BLINATUMOMAB for Acute lymphoblastic leukaemia

Stratification factors

• Risk group (SR / IR-low / IR-high)
• MRD at TP1 (measurable residual disease levels / thresholds)
• Genetic subgroup (e.g. High hyperdiploidy (HeH), ETV6-RUNX1, CNA risk profiles)

Inclusion criteria

• {"criterion_text":"- Patients newly diagnosed with T-lymphoblastic (T-cell) or B-lymphoblastic precursor (BCP) leukaemia (ALL) according to the WHO-classification of Tumours of Haematopetic and Lymphoid Tissues (Revised 4th edition 2017) and with a diagnosis confirmed by an accredited laboratory at a participating paediatric oncology or adult haematology centre."}
• {"criterion_text":"- Age ≥ 0 days and < 46 years (one day before 46th birthday) at the time of diagnosis."}
• {"criterion_text":"- Patients with surface IG negative BCP-ALL and an IG::MYC rearrangement unless they have a concurrent BCL2/6 rearrangement. T-ALL patients with MYC translocations."}
• {"criterion_text":"- Informed consent signed by the patient and/or parents/legal guardians according to country-specific age-related guidelines (http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/12/WC500199234.pdf )."}
• {"criterion_text":"- The ALL diagnosis should be confirmed by an accredited laboratory at a participating paediatric oncology or adult haematology centre."}
• {"criterion_text":"- The patient should be diagnosed and treated at a participating paediatric oncology or adult haematology centre in the participating countries."}
• {"criterion_text":"- The patient should be a resident in one of the participating countries on a permanent basis or should intend to settle in a participating country, for instance by an application for asylum. Patients who are visiting the country as tourists should not be included. However, returning expatriots with primary diagnosis abroad may be included if no treatment has been administered and the diagnostic procedures are repeated at a participating centre."}
• {"criterion_text":"- All women of childbearing potential (WOCBP) have to have a negative pregnancy test within 2 weeks prior to the start of treatment."}
• {"criterion_text":"- For each intervention/randomisation an additional set of inclusion-criteria is provided."}

Exclusion criteria

• {"criterion_text":"- Age < 365 days at diagnosis and KMT2A-r BCP-ALL (documented presence of a KMT2A-split by FISH and/or a KMT2A transcript). These patients will be transferred to an appropriate trial for KMT2A-r BCP infant ALL if available."}
• {"criterion_text":"- Age >45 years at diagnosis (from the 46th birthday onwards)"}
• {"criterion_text":"- Patients with a previous malignant diagnosis (ALL as a second malignant neoplasm - SMN)."}
• {"criterion_text":"- Relapse of ALL."}
• {"criterion_text":"- Patients with mature B-ALL (as defined by surface IG positivity) or any patients with IG::MYC and a concurrent BCL2/6 rearrangement."}
• {"criterion_text":"- Patients with Ph-positive ALL (documented presence of t(9;22)(q34;q11) and/or of the BCR::ABL1 fusion transcript). These patients will be transferred to an adequate trial for t(9;22) if available."}
• {"criterion_text":"- Previously known ALL prone syndromes (e.g. Li-Fraumeni syndrome, germline ETV6 mutation), except for Down syndrome. Exploration for such ALL prone syndromes is not mandatory and patients in whom genetic work-up reveals a new germ-line mutation (index-cases) will remain in the study."}
• {"criterion_text":"- Treatment with systemic corticosteroids (corresponding to >10mg prednisolone/m2/day) for more than one week and/or other chemotherapeutic agents in a 4-week interval prior to diagnosis (pre-treatment)."}
• {"criterion_text":"- Pre-existing contraindications to any treatment according to the ALLTogether protocol (constitutional or acquired disease prior to the diagnosis of ALL preventing adequate treatment)."}
• {"criterion_text":"- Any other disease or condition, as determined by the investigator, which could interfere with the participation in the study according to the study protocol, or with the ability of the patients to cooperate and comply with the study procedures."}
• {"criterion_text":"- Women of childbearing potential who are pregnant at the time of diagnosis."}
• {"criterion_text":"- Women of childbearing potential and fertile men who are sexually active and are unwilling to use adequate contraception during therapy. Efficient birth control is required, see section 18.9."}
• {"criterion_text":"- Female patients, who are breast-feeding."}
• {"criterion_text":"- Essential data missing from the registration of characteristics at diagnosis (in consultation with the protocol chair)."}
• {"criterion_text":"- For each intervention/randomisation an additional set of exclusion-criteria is provided."}

Primary endpoints

• {"endpoint_text":"- The primary endpoint for the whole protocol (compared with the legacy protocols of the participating study-groups forming the consortium) is event-free survival (EFS) - as defined in the protocol.","definition_or_measurement_approach":"Event-free survival (EFS) as defined in the protocol (protocol-specified definition)."}
• {"endpoint_text":"- The primary endpoint for the randomised interventions is disease-free survival (DFS) - as defined in the protocol.","definition_or_measurement_approach":"Disease-free survival (DFS) as defined in the protocol (protocol-specified definition)."}
• {"endpoint_text":"- The primary endpoint for the replacement of conventional chemotherapy for patients with Down syndrome and detectable MRD at the end of induction (ALLTogether1 DS) is the fraction of patients with undetectable MRD after one cycle of blinatumomab. This fraction will be compared with a well defined historic control cohort from the UKALL2011 protocol.","definition_or_measurement_approach":"Fraction of patients with undetectable measurable residual disease (MRD) after one cycle of blinatumomab; compared to a historic control cohort (UKALL2011)."}

Secondary endpoints

• {"endpoint_text":"- Main study - The most important secondary outcome is overall survival (OS).","definition_or_measurement_approach":"Overall survival measured from diagnosis (protocol-specified)."}
• {"endpoint_text":"- Main study - Additional secondary measures of antileukaemic efficacy are: rate of -death during induction, -resistant disease, cumulative incidence of: -relapse (ciR), -death in first complete remission (ciDCR1) and -second malignancy (ciSMN).","definition_or_measurement_approach":"Rates and cumulative incidence measures as specified in the protocol (death during induction, resistant disease, ciR, ciDCR1, ciSMN)."}
• {"endpoint_text":"- Main study - Over- and under-treatment will also be combined into resulting treatment-related mortality (TRM) and leukaemia specific mortality (LSM) rates.","definition_or_measurement_approach":"Rates of TRM and LSM computed per protocol definitions."}
• {"endpoint_text":"- Main study - Since over-treatment also includes cured patients who suffer potentially permanent side-effects, data will be collected regarding the incidence of some adverse events of special interest. De-escalation of therapy may also result in relapses that have to be rescued with allogeneic stem-cell transplant (allo-SCT), which is associated with serious permanent side effects. Therefore, the incidence of allo-HSCT in CR1 and CR2 will also be measured.","definition_or_measurement_approach":"Incidence of specified adverse events of special interest and incidence of allo-HSCT in CR1 and CR2."}
• {"endpoint_text":"- Main study - An important aspect of evaluation of the quality of survival is measurement of quality of life (QoL). The whole protocol, as well as each of the non-randomised and randomised interventions will also be evaluated by measurements of quality of life (QoL). QoL will be measured by EQ5D-based instruments before and after all the randomised phases in all randomisations as well as later in the therapy and after cessation of treatment.","definition_or_measurement_approach":"Quality of life measured using EQ-5D-based instruments at protocol-specified timepoints (before/after randomised phases and during follow-up)."}
• {"endpoint_text":"- R1 and R2 - Efficacy: - Overall survival (OS), - Cumulative incidence of relapse (ciR), - Cumulative incidence of Death in CR1 (ciDCR1), - Cumulative incidence of SMN (ciSMN), - Fraction of surviving patients treated with allogenic stem-cell transplant in second remission, - Cumulative incidence of HSCT in CR2","definition_or_measurement_approach":"Efficacy measures (OS, ciR, ciDCR1, ciSMN, fraction undergoing allo-SCT in CR2) per protocol definitions."}
• {"endpoint_text":"- R1 and R2 - Toxicity: The studies are powered to answer the primary end-point non-inferiority question with a certain safety-margin. Even if reduction of exposure to potentially toxic therapy is an objective in itself, it is also reasonable to show some immediately measurable benefit from the reduction of therapy if the study is successful and non-inferiority can be shown.","definition_or_measurement_approach":"Toxicity endpoints measured as per CTCAE and protocol-defined safety margins; used to support non-inferiority analyses."}
• {"endpoint_text":"- Non-lethal toxicities for the DI-phase (R1 and R2): - Rate of febrile neutropenia (yes/no) and agent (if isolated from a sterile site/blood), -Rate of invasive fungal infection (yes/no) together with assessment if \"possible\"/\"probable\"/\"proven\" and agent (if isolated from sterile site/blood/BAL), -Rate of serious viral reactivation (EBV, VZV, HSV, CMV), mucositis with need for intravenous analgesic and/or nutritional support with parenteral nutrition, - The incidence of SAEs (except AESI)","definition_or_measurement_approach":"Rates of specified non-lethal toxicities in DI phase, with microbiological confirmation and CTCAE grading."}
• {"endpoint_text":"- Non-lethal toxicities for the DI-phase (R1 and R2): -The time-interval between the start of DI and the start of the next treatment- phase in days, - Rate of cardiac failure or serious arrhytmia (CTCAE ≥ grade 3).","definition_or_measurement_approach":"Time interval (days) between DI start and next phase; cardiac events graded CTCAE ≥3."}
• {"endpoint_text":"- Quantifiable measures of the toxicities listed above (measured at the same time-points): -Days admitted to hospital during the randomised phase and until the start of the next treatment phase, -days on iv antibiotics, - days on advanced antifungals, -days on iv analgesics and/or nutritional support with parenteral nutrition.","definition_or_measurement_approach":"Quantitative counts of days in hospital, days on IV antibiotics, advanced antifungals, IV analgesics/PN during defined periods."}
• {"endpoint_text":"- Non-lethal toxicity for the Maintenance-phase (R2) Measured at the beginning of Maintenance and every 4 months during the maintenance-phase: -Rate of VCR-neuropathy Grade ≥3 according to the PdL definition, -The number of doses of VCR that had to be reduced or omitted, -Cumulative incidence of symptomatic osteonecrosis + grade.","definition_or_measurement_approach":"Maintenance-phase toxicity measures assessed at specified intervals; CTCAE/PdL definitions used."}
• {"endpoint_text":"- Follow-up end-point of obesity: Body-mass index at the time of cessation of therapy and 5 years after the end of therapy.","definition_or_measurement_approach":"BMI at end of therapy and at 5-year follow-up."}
• {"endpoint_text":"- R3-InO and R3-TEAM secondary endpoints - Efficacy: -Overall survival (OS), - Cumulative incidence of relapse (ciR), -Occurence of CD22 negative relapse (InO), -Relation of all adverse outcomes with DNA-TG (TEAM).","definition_or_measurement_approach":"Efficacy endpoints for R3 arms including CD22-negative relapse occurrence (for InO) and relationship with DNA-TG (for TEAM)."}
• {"endpoint_text":"- R3-InO and R3-TEAM - Toxicity: -Incidence and severity of SOS/VOD all grades, - Incidence and severity of other liver toxicity (defined as AST/ALT elevations grade > 3 and bilirubin grade >3)","definition_or_measurement_approach":"Liver toxicity measured by incidence/severity of SOS/VOD and AST/ALT/bilirubin thresholds per CTCAE."}
• {"endpoint_text":"- Toxicity InO: -Incidence and severity of infections CTCAE grade > 3, -Incidence and duration of B-cell depletion reflected by immunoglobulin levels/IV immunoglobulin supplementation","definition_or_measurement_approach":"Infection rates CTCAE >3; measurement of B-cell depletion via immunoglobulin levels and IVIG use."}
• {"endpoint_text":"- Toxicity TEAM: -Cumulative incidence of SMN (ciSMN; TEAM), -Cumulative Incidence of NRH, -Cumulative Incidence of osteonecrosis, -Cumulative Incidence of hypoglycaemia","definition_or_measurement_approach":"Cumulative incidence measures of SMN, NRH, osteonecrosis and hypoglycaemia per protocol definitions."}
• {"endpoint_text":"- Exploratory endpoint (InO): CD22 expression level of leukemic cells in bone marrow samples at diagnosis and at TP2 (day 71).","definition_or_measurement_approach":"CD22 expression measured on leukemic cells in bone marrow at diagnosis and at TP2 (day 71)."}
• {"endpoint_text":"- ALLTogether1 DS secondary endpoints: -Event-Free Survival (EFS), -Overall Survival (OS), -Cumulative incidence of relapse (ciR) and CD19 negative relapse, -Cumulative incidence of Death in CR1 (ciDCR1), -Cumulative incidence of SMN (ciSMN), -Cumulative incidence of blinatumomab refractory disease, -Cumulative incidence of Protocol Therapy Failure","definition_or_measurement_approach":"EFS, OS and cumulative incidence measures including CD19-negative relapse and blinatumomab-refractory disease as specified for the DS subgroup."}
• {"endpoint_text":"- Exploratory endpoint ALLTogether1 DS: MRD response at any timepoint within 2 cycles of blinatumomab","definition_or_measurement_approach":"MRD response measured at any timepoint within 2 cycles of blinatumomab."}

Primary sponsor

Full Name

Karolinska University Hospital

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Sweden

Contract research organisations

Name

Ciwit B.V.

Responsibilities

sponsorDuties codes: [7]; contact email: chinmay.mulye@castoredc.com

Third parties

• {"country":"Norway","full_name":"Oslo University Hospital HF","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United Kingdom","full_name":"University Of Glasgow","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Educational Institution"}
• {"country":"Germany","full_name":"GPOH gGmbH","duties_or_roles":"sponsorDuties codes: [12]","organisation_type":"Patient organisation/association"}
• {"country":"Denmark","full_name":"Rigshospitalet","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"Paediatrisches Forschungsnetzwerk gGmbH","duties_or_roles":"sponsorDuties codes: [1,12]","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Netherlands","full_name":"Prinses Maxima Centrum voor Kinderoncologie B.V.","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Sweden","full_name":"Karolinska University Hospital","duties_or_roles":"sponsorDuties codes: [15] (IVRS - treatment randomisation)","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Denmark","full_name":"Frederiksberg Hospital","duties_or_roles":"sponsorDuties codes: [1]","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Netherlands","full_name":"Ciwit B.V.","duties_or_roles":"sponsorDuties codes: [7]","organisation_type":"Industry"}
• {"country":"Germany","full_name":"University Medical Center Hamburg-Eppendorf","duties_or_roles":"sponsorDuties codes: [5,6]","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"Zentrum fuer Forschungsfoerderung in der Paediatrie GmbH","duties_or_roles":"sponsorDuties codes: [1,12]","organisation_type":"Laboratory/Research/Testing facility"}