Clinical trial NCT02670564: ALL SCTped FORUM - Pharmacogenomic Study (add-on Study)
Official title: Allogeneic Stem Cell Transplant for Children and Adolescents With Acute Lymoblastic Leukemia FORUM - Pharmacogenomic Study (add-on Study)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Acute Lymphoblastic Leukemia
Keywords: 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
Lead sponsor: Swiss Pediatric Oncology Group
Sponsor class: OTHER
Collaborators: name: ALL SCTped Forum
First posted: 2016-02-02
Enrollment: 1000
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility 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

Primary outcomes:
measure: Genetic variants in participants as a marker of risk of Adverse events and/or Efficacy of the studied agents
timeFrame: through study completion, an average of 2 years
Secondary outcomes:
measure: Number of participants with acute Graft-versus-host disease (aGvHD) according to the Glucksberg scale and Seattle criteria
timeFrame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
measure: Number of participants with chronic Graft-versus-host disease (cGvHD) according to the Glucksberg scale and Seattle criteria
timeFrame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
measure: Number of participants with VOD/SOS according to the Seattle criteria
timeFrame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
measure: Number of participants with Neutrophil recovery as a measure of Safety and Tolerability
timeFrame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
measure: Number of participants with Platelet recovery as a measure of Safety and Tolerability
timeFrame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
measure: Number of participants with Primary graft failure or rejection as a measure of Safety and Tolerability
timeFrame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
measure: Transplant related mortality (TRM)
timeFrame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
measure: Event free survival (EFS)
timeFrame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
measure: Overall survival (OS)
timeFrame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
measure: Cumulative incidence of relapse
timeFrame: 18 months after inclusion of first patient, afterwards, annually up to 10 years
Other outcomes:
measure: Administered Bu dose(mg) per day
timeFrame: Measures assessed at time of conditioning (up to 5days)
measure: Target Bu plasma concentration(ng/ml)
timeFrame: Measures assessed at time of conditioning (up to 5days)
measure: Target Bu Area under the plasma concentration versus time curve (AUC) (min*ng/ml)
timeFrame: Measures assessed at time of conditioning (up to 5days)
measure: Measured Area under the plasma concentration versus time curve (AUC) of Bu (min*ng/ml)
timeFrame: Measures assessed at time of conditioning (up to 5days)
measure: Measured maximum plasma Bu concentration (Cmax, ng/ml)
timeFrame: Measures assessed at time of conditioning (up to 5days)
measure: Measured minimum plasma Bu concentration (Cmin, ng/ml)
timeFrame: Measures assessed at time of conditioning (up to 5days)
measure: Measured steady state plasma Bu concentration (Css, ng/ml)
timeFrame: Measures assessed at time of conditioning (up to 5days)
measure: Measured Clearance of Bu (ml/min/kg)
timeFrame: Measures assessed at time of conditioning (up to 5days)
Locations:
city: Geneva
country: Switzerland
facility: Hôpital Cantonal de Genève, Département de Pédiatrie
state: Cansearch Laboratory
city: Basel
country: Switzerland
facility: Universitäts-Kinderspital beider Basel (UKBB), Onkologie/Hämatologie
city: Geneva
country: Switzerland
facility: HUG Hôpitaux Universitaire de Genève, Unité d'onco-hématologie pédiatrique
city: Zurich
country: Switzerland
facility: Universitäts-Kinderspital
Study officials:
affiliation: St. Anna Kinderspital, Vienna, Austria
name: Christina Peters, Prof. MD PhD
role: STUDY_CHAIR
affiliation: Klinik für Kinder- u. Jugendheilkunde III, Johann Wolfgang Goethe Universität, Frankfurt, Germany
name: Peter Bader, Prof. MD PhD
role: STUDY_CHAIR
affiliation: Department of Pediatric Hematology and Oncology IRCCS Ospedale, Rome, Italy
name: Franco Locatelli, Prof. MD PhD
role: STUDY_CHAIR
affiliation: Département de Pédiatrie, Hôpital Cantonal de Genève
name: Marc Ansari, MD, PD
role: PRINCIPAL_INVESTIGATOR
References: