Study of 6-Thioguanine in Combination With 6-Mercaptopurine During Maintenance Therapy of Childhood Lymphoma

Non-Hodgkin Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT02141100
• Other study ID #: JMC-2014-6TG/6MP
• Status: Withdrawn
• Phase: Phase 1/Phase 2
• First received: May 7, 2014
• Last updated: October 6, 2016
• Start date: July 2014
• Est. completion date: October 2016

Study information

• Verified date: October 2016
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Health authority: Denmark: Danish Dataprotection AgencyDenmark: Danish Health and Medicines AuthorityDenmark: The Regional Committee on Biomedical Research Ethics
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: October 2016
• Est. primary completion date: October 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 2 Years to 18 Years

Eligibility

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.

Study Design

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Non-Hodgkin
• Non-Hodgkin Lymphoma

Intervention

Drug:
• 6-thioguanine
All eligible patients will be supplemented with 6-thioguanine in addition to the standard therapy with 6-mercaptopurine and methotrexate. In case of significant myelo-/hepatotoxicity all therapy will be paused. If patients develop VOD they will be excluded from further 6TG therapy.

Locations

Country	Name	City	State
Denmark	Dept. of Pediatric Oncology, JMC, Rigshospitalet	Copenhagen

Sponsors (4)

Lead Sponsor	Collaborator
Kjeld Schmiegelow	Aalborg Universitetshospital, Aarhus University Hospital Skejby, Odense University Hospital

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in median thiopurine metabolite index	Change in Ery-TGN/Ery-MeMP after addition of 6-thioguanine to therapy. The thiopurine metabolites will be measured every 2 weeks during the trial period. The trial period is max. 12 months.	Every 2 weeks up to the max. trial period of 12 months	Yes
Secondary	Toxicities	Myelo- and hepatotoxicity. Blood samples (WBC, neutrophil count, thrombocyte count, ALAT, bilirubin, factors 2-7-10) will be taken every 2 weeks throughout the trial period and at additional time points in case of clinical signs/symptoms of toxicity.	Minimum every 2 weeks, up to 12 months	Yes
Secondary	Change in median DNA-TG	Change in DNA-TG (incorporation of thioguanine nucleotides in to DNA) after addition of 6-thioguanine. This parameter will be measured every 2 weeks during the trial period. The max. trial period is 12 months.	Every 2 weeks, up to 12 months	No