ALL SCTped FORUM - Pharmacogenomic Study (add-on Study)
キーワード
概要
説明
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.
日付
| 最終確認済み: | 03/31/2019 |
| 最初に提出された: | 07/02/2015 |
| 提出された推定登録数: | 01/26/2016 |
| 最初の投稿: | 02/01/2016 |
| 最終更新が送信されました: | 04/14/2019 |
| 最終更新日: | 04/15/2019 |
| 実際の研究開始日: | 03/31/2013 |
| 一次完了予定日: | 03/31/2021 |
| 研究完了予定日: | 03/31/2026 |
状態または病気
介入/治療
Genetic: Pharmacogenomics
Other: Busulfan
段階
アームグループ
| 腕 | 介入/治療 |
|---|---|
| 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. | |
| 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. | Other: Busulfan 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. |
適格基準
| 研究に適格な性別 | All |
| 健康なボランティアを受け入れる | はい |
| 基準 | 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 |
結果
主な結果の測定
1. Genetic variants in participants as a marker of risk of Adverse events and/or Efficacy of the studied agents [through study completion, an average of 2 years]
二次的な結果の測定
1. 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]
2. 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]
3. Number of participants with VOD/SOS according to the Seattle criteria [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 [18 months after inclusion of first patient, afterwards, annually up to 10 years]
5. Number of participants with Platelet recovery as a measure of Safety and Tolerability [18 months after inclusion of first patient, afterwards, annually up to 10 years]
6. Number of participants with Primary graft failure or rejection as a measure of Safety and Tolerability [18 months after inclusion of first patient, afterwards, annually up to 10 years]
7. Transplant related mortality (TRM) [18 months after inclusion of first patient, afterwards, annually up to 10 years]
8. Event free survival (EFS) [18 months after inclusion of first patient, afterwards, annually up to 10 years]
9. Overall survival (OS) [18 months after inclusion of first patient, afterwards, annually up to 10 years]
10. Cumulative incidence of relapse [18 months after inclusion of first patient, afterwards, annually up to 10 years]
その他の成果対策
1. Administered Bu dose(mg) per day [Measures assessed at time of conditioning (up to 5days)]
2. Target Bu plasma concentration(ng/ml) [Measures assessed at time of conditioning (up to 5days)]
3. Target Bu Area under the plasma concentration versus time curve (AUC) (min*ng/ml) [Measures assessed at time of conditioning (up to 5days)]
4. Measured Area under the plasma concentration versus time curve (AUC) of Bu (min*ng/ml) [Measures assessed at time of conditioning (up to 5days)]
5. Measured maximum plasma Bu concentration (Cmax, ng/ml) [Measures assessed at time of conditioning (up to 5days)]
6. Measured minimum plasma Bu concentration (Cmin, ng/ml) [Measures assessed at time of conditioning (up to 5days)]
7. Measured steady state plasma Bu concentration (Css, ng/ml) [Measures assessed at time of conditioning (up to 5days)]
8. Measured Clearance of Bu (ml/min/kg) [Measures assessed at time of conditioning (up to 5days)]
