Safety and Efficacy of Avapritinib in Relapsed or Refractory Pediatric CBF-AML With KIT Mutation

Phase 2

Recruiting

• Conditions: Relapse/Recurrence; C-KIT Mutation; Core Binding Factor Acute Myeloid Leukemia; AML, Childhood; Refractory AML
• Interventions: Drug: Avapritinib; Drug: Azacitidine Injection; Drug: Decitabine Injection; Drug: Idarubicin Hydrochloride; Drug: Cytarabine; Drug: Granulocyte Colony-Stimulating Factor

• Registration Number: NCT06316960
• Lead Sponsor: Children's Hospital of Soochow University

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of avapritinib in relapsed or refractory pediatric core binding factor acute myeloid leukemia with KIT mutation.

Detailed Description

This is a multicenter, single-arm, prospective, and intervention trial. About 30% of core binding factor acute myeloid leukemia (CBF-AML) patients still relapse under current treatment. Some studies have found that KIT mutations, especially the D816V mutation, may predict relapse and decrease overall survival (OS) in CBF-AML. Avapritinib has been approved for the treatment of gastrointestinal stromal tumors with KIT or PDGFRA mutations. Avapritinib was also effective for the treatment of minimal residual disease in acute myeloid leukemia with t (8;21) and KIT mutation failing to immunotherapy after allogeneic hematopoietic stem cell transplantation in a single-center, retrospective report. 11 centers from China carry out the AVACBFKIT regimen including Avapritinib, hypomethylating agents and low dose chemotherapy for the treatment of relapsed or refractory pediatric CBF-AML with KIT mutation. The main focus of this study is to evaluate the efficacy and safety of avapritinib in the regimen.

Study Timeline

• Study Start: 2024-03-01
• Study First Submitted: 2024-03-12
• Study First Submitted QC: 2024-03-12
• Study First Posted: 2024-03-19
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-21
• Last Update Posted: 2024-08-22
• Primary Completion: 2026-03
• Study Completion: 2027-03

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 50

Inclusion Criteria

1. Gender unlimited;
2. Under 18 years;
3. Diagnosis of acute myeloid leukemia (according to the 2022 WHO classification).
4. Presence of t(8;21)/RUNX1::RUNX1T1 or inv(16)/t(16;16)/CBFβ::MYH11;
5. KIT mutation;
6. Refractory AML: AML patients who do not achieve CR or CRi after induction therapy;
7. Relapsed AML: patients who achieved remission after consolidation therapy or transplantation, FISH confirmed that the fusion gene turned positive, or extramedullary leukemia infiltration;
8. No active infections;
9. Liver function: Tbil ≤2×ULN, ALT/AST ≤3×ULN, creatinine clearance ≥50ml/min;
10. ECOG score <2;
11. Expected survival time >12 weeks;
12. Participants must have the ability to understand and be willing to participate in this study and must sign an informed consent form.

Exclusion Criteria

1. Have received prior treatment with avapritinib;
2. Receiving other targeted therapies for AML at the same time, such as dasatinib, sorafenib, gilteritinib, venetoclax, etc;
3. Presence of active uncontrolled infection (including bacterial, fungal, or viral infection);
4. Present of significant underlying organ diseases: such as myocardial infarction, chronic heart failure, decompensated liver or kidney dysfunction；
5. With other malignancies requiring treatment；
6. Already enrolled in another interventional clinical study；
7. The researchers determined that the individual is not suitable to participate in this trial.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Relapsed/Refractory CBF-AML with KIT mutation	Idarubicin Hydrochloride	The relapsed/refractory patients will receive a combination treatment of decitabine/azacitidine+ IdAG (idarubicine + cytarabine + granulocyte stimulating factor)regimen along with avapritinib. CBF-AML with KIT mutated patients with molecular relapse after hematopoietic stem cell transplantation may receive avapritinib combined with demethylating agents or interferon or donor lymphocyte infusion without low-dose chemotherapy. The dose of avapritinib will start at 50mg/m2/d, and if platelets stabilize at 50 ×10\^9/L and neutrophils stabilize above 1.0 ×10\^9/L after one week, the dose can be increased to 100mg/m2/d, with a maximum daily dose of 100mg. Avapritinib should be discontinued in the presence of febrile neutropenia or active infection, and avapritinib can be resumed once the infection is controlled, with each treatment cycle not exceeding 28 days.
Relapsed/Refractory CBF-AML with KIT mutation	Decitabine Injection	The relapsed/refractory patients will receive a combination treatment of decitabine/azacitidine+ IdAG (idarubicine + cytarabine + granulocyte stimulating factor)regimen along with avapritinib. CBF-AML with KIT mutated patients with molecular relapse after hematopoietic stem cell transplantation may receive avapritinib combined with demethylating agents or interferon or donor lymphocyte infusion without low-dose chemotherapy. The dose of avapritinib will start at 50mg/m2/d, and if platelets stabilize at 50 ×10\^9/L and neutrophils stabilize above 1.0 ×10\^9/L after one week, the dose can be increased to 100mg/m2/d, with a maximum daily dose of 100mg. Avapritinib should be discontinued in the presence of febrile neutropenia or active infection, and avapritinib can be resumed once the infection is controlled, with each treatment cycle not exceeding 28 days.
Relapsed/Refractory CBF-AML with KIT mutation	Azacitidine Injection	The relapsed/refractory patients will receive a combination treatment of decitabine/azacitidine+ IdAG (idarubicine + cytarabine + granulocyte stimulating factor)regimen along with avapritinib. CBF-AML with KIT mutated patients with molecular relapse after hematopoietic stem cell transplantation may receive avapritinib combined with demethylating agents or interferon or donor lymphocyte infusion without low-dose chemotherapy. The dose of avapritinib will start at 50mg/m2/d, and if platelets stabilize at 50 ×10\^9/L and neutrophils stabilize above 1.0 ×10\^9/L after one week, the dose can be increased to 100mg/m2/d, with a maximum daily dose of 100mg. Avapritinib should be discontinued in the presence of febrile neutropenia or active infection, and avapritinib can be resumed once the infection is controlled, with each treatment cycle not exceeding 28 days.
Relapsed/Refractory CBF-AML with KIT mutation	Granulocyte Colony-Stimulating Factor	The relapsed/refractory patients will receive a combination treatment of decitabine/azacitidine+ IdAG (idarubicine + cytarabine + granulocyte stimulating factor)regimen along with avapritinib. CBF-AML with KIT mutated patients with molecular relapse after hematopoietic stem cell transplantation may receive avapritinib combined with demethylating agents or interferon or donor lymphocyte infusion without low-dose chemotherapy. The dose of avapritinib will start at 50mg/m2/d, and if platelets stabilize at 50 ×10\^9/L and neutrophils stabilize above 1.0 ×10\^9/L after one week, the dose can be increased to 100mg/m2/d, with a maximum daily dose of 100mg. Avapritinib should be discontinued in the presence of febrile neutropenia or active infection, and avapritinib can be resumed once the infection is controlled, with each treatment cycle not exceeding 28 days.
Relapsed/Refractory CBF-AML with KIT mutation	Avapritinib	The relapsed/refractory patients will receive a combination treatment of decitabine/azacitidine+ IdAG (idarubicine + cytarabine + granulocyte stimulating factor)regimen along with avapritinib. CBF-AML with KIT mutated patients with molecular relapse after hematopoietic stem cell transplantation may receive avapritinib combined with demethylating agents or interferon or donor lymphocyte infusion without low-dose chemotherapy. The dose of avapritinib will start at 50mg/m2/d, and if platelets stabilize at 50 ×10\^9/L and neutrophils stabilize above 1.0 ×10\^9/L after one week, the dose can be increased to 100mg/m2/d, with a maximum daily dose of 100mg. Avapritinib should be discontinued in the presence of febrile neutropenia or active infection, and avapritinib can be resumed once the infection is controlled, with each treatment cycle not exceeding 28 days.
Relapsed/Refractory CBF-AML with KIT mutation	Cytarabine	The relapsed/refractory patients will receive a combination treatment of decitabine/azacitidine+ IdAG (idarubicine + cytarabine + granulocyte stimulating factor)regimen along with avapritinib. CBF-AML with KIT mutated patients with molecular relapse after hematopoietic stem cell transplantation may receive avapritinib combined with demethylating agents or interferon or donor lymphocyte infusion without low-dose chemotherapy. The dose of avapritinib will start at 50mg/m2/d, and if platelets stabilize at 50 ×10\^9/L and neutrophils stabilize above 1.0 ×10\^9/L after one week, the dose can be increased to 100mg/m2/d, with a maximum daily dose of 100mg. Avapritinib should be discontinued in the presence of febrile neutropenia or active infection, and avapritinib can be resumed once the infection is controlled, with each treatment cycle not exceeding 28 days.

Primary Outcome Measures

Name	Time	Method
Composite remission rate (CRc)	The evaluation time point is day28-day35 from the start of regimen.	Composite remission rate (CRc), including the sum of the number of patients with complete remission (CR), complete remission with partial hematologic recovery (CRh), complete remission with incomplete blood count recovery (CRi), and morphologically leukemia-free (MLFS) as a percentage of the total number of patients who participated in the efficacy analysis.

Secondary Outcome Measures

Name	Time	Method
Progression-free survival	From date of enrollment until the date of disease progression, confirmed relapse, or death, whichever occurred first, assessed up to 60 months.	Progression-free survival (PFS) was defined as the date from enrollment to the date of disease progression, confirmed relapse, or death, whichever occurred first.
Overall survival	From date of enrollment until the date of the occurrence of death or last follow-up, assessed up to 60 months.	Overall survival (OS) was defined as the date from enrollment to the date of death or last follow-up for surviving patients.

Trial Locations

Locations (12)

The First Affiliated Hospital of Guangxi Medical University; 🇨🇳 Nanning, Guangxi, China

Kaifeng Children's Hospital; 🇨🇳 Kaifeng, Henan, China

Third Xiangya Hospital of Central South University; 🇨🇳 Changsha, Hunan, China

Qilu Hospital of Shandong University; 🇨🇳 Jinan, Shandong, China

Children's Hospital Of Fudan University; 🇨🇳 Shanghai, Shanghai, China

The First Affiliated Hospital of Zhengzhou University; 🇨🇳 Zhengzhou, Henan, China

Xuzhou Children's Hospital; 🇨🇳 Xuzhou, Jiangsu, China

The Second Hospital of Anhui Medical University; 🇨🇳 Hefei, Anhui, China

Children's Hospital of Soochow University; 🇨🇳 Suzhou, Jiangsu, China

First Affiliated Hospital Of University of Science and Technology of China; 🇨🇳 Hefei, Anhui, China

XiangYa Hospital Central South University; 🇨🇳 Changsha, Hunan, China

Guangzhou Women and Children Medical Center; 🇨🇳 Guangzhou, Guangdong, China