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

Acute Lymphoblastic Leukemia (ALL) Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02046694
• Other study ID #: J1357
• Secondary ID: J1357NA_00084984
• Status: Completed
• Phase: Early Phase 1
• Start date: January 6, 2014
• Est. completion date: April 6, 2020

Study information

• Verified date: June 2022
• Source: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. completion date: April 6, 2020
• Est. primary completion date: April 6, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 30 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia (ALL)
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

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).

Locations

Country	Name	City	State
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	Texas Children's Cancer and Hematology Centers	Houston	Texas
United States	Seattle Children's Hospital	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Country where clinical trial is conducted

United States, 

References & Publications (12)

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. — View Citation

Balis FM, Holcenberg JS, Poplack DG, Ge J, Sather HN, Murphy RF, Ames MM, Waskerwitz MJ, Tubergen DG, Zimm S, Gilchrist GS, Bleyer WA. Pharmacokinetics and pharmacodynamics of oral methotrexate and mercaptopurine in children with lower risk acute lymphoblastic leukemia: a joint children's cancer group and pediatric oncology branch study. Blood. 1998 Nov 15;92(10):3569-77. — View Citation

Brackett J, Schafer ES, Leung DH, Bernhardt MB. Use of allopurinol in children with acute lymphoblastic leukemia to reduce skewed thiopurine metabolism. Pediatr Blood Cancer. 2014 Jun;61(6):1114-7. doi: 10.1002/pbc.24913. Epub 2013 Dec 27. — View Citation

Elion GB. The purine path to chemotherapy. Science. 1989 Apr 7;244(4900):41-7. Review. — View Citation

Jharap B, Seinen ML, de Boer NK, van Ginkel JR, Linskens RK, Kneppelhout JC, Mulder CJ, van Bodegraven AA. Thiopurine therapy in inflammatory bowel disease patients: analyses of two 8-year intercept cohorts. Inflamm Bowel Dis. 2010 Sep;16(9):1541-9. doi: 10.1002/ibd.21221. — View Citation

Koren G, Ferrazini G, Sulh H, Langevin AM, Kapelushnik J, Klein J, Giesbrecht E, Soldin S, Greenberg M. Systemic exposure to mercaptopurine as a prognostic factor in acute lymphocytic leukemia in children. N Engl J Med. 1990 Jul 5;323(1):17-21. — View Citation

Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006 Jan 12;354(2):166-78. Review. — View Citation

Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood. 2012 Aug 9;120(6):1165-74. doi: 10.1182/blood-2012-05-378943. Epub 2012 Jun 22. Review. — View 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. — View Citation

Sparrow MP, Hande SA, Friedman S, Cao D, Hanauer SB. Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. Clin Gastroenterol Hepatol. 2007 Feb;5(2):209-14. — View 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. — View Citation

Zimm S, Collins JM, O'Neill D, Chabner BA, Poplack DG. Inhibition of first-pass metabolism in cancer chemotherapy: interaction of 6-mercaptopurine and allopurinol. Clin Pharmacol Ther. 1983 Dec;34(6):810-7. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Absolute neutrophil count	Absolute neutrophil count (ANC) measured 8 weeks after the addition of allopurinol (study week 9).	8 weeks
Secondary	Feasibility of the addition of allopurinol to ALL maintenance therapy	Allopurinol compliance rate during ALL maintenance therapy.	8 weeks
Secondary	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.	8 weeks
Secondary	Effects of allopurinol on liver function tests	Measurement of ALT, AST, and direct bilirubin before and after adding allopurinol.	8 weeks
Secondary	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.	8 weeks