Optimizing 6-mercaptopurine Therapy in Pediatric Acute Lymphoblastic Leukemia by Using Allopurinol

Optimizing 6-mercaptopurine Therapy in Pediatric Acute Lymphoblastic Leukemia by Using Allopurinol Clinical Study in Children 1-19 Years on Maintenance Therapy for Acute Lymphoblastic Leukemia.

The study will investigate, in children with acute lymphoblastic leukemia during maintenance treatment, if addition of allopurinol to conventional oral 6-mercaptopurine and methotrexate therapy, affects erythrocyte concentrations of 6-thioguanine and 6 methylmercaptopurine. The effect on hematological and liver toxicity parameters in blood will also be investigated as well as clinical toxicity.

Study Overview

• Status: Unknown
• Conditions: Lymphoblastic Leukemia, Acute, Childhood
• Intervention / Treatment: Drug: Standard treatment; Drug: Allopurinol

Detailed Description

After one month of conventional maintenance therapy (MT) children and adolescents, treated for acute lymphoblastic leukemia on Nordic protocols and with wild type thiopurine methyltransferase (TPMT) are eligible for the study. They will first receive a 12 week phase with normal MT during which time repeated sampling of 6-mercaptopurine (6MP) metabolite levels and other laboratory parameters will be performed. After 12 weeks, allopurinol at a dose of 50 mg/sqm is added (simultaneously reducing the dose of 6MP by 50%) and during the next 12 weeks patients are monitored closely for toxicity and samples for determination of metabolite levels and hematological and liver toxicity are obtained regularly. If, after 4 weeks of allopurinol treatment, the levels of 6-thioguanine are below 200 nmol/mmol hemoglobin, the dose of allopurinol will be increased to 100 mg/sqm. Allopurinol treatment is continued for 12 weeks after which the patients switch to their original maintenance therapy.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• Finland
  • Oulu, Finland, 90029 OYS
    • Not yet recruiting
    • Dept of Pediatrics and Adolescents, Oulu University Hospital, Box 23, 90029 OYS, Finland
    • Contact: Riita Niinimäki, MD, PhD; Phone Number: +358 8 3155832; Email: riita.niinimaki@ppshp.fi
• Sweden
  • Gothenburg, Sweden, 416 85
    • Recruiting
    • Childrens' Cancer Centre, Queen Silvias Childrens and Adolescents Hospital
    • Contact: Lene Karlsson, MD; Phone Number: +46 313435610; Email: lene.karlsson@vgregion.se
  • Linköping, Sweden, 58185
    • Not yet recruiting
    • Linköping University Hospital, Dept of Pediatrics
    • Contact: Hartmut Vogt, MD, PhD; Phone Number: +46 101031343; Email: hartmut.vogt@regionostergotland.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 15 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Confirmed diagnosis of acute lymphoblastic leukemia
• Treatment according to Nordic Society for pediatric hematology/oncology (NOPHO) ALL2008 based protocols
• Age 0-18y at time of initial diagnosis
• TPMT wild type
• Written informed consent

Exclusion Criteria:

• Mature B cell lymphoblastic leukemia
• t(9;22) positive acute lymphoblastic leukemia
• Unknown TPMT status or presence of TPMT mutation (both heterozygous and homozygous)
• Known intolerance to any of the chemotherapeutic drugs in the protocol
• Major organ failure precluding administration of planned chemotherapy
• Severe liver toxicity defined as persistent (≥ two weeks) elevation of either S-bilirubin > 50 μmol/l or S-GPT > 20 x Upper normal limit (UNL) or P-Prothrombin complex > 1.5.
• Reduced kidney function defined as S-creatinine ≥ 1.5 x UNL.
• Lactating female or female of childbearing potential not using adequate contraception.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard maintenance therapy; Standard maintenance therapy with 6 mercaptopurine and methotrexate	Drug: Standard treatment; Oral 6-mercaptopurine and methotrexate
Experimental: Allopurinol treatment; The second 12 week phase during which allopurinol is added to oral 6-mercaptopurine and methotrexate therapy	Drug: Allopurinol; Allopurinol is added to standard oral 6-mercaptopurine and methotrexate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6-thioguanine (6TG) levels in erythrocytes	The fraction of patients with 6TG levels over 200 nmol/mmol Hb at week 13 and 25 (ie after 12 weeks standard and allopurinol treatment respectively)	Up to week 25

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean level of 6-thioguanine	The mean level of 6TG at week 13 and 25	Up to week 25
Mean level of DNA-incorporated thioguanine (DNA-TGN)	The mean level of DNA-TGN at week 13 and 25	Up to week 25
Mean level of 6-methylmercaptopurine (6MMP)	The mean level of 6MMP at week 13 and 25	Up to week 25
Mean levels of platelets	Comparison of weighted mean of platelets in the treatment phases	Up to week 25
Mean levels of hemoglobin	Comparison of weighted mean of hemoglobin in the treatment phases	Up to week 25
Mean levels of absolute neutrophil count (ANC)	Comparison of weighted mean of ANC in the treatment phases	Up to week 25
Mean levels of white blood cells (WBC)	Comparison of weighted mean of WBC in the treatment phases	Up to week 25
Glutamate pyruvate transaminase (GPT)	Comparison of weighted means of serum GPT in the treatment phases	Up to week 25
Bilirubin	Comparison of weighted means of serum bilirubin in the treatment phases	Up to week 25
Hypoglycemia	Comparison of incidence of hypoglycemia and laboratory measures of metabolic disturbance during the treatment phases	Up to week 25
Metabolic disturbance	Comparison of incidence of laboratory measures of metabolic disturbance during the treatment phases	Up to week 25
Incidence of serious adverse events (SAE)	Comparison of the frequency of SAE in the treatment phases	Up to week 29
Cumulative dose of 6-mercaptopurine and methotrexate	Comparison of the cumulative dose of 6MP and methotrexate and days with treatment interruption in the two treatment arms	Up to week 29

Collaborators and Investigators

• Sponsor: Vastra Gotaland Region
• Investigators: Study Chair: Jonas Abrahamsson, PhD, MD, Childrens Cancer Center, Queen Silvia Children Hospital, Sahlgrenska Academy, Gothenburg, Sweden; Principal Investigator: Riita Niinimäki, PhD, MD, Dept of Pediatrics and Adolescents, Oulu University Hospital, Box 23, 90029 OYS, Finland

Study record dates

Study Major Dates

• Study Start: January 1, 2017
• Primary Completion (Anticipated): December 1, 2018
• Study Completion (Anticipated): April 1, 2019

Study Registration Dates

• First Submitted: January 9, 2017
• First Submitted That Met QC Criteria: January 11, 2017
• First Posted (Estimate): January 16, 2017

Study Record Updates

• Last Update Posted (Estimate): January 16, 2017
• Last Update Submitted That Met QC Criteria: January 11, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites; Protective Agents; Antioxidants; Free Radical Scavengers; Gout Suppressants; Allopurinol
• Other Study ID Numbers: Allopurinol Study V3.0

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No