Clinical Study of Induction Therapy Options Based on Molecular Subtyping and MRD in Children and Adolescents With AML

Official title

A Multicenter Clinical Study of Molecular Subtyping Combined With MRD-driven Remission Induction Regimen in Children and Adolescents With AML: A Phase II Cohort Study (GMCAII)

Overview

The goal of this clinical trial is to estimate the rate (probability) of complete remission or complete remission with incomplete count recovery (CR/CRi) with negative MRD after induction I and II, event-free survival (EFS), and cumulative incidence (probability) of relapse (CIR), in patients receiving molecular/precision medicine and MRD-driven remission inductions, and to assess secondarily if there is an improvement over the AML2018 protocol.

Detailed description

Advances in risk stratification and therapy, have improved the event-free survival (EFS) and overall survival (OS) for pediatric acute myeloid leukemia (AML) with current treatment strategies. Investigators previously conducted a multicenter, randomized controlled trial (AML18) to compare the efficacy and safety of low-dose chemotherapy versus standard-dose chemotherapy. The results showed that low-dose chemotherapy was non-inferior to standard-dose chemotherapy in terms of efficacy and had fewer adverse events. However, different subtypes exhibited varying treatment responses to both chemotherapy regimens. The MRD (Measurable Residual Disease) after induction therapy in both groups had an impact on prognosis. According to the backbone of the 2018 protocol, investigators decide whether to use low-dose or standard-dose for the first induction according to the patient's fusion gene, and the second induction and subsequent treatment are adjusted according to the treatment response. Patients with the following 5 fusion genes RUNX1: RUNX1T1, CBFβ: MYH11, KMT2A: MLLT3 (AF9), KMT2A: MLLT10 (AF10), KMT2A: MLLT4 (AF6) fusion or KIT mutation will be assigned to the standard dose remission induction regimen (HHT + Ara-C + VP16), others will be assigned to the standard dose regimen (Mitoxantrone/Idarubicin + Ara-C + G-CSF). At the same time, investigators will add targeted drugs such as venetoclax, avaptitinib, and gilteritinib/sorafenib to the chemotherapy regimen and assess their safety and efficacy. Post-induction consolidation consisted of 3 to 4 cycles of standard-dose chemotherapy according to risk classification. Patients classified as high-risk are candidates for allogeneic bone marrow transplantation after 1 or 2 courses of consolidation.

Interventions

• Drug Homoharringtonine
  3mg/m2/day for weighing \>10kg, 0.1mg/kg/day for weighing ≤10kg, d1-7, ivgtt, qd, more than 6 hours
• Drug Cytarabine
  100mg/m2/q12h for weighing \>10kg, 3.3mg/kg/q12h for weighing ≤10kg, d1-7, ivgtt, q12h, more than 30 minutes in SDC group; 10mg/m2/q12h for weighing \>10kg, 0.33mg/kg/q12h for weighing ≤10kg, d1-10, s.c.,q12h (the first dose at 8 am) in the LDC group;
• Drug Etoposide
  100mg/m2/d for weighing \>10kg, 3.3mg/kg/d for weighing ≤ 10kg, d1-5, ivgtt, qd, more than 4 hours
• Drug Venetoclax
  100mg/m2/d for weighing \>10kg, 3.33mg/kg/d for weighing ≤10kg, d12-25, po, qd
• Drug Mitoxantrone hydrochloride liposome
  5mg/m2/d for weighing \>10kg, 0.17mg/kg/d for weighing ≤ 10kg, d1, 3, 5, ivgtt, qod, more than 2 hours at 10 am.
• Drug Recombinant Human Granulocyte Colony-Stimulating Factor
  5ug/kg/d, d1-10, s.c., qd, at 1pm
• Drug Idarubicin Hydrochloride
  3mg/m2/day for weighing \>10kg, 0.1mg/kg/day for weighing ≤ 10kg, d1-7, ivgtt, qd, more than 6 hours.
• Drug Sorafenib
  100mg/m2/day for weighing \>10kg, 3.3mg/kg/day for weighing ≤10kg, from identification, po, qd
• Drug Gilteritinib
  20mg/m2/day for weighing \>10kg, 0.7mg/kg/day for weighing ≤ 10kg, from identification, po, qd
• Drug Avapritinib
  50mg/m2/day for weighing bodyweight \>10kg, 1.65mg/kg/day for weighing ≤ 10kg, po, qd

Primary outcome measures

• Rate of CR/CRi with negative MRD [Time frame: Day 26 (HAE group) and Day 32 (MAG+Ven group) for remission induction 1 and 2 are the necessary time points for response evaluation.]
• Event-free survival [Time frame: From date of treatment until the date of the occurrence of the event, whichever comes first, assessed up to 72 months. Patients remaining event-free are censored at the last follow-up time.]
• Cumulative incidence of relapse [Time frame: From date of treatment until the date of when a failure of CIR occurs, whichever comes first, assessed up to 72 months.]

Eligibility criteria

Inclusion criteria

• 1、Newly diagnosed, untreated AML；
• 2、Under 18 years old;
• 3、Patients who have used hydroxyurea or cytarabine before diagnosis, but the dosage of cytarabine does not exceed 5 days, and the total dose does not exceed 500 mg/m2 (50 mg/m2, q12h × 5d)；
• 4、 Liver function：Tbil≤2×ULN, ALT/AST≤3×ULN, creatinine clearance ≥50ml/min；Cardiac NYHA grading<3；SaO2>92%;
• 5、No active infection (symptoms resolved for more than 3 days if infected)
• 6、ECOG<2;
• 7、Expected survival time greater than 12 weeks;
• 9、Obtain the consent of the child and/or guardian and sign the informed consent form.

Exclusion criteria

• 1、Acute megakaryocytic leukemia (AMKL)；
• 2、Acute promyelocytic leukemia (APL);
• 3、Treatment-related secondary AML and AML with definite MDS transformation；
• 4、Myeloproliferative neoplasm (such as Juvenile myelomonocytic leukemia, JMML);
• 5、AML secondary to congenital bone marrow failure (such as AML secondary to Fanconi anemia (FA)；
• 6、AML secondary to Down syndrome;
• 7、Only temporary chemotherapy, radiotherapy, or immunotherapy, but not systematic treatment according to the treatment plan;
• 8、 Temporary chemotherapy, radiotherapy, or immunotherapy only, not systemic therapy per protocol;
• 9、Having any significant abnormal concurrent disease or mental illness that impacts the life safety and compliance of the patient and impacts informed consent, study participation, follow-up, or interpretation of results. In this case, all the participating units are required to report directly to the responsible person for this project to jointly decide whether they meet the exclusion criteria；
• 10、Patients with very poor nutritional status, severe infection, cardiac insufficiency, and intolerance to chemotherapy;
• 11、Relapsed AML at any time；
• 12、The attending physician considers that the patient is not suitable for entering the study protocol based on the patient's physical condition, economic status, and other factors.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Factorial

Masking

Open label

Primary purpose

Treatment

Study locations

China · 13 centers

• First Affiliated Hospital Of University of Science and Technology of China — Hefei
• The Second Hospital of Anhui Medical University — Hefei
• Guangzhou Women and Children Medical Center — Guangzhou
• The First Affiliated Hospital of Guangxi Medical University — Nanning
• Kaifeng Children's Hospital — Kaifeng
• The First Affiliated Hospital of Zhengzhou University — Zhengzhou
• Third Xiangya Hospital of Central South University — Changsha
• XiangYa Hospital Central South University — Changsha
• … and 5 more centers

Identifiers

NCT: NCT06221683 · GMCAII

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗