Clinical trial NCT03022747: Optimizing 6-mercaptopurine Therapy in Pediatric Acute Lymphoblastic Leukemia by Using Allopurinol
Official title: 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.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Lymphoblastic Leukemia, Acute, Childhood
Lead sponsor: Vastra Gotaland Region
Sponsor class: OTHER_GOV
First posted: 2017-01-16
Enrollment: 60
Sex: ALL
Minimum age (years): 6
Maximum age (years): 19
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 6-thioguanine (6TG) levels in erythrocytes
timeFrame: Up to week 25
Secondary outcomes:
measure: Mean level of 6-thioguanine
timeFrame: Up to week 25
measure: Mean level of DNA-incorporated thioguanine (DNA-TGN)
timeFrame: Up to week 25
measure: Mean level of 6-methylmercaptopurine (6MMP)
timeFrame: Up to week 25
measure: Mean levels of platelets
timeFrame: Up to week 25
measure: Mean levels of hemoglobin
timeFrame: Up to week 25
measure: Mean levels of absolute neutrophil count (ANC)
timeFrame: Up to week 25
measure: Mean levels of white blood cells (WBC)
timeFrame: Up to week 25
measure: Glutamate pyruvate transaminase (GPT)
timeFrame: Up to week 25
measure: Bilirubin
timeFrame: Up to week 25
measure: Hypoglycemia
timeFrame: Up to week 25
measure: Metabolic disturbance
timeFrame: Up to week 25
measure: Incidence of serious adverse events (SAE)
timeFrame: Up to week 29
measure: Cumulative dose of 6-mercaptopurine and methotrexate
timeFrame: Up to week 29
Other outcomes:
Locations:
city: Oulu
country: Finland
facility: Dept of Pediatrics and Adolescents, Oulu University Hospital, Box 23, 90029 OYS, Finland
city: Gothenburg
country: Sweden
facility: Childrens' Cancer Centre, Queen Silvias Childrens and Adolescents Hospital
city: Linköping
country: Sweden
facility: Linköping University Hospital, Dept of Pediatrics
Study officials:
affiliation: Childrens Cancer Center, Queen Silvia Children Hospital, Sahlgrenska Academy, Gothenburg, Sweden
name: Jonas Abrahamsson, PhD, MD
role: STUDY_CHAIR
affiliation: Dept of Pediatrics and Adolescents, Oulu University Hospital, Box 23, 90029 OYS, Finland
name: Riita Niinimäki, PhD, MD
role: PRINCIPAL_INVESTIGATOR
References: