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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Genetic: Pharmacogenomics
* Other: Busulfan plasma level measurements


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Total body irradiation (TBI)<br>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<br>* 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.<br>* Other names: DNA analyses;|
| Experimental: Busulfan<br>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<br>* 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.<br>* Other names: DNA analyses;Other: Busulfan plasma level measurements<br>* 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<br>|
| Experimental: Treosulfan<br>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<br>* 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.<br>* Other names: DNA analyses;|

What is the study measuring?
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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 | 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 |  | 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 |  | 18 months after inclusion of first patient, afterwards, annually up to 10 years | 
| Number of participants with VOD/SOS according to the Seattle criteria |  | 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 | 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 | 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 | 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) | 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) | 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) | 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 |  | 18 months after inclusion of first patient, afterwards, annually up to 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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