Evaluation of Treatment Efficacy According to Risk Group in Relapsed Childhood Acute Lymphoblastic Leukemia

Обзор

This study is open-label, multi-center, prospective study, which targets childhood patients with relapsed acute lymphostatic leukemia including bone marrow recurrence. Aim of this study is to investigate the outcome of NGS MRD based risk stratified treatment for relapsed acute lymphoblastic leukemia in children and adolescents.

Подробное описание

The Risk Assessment is classified as follows based on the NGS-MRD results evaluated after EOI(End of Induction).

\<Standard Risk\>

* Late (Relapse ≥ 1 year after off treatment) B-ALL marrow or Combined relapse AND * End of induction MRD \< 0.01%

\<High Risk\>

* T-ALL marrow or combined relapse (any timing) * All other B-ALL marrow or combined relapse cases

\<Very High Risk\>

• End of Induction BM ≥ M2 AND B -ALL marrow or combined relapse

Вмешательства

• Препарат Reinduction(4weeks)
  Prednisolone 60 mg/m2/day tid days 1-28, Vincristine 1.5 mg/m2 on days 1, 8, 15, 22, L-asparaginase 6,000 IU/m2(days 2-4 start, total 9 doses for 3 weeks), Idarubicin 10 mg/m2 on days 1, 8, (15\~17), IT Ara-C on days 1, IT MTX on days 8, 29
• Препарат Cosolodation 1st(3weeks)
  Ifosfamide: 1.8 g/m2 (days 1, 2, 3, 4, 5), Etoposide: 100 mg/m2 (days 1, 2, 3, 4, 5), IT MTX on day 1
• Препарат Consolidation 2nd(3weeks)
  MTX: 500 mg/m2 over 30 min followed by 1,000 mg/m2 over 23.5 hr (day 1), Ara-C: 3,000 mg/m2/dose (day 2, 3), IT MTX on day 1
• Препарат Blinatumomab 1st(High Risk Group)_4 Weeks
  Blinatumomab 15 mcg/m²/day(Days: 1-28), Dexamethasone 5 mg/m2/dose on Day 1, IT MTX on day 15, 29 (CNS 1, 2 patients), TIT on day 15, 29 (CNS 3 patient)
• Препарат Blinatumomab 2nd (High Risk Group)_4 Weeks
  Blinatumomab 15 mcg/m²/day(Days: 1-28), IT MTX on day 15, 29 (CNS 1, 2 patients), TIT on day 15, 29 (CNS 3 patient)
• Препарат Blinatumomab-Salvage 1st (Very High Risk Group)_4 Weeks
  Blinatumomab 9 mcg/day(Weight ≥ 45kg) or 5 mcg/m²/day(Weight \< 45kg) on 1-7 days, 28 mcg/day(Weight ≥ 45kg) or 15 mcg/m²/day(Weight \< 45kg) on 8-28 days, Dexamethasone 5 mg/m2/dose on day 1 and day 8, IT MTX on day 15, 29 (CNS 1, 2 patients), TIT on day 15, 29 (CNS 3 patient)
• Препарат Blinatumomab-Salvage 2nd (Very High Risk Group)_4 Weeks
  Blinatumomab 28 mcg/day(Weight ≥ 45kg) or 15 mcg/m²/day(Weight \< 45kg) on 1-28 days, IT MTX on day 15, 29 (CNS 1, 2 patients), TIT on day 15, 29 (CNS 3 patient)
• Препарат Intensification course
  \<Intensification 1st(3 Weeks)\> Etoposide: 100 mg/m2 on day 1, 2, 3, Ifosfamide 3.4 g/m2 on day 1, 2, 3 \<Intensification 2nd(2 Weeks)\> Oral 6-mercaptopurine 50 mg/m2/day PO (days 1-14), Methotrexate: 25 mg/m2 on day 1, 8, TIT on day 1 \<Intensification 3rd(3 Weeks)\> Ara-C 1.0 g/m2 (days 1-3), Idarubicin: 5mg/m2 (days 1- 3) \<Intensification 4th(2 Weeks)\> Dexamethasone 8 mg/m2/day on days 1-14, Vincristine 2 mg/m2 on days 1 and 8, L-asparaginase 10,000 IU/m2 on days 1 and 8
• Препарат Maintenance(12 Weeks/Cycle)
  Prednisolone: 15 mg/m²/dose(Days 1-5, 29-33, 57-61), Vincristine: 1.5 mg/m²/dose(Day 1, 29, 57), Oral 6-mercaptopurine: 50 mg/m²/dose (Days 1-84), Methotrexate: 20 mg/m²/dose (Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78), Intrathecal methotrexate (Day 1)
• Процедура Stem Cell Transplantation
  All matters related to hematopoietic stem cell transplantation are subject to each institution's practice.

Первичные конечные точки

• Safety/Efficacy [Срок оценки: through study completion, an average of 9 year]

Вторичные конечные точки (6)

• Disease-free survival rate (Blinatumomab) [Срок оценки: through study completion, an average of 9 year]
• Disease-free survival rate (standard risk) [Срок оценки: through study completion, an average of 9 year]
• Disease-free survival rate (Comparing minimal residual disease) [Срок оценки: through study completion, an average of 9 year]
• Death rate related to treatment [Срок оценки: through study completion, an average of 9 year]
• Death rate related to toxicity [Срок оценки: through study completion, an average of 9 year]
• Toxicity rate during consolidation therapy [Срок оценки: through study completion, an average of 9 year]

Критерии участия

Критерии включения

• Patients <= 1 year and >22 years of age at the time of relapse will be eligible
• Participants must have a histologic diagnosis of acute lymphoblastic leukemia:

• B-ALL: Precursor B-cell acute lymphoblastic leukemia
• T-ALL: Precursor T-cell acute lymphoblastic leukemia
• 1st recurred acute lymphoblastic leukemia patients, recurred parts including marrow. Enrolling patients with combined extra medullary relapse including bone marrow is acceptable. (No limits for extra medullary site) Additionally, subjects whose blast cells in bone marrow are less than 5% (ALL whether type M2 or M3 must be definite)
• Patients who have never received allogeneic stem cell transplant
• Patients who have never received blinatumomab before
• Adequate Renal Function

-A serum creatinine based on age/gender as follows:

1 to \&lt; 2 years - Male (0.6) Female (0.6) 2 to \&lt; 6 years - Male (0.8) Female (0.8) 6 to \&lt; 10 years - Male (1) Female (1) 10 to \&lt; 13 years - Male (1.2) Female (1.2) 13 to \&lt; 16 years - Male (1.5) Female (1.4)

≥ 16 years - Male (1.7) Female (1.4)

• Adequate Liver Function defined as a direct bilirubin \&lt;3.0 mg/dL
• Adequate Cardiac Function defined as: Shortening fraction of ≥ 27% by echocardiogram, or Ejection fraction of ≥ 50% by echocardiogram
• Lansky (age \&lt; 16 years) or Karnofsky (age ≥ 16 years) performance status ≥ 60% at screening
• Patients with a life expectancy of 1 or more year
• Patients who are expected to comply with all required study procedures and follow the study protocol in the opinion of the investigator
• Signed written informed consent and assent forms must be obtained prior to any study procedures

Критерии исключения

• Patients with Burkitt leukemia/lymphoma or mature B-cell leukemia
• Patients with Philadelphia chromosome positive (Ph+) ALL
• Patients with CD19-negative recurrent progenitor B-cell acute lymphoblastic leukemia (non-expression of CD19 in peripheral blood or bone marrow by flow cytometry) are not eligible for administration of Blinatumomab
• In case of relapsed within 1 month after the end of induction with the same 4-drug therapy used in this study
• Patients with mixed phenotype leukemia
• patient who was relapsed within 1 month after the end of induction therapy with the same 4-drug regimen to be used in this study.
• Patients with genetic syndrome: Down syndrome, Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome bone marrow failure syndrome
• Patients with known HIV
• Female patients who are not proved as infertile or pregnant (Evidence of infertility: History taking of possibilities of pregnancy or urine human chorionic gonadotrophin test negative, amenorrhea more than a year, Natural or artificial (Ex.hormone therapy) menopause status more than a year, surgical sterilization(Ex.Hysterectomy or ovariotomy etc)
• Currently receiving treatment in another investigational drug study or clinical trial
• Evidence of unstable conditions that would pose a risk to subject safety or interfere with the patients\&#39; compliance
• Patients with clinically relevant central nervous system (CNS) pathology or active CNS involvement including: unstable epilepsy, uncontrolled seizure, paralysis, aphasia, history of severe brain injury, cerebellar disease, organic brain syndrome, psychosis, coordination/movement disorder
• Known hypersensitivity to drugs or components to be administered: Idarubicin, Etoposide, Ifosfamide, Cytarabine, Vincristine, Mercaptopurine, Blinatumomab

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

South Korea · 10 центров

• Kyungpook National University Chilgok Hospital — Daegu
• Chungnam National University Hospital — Daejeon
• Chonnam National University Hwasun Hospital — Hwasun
• Jeju National University Hospital — Jeju City
• Seoul National University Hospital — Seoul
• Severance Hospital — Seoul
• Asan Medical Center — Seoul
• Samsung Medical Center — Seoul
• … и ещё 2 центра

Идентификаторы

NCT: NCT05827549 · KPHOG_T1RALL2201

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗