refractory/relapsed acute myeloid leukemia
Conditions
Interventions
Phase I monotherapy group (avapritinib):avapritinib
Phase I combination group (avapritinib + FLAG):avapritinib + FLAG
Phase II monotherapy group (avapritinib):avapritinib
Phase II combination group (avapritinib + FLAG):avapritinib + FLAG
Sponsors
The First Affiliated Hospital, Zhejiang University
Eligibility
Sex/Gender
All
Age
14 Years to No maximum
Inclusion criteria
Inclusion criteria: 1) The subject is able to understand and willing to sign the informed consent form (for minor subjects, legal guardian is required to agree to participate in this study and sign the informed consent form); 2) Subjects must have R/R AML, i.e., meet the Chinese Guidelines for the Diagnosis and Treatment of Relapsed/Refractory Acute Myelogenous Leukemia (2021): • Diagnostic criteria for relapsed AML: Recurrence of leukemic cells in peripheral blood or blasts in bone marrow > 0.050 (except for other causes such as bone marrow regeneration after consolidation chemotherapy) or extramedullary leukemic cell infiltration after complete remission (CR). • Diagnostic criteria for refractory AML: Treatment-naïve patients refractory to 2 courses of standard regimen; patients who relapse within 12 months after consolidation and intensive treatment after CR; patients who relapse after 12 months but fail to respond to conventional chemotherapy; patients who relapse twice or more; and patients with persistent extramedullary leukemia; 3) Aged = 14 years old (body surface area = 1.2 m2 for patients aged 14 years), male or female (including 14 years old); 4) Patients with C-KIT D816 or C-KIT N822 mutation detected by bone marrow molecular biology, and with CBFB::MYH11 gene, or with RUNX1::RUNX1T1 fusion gene detected; 5) Performance status (ECOG PS) 0-2; 6) Adequate organ and bone marrow function, defined as follows: • Serum total bilirubin = 1.5 × upper limit of normal (ULN), unless it is considered to be due to Gilbert’s syndrome or leukemia; • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) = 3.0 × ULN, unless considered to be due to leukemia; • Platelet count = 20 × 109/L; • Serum creatinine = 2.0 × ULN • Creatinine clearance rate > 40 mL/min based on estimated Cockcroft-Gault glomerular filtration rate (GFR); Note: Estimated glomerular filtration rate (eGFR, Cockcroft-Gault formula): Ccr = (140 - age) × weight (kg)/(72 × Scr (mg/dl)), calculated as × 0.85 for female; 7) Subjects must undergo bone marrow aspiration and/or biopsy to confirm diagnosis and evaluate AML; 8) Females of childbearing potential must agree to use contraception (e.g., intrauterine device, contraceptive pill, or condom) during the study and for 3 months after the end of the study; must have a negative serum pregnancy test within 7 days before study enrollment and must be non-lactating; male subjects must agree to use contraception during the study and for 3 months after the end of the study period.
Exclusion criteria
Exclusion criteria: 1) Patients who are allergic to analogue of KIT inhibitors; 2) Patients who have received prior treatment with midostaurin; 3) Patients who have received prior treatment with mutation-specific C-KIT inhibitor and experienced disease progression during the treatment; 4) Patients with TP53 or FIT3-ITD mutation at the time of relapse; 5) Patients who have other malignant tumors within 3 years before enrollment and are still receiving/requiring anti-tumor treatment; 6) Patients who have clinically significant cardiac diseases, including: • Myocardial infarction or unstable or uncontrolled condition (e.g., unstable angina, congestive heart failure, New York Heart Association (NYHA) Class ?-?) within 6 months prior to initiation of study treatment); • Arrhythmia (NCI CTCAE V5.0 criteria Grade = 3) or clinically significant electrocardiogram (ECG) abnormalities; • ECG showing baseline corrected QT (QTc) interval > 470 ms; 7) Grade > 2 peripheral neuropathy or neuralgia (CTCAE 5.0 criteria); 8) Patients with intracranial hemorrhage by brain CT 9) Major surgery within 3 months prior to enrollment, or incomplete recover from earlier surgery, or plan to have surgery during the study period or within 3 months after the last dose of study drug (note: surgery under local anesthesia or kyphoplasty or vertebroplasty is not included); 10) Patients with concomitant diseases (uncontrolled diabetes, acute diffuse infiltrative lung disease, neurological or psychiatric disorders, etc.) or any other conditions that may confound the study results or affect the completion of this study as determined by the investigator; 11) Patients who are receiving any other investigational drugs or investigational medical devices; 12) Patients develop severe complications of leukemia that are immediately life-threatening, e.g., uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation; 13) Patients with other conditions that, as determined by the investigator, make them unsuitable for this study; 14) Patients who have received cell therapy within 6 months before the first dose, or radiotherapy/chemotherapy/targeted therapy/immunotherapy within 4 weeks before the first dose (if the 5 half-lives of the drug metabolism are less than 4 weeks, the 5 half-lives shall prevail).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| incidence of dose-limiting toxicity (DLT);incidence and severity of adverse events and serious adverse events;clinically significant abnormal changes in laboratory tests and other examinations (physical examination, ECOG score, laboratory tests, ECG, vital signs, etc.);recommended dose for phase II (RP2D); | — |
Secondary
| Measure | Time frame |
|---|---|
| pharmacokinetics;objective response rate;complete remission;CR was associated with incomplete recovery of blood cells;time to complete response;duration of remission;MRD-negative rate;progression-free survival (PFS);overall survival;PR;MLFS; | — |
Countries
China
Contacts
Public ContactJin Jie
The First Affiliated Hospital, Zhejiang University School of Medicine
Outcome results
None listed