8 weeks

Secondary Outcome Measure Information:

Title

Feasibility of the addition of allopurinol to ALL maintenance therapy

Description

Allopurinol compliance rate during ALL maintenance therapy.

Time Frame

8 weeks

Title

Safety of the addition of allopurinol to ALL maintenance therapy

Description

Occurence of grade 4 adverse events that are possibly, probably, or definitely attributable to allopurinol.

Time Frame

8 weeks

Title

Effects of allopurinol on liver function tests

Description

Measurement of ALT, AST, and direct bilirubin before and after adding allopurinol.

Time Frame

8 weeks

Title

Alteration of 6-MP metabolism through the addition of allopurinol

Description

Measurement of 6-thioguanine (6-TGN) and 6-methylmercaptopurine (6-MMP) before and after adding allopurinol.

Time Frame

8 weeks

10. Eligibility

Sex

All

Maximum Age & Unit of Time

30 Years

Accepts Healthy Volunteers

Eligibility Criteria

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: 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 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 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Stacy Cooper, MD

Organizational Affiliation

Johns Hopkins University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Johns Hopkins Hospital

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21287

Country

United States

Facility Name

Texas Children's Cancer and Hematology Centers

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

Seattle Children's Hospital

City

Seattle

State/Province

Washington

ZIP/Postal Code

98105

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

16407512

Citation

Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006 Jan 12;354(2):166-78. doi: 10.1056/NEJMra052603. No abstract available.

Results Reference

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PubMed Identifier

19145729

Citation

Ansari A, Elliott T, Baburajan B, Mayhead P, O'Donohue J, Chocair P, Sanderson J, Duley J. Long-term outcome of using allopurinol co-therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease. Aliment Pharmacol Ther. 2008 Sep 15;28(6):734-41. doi: 10.1111/j.1365-2036.2008.03782.x.

Results Reference

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PubMed Identifier

18521913

Citation

Rahhal RM, Bishop WP. Initial clinical experience with allopurinol-thiopurine combination therapy in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2008 Dec;14(12):1678-82. doi: 10.1002/ibd.20522.

Results Reference

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PubMed Identifier

16128682

Citation

Sparrow MP, Hande SA, Friedman S, Lim WC, Reddy SI, Cao D, Hanauer SB. Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine. Aliment Pharmacol Ther. 2005 Sep 1;22(5):441-6. doi: 10.1111/j.1365-2036.2005.02583.x.

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PubMed Identifier

17296529

Citation

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PubMed Identifier

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Citation

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Citation

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

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