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

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ClinicalTrials.gov Identifier: NCT02670564
Recruitment Status : Recruiting
First Posted : February 2, 2016
Last Update Posted : February 28, 2017
Sponsor:
Collaborator:
ALL SCTped Forum
Information provided by (Responsible Party):
Swiss Pediatric Oncology Group

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia Genetic: Pharmacogenomics Other: Busulfan plasma level measurements Phase 4

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  (Clinical Trial)
Estimated Enrollment : 1000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Allogeneic Stem Cell Transplant for Children and Adolescents With Acute Lymoblastic Leukemia FORUM - Pharmacogenomic Study (add-on Study)
Study Start Date : April 2013
Estimated Primary Completion Date : April 2018
Estimated Study Completion Date : April 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Leukemia
Drug Information available for: Busulfan

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.

Genetic: Pharmacogenomics

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 Name: 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.

Genetic: Pharmacogenomics

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 Name: DNA analyses

Other: Busulfan plasma level measurements

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.

Genetic: Pharmacogenomics

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 Name: DNA analyses




Primary Outcome Measures :
  1. 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).



Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. 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 ]
  4. 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

  5. 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

  6. 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

  7. 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

  8. 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.

  9. 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

  10. Cumulative incidence of relapse [ Time Frame: 18 months after inclusion of first patient, afterwards, annually up to 10 years ]

Other Outcome Measures:
  1. Administered Bu dose(mg) per day [ Time Frame: Measures assessed at time of conditioning (up to 5days) ]
    Bu pharmacokinetics profile

  2. Target Bu plasma concentration(ng/ml) [ Time Frame: Measures assessed at time of conditioning (up to 5days) ]
    Bu pharmacokinetics profile

  3. 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

  4. 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

  5. Measured maximum plasma Bu concentration (Cmax, ng/ml) [ Time Frame: Measures assessed at time of conditioning (up to 5days) ]
    Bu pharmacokinetics profile

  6. Measured minimum plasma Bu concentration (Cmin, ng/ml) [ Time Frame: Measures assessed at time of conditioning (up to 5days) ]
    Bu pharmacokinetics profile

  7. Measured steady state plasma Bu concentration (Css, ng/ml) [ Time Frame: Measures assessed at time of conditioning (up to 5days) ]
    Bu pharmacokinetics profile

  8. Measured Clearance of Bu (ml/min/kg) [ Time Frame: Measures assessed at time of conditioning (up to 5days) ]
    Bu pharmacokinetics profile



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02670564


Contacts
Contact: Marc Ansari, MD, PD +41 22 382 47 31 ext +41 79 502 338 Marc.Ansari@hcuge.ch
Contact: Patricia Huezo-Diaz Curtis, PhD +41 22 372 99 65 research@cansearch.ch

Locations
Switzerland
Hôpital Cantonal de Genève, Département de Pédiatrie Recruiting
Geneva, Cansearch Laboratory, Switzerland, 1211
Contact: Marc Ansari, MD, PD    +41 22 382 47 31    Marc.Ansari@hcuge.ch   
Universitäts-Kinderspital beider Basel (UKBB), Onkologie/Hämatologie Recruiting
Basel, Switzerland, 4056
Contact: Nicolas Von der Weid    + 41 61 704 12 12    nicolas.vonderweid@ukbb.ch   
HUG Hôpitaux Universitaire de Genève, Unité d'onco-hématologie pédiatrique Recruiting
Geneva, Switzerland, 1211
Contact: Marc Ansari    +41 22 372 47 31    Marc.Ansari@hcuge.ch   
Universitäts-Kinderspital Recruiting
Zurich, Switzerland, 8032
Contact: Güngör Tayfun    +41 44 266 74 92    tayfun.guengoer@kispi.uzh.ch   
Sponsors and Collaborators
Swiss Pediatric Oncology Group
ALL SCTped Forum
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

Additional Information:
Responsible Party: Swiss Pediatric Oncology Group
ClinicalTrials.gov Identifier: NCT02670564     History of Changes
Other Study ID Numbers: ZH 2014-0535
NZ 2015-069 ( Registry Identifier: Commission compétente )
GE 15-034 ( Registry Identifier: Commission compétente )
First Posted: February 2, 2016    Key Record Dates
Last Update Posted: February 28, 2017
Last Verified: February 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Swiss Pediatric Oncology Group:
pharmacogenetics
busulfan
treosulfan
hematopoietic stem cell transplantation
fludarabine
pediatric patients
TBI
leukemia
leukemia, lymphoid
precursor cell lymphoblastic Leukemia-Lymphoma
Immune System disease
Immunoproliferative Disorders
stem cell transplantation
children and adolescent
high risk acute lymphoblastic leukemia
NCT01949129 add-on
ALL SCTped FORUM

Additional relevant MeSH terms:
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Busulfan
Treosulfan
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Antineoplastic Agents
Myeloablative Agonists