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

Lymphoblastic Leukemia, Acute, Childhood Clinical Trial

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03022747
• Other study ID #: Allopurinol Study V3.0
• Status: Recruiting
• Phase: Phase 2
• First received: January 9, 2017
• Last updated: January 11, 2017
• Start date: January 2017
• Est. completion date: April 2019

Study information

• Verified date: January 2017
• Source: Vastra Gotaland Region
• Contact: Jonas Abrahamsson, PhD, MD
• Phone: +46 707 695159
• Email: vobjab[@]gmail.com
• Is FDA regulated: No
• Health authority: Sweden: The medical product agency in Sweden, läkemedelsverket.Finland: Finnish Medicines Agency
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: April 2019
• Est. primary completion date: December 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 19 Years

Eligibility

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 Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphoid
• Lymphoblastic Leukemia, Acute, Childhood
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Allopurinol
Allopurinol is added to standard oral 6-mercaptopurine and methotrexate
• Standard treatment
Oral 6-mercaptopurine and methotrexate

Locations

Country	Name	City	State
Finland	Dept of Pediatrics and Adolescents, Oulu University Hospital, Box 23, 90029 OYS, Finland	Oulu
Sweden	Childrens' Cancer Centre, Queen Silvias Childrens and Adolescents Hospital	Gothenburg
Sweden	Linköping University Hospital, Dept of Pediatrics	Linköping

Sponsors (1)

Lead Sponsor	Collaborator
Vastra Gotaland Region

Countries where clinical trial is conducted

Finland,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Mean level of 6-thioguanine	The mean level of 6TG at week 13 and 25	Up to week 25	No
Secondary	Mean level of DNA-incorporated thioguanine (DNA-TGN)	The mean level of DNA-TGN at week 13 and 25	Up to week 25	No
Secondary	Mean level of 6-methylmercaptopurine (6MMP)	The mean level of 6MMP at week 13 and 25	Up to week 25	No
Secondary	Mean levels of platelets	Comparison of weighted mean of platelets in the treatment phases	Up to week 25	Yes
Secondary	Mean levels of hemoglobin	Comparison of weighted mean of hemoglobin in the treatment phases	Up to week 25	Yes
Secondary	Mean levels of absolute neutrophil count (ANC)	Comparison of weighted mean of ANC in the treatment phases	Up to week 25	Yes
Secondary	Mean levels of white blood cells (WBC)	Comparison of weighted mean of WBC in the treatment phases	Up to week 25	Yes
Secondary	Glutamate pyruvate transaminase (GPT)	Comparison of weighted means of serum GPT in the treatment phases	Up to week 25	Yes
Secondary	Bilirubin	Comparison of weighted means of serum bilirubin in the treatment phases	Up to week 25	Yes
Secondary	Hypoglycemia	Comparison of incidence of hypoglycemia and laboratory measures of metabolic disturbance during the treatment phases	Up to week 25	Yes
Secondary	Metabolic disturbance	Comparison of incidence of laboratory measures of metabolic disturbance during the treatment phases	Up to week 25	Yes
Secondary	Incidence of serious adverse events (SAE)	Comparison of the frequency of SAE in the treatment phases	Up to week 29	Yes
Secondary	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	Yes