Clinical trial NCT02141100: Study of 6-Thioguanine in Combination With 6-Mercaptopurine During Maintenance Therapy of Childhood Lymphoma
Official title: A Phase 1-2 Study of 6-Thioguanine in Combination With Methotrexate and 6-Mercaptopurine During Maintenance Therapy of Childhood Non-Hodgkin's Lymphoma
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: Non-Hodgkin Lymphoma
Keywords: thioguanine
mercaptopurine
methotrexate
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Aalborg University Hospital
name: Aarhus University Hospital Skejby
name: Odense University Hospital
First posted: 2014-05-19
Enrollment: 0
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this phase 1-2 study is to explore the applicability of supplementing standard methotrexate/6-mercaptopurine (MTX/6MP) maintenance therapy of children with non-Hodgkin lymphoma with 6-thioguanine (6TG).

The investigators hypothesize that addition of 6TG to 6MP-based maintenance therapy of patients with high TPMT activity will mimic the more favourable thiopurine metabolism of patients with low TPMT activity and ultimately reduce relapse rates.

Detailed description: MTX/6MP maintenance therapy is challenged by treatment related liver toxicity, failure to achieve the target treatment parameter in all patients, and lack of direct parameters for monitoring treatment efficacy or even intensity. Patients with low activity of thiopurine methyltransferase (TPMT), an enzyme involved in the metabolism of 6MP, have lower levels of liver toxic metabolites (MeMPs), higher levels of the major active metabolites (TGNs), and reduced relapse rates. Most patients (90%) have high TPMT activity. Nearly all patients with high TPMT activity and high MeMP levels experience elevated liver enzymes. Increasing the 6MP dose in patients with high TPMT activity, to intensify therapy, will mainly lead to further increase in the MeMP level. A novel approach compensating the adverse thiopurine metabolism of the majority of patients is warranted.

Eligibility criteria: Inclusion Criteria:

* Confirmed histomorphological or cytomorphological diagnosis of NHL or ALL.
* Meets just one of the following:

  1. Patient with NHL treated after the EURO-LB 02 protocol with at least 3.5 months of 6MP/MTX maintenance therapy remaining or
  2. Patient with ALL or NHL not achieving the target WBC (patients with a WBC \> 3.0 x10\^9/L) and/or experience elevated liver enzymes (ALAT \> UNL) attributed to a simultaneous high Ery-MeMP level on standard MTX/6MP maintenance therapy.
* TPMT wild-type genotype or TPMT high activity phenotype (TPMT activity above 14 IU/mL or during maintenance therapy TPMT above 8 IU/mL measured in erythrocytes).
* Bilirubin \< 35 micromol/L, factor 2-7-10 \> 0.5 or INR \< 1.5 and normal hepatic blood flow (verified by ultrasound) within 1 week prior to inclusion.
* WBC \> 1.5 x10\^9/L, ANC \> 0.5 x10\^9/L and TBC \> 50 x10\^9/L within 1 week prior to inclusion.
* Pubertal females, Tanner stage B3/PH3 or higher, must present with a negative pregnancy test.
* Sexually active females must use accepted safe contraception (OCPs, IUD, transdermal hormonal patch, vaginal hormonal ring or subdermal hormonal implants) during therapy and until a month after completion of therapy.
* Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
* Oral and written informed consent to participate have been provided by both the parents (and when appropriate by the patient) according to the ICH/GCP guidelines and the Helsinki II Declaration.
* Patients with acute lymphoblastic lymphoma (0-17.9 yrs) not achieving the target WBC (patients with a WBC \> 3.0 x10\^9/L) and/or experience elevated liver enzymes (ALAT \> UNL) attributed to a simultaneous high Ery-MeMP level on standard MTX/6MP maintenance therapy.

Exclusion Criteria:

* Any clinical suspicion of relapse or disease progression on routine imaging or in laboratory results.
* Previous veno-occlusive disease (VOD).
* Allergy towards any of the ingredients in the three medicinal products used in the study.

Primary outcomes:
measure: Change in median thiopurine metabolite index
timeFrame: Every 2 weeks up to the max. trial period of 12 months
Secondary outcomes:
measure: Toxicities
timeFrame: Minimum every 2 weeks, up to 12 months
measure: Change in median DNA-TG
timeFrame: Every 2 weeks, up to 12 months
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Dept. of Pediatric Oncology, JMC, Rigshospitalet
Study officials:
affiliation: Rigshospitalet, Denmark
name: Kjeld Schmiegelow, M.D.
role: STUDY_CHAIR
References: