Trial Title:
Capizzi Escalating Methotrexate Versus High Dose Methotrexate in Children With Newly Diagnosed T-cell Lymphoblastic Lymphoma (T-LBL)
NCT ID:
NCT05681260
Condition:
T-cell Lymphoblastic Lymphoma
Conditions: Official terms:
Lymphoma
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Lymphoma, Non-Hodgkin
Cytarabine
Dexamethasone
Dexamethasone acetate
Prednisone
Cyclophosphamide
Ifosfamide
Doxorubicin
Liposomal doxorubicin
Methotrexate
Etoposide
Vincristine
Bortezomib
Daunorubicin
Asparaginase
Mercaptopurine
Vindesine
Pegaspargase
BB 1101
Conditions: Keywords:
T-cell lymphoblastic lymphoma
Pediatric
Capizzi-style Methotrexate
High dose Methotrexate
bortezomib
treatment
survival
PET scan
Study type:
Interventional
Study phase:
Phase 3
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Prednisone,Vincristine, Pegylated-asparaginase, Bortezomib,Cytarabine, Cyclophosphamide, Daunorubicin, 6-mercaptopurine, methotrexate, Dexamethasone, Doxorubicin
Description:
Standard risk Arm A: Induction I followed by Consolidation, extracompartmental Capizzi
MTX, delayed intensification and 96 weeks' maintenance therapy. Twenty-one or twenty-six
triple intrathecal injections for CNS negative or positive patients, respectively.
Arm group label:
Standard risk Arm A
Intervention type:
Drug
Intervention name:
Prednisone,Vincristine, Pegylated-asparaginase, Bortezomib,Cytarabine, Cyclophosphamide, Daunorubicin, 6-mercaptopurine, methotrexate, Dexamethasone, Doxorubicin
Description:
Standard risk Arm B: Induction I followed by Consolidation, extracompartmental high dose
MTX, delayed intensification and 96 weeks' maintenance therapy. Twenty-one or twenty-six
triple intrathecal injections for CNS negative or positive patients, respectively.
Arm group label:
Standard risk Arm B
Intervention type:
Drug
Intervention name:
Prednisone,Vincristine, Pegylated-asparaginase, Bortezomib,Cytarabine, Cyclophosphamide, Daunorubicin, 6-mercaptopurine, methotrexate, Dexamethasone, Doxorubicin, Vindesine, Etoposide, Ifosfamide
Description:
High Risk T-LBL: Induction I followed by 2 cycles of BFM HR Blocks, delayed
intensification and 96 weeks' maintenance therapy. Twenty-four or twenty-eight triple
intrathecal injections for CNS negative or positive patients, respectively.
Arm group label:
High Risk T-LBL
Summary:
T-cell lymphoblastic lymphoma (T-LBL) is the second most common subtype of non-Hodgkin
lymphoma (NHL) in children and adolescents. With current treatment, event-free survival
(EFS) rates vary between 75%~85%. Two different MTX intensification strategies are used
commonly: HD-MTX with leucovorin rescue, and Capizzi-style MTX without leucovorin rescue
plus PEG-ASP (C-MTX). Although superior outcome of patients with T-ALL receiving C-MTX
compared with HD-MTX on the AALL0434 trial, the 2 approaches had not been compared
directly in patients with T-LBL. There remains controversy on PET/CT interpretation in
children with NHL. Large prospective studies in pediatric patients with T-LBL regarding
PET/CT value for this is scarce. Around 1% pediatric patients with T-LBL will not achieve
remission at the end of Induction (induction failure). The optimal treatment for this
small subgroup is largely unclear. The BFM HR Blocks usually are applied to these
patients even though the efficacy is unknown. Novel targeted therapies are needed for
use. Dasatinib is identified as a targeted therapy for T-cell ALL in preclinical drug
screening.
Detailed description:
1. T-cell lymphoblastic lymphoma (T-LBL) which involves 90% of LBL cases is the second
most common subtype of non-Hodgkin lymphoma (NHL) in children and adolescents. With
current treatment, event-free survival (EFS) rates vary between 75%~85%. Poor
probabilities of survival (10~15%) for patients after relapse leave no room for
treatment de-escalation in frontline protocols. Limitations in numbers of newly
diagnosed patients impeded evaluation potential prognostic markers and validation or
conducting clinical studies.
2. In the GER-GPOH-NHL-BFM-95 study, the prophylactic cranial radiation was omitted,
and the intensity of induction therapy was decreased slightly. There were no
significant increases in CNS relapses, suggesting cranial radiation may be reserved
for patients with CNS disease at diagnosis. The 5-year EFS was worse in NHL-BFM-95
(82%) than in NHL-BFM-90 (90%). It was proposed that the major difference in EFS
between NHL-BFM-90 and NHL-BFM-95 resulted from the increased number of subsequent
neoplasms observed in NHL-BFM-95.
3. Two different MTX intensification strategies are used commonly: HD-MTX with
leucovorin rescue, and Capizzi-style MTX without leucovorin rescue plus PEG-ASP
(C-MTX). Although superior outcome of patients with T-ALL receiving C-MTX compared
with HD-MTX on the AALL0434 trial, the 2 approaches had not been compared directly
in patients with T-LBL.
4. POG 9404: the small cohort (n = 66) of lymphoma patients who did not receive HD-MTX,
the 5-year EFS was 88%. Of note, all of these patients received prophylactic cranial
radiation therapy, which has been demonstrated not to be required in T-cell
lymphoblastic lymphoma (T-LBL) patients.
5. COG-A5971 evaluated 2 strategies for CNS prophylaxis without CNS irradiation [5].
Patients were randomly assigned to receive HD-MTX in interim maintenance (BFM-95) or
intrathecal chemotherapy throughout maintenance (CCG-BFM). The overall incidence of
CNS relapse was 1.2%, and there was no difference between the treatment arms for CNS
relapse, DFS, or OS. Minimal disseminated disease (MDD) >1% by FLOW at diagnosis was
shown to be associated with a worse outcome in this trial (a BFM backbone containing
HD-MTX). Measurement of bone marrow MDD at diagnosis with sequential response
monitoring through peripheral blood during remission induction to aid treatment
stratification was also suggested in an early COG study. The prognostic significance
of MDD at End-of-Induction (EOI) or End-of-Consolidation (EOC) for T-LBL patients
with positive MDD at diagnosis is still unclear.
6. COG AALL0434: the COG ABFM regimen with C-MTX provided excellent DFS without cranial
radiation for patients with standard risk T-LBL (85%, Arm A, n=82, completed 64) and
high risk T-LBL (85%, Arm A, n=61, completed 51) although patients with CNS 3 were
not included. It appears that C-MTX may have negated the prognostic impact of MDD.
7. Nelarabine is unavailable in mainland China at this time, which did not show benefit
in COG AALL0434 study.
8. AALL07P1: 10 patients with T-LBL in first relapse treated with a 4-drug induction
regimen adding bortezomib: 7 had a response (1 had a complete response, 2 had
unconfirmed complete responses, and 4 had partial responses)
9. COG AALL1231 for T-LBL: the 4-year EFS and OS were better in bortezomib group than
the control group (86.4% and 89.5% vs. 76.5% and 78.3%, p=0.041 and 0.009,
respectively.). Incorporating bortezomib into standard therapy for de novo T-LBL
appears beneficial.
10. A biopsy for pathological examination of a mediastinal residual mass is a clinical
dilemma. Currently, conventional imaging is still considered as the "standard"
modality for evaluating pediatric patients with NHL at diagnosis and subsequent
response. There remains controversy on PET/CT interpretation in children with NHL.
Large prospective studies in pediatric patients with T-LBL regarding PET/CT value
for this is scarce.
11. Although an overlap in morphology and immune-phenotyping exists in T-LBL and T-cell
acute lymphoblastic leukemia (T-ALL), different disease distribution suggests
possible different genetic profiles and pathogenesis. Except for stage, none of
other parameters is used in the current stratification system outside of clinical
trials for T-LBL (several candidates, but none have been validated sufficiently).
Little is known about biomarkers with prognostic relevance for T-LBL. To improve
risk stratification strategy and better understand biologic rationale for
incorporating novel therapies (chemicals, target agents and immunotherapy) into a
conventional chemotherapy backbone, translational research to identify molecular
markers with prognostic relevance in T-LBL is highly recommended.
12. With the current treatment, around 1% pediatric patients with T-LBL will not achieve
remission at the end of Induction (induction failure). The optimal treatment for
this small subgroup is largely unclear. The BFM HR Blocks usually are applied to
these patients even though the efficacy is unknown. Novel targeted therapies are
needed for use. Dasatinib is identified as a targeted therapy for T-cell ALL in
preclinical drug screening.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Newly diagnosed T-lineage lymphoblastic lymphoma (T-LBL) Stage II-IV
Exclusion Criteria:
- Patients with Down syndrome or primary immune comprised disease.
- Ph+ T-LBL
- Patients must not have received any prior cytotoxic chemotherapy
- Any steroids pretreatment for > 5 days in the 7 days or for >14 days in the 28 days
before the initiation of Induction chemotherapy. The dose of prednisone or
methylprednisone pretreatment does not affect eligibility. Any steroids exposure
that occurred > 28 days before the initiation of Induction chemotherapy is allowed.
Inhalation and topical steroids are not considered pretreatment. A single dose of
vincristine is allowed.
Gender:
All
Minimum age:
12 Months
Maximum age:
18 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Shanghai Children's Medical Center
Address:
City:
Shanghai
Zip:
200127
Country:
China
Status:
Recruiting
Contact:
Last name:
Yi-Jin Gao, MD
Phone:
0086-21-38087513
Email:
gaoyijin@scmc.com.cn
Contact backup:
Last name:
Qing Yuan, MD
Phone:
0086-21-38626161
Email:
yuanqing@scmc.com.cn
Facility:
Name:
West China Second University Hospital
Address:
City:
Chengdu
Country:
China
Status:
Not yet recruiting
Contact:
Last name:
Xia Guo, MD
Start date:
February 6, 2023
Completion date:
December 31, 2029
Lead sponsor:
Agency:
Children's Cancer Group, China
Agency class:
Other
Collaborator:
Agency:
Shanghai Children's Medical Center
Agency class:
Other
Collaborator:
Agency:
Beijing Children's Hospital
Agency class:
Other
Collaborator:
Agency:
Children's Hospital of Scow University
Agency class:
Other
Collaborator:
Agency:
West China Second University Hospital
Agency class:
Other
Collaborator:
Agency:
Nanjing Children's Hospital
Agency class:
Other
Collaborator:
Agency:
Qilu Hospital of Shandong University
Agency class:
Other
Collaborator:
Agency:
Tianjin Medical University Cancer Institute and Hospital
Agency class:
Other
Collaborator:
Agency:
Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science & Technology
Agency class:
Other
Collaborator:
Agency:
Xiangya Hospital of Central South University
Agency class:
Other
Collaborator:
Agency:
The First Affiliated Hospital of Zhengzhou University
Agency class:
Other
Collaborator:
Agency:
Cancer hospital of Shandong Province
Agency class:
Other
Collaborator:
Agency:
Shenzhen Children's Hospital
Agency class:
Other
Collaborator:
Agency:
Wuhan Children's Hospital
Agency class:
Other
Collaborator:
Agency:
Zhejiang University School of Medicine Children's Hospital
Agency class:
Other
Collaborator:
Agency:
Shanghai Children's Hospital
Agency class:
Other
Collaborator:
Agency:
Ruijin Hospital
Agency class:
Other
Collaborator:
Agency:
Second Affiliated Hospital of Anhui Medical University
Agency class:
Other
Collaborator:
Agency:
Children's Hospital of Hebei Province
Agency class:
Other
Collaborator:
Agency:
Cancer Hospital of Henan Province
Agency class:
Other
Collaborator:
Agency:
Sun Yat-Sen Memorial Hospital Zhongshan University
Agency class:
Other
Collaborator:
Agency:
Qilu Children's Hospital
Agency class:
Other
Source:
Children's Cancer Group, China
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05681260
