LBL 2018, International Cooperative Therapeutic Protocol for Children and Adolescents with Lymphoblastic Lymphoma

Austria, Belgium, Czech Republic, Czechia, Denmark, Finland, France, Germany, Hong Kong, Hungary, Ireland, Israel, Italy, Netherlands, Norway, Poland, Portugal, Russian Federation, Slovakia, Slovenia, Spain, Sweden, Switzerland (ICTRP)

ICTRP Trial ID
EUCTR2017-001691-39 (ICTRP)

Official title (approved by ethics committee)
International cooperative treatment protocol for children and adolescents with lymphoblastic lymphoma (BASEC)

Academic title
LBL 2018 - International cooperative treatment protocol for children and adolescents with lymphoblastic lymphoma - LBL 2018 (ICTRP)

Public title
LBL 2018 - International cooperative treatment protocol for children and adolescents with lymphoblastic lymphoma (ICTRP)

Disease under investigation
Lymphoblastic lymphoma
MedDRA version: 21.0Level: LLTClassification code 10065923Term: Lymphoblastic lymphomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps);Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15] (ICTRP)

Intervention under investigation

Product Name: cyclophosphamide
Product Code: [NA]
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: CICLOFOSFAMIDE
CAS Number: 50-18-0
Current Sponsor code: PR1
Other descriptive name: CYCLOPHOSPHAMIDE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Product Name: DEXAMETHASONE
Product Code: [NA]
Pharmaceutical Form: Solution for injection
INN or Proposed INN: DESAMETASONE
CAS Number: 50-02-2
Current Sponsor code: PR2
Other descriptive name: DEXAMETHASONE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 4-

Product Name: Cytarabine
Product Code: [NA]
Pharmaceutical Form: Powder and solvent for solution for injection
INN or Proposed INN: CITARABINA
CAS Number: 147-94-4
Current Sponsor code: PR3
Other descriptive name: CYTARABINE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 100-

Product Name: Doxorubicine
Product Code: [NA]
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: DOXORUBICINA CLORIDRATO
CAS Number: 23214-92-8
Current Sponsor code: Doxorubicina
Other descriptive name: DOXORUBICIN
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2-

Product Name: Daunorubicin
Product Code: [NA]
Pharmaceutical Form: Powder and solvent for solution for injection
INN or Proposed INN: DAUNORUBICINA
CAS Number: 20830-81-3
Current Sponsor code: DAUNORUBICIN
Other descriptive name: DAUNORUBICIN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-

Product Name: Ifosfamide
Product Code: [Na]
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: IFOSFAMIDE
CAS Number: 3778-73-2
Current Sp (ICTRP)

Type of trial
Interventional clinical trial of medicinal product (ICTRP)

Trial design
Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 8 (ICTRP)

Inclusion/Exclusion criteria
Gender:
Female: yes
Male: yes

Inclusion criteria:
Patients meeting the following criteria are eligible to the study (inclusion criteria):
?newly diagnosed lymphoblastic lymphoma
?age <18 years at diagnosis
?patient enrolled in a participating center
?written informed consent of patient (>14 years of age or according to local law and regulation) and parents to trial participation and transfer and processing of data
?Willingness of patients and the investigator/pathologist to provide adequate slides/blocks for reference (molecular)pathology and international pathology panel and/or fresh or fresh frozen samples for genetic risk group stratification if these samples are available after standard diagnostic procedures
Are the trial subjects under 18? yes
Number of subjects for this age range:
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range
(ICTRP)

Exclusion criteria:
Patients meeting the following criteria are not eligible to the study (exclusion criteria):
?lymphoblastic lymphoma as secondary malignancy
?non-lymphoma related relevant medical, psychiatric or social conditions incompatible with trial treatment including among others :
- prior organ transplant
- severe immunodeficiency
- demyelinating Charcot-Marie Tooth syndrome
- serious acute or chronic infections, such as HIV, VZV and
tuberculosis
- urinary tract infection, cystitis, urinary outflow obstruction, severe
renal impairment (creatinine clearance less than 20 ml/min)
- severe hepatic impairment (bilirubin >3 times ULN, transaminases
>10 times ULN)
- myocardial insufficiency, severe arrhythmias
- ulcers of the oral cavity and known active gastrointestinal ulcer
disease
- known hypersensitivity to any IMP and to any excipient
?steroid pre-treatment with = 1 mg/kg/d for more than two weeks during the last month before diagnosis
?vaccination with live vaccines within 2 weeks before start of protocol Treatment
?treatment started according to another protocol or pre-treatment with cytostatic drugs
?participation in another clinical trial that interferes with the protocol, except NHL-BFM Registry 2012 and trials with different endpoints, involving aspects of supportive treatment, which can run parallel to LBL 2018 without influencing the outcome of this trial (e.g. trials on antiemetics, antibiotics, strategies for psychosocial support)
?evidence of pregnancy or lactation period
?sexually active adolescents not willing to use highly effective contraceptive method (pearl index < 1) until 12 months after end of cytostatic therapy


Primary and secondary end points
Main Objective: The primary objective of the first randomized question (R1) open for all LBL patients (pts) of the core study cohort, is to evaluate whether the cumulative incidence of relapses in the central nervous system can be decreased by substituting prednisone (60 mg/m?/d for 21 days plus a 9 day tapering) (standard arm, SA) by dexamethasone (10 mg/m?/d for 14 days without tapering) (experimental arm, EA) in induction therapy. The primary objective of the second randomized question (R2) open for high-risk pts of the core study cohort, is to test whether the probability of pEFS can be improved by an intensified treatment arm (EA) compared to the standard treatment arm (SA). In the EA pts receive 2 additional doses of PEG asparaginase during protocol Ib* and an intensified protocol M consisting of one course for high-risk (HR) ALL (HR-1?), followed by one standard high-dose methotrexate (MTX) course, followed by another intense course for HR ALL (HR-2?) and a second standard high-dose MTX course.;Secondary Objective: Here we aim to analyze:
?the pEFS and cumulative incidence of relapse/CNS-relapse as compared to study EURO-LB 02
?overall survival (pOS) defined as time from diagnosis to death of any cause or to date of last contact for patients alive as compared to study EURO-LB 02
?treatment related mortality in the randomized arms and compared to study EURO-LB 02
?adverse event and severe adverse event profile in specific protocol elements or randomized arms and during follow-up and compared to study EURO-LB 02
?feasibility and results of risk group stratification
?feasibility of minimal residual disease evaluation in children and adolescents with LBL
?identification of prognostic molecular markers for T-LBL which can be added to the risk group stratification system in a subsequent trial(PTEN mutations and deletions, PIK3CA, PIK3R1, KRAS, NRAS, chromosome 6q alterations, status of TRG locus and further molecular markers identified in the targeted panel of molecular markers for T-LBL).;Primary end point(s): Primary endpoints of randomization 1:
For the randomized question 1 the cumulative incidence of relapse with involvement of the CNS (CNS-relapse, pCICR) is the primary endpoint. The time to relapse is the time from randomization to the first relapse or the date of last follow-up. Other events will be taken into account as competing events.

CNS-relapse is defined as follows:
?=5/?l nucleated cells in CSF and morphologically unequivocal evidence of lymphoblasts
?histologically proven LBL in cases of intracranial mass without evidence of blasts in CSF

Primary endpoints of randomization 2
For the randomized question 2 the estimated probability of event-free survival (pEFS) is the primary endpoint. The pEFS is the time from randomization to the first event or date of last follow-up.

The following occurrences are defined as an event
?non-response
?disease progression/relapse
?secondary malignancy
?death from any cause;Timepoint(s) of evaluation of this end point: Interim analysis:
- First randomization: intended to be performed after 3 years
- Second randomization: intended to be performed after 3 and 5 years

Final analysis:
- intended to be performed 3 years after randomization of the last patient (ICTRP)

Secondary end point(s): The secondary endpoints of the trial LBL 2018 are the following
?survival (pOS) defined as time from diagnosis to death due to any cause or to the date of last contact for patients alive
?frequency of treatment-related toxicity and mortality overall and in specific protocol elements, randomized arms and during follow-up
?frequency of adverse events of interest and severe adverse events overall
?rate of evaluable patients for risk group stratification
?cumulative incidence of relapses in association with molecular markers of the published genetic classifier in T-LBL patients and molecular markers identified in the targeted panel of molecular markers for T-LBL.
?cumulative incidence of relapses in association with minimal residual disease results.;Timepoint(s) of evaluation of this end point: Final analysis: intended to be performed 3 years after randomization of the last patient (ICTRP)

Registration date
21.01.2021 (ICTRP)

Incorporation of the first participant
20.01.2022 (ICTRP)

Secondary sponsors
not available

Additional contacts
NHL-BFM study center, birgit.burkhardt@ukmuenster.de, 00492518343405, Universit?tsklinikum M?nster (ICTRP)

Secondary trial IDs
UKM17_0023, 2017-001691-39-BE (ICTRP)

Results-Individual Participant Data (IPD)
not available

Further information on the trial
https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-001691-39 (ICTRP)