ALL SCTped FORUM - Pharmacogenomic Study (add-on Study)

April 15, 2019 updated by: Swiss Pediatric Oncology Group

Allogeneic Stem Cell Transplant for Children and Adolescents With Acute Lymoblastic Leukemia FORUM - Pharmacogenomic Study (add-on Study)

Pharmacogenomics (PG) offers the opportunity to individualize treatment according to patient genetic variations which influence activity of enzyme metabolizing or acting in the pathway of prescribed chemotherapy drugs.

This add-on research aims to prospectively investigate variations in several candidate genes related to all types of chemotherapeutic drugs and TBI used in the main related study NCT 01949129, THE ALL SCTped FORUM study for their potential role as predictive biomarkers of PK variability and outcome of myeloablative therapy for pediatric patients receiving an allogeneic hematopoietic stem cell transplantation in acute lymphoblastic leukemia.

Study Overview

Detailed Description

Note this is an add-on study to NCT 01949129, THE ALL SCTped FORUM study. Please refer to the main study for further details.

Busulfan (Bu) is a key compound in conditioning myeloablative regimens for patients undergoing hematopoietic stem cell transplantation (HSCT). Bu has been long used for the treatment of patients with leukemia and some congenital disorders; advantages and disadvantages of such treatment are well described. However, although Bu treatment has been shown to be effective, its use may be limited by related adverse events such as veno-occlusive disease (VOD), interstitial pneumonitis, acute Graft vs Host Disease (GVHD), and seizures. Thus, novel therapies are being investigated as well as the pharmacogenetics of these drugs. One of alternative drugs that may replace Bu due to its lower toxicity profile is Treosulfan (Treo). Fludarabine (Flu) is usually used in combination with Bu or Treo as an alternative to cyclophosphamide (Cy) also due to its lower toxicity. Thus, the Bu/Flu regimen is now being used more often than the previously more common Bu/Cy regimen. However, improvement to the regimen is still needed for reducing adverse drug effects. Pharmacogenomics (PG) offers the opportunity to individualize treatment according to patient genetic variations which influence activity of enzyme metabolizing or acting in the pathway of prescribed chemotherapy drugs.

This add-on research aims to prospectively investigate variations in several candidate genes (e.g GST, DCK and DNA repair pathway genes) related to all types of chemotherapeutic drugs (Bu/Flu/Thio; Treo/Flu/Thio and TBI/VP16) used in this protocol for their potential role as predictive biomarkers of pharmacokinetics (PK) variability and outcome of myeloablative therapy for pediatric patients receiving an allogeneic HSCT in acute lymphoblastic leukemia

For the busulfan arm countries: a cross-validation of busulfan quantification is performed. All Bu Therapeutic Drug Monitoring participating at the main ALL SCTped FORUM study will be assessed for the accuracy (%) and trueness (%) of 8 blinded Bu Quality Control samples. Criteria of acceptance are set according to FDA and ICH guidelines.

Blood samples will be collected prior to initiation of therapy for DNA banking and DNA analysis (for all patients), for DNA analysis (TBI/VP16, Bu/Flu/Thiotepa and Treo/Flu/Thiotepa groups) and PK analysis (only for the Bu group). PK and pharmacogenomic data will then be correlated with the studied outcomes (e.g.Veno-occlusive disease, Graft vs host disease, Treatment Related Mortality, Events Free Survival, Overall Survival).

Recruitment:

Patients (children) age 0-18 will be recruited in each arm. No oral Bu is allowed in this study.

Shipment (when there is a minimum of 10 patients) Send all the materials listed to: Dr Marc Ansari, Plateforme d'Hématologie et Oncologie Pédiatrique (CANSEARCH research laboratory), Faculté de Médecine, Bâtiment Tulipe, 5th floor, Av De La Roseraie 64, GENEVE 1205 Switzerland.

Contact Dr. Ansari's laboratory prior to shipment: Phone (+41 79 55 36 100) and e-mail (research@cansearch.ch). All shipments must be sent frozen by a carrier guaranteeing overnight delivery with the indication "Pharmacogenomic study" on the face of the parcel.

Study Type

Interventional

Enrollment (Anticipated)

1000

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Marc Ansari, MD, PD
  • Phone Number: +41 79 502 338 +41 22 382 47 31
  • Email: Marc.Ansari@hcuge.ch

Study Contact Backup

Study Locations

      • Basel, Switzerland, 4056
        • Recruiting
        • Universitäts-Kinderspital beider Basel (UKBB), Onkologie/Hämatologie
        • Contact:
      • Geneva, Switzerland, 1211
        • Recruiting
        • HUG Hôpitaux Universitaire de Genève, Unité d'onco-hématologie pédiatrique
        • Contact:
      • Zurich, Switzerland, 8032
    • Cansearch Laboratory
      • Geneva, Cansearch Laboratory, Switzerland, 1211
        • Recruiting
        • Hôpital Cantonal de Genève, Département de Pédiatrie
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 18 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Note this is an add-on study to NCT 01949129, THE ALL SCTped FORUM study. Please refer to the main study for further details.

Gender

  • Both: both female and male participants are being studied

Age Limits

  • Minimum Age: N/A
  • Maximum Age: age at time of screening less than 18 years old

Accepts Healthy Volunteers: no

Eligibility Criteria

Inclusion Criteria:

  • Patients with ALL (except for patients with B-ALL)
  • indication for allogeneic HSCT
  • complete remission (CR) before HSCT
  • written consent of the parents (legal guardian) and, if necessary, the minor patient via "Informed Consent Form"
  • no pregnancy
  • no secondary malignancy
  • no previous HSCT
  • HSCT is performed in a study participating centre

Exclusion Criteria:

  • Non Hodgkin-Lymphoma
  • ALL with extramedullary involvement with indication for TBI
  • CNS involvement at the timepoint of screening
  • Trisomy 21
  • The whole protocol or essential parts are declined either by patient himself/herself or the respective legal guardian
  • No consent is given for saving and propagation of anonymous medical data for study reasons
  • Severe concomitant disease that does not allow treatment according to the protocol at the investigator's discretion (e.g. malformation syndromes, cardiac malformations, metabolic disorders)
  • Karnofsky / Lansky score < 50%
  • Subjects unwilling or unable to comply with the study procedures

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Total body irradiation (TBI)

The Pharmacogenomics add-on requires 2X 5ml blood EDTA for further DNA analyses.

Note this is an add-on study to NCT 01949129, THE ALL SCTped FORUM study. Please refer to the main study for further details.

Blood samples (2x5ml EDTA tubes) should be collected just before the start of the conditioning regimen from every patient regardless of therapeutic arm by every centre and stored ≤-20°C Patient should be in remission (MRD negative) for this sampling, otherwise the sample should be taken using a mouth swab/saliva (not intravenously).

For second transplant patients, please provide DNA taken before first transplant or a fresh saliva samples.

Other Names:
  • DNA analyses
Experimental: Busulfan

The Pharmacogenomics add-on requires 2X 5ml blood EDTA for further DNA analyses.

Note this is an add-on study to NCT 01949129, THE ALL SCTped FORUM study. Please refer to the main study for further details.

Blood samples (2x5ml EDTA tubes) should be collected just before the start of the conditioning regimen from every patient regardless of therapeutic arm by every centre and stored ≤-20°C Patient should be in remission (MRD negative) for this sampling, otherwise the sample should be taken using a mouth swab/saliva (not intravenously).

For second transplant patients, please provide DNA taken before first transplant or a fresh saliva samples.

Other Names:
  • DNA analyses

Bu PK analysis after the first dose of IV Bu (+potential subsequent ones).

Blood sampling:

->For Bu 4 X/d: Before the first Bu dose (Time 0), then straight after the end of infusion (Time 1), then at 15 min (Time 2), 30 min (Time 3), 1 hour (Time 4) and 4 hour (Time 5) after the end of infusion

->For Bu 1 X/d: Before the first Bu dose (Time 0), then straight after the end of infusion (Time 1), then at 1 hour (Time 2), 3 hour (Time 3), 5 hour (Time 4), 7 hour (Time 5) and 11 hour (Time 6) after the end of infusion.

For centers not performing BU TDM, perform Dried Blood Sampling (DBS) analysis:

-> 0.5ml blood sample should be collected and 5µl spotted onto DBS cards in duplicate. Dry them max 5 hours and then keep in a sealed envelope and store at -80°C, as below

Experimental: Treosulfan

The Pharmacogenomics add-on requires 2X 5ml blood EDTA for further DNA analyses.

Note this is an add-on study to NCT 01949129, THE ALL SCTped FORUM study. Please refer to the main study for further details.

Blood samples (2x5ml EDTA tubes) should be collected just before the start of the conditioning regimen from every patient regardless of therapeutic arm by every centre and stored ≤-20°C Patient should be in remission (MRD negative) for this sampling, otherwise the sample should be taken using a mouth swab/saliva (not intravenously).

For second transplant patients, please provide DNA taken before first transplant or a fresh saliva samples.

Other Names:
  • DNA analyses

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Genetic variants in participants as a marker of risk of Adverse events and/or Efficacy of the studied agents
Time Frame: through study completion, an average of 2 years

Genotyping of candidates genes related to pharmacokinetics and pharmacodynamics of the studied agents.

Association study between the herein genetic variants and the below mentioned phenotypes (odd ratio).

through study completion, an average of 2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of participants with acute Graft-versus-host disease (aGvHD) according to the Glucksberg scale and Seattle criteria
Time Frame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
18 months after inclusion of first patient, afterwards, annually up to 10 years
Number of participants with chronic Graft-versus-host disease (cGvHD) according to the Glucksberg scale and Seattle criteria
Time Frame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
18 months after inclusion of first patient, afterwards, annually up to 10 years
Number of participants with VOD/SOS according to the Seattle criteria
Time Frame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
18 months after inclusion of first patient, afterwards, annually up to 10 years
Number of participants with Neutrophil recovery as a measure of Safety and Tolerability
Time Frame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
defined as the first of 3 consecutive days with an absolute neutrophil count of 0.5x10^9/L or higher
18 months after inclusion of first patient, afterwards, annually up to 10 years
Number of participants with Platelet recovery as a measure of Safety and Tolerability
Time Frame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
Defined as the first of 3 consecutive days with platelet counts higher that 20x10^9/L without transfusion
18 months after inclusion of first patient, afterwards, annually up to 10 years
Number of participants with Primary graft failure or rejection as a measure of Safety and Tolerability
Time Frame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
Defined by persistent pancytopenia with no evidence of hematologic recovery of donor cells beyond 28 days after transplantation, and secondary graft failure by a rapid decrease in neutrophil count after successful engraftment
18 months after inclusion of first patient, afterwards, annually up to 10 years
Transplant related mortality (TRM)
Time Frame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
the time of transplant until all causes of death after transplant not related to relapse
18 months after inclusion of first patient, afterwards, annually up to 10 years
Event free survival (EFS)
Time Frame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
the time of transplant until death, relapse or graft failure, whichever occurs first.
18 months after inclusion of first patient, afterwards, annually up to 10 years
Overall survival (OS)
Time Frame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
the time between transplantation and death due to any causes
18 months after inclusion of first patient, afterwards, annually up to 10 years
Cumulative incidence of relapse
Time Frame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
18 months after inclusion of first patient, afterwards, annually up to 10 years

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Administered Bu dose(mg) per day
Time Frame: Measures assessed at time of conditioning (up to 5days)
Bu pharmacokinetics profile
Measures assessed at time of conditioning (up to 5days)
Target Bu plasma concentration(ng/ml)
Time Frame: Measures assessed at time of conditioning (up to 5days)
Bu pharmacokinetics profile
Measures assessed at time of conditioning (up to 5days)
Target Bu Area under the plasma concentration versus time curve (AUC) (min*ng/ml)
Time Frame: Measures assessed at time of conditioning (up to 5days)
Bu pharmacokinetics profile
Measures assessed at time of conditioning (up to 5days)
Measured Area under the plasma concentration versus time curve (AUC) of Bu (min*ng/ml)
Time Frame: Measures assessed at time of conditioning (up to 5days)
Bu pharmacokinetics profile
Measures assessed at time of conditioning (up to 5days)
Measured maximum plasma Bu concentration (Cmax, ng/ml)
Time Frame: Measures assessed at time of conditioning (up to 5days)
Bu pharmacokinetics profile
Measures assessed at time of conditioning (up to 5days)
Measured minimum plasma Bu concentration (Cmin, ng/ml)
Time Frame: Measures assessed at time of conditioning (up to 5days)
Bu pharmacokinetics profile
Measures assessed at time of conditioning (up to 5days)
Measured steady state plasma Bu concentration (Css, ng/ml)
Time Frame: Measures assessed at time of conditioning (up to 5days)
Bu pharmacokinetics profile
Measures assessed at time of conditioning (up to 5days)
Measured Clearance of Bu (ml/min/kg)
Time Frame: Measures assessed at time of conditioning (up to 5days)
Bu pharmacokinetics profile
Measures assessed at time of conditioning (up to 5days)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Collaborators

Investigators

  • Study Chair: Christina Peters, Prof. MD PhD, St. Anna Kinderspital, Vienna, Austria
  • Study Chair: Peter Bader, Prof. MD PhD, Klinik für Kinder- u. Jugendheilkunde III, Johann Wolfgang Goethe Universität, Frankfurt, Germany
  • Study Chair: Franco Locatelli, Prof. MD PhD, Department of Pediatric Hematology and Oncology IRCCS Ospedale, Rome, Italy
  • Principal Investigator: Marc Ansari, MD, PD, Département de Pédiatrie, Hôpital Cantonal de Genève

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2013

Primary Completion (Anticipated)

April 1, 2021

Study Completion (Anticipated)

April 1, 2026

Study Registration Dates

First Submitted

July 3, 2015

First Submitted That Met QC Criteria

January 27, 2016

First Posted (Estimate)

February 2, 2016

Study Record Updates

Last Update Posted (Actual)

April 16, 2019

Last Update Submitted That Met QC Criteria

April 15, 2019

Last Verified

April 1, 2019

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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