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

August 21, 2024 updated by: Shaoyan Hu, Children's Hospital of Soochow University

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)

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

500

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Shaoyan Hu, MD, PhD
  • Phone Number: +86-13771870462
  • Email: hsy139@126.com

Study Contact Backup

Study Locations

  • China
      • Beijing, China, 100000
        • Not yet recruiting
        • Beijing Institute of Genomics, Chinese Academy of Sciences
        • Contact:
    • Anhui
      • Hefei, Anhui, China, 230000
        • Not yet recruiting
        • The Second Hospital of Anhui Medical University
        • Contact:
          • Ninglin Wang, MD
          • Phone Number: +86-13721113063
          • Email: zwnltt@126.com
      • Hefei, Anhui, China, 230000
        • Not yet recruiting
        • First Affiliated Hospital Of University of Science and Technology of China
        • Contact:
    • Guangdong
      • Guangzhou, Guangdong, China, 510000
        • Not yet recruiting
        • Guangzhou Women and Children Medical Center
        • Contact:
    • Guangxi
      • Nanning, Guangxi, China, 530000
        • Not yet recruiting
        • The First Affiliated Hospital of Guangxi Medical University
        • Contact:
    • Henan
      • Kai Feng, Henan, China, 475000
        • Not yet recruiting
        • Kaifeng Children's Hospital
        • Contact:
      • Zhengzhou, Henan, China, 450052
        • Not yet recruiting
        • The First Affiliated Hospital of Zhengzhou University
        • Contact:
    • Hunan
      • Changsha, Hunan, China, 410008
        • Not yet recruiting
        • Xiangya Hospital Central South University
        • Contact:
      • Changsha, Hunan, China, 410000
        • Not yet recruiting
        • Third Xiangya Hospital of Central South University
        • Contact:
    • Jiangsu
      • Suzhou, Jiangsu, China, 215000
        • Recruiting
        • Children's Hospital of Soochow University
        • Contact:
          • Shaoyan Hu, MD, PhD
          • Phone Number: +8613771835430
          • Email: hsy139@126.com
        • Principal Investigator:
          • Shaoyan Hu, MD,PhD
        • Sub-Investigator:
          • Hailong HE, MD
        • Sub-Investigator:
          • YI Wang, MD,PhD
        • Sub-Investigator:
          • Jun Lu, MD,PhD
        • Sub-Investigator:
          • Peifang Xiao, MD,PhD
        • Sub-Investigator:
          • Jie Li, MD
        • Sub-Investigator:
          • Li Gao, MD
      • Xuzhou, Jiangsu, China, 221000
        • Not yet recruiting
        • Xuzhou Children's Hospital
        • Contact:
    • Shandong
      • Jinan, Shandong, China, 250000
        • Not yet recruiting
        • Qilu Hospital of Shandong University
        • Contact:
    • Shanghai
      • Shanghai, Shanghai, China, 200000
        • Not yet recruiting
        • Children's Hospital of Fudan University
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Factorial Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: SDC group
Patients with CBF fusion gene (RUNX1: : RUNX1T1 and CBFB: : MYH11) or KMT2A: : MLLT3(AF9) , KMT2A: : MLLT10(AF10) , KMT2A: : MLLT4(AF6) fusion gene or KIT mutation will receive SDC regimen, including one course of HAE (Homoharringtonine, cytarabine, etoposide) in induction I. These patients will continue on the SDC (HAE) regimen in the second course if the MRD is < 1% after induction I, otherwise venetoclax will be added to the SDC group sequentially on Day 2 after the end of HAE. FLT3-ITD will be given sorafenib or gilteritinib as early as possible, and patients with KIT mutations will be recommended to add avapritinib as appropriate. These targeted drugs will not be combined with venetoclax.
Drug: Homoharringtonine
3mg/m2/day for weighing >10kg, 0.1mg/kg/day for weighing ≤10kg, d1-7, ivgtt, qd, more than 6 hours
Other Names:
  • Homoharringtonine injection
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;
Other Names:
  • Cytosar
Drug: Etoposide
100mg/m2/d for weighing >10kg, 3.3mg/kg/d for weighing ≤ 10kg, d1-5, ivgtt, qd, more than 4 hours
Other Names:
  • Etoposide injection
Drug: Venetoclax
100mg/m2/d for weighing >10kg, 3.33mg/kg/d for weighing ≤10kg, d12-25, po, qd
Other Names:
  • Venclexta
Drug: Sorafenib
100mg/m2/day for weighing >10kg, 3.3mg/kg/day for weighing ≤10kg, from identification, po, qd
Other Names:
  • Nexavar
Drug: Gilteritinib
20mg/m2/day for weighing >10kg, 0.7mg/kg/day for weighing ≤ 10kg, from identification, po, qd
Other Names:
  • Xospata Pill
Drug: Avapritinib
50mg/m2/day for weighing bodyweight >10kg, 1.65mg/kg/day for weighing ≤ 10kg, po, qd
Other Names:
  • AYVAKIT
Experimental: LDC group
Patients with the exception of the CBF fusion gene (RUNX1: : RUNX1T1 and CBFB: : MYH11) or those with the KMT2A: : MLLT3(AF9) , KMT2A: : MLLT10(AF10) , KMT2A: : MLLT4(AF6) fusion gene or KIT mutation will receive the LDC (MAG/IDAG+ venetoclax) regimen in induction I. Patients with MRD ≥1% or KIT mutations, assessed after induction I, will receive the HAE plus venetoclax (or targeted drugs) regimen, otherwise, they will receive MAG/IDAG + venetoclax. FLT3-ITD will be given sorafenib or gilteritinib as early as possible, and patients with KIT mutations will be recommended to add avapritinib as appropriate. These targeted drugs will not be combined with venetoclax.
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;
Other Names:
  • Cytosar
Drug: Sorafenib
100mg/m2/day for weighing >10kg, 3.3mg/kg/day for weighing ≤10kg, from identification, po, qd
Other Names:
  • Nexavar
Drug: Gilteritinib
20mg/m2/day for weighing >10kg, 0.7mg/kg/day for weighing ≤ 10kg, from identification, po, qd
Other Names:
  • Xospata Pill
Drug: Avapritinib
50mg/m2/day for weighing bodyweight >10kg, 1.65mg/kg/day for weighing ≤ 10kg, po, qd
Other Names:
  • AYVAKIT
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.
Other Names:
  • Mitoxantrone hydrochloride liposome injection
Drug: Recombinant Human Granulocyte Colony-Stimulating Factor
5ug/kg/d, d1-10, s.c., qd, at 1pm
Other Names:
  • Recombinant Human Granulocyte Colony-Stimulating Factor Injection
Drug: Idarubicin Hydrochloride
3mg/m2/day for weighing >10kg, 0.1mg/kg/day for weighing ≤ 10kg, d1-7, ivgtt, qd, more than 6 hours.
Other Names:
  • Idarubicin hydrochloride injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.

Events/failures of EFS include any-cause death, relapse, second malignancy, no CR after Indiction II and off-therapy due to abandonment or attending physician's decision.

Induction II and off-therapy due to abandonment or attending physician's decision.
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.
Failures of CIR only include relapse and no CR after Induction 2. Other failures including death in resission (before repalse), second malignancy, and off-therapy due to abandonment or attending physician's decision are considered competing risk.
From date of treatment until the date of when a failure of CIR occurs, whichever comes first, assessed up to 72 months.
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.
CR/CRi with negative MRD was defined as less than 5% blasts in bone marrow and MRD <0.1%.
Day 26 (HAE group) and Day 32 (MAG+Ven group) for remission induction 1 and 2 are the necessary time points for response evaluation.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Children's Hospital of Soochow University

Investigators

  • Study Chair: Shaoyan Hu, MD, PhD, Children 's Hospital of Soochow University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2024

Primary Completion (Estimated)

December 1, 2028

Study Completion (Estimated)

December 1, 2029

Study Registration Dates

First Submitted

January 4, 2024

First Submitted That Met QC Criteria

January 15, 2024

First Posted (Actual)

January 24, 2024

Study Record Updates

Last Update Posted (Actual)

August 22, 2024

Last Update Submitted That Met QC Criteria

August 21, 2024

Last Verified

August 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GMCAII

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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