A Study of BN104 in the Treatment of Acute Leukemia

The study is divided into 2 phases. Phase1 part will enroll 98 patients to evaluate safety and tolerance of BN104 in patients with relapsed/refractory (R/R) Acute Leukemia to determine maximum tolerated dose and recommended phase2 dose (RP2D), including approximately 66 adult patients and 32 adolescent patients with specific mutations (KMT2A gene rearrangement, NPM1 gene mutation, NUP98 mutation) enrolled at phaseI.

Phase II expansion part will enroll 168 patients and be conducted at the selected dose level to further evaluate the safety and tolerability of BN104, as well as preliminary efficacy in Acute leukemia subjects with specific mutations (KMT2A gene rearrangement or NPM1 gene mutation). Patients will be allocated into 2 Acute Leukemia subgroup cohorts depends on their genotype.

• Cohort A: Patients with Relapsed/refractory AML subjects with NPM1 mutations
• Cohort B: Patients with relapsed/refractory acute leukaemia with KMT2A rearrangement (including AML, ALL, or MPL)

Patients will receive orally administrated BN104 once daily or twice daily. Study drug will be administered in 28-day cycles until disease progression or unacceptable toxicity, death, Informed consent withdraw ect.

Laboratory tests will be performed weekly in Cycles 1-2, bi-weekly in Cycle3 and every 4weeks from Cycle 4 onwards. Efficacy assessment will be performed on baseline, C2D1, C3D1 and every 2 cycles from Cycle3 onwards. Additional clinical assessments and laboratory tests may be performed at discretion of the investigator as clinically indicated.

Inclusion criteria

• Have been fully informed about the study and have voluntarily signed the ICF;
• Patients diagnosed with relapsed/refractory acute leukaemia (including AML, ALL, and mixed-phenotype acute leukaemia, excluding acute promyelocytic leukaemia) according to the World Health Organization (WHO) criteria in 2022, with bone marrow morphological changes (blasts/immature cells ≥ 5%), and who have been evaluated by the investigator to have no better treatment options, must meet at least one of the following conditions:

• Primary refractory disease, newly diagnosed disease that show no response after 2 cycles of standard treatment;
• First relapse, relapsed within 12 months after CR/CRh/CRi following consolidation/intensive therapy;
• Relapsed after 12 months and unresponsive to conventional salvage chemotherapy;
• Patients with 2 or more relapses;
• Patients intolerant to intensive chemotherapy who experience disease progression during continuous low-intensity therapy; Note: Patients with secondary AML or AML transformed from MDS, MPN, can also be enrolled, but they need to meet the above criteria after the disease has transformed into AML;
• For all Phase I patients, the presence of NPM1 mutation, or KMT2A rearrangement, or NUP98 rearrangement must be confirmed,During Phase I, patients with other acute leukemia subtypes shown to depend on menin-KMT2A interaction (e.g., UBTF-TD) or driven by HOXA/MEIS1 overexpression may also be eligible after consultation with the Sponsor's Medical Monitor;
• Patients in the Phase II (single-arm pivotal clinical study) must have a confirmed NPM1 mutation or KMT2A rearrangement. Enrollment based on local testing results is acceptable with a copy of the test report provided; however, all patients are required to submit screening bone marrow samples to the central laboratory ,Eligible NPM1 mutations include exon12 type A, B, and D mutations ; other NPM1 mutations causing cytoplasmic localization require sponsor pre-approval for enrollment. KMT2A rearrangements exclude non-fusion rearrangements involving KMT2A partial tandem duplication (KMT2A-PTD).
• Peripheral blood white blood cell count ≤ 35 × 109/L (use of hydroxyurea to control peripheral white blood cell count is permitted);
• Age ≥ 12 years (for adolescent patients aged 12 years or older but not yet 18 years old, weight must be ≥ 40 kg);
• ECOG score 0-2;
• Adequate hepatic, renal, and cardiac functions
• Expected survival of more than 12 weeks as judged by the investigator
• For patients with D-dimer test results > 5 × ULN during screening, relevant tests (such as rechecking coagulation function after a certain interval, lower extremity deep vein ultrasound, etc.) are required to exclude deep vein thrombosis, hypercoagulation, and disseminated intravascular coagulation before enrollment;
• Able to undergo treatment, visits, and study-related examinations as required by the protocol;
• Female patients of childbearing potential or male patients whose female partners are of childbearing potential must agree to use effective methods of contraception during the study and for 30 days after the last dose of study drug, such as double barrier methods, condoms, oral or injectable contraceptives, intrauterine devices, etc. Postmenopausal women (> 45 years old and amenorrheic for more than 1 year) and surgically sterilized women are not subject to this condition.

Exclusion criteria

• Known active central nervous system (CNS) leukaemia (including imaging abnormalities and CSF smear or flow cytometry indicating leukaemia cells; prior CNS leukaemia that has been treated and controlled is acceptable, but requires screening lumbar puncture and CSF test for confirmation, or routine standard CNS prophylaxis is acceptable);
• Known history of clinically significant liver disease, including viral or other hepatitis or hepatic cirrhosis:

• Hepatitis B surface antigen (HBsAg) seropositive, requires Hepatitis B virus (HBV) DNA negative for enrollment;
• For Hepatitis C virus (HCV) antibody seropositive patients, HCV RNA negative result is required for enrollment.
• Known human immunodeficiency virus (HIV) infection;
• Pregnancy (positive pregnancy test at screening) or lactating females;
• Any of the following cardiac-related criteria is met:

• Hereditary long QT syndrome or QTcF > 450 msec;
• Various clinically significant cardiovascular disorders, including acute myocardial infarction, unstable angina pectoris, coronary artery bypass surgery within 6 months prior to enrollment, cardiac failure congestive of New York Heart Association (NYHA) Class 2 or higher (including Class 2), etc.;
• Patient has other concomitant malignant tumours, except for:

• Curatively treated skin basal cell carcinoma, breast cancer in situ, or cervical carcinoma in situ, etc.;
• Patients with low-grade lymphoma who are in CR, asymptomatic, without large mass lesions, and do not require systemic therapy or radiotherapy;
• Other malignant tumours treated with curative intent, with CR achieved for at least 2 years, and no requirement for systemic maintenance therapy or radiotherapy;
• Received autologous haematopoietic stem cell transplant (ASCT) or Chimeric Antigen Receptor T-cell (CAR-T) therapy within 60 days prior to screening, or toxicity related to ASCT or CAR-T therapy has not yet resolved;
• Underwent allogeneic HSCT within 100 days prior to screening, or the patient still has Grade ≥ 2 acute graft versus host disease or chronic graft versus host disease requiring systemic treatment, or the patient still requires immunosuppression (prednisone ≤ 10 mg/day or equivalent dose of other corticosteroids is permissible for screening; corticosteroids need to be gradually tapered and discontinued after enrolment unless there is a specific reason);
• Received donor lymphocyte infusion (DLI) within 28 days prior to screening;
• Prior anti-leukaemia therapy, including chemotherapy, radiotherapy, hormone therapy, targeted therapy, or immunotherapy (excluding hydroxyurea), etc., less than 2 weeks or 5 half-lives (whichever is shorter) before the start of study treatment;
• Previous participation in other drug clinical studies, with less than 2 weeks or 5 half-lives since the last use of a small molecule drug, or less than 4 weeks or 5 half-lives for large molecule drugs (such as antibody drugs), whichever is shorter;
• Previous treatment targeting menin;
• Toxicity from previous anti-leukaemia therapy has not recovered to Grade 0 or 1 (except for alopecia and cytopenias reasonably considered related to the underlying disease);
• Patients who had a chest CT scan within 1 month prior to screening showing pulmonary nodules need to undergo a T-SPOT.TB test (Tuberculosis infection T-cell spot test) during screening; those with a positive result must be excluded (no additional test required if no chest CT scan was performed within 1 month prior to screening);
• Uncontrolled active infection:

• Patients with non-severe infectious complications (such as oral candida infection or uncomplicated urinary tract infection) currently receiving oral/topical anti-infective therapy may be enrolled;
• Patients with severe infection requiring hospitalisation or intravenous antibiotic therapy within 14 days prior to enrollment, patients with no evidence of infection receiving prophylactic anti-infective, anti-fungal, or anti-viral therapy due to prolonged neutropenia may be enrolled;
• Patients receiving intravenous antibiotic therapy or hospitalized for febrile neutropenia, but with no evidence of infectious etiology found, and whose body temperature has been normal for more than 72 hours without antipyretics, may be enrolled;
• Patient has known dysphagia, short-bowel syndrome, gastroparesis, or other conditions limiting oral drug intake or gastrointestinal absorption;
• History of severe allergy to menin inhibitors or allergy to any component of BN104;
• Investigator-judged insufficient compliance of the patient to participate in this clinical study;
• Any other disease, metabolic abnormality, physical examination abnormal, or clinically significant laboratory test abnormal that, in the investigator's judgment, gives reason to suspect that the patient has a disease or condition unsuitable for the use of the study drug, or that will affect the interpretation of the study results, or place the patient at high risk.