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Acute Lymphoblastic Leukemia (ALL)Early Phase 1NCT02046694

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

A Early Phase 1 study testing Allopurinol in people with Acute Lymphoblastic Leukemia (ALL), run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 3 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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). Read more about this study

Who is it for?
Ages Up to 30 years
Conditions the study is for
Acute Lymphoblastic Leukemia (ALL)
What is being tested?
Allopurinol
Could I receive a placebo?
No, everyone receives an active treatment
How many people
34 participants
Where
3 sitesUnited States
Study dates
6 Jan 2014to 6 Apr 2020
Phase
Early Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 30 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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
Show all 9Show fewer
  • 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)

Who cannot join

  • 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

Trial locations and contacts

3 sites in 1 country.

United States3 sites

  • Johns Hopkins Hospital

    Baltimore, Maryland, 21287

  • Texas Children's Cancer and Hematology Centers

    Houston, Texas, 77030

  • Seattle Children's Hospital

    Seattle, Washington, 98105

Other trials in United States

About this study

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.

Read the 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.
Being tested
Allopurinol
Keywords
acute lymphoblastic leukemia, ALL, pediatric, maintenance, allopurinol, 6-MP, 6-mercaptopurine
Medical subject headings
Precursor Cell Lymphoblastic Leukemia-Lymphoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AllopurinolDrug

    Also called Zyloprim

    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).

Study groups in NCT02046694
Study groupRoleWhat they receive
AllopurinolExperimentalPatients 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.
Receives: Drug: Allopurinol

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Absolute neutrophil count

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

    Measured: 8 weeks

Secondary outcomes (4)

  1. Feasibility of the addition of allopurinol to ALL maintenance therapy

    Allopurinol compliance rate during ALL maintenance therapy.

    Measured: 8 weeks

  2. 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.

    Measured: 8 weeks

  3. Effects of allopurinol on liver function tests

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

    Measured: 8 weeks

  4. 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.

    Measured: 8 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Jan 2014 (estimated)
  2. Study start6 Jan 2014
  3. Primary completion6 Apr 2020
  4. Study completion6 Apr 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Early Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
Pilot Study
Masking
None (open label)
Enrolment
34 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02046694
Sponsor's protocol ID
J1357
Other IDs
J1357, NA_00084984
Status last verified
Jun 2022
First submitted
23 Jan 2014
Last updated
21 Jun 2022
Results posted
No
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 16407512

  • 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.

    PubMed 19145729

  • 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.

    PubMed 18521913

  • 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.

    PubMed 16128682

  • 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. doi: 10.1016/j.cgh.2006.11.020.

    PubMed 17296529

  • 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. doi: 10.1056/NEJM199007053230104.

    PubMed 2355954

  • 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.

    PubMed 9808549

  • 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.

    PubMed 22730540

  • 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. doi: 10.1038/clpt.1983.254.

    PubMed 6580097

  • Elion GB. The purine path to chemotherapy. Science. 1989 Apr 7;244(4900):41-7. doi: 10.1126/science.2649979.

    PubMed 2649979

  • 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.

    PubMed 24376133

  • 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.

    PubMed 20155846

Questions about this trial

What is this clinical trial studying?

A Early Phase 1 study testing Allopurinol in people with Acute Lymphoblastic Leukemia (ALL), run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 21 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Absolute neutrophil count (time frame: 8 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02046694, which also lists 12 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Jun 2022.

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