This study has been transitioned to CTIS with ID 2023-508101-24-00 check the CTIS register for the current data. The primary objective of the first randomized question (R1) open for allLBL patients (pts) of the core study cohort, is to evaluate…
ID
Source
Brief title
Condition
- Haematopoietic neoplasms (excl leukaemias and lymphomas)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Randomization R1: Cumulative incidence of relapse with involvement of the CNS
(CNS-relapse, pCICR). The time to relapse is the time from randomization to the
first relapse or the date of last follow-up. Other events (non-response,
progressive disease, relapse, second malignancy or death before and in CR) will
be taken into account as competing events.
• Randomization R2: Estimated probability of event-free survival (pEFS). The
pEFS is the time from randomization to the first event (non-response,
progressive disease, relapse, second malignancy or death from any cause) or
date of last follow-up.
Secondary outcome
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 (PTEN mutations and deletions, PIK3R1, PIK3CA,
KRAS, NRAS, chromosome 6q alterations, status of TRG locus) and targeted panel.
•cumulative incidence of relapses in association with minimal residual disease
results.
Background summary
Non-Hodgkin lymphoma (NHL) is the fourth most common type of malignancy in
children and
adolescents. Lymphoblastic lymphoma (LBL) accounts for about 25-35% of NHL in
childhood
and adolescence. About 75-80% of patients are diagnosed with a T-cell
lymphoblastic
lymphoma (T-LBL) and 20-25% with a precursor B-cell lymphoblastic lymphoma
(pB-LBL).
Both LBL subtypes are treated according to the same treatment strategy. LBL
share
morphological, immunophenotypic and clinical characteristics with acute
lymphoblastic
leukemia (ALL).
Although the 5-year event-free-survival and overall survival for pediatric LBL
patients
substantially increased during the last decades, the prognosis of relapsed
patients remains
poor. On the other hand the intensive treatment regimens are accompanied by
high toxicity with considerable mortality and morbidity.
The BFM treatment strategy for lymphoblastic lymphoma is based on the treatment
regimen
of the ALL-BFM protocol. It consists of a 9-week induction, an 8-week
consolidation and a 7-
week re-induction treatment followed by an oral maintenance up to total therapy
duration of 2
years. Best results were achieved in the trial NHL-BFM 90 with pEFS of 90%.
The subsequent clinical trial EURO-LB 02 was run by the European Inter-group
Co-operation
on childhood and adolescent NHL (eicnhl). For the trial EURO-LB 02 it was
accepted that the treatment regimen of the trial NHL-BFM 90 should serve as the
reference arm of the study.
The 90% pEFS rate for T-LBL shown in study NHL-BFM 90 could not be replicated
mainly due to more toxic deaths and CNS relapses.
The conclusion of the international co-operative trial is that dexamethasone in
induction may
prevent CNS relapse more effectively than prednisone but produces a higher
burden of
toxicity. Therefore in this study the duration of dexamethasone exposure is
limited to 14 days to reduce the risk of toxicities. It was decided to evaluate
prospectively whether a short 14-day dexamethasone arm (experimental arm)
compared to standard 21-day prednisone (standard arm) in the induction phase
protocol Ia may reduce CNS related relapses.
It is agreed that prognostic parameters are most urgently needed for pediatric
LBL patients to
prevent overtreatment and subsequent acute and long term toxicities as e.g.
osteonecrosis in
low risk patients. And on the other hand, prognostic parameters identifying
high risk patients
allowing subsequent treatment intensification to prevent often fatal relapses
are highly
warranted. Molecular studies and an international meta-analysis have led to a
new stratification system based on the mutational profile of distinct genes in
(NOTCH1 and FBXW7) in patients with T-LBL. The aim of introducing this
stratification system in parallel with stratification according to CNS status,
immunophenotype and stage of disease is to improve the pEFS and OS and to
reduce the risk of CNS-related relapses in pediatric patients with LBL.
Therefore a new stratification system based on NOTCH1 and FBXW7 mutational
status for T-LBL and stage of disease for pB-LBL is introduced in this study
Additionally, in the medium term, patients with T-LBL may not only benefit from
the proposed risk group stratification system including genetic markers but
also of the identification of potential additional prognostic molecular markers
that can be added in subsequent trials.
Study objective
This study has been transitioned to CTIS with ID 2023-508101-24-00 check the CTIS register for the current data.
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/m²/d for 21 days plus a 9
day tapering) (standard arm, SA) by dexamethasone (10 mg/m²/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.
Study design
International inter-group multi-centre open-label randomized prospective
clinical trial
Intervention
N.A.
Study burden and risks
De primaire reden voor randomisatie 1 (prednison versus dexamethason) is het
verminderen van het aantal CNS recidieven. Inductie van dexamethason kan
gepaard gaan met een verhoogd risico op behandeling gerelateerde morbiditeit
(infecties, hematologische toxiciteit, hepatische toxiciteit) en mortaliteit.
Daarom is de duur van blootstelling aan dexamethason beperkt tot 14 dagen om
het risico op toxiciteit te verminderen. De deelnemende groepen gaan ervan uit
dat de potentiële voordelen van dexamethason in dit onderzoek opwegen tegen de
potentiële risico's die aan studieparticipatie zijn verbonden.
De primaire reden voor randomisatie 2 met behandelintensificatie voor hoog
risicopatiënten met LBL via de introductie van ALL hoog risico kuren in het
geïntensiveerde protocol M is het verbeteren van de event-free survival en
overall survival volgens de gevestigde ALL-BFM behandelstrategie voor hoge
risicopatiënten. Vanwege de relevante toxiciteit van behandelplannen met 3 tot
6 opeenvolgende hoog risicovolle kuren waargenomen bij ALL-patiënten met een
hoog risico, is overeengekomen om 2 hoge risicokuren in het protocol M te
introduceren, maar om twee standaardkuren met hoge dosis methotrexaat van
protocol M te behouden in de LBL 2018 studie. Potentiële risico's zijn een
toename van behandeling gerelateerde morbiditeit en mortaliteit, evenals
vertragingen in de behandeling. Verbetering van de overleving bij hoog
risicopatiënten zou echter de overweging van deze intensievere behandeling
kunnen rechtvaardigen.
Een ander beoogd voordeel van de LBL 2018 studie met de prospectieve validatie
van de nieuw geïntroduceerde risicogroep stratificatie is om de behandeling aan
te passen aan het individuele risico op recidief. Op de middellange termijn kan
dit een verdere verlaging van de behandelingsintensiteit mogelijk maken bij
patiënten met een laag risico die de acute en langdurige toxiciteit bij deze
patiënten verminderen.
Albert Schweitzer Campus 1
Münster 48149
DE
Albert Schweitzer Campus 1
Münster 48149
DE
Listed location countries
Age
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
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 (e.g. 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 (listed in section 6.1
of the respective SmPC)
•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 (except INITIAL EMERGENCIES, see page 73)
•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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-508101-24-00 |
| EudraCT | EUCTR2017-001691-39-NL |
| CCMO | NL67395.078.19 |