A Study of BN104 in the Treatment of Acute Leukemia

Study Overview
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Brief Summary
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The Phase I/II trial is to learn the safety, pharmacokinetics, and preliminary efficacy of BN104 taken once daily or twice daily in patients with acute lymphocytic leukemia or acute myeloblastic leukemia.

Detailed Description
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The study is divided into 2 phases. Phase1 dose escalation part will enroll 19-42 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 10-12 patient with specific mutations (KMT2A gene rearrangement or NPM1 gene mutation) enrolled at dose optimization phase. Phase II expansion part will enroll 30-48 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 3 Acute Leukemia subgroup cohorts depends on their genotype. Cohort A: Subjects with Relapsed/refractory AML subjects with NPM1 mutations Cohort B: Subjects with relapsed/refractory AML with KMT2A rearrangements. Cohort C: Subjects with relapsed/refractory ALL or mixed spectrum leukemia with KMT2A rearrangements 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.

Official Title
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A PhaseI/II, Multicenter, Open-label Clinical Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of the Menin Inhibitor BN104 in the Treatment of Patients With Relapsed/Refractory Acute Leukemia

Conditions
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ALL, Adult, AML, Adult

Intervention / Treatment
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* Drug: BN104


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have been fully informed about the study and have voluntarily signed the ICF; patients with relapsed/refractory acute leukemia (including AML, ALL, and mixed-spectrum leukemias, except acute promyelocytic leukemia) diagnosed according to the 2022 World Health Organization (WHO) criteria, and for whom there are no superior therapeutic alternatives as assessed by the investigator, and who meet at least one of the following criteria: Primary refractory disease; First relapse with duration of first remission ≤ 12 months Relapsed/refractory disease after 2 or more lines of therapy; Relapse after allogeneic hematopoietic stem cell transplantation (patients who relapse after autologous hematopoietic stem cell transplantation and immune cell therapy [including, but not limited to, chimeric antigen receptor T-cells] may also be enrolled if there is no superior therapeutic regimen in the investigator's assessment); Notes: Secondary AML or AML transformed by myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) may also be enrolled; Control of peripheral blood leukocyte counts with hydroxyurea is allowed prior to study drug administration and for 2 weeks after initiation of study drug administration. For Phase I dose-optimization and Phase II subjects, the combination of NPM1 mutation or KMT2A rearrangement should also be specified. Age ≥ 18 years; ECOG score 0-2; Adequate hepatic, renal, and cardiac functions Expected survival of more than 12 weeks as judged by the investigator Be able to perform treatments, visits, and undergo study-related testing as required by the protocol Female patients of childbearing potential or male patients whose female partners are of childbearing potential must agree to use an effective method of contraception, such as a double-barrier method of contraception, condoms, oral or injectable contraceptives, and intrauterine devices (IUDs), for the duration of the study and for 30 days after the last study dose. Postmenopausal women (>45 years of age and menopause for more than 1 year) and surgically sterilized women are not subject to this condition. Exclusion Criteria: definite active central nervous system (CNS) leukemia (previous CNS leukemia that has been treated and controlled, but requires screening period lumbar puncture for cerebrospinal fluid examination for confirmation, or routine receipt of standard CNS prophylaxis are acceptable); a known history of clinically significant liver disease, including viral or other hepatitis or cirrhosis known human immunodeficiency virus (HIV) infection; pregnant (positive screening pregnancy test) or lactating females; meet any of the following cardiac-related criteria: Hereditary long QT interval syndrome or QTcF > 450 msec; Various clinically significant cardiovascular diseases, including acute myocardial infarction, unstable angina pectoris, coronary artery bypass grafting within 6 months prior to enrollment, congestive heart failure graded by the New York Heart Association (NYHA) as grade 2 or higher (inclusive); the patient has suffered from other malignant tumors within the past 5 years, except for radically treated basal cell carcinoma of the skin, carcinoma in situ of the breast or carcinoma in situ of the cervix; has received autologous hematopoietic stem cell transplantation (ASCT) or chimeric antigen receptor T cell (CAR T) therapy within 60 days prior to screening, or has not recovered from toxicity associated with ASCT or CAR-T therapy allogeneic hematopoietic stem cell transplantation has been performed within 100 days prior to screening, or the patient is still comorbid with active acute or chronic graft-versus-host disease, or the patient is still in need of immunosuppressive therapy; anti-leukemia therapy, including chemotherapy, radiotherapy, hormone therapy, or immunotherapy (excluding hydroxyurea) within 2 weeks prior to the start of study treatment; prior participation in a clinical study of another drug less than 2 weeks or 5 half-lives for small molecules and less than 4 weeks or 5 half-lives for large molecules (e.g., antibody-based drugs) from the last dose, whichever is shorter prior treatment with targeted menin; prior toxic reactions to anti-leukemia therapy that have not returned to grade 0 or 1 levels (except alopecia areata) uncontrolled active infection: Patients with non-serious infectious complications (e.g., oral Candida infection or uncomplicated urinary tract infection) for which oral/topical anti-infective therapy is being applied may be enrolled; Patients with severe infections requiring hospitalization or intravenous antibiotic therapy within 14 days prior to enrollment, patients with no evidence of infection, and patients receiving prophylactic anti-infective, antifungal, or antiviral therapy for prolonged neutropenia may be enrolled; Patients treated with intravenous antibiotics or hospitalized for febrile neutropenia, but no evidence of infectious etiology has been found, and patients with normal body temperature for more than 72 hours without antipyretic medication may be enrolled; subjects with known dysphagia, short bowel syndrome, gastroparesis, or other conditions that limit oral drug intake or gastrointestinal absorption; a history of severe allergy to menin inhibitors or hypersensitivity to any of the components of BN104 inadequate patient compliance with participation in this clinical study as judged by the investigator; any other disease, metabolic abnormality, physical examination abnormality, or clinically significant laboratory test abnormality that, in the judgment of the investigator, gives reason to suspect that the patient has a disease or condition that is inappropriate for the use of the study medication, or that will interfere with the interpretation of the results of the study, or that places the patient at high risk.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 200mg QD<br>The starting dose cohort(200mg QD) where accelerated titrated dose-escalation method is applied, a patient will initially receive a single dose BN104 on Day 1 of Cycle 0 (3 days prior to Day 1 of Cycle 1) to evaluate the concentration of BN104 up to 72 hours after administration and the safety of single dose of BN104. Then the patient begins continuous treatment with BN104 200 mg QD on Day 1 of Cycle 1 by every 28-day treatment cycle until disease progression, intolerable toxicity, withdrawal of consent, loss to follow-up, death, or other conditions in which patients are not suitable for study treatment, whichever occurs first. | Drug: BN104<br>* Will be administered orally once daily (approximately every 24 hours) for the first cohort or twice daily (approximately every 12 hours) for the subsequent cohorts.<br>|
| Experimental: 200mg BID<br>After completion of DLT evaluation for the first dose cohort (200 mg QD), patients will begin to receive twice daily (BID) dosing frequency in each 28-day treatment cycle for the subsequent dose cohorts for which conventional 3+3 design is used until disease progression, intolerable toxicity, withdrawal of consent, loss to follow-up, death, or other conditions in which patients are not suitable for study treatment, whichever occurs first. | Drug: BN104<br>* Will be administered orally once daily (approximately every 24 hours) for the first cohort or twice daily (approximately every 12 hours) for the subsequent cohorts.<br>|
| Experimental: 400mg BID<br>After completion of DLT evaluation for the first dose cohort (200 mg QD), patients will begin to receive twice daily (BID) dosing frequency in each 28-day treatment cycle for the subsequent dose cohorts for which conventional 3+3 design is used until disease progression, intolerable toxicity, withdrawal of consent, loss to follow-up, death, or other conditions in which patients are not suitable for study treatment, whichever occurs first. | Drug: BN104<br>* Will be administered orally once daily (approximately every 24 hours) for the first cohort or twice daily (approximately every 12 hours) for the subsequent cohorts.<br>|
| Experimental: 600 BID<br>After completion of DLT evaluation for the first dose cohort (200 mg QD), patients will begin to receive twice daily (BID) dosing frequency in each 28-day treatment cycle for the subsequent dose cohorts for which conventional 3+3 design is used until disease progression, intolerable toxicity, withdrawal of consent, loss to follow-up, death, or other conditions in which patients are not suitable for study treatment, whichever occurs first. | Drug: BN104<br>* Will be administered orally once daily (approximately every 24 hours) for the first cohort or twice daily (approximately every 12 hours) for the subsequent cohorts.<br>|
| Experimental: 800 BID<br>After completion of DLT evaluation for the first dose cohort (200 mg QD), patients will begin to receive twice daily (BID) dosing frequency in each 28-day treatment cycle for the subsequent dose cohorts for which conventional 3+3 design is used until disease progression, intolerable toxicity, withdrawal of consent, loss to follow-up, death, or other conditions in which patients are not suitable for study treatment, whichever occurs first. | Drug: BN104<br>* Will be administered orally once daily (approximately every 24 hours) for the first cohort or twice daily (approximately every 12 hours) for the subsequent cohorts.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PhaseI Incidence of Dose Dose limiting toxicities(DLTs) | DLTs will be evaluated at the end of cycle 1(28 days after receiving BN104) for each dose level by evaluating abnormal laboratory examinations by the Investigator. | DLT last 28days(at the end of cycle 1 for each dose) | 
| PhaseI Incidence of serious adverse events(SAEs) | SAEs will be recorded in the eCRF from time of the signing informed consent through 30 days after the last dose of BN104. | 36 month | 
| PhaseII efficacy assessment | To assess the preliminary anti-tumor activity of BN104 based on Complete response (CR), Complete response with partial recovery of hematology (CRh), Complete response with incomplete hematological recovery (CRi) assessed by the Investigator | 36 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I/II Evaluate the number and frequency of adverse events (AEs) | Evaluate the number and frequency of adverse events (AEs) by evaluating abnormal laboratory examinations by the Investigator at each clinical visit from time of the signing informed consent through 30 days after the last dose of BN104. | 36 months | 
| Phase I/II Evaluate patient vital signs | Evaluate vital signs, including body temperature, heart rate, respiration rate, and blood pressure by the Investigator at each clinical visit before taking BN104. | 36 months | 
| Phase I/II Evaluate electrocardiogram (ECG) assessments | Evaluate electrocardiogram (ECG) assessments by the Investigator Prior to any examination at each clinical visit to monitor heart rate, R-R interval, QT interval and QTcF interval, QRS, and P-R interval times. | 36 months | 
| Phase I/II pharmacokinetic Maximum concentration (Cmax) | To characterized Maximum Plasma Concentration [Cmax] of BN104 by collecting and evaluating the serum at the protocol specified time points. | 36 months | 
| Phase I/II pharmacokinetic Peak time(Tmax) | To characterized Peak time(Tmax) of BN104 by collecting and evaluating the serum at the protocol specified time points | 36 months | 
| Phase I/II pharmacokinetic Clearance half-life (T1/2) | To characterized Clearance half-life (T1/2) of BN104 by collecting and evaluating the serum at the protocol specified time points | 36 months | 
| Phase I/II pharmacokinetic Area under the blood concentration-time curve (AUC0-t) | To characterized Area under the blood concentration-time curve (AUC0-t) of BN104 by collecting and evaluating the serum at the protocol specified time points. | 36 months | 
| Phase I/II pharmacokinetic metabolite M1 | To characterized BN104 major metabolite M1 by collecting and evaluating the serum at the protocol specified time points. | 36 months | 
| Phase I/II efficacy assessment based on Complete response (CR) | To assess the preliminary anti-tumor activity of BN104 based on Complete response (CR) assessed by the Investigator at Cycle2. cycle3 and every 2 cycles thereafter through peripheral blood tests, detection of bone marrow primitive cell ratio and other morphological changes by bone marrow aspiration/biopsy | 36 months | 
| Phase I/II efficacy assessment based on Complete response with partial recovery of hematology (CRh) | To assess the preliminary anti-tumor activity of BN104 based on Complete response with partial recovery of hematology (CRh) assessed by the Investigator at Cycle2. cycle3 and every 2 cycles thereafter through peripheral blood tests, detection of bone marrow primitive cell ratio and other morphological changes by bone marrow aspiration/biopsy | 36 months | 
| Phase I/II efficacy assessment based on Complete response with incomplete hematological recovery (CRi) | To assess the preliminary anti-tumor activity of BN104 based on Complete response with incomplete hematological recovery (CRi) assessed by the Investigator at Cycle2. cycle3 and every 2 cycles thereafter through peripheral blood tests, detection of bone marrow primitive cell ratio and other morphological changes by bone marrow aspiration/biopsy | 36 months | 
| Phase I/II efficacy assessment Objective response rate (ORR) | To assess the preliminary anti-tumor activity of BN104 based on Objective response rate (ORR) assessed by the Investigator at Cycle2. cycle3 and every 2 cycles thereafter through peripheral blood tests, detection of bone marrow primitive cell ratio and other morphological changes by bone marrow aspiration/biopsy | 36 months | 
| Phase I/II efficacy assessment based on Duration of response (DOR) | To assess the preliminary anti-tumor activity of BN104 based on Duration of response (DOR) assessed by the Investigator at Cycle2. cycle3 and every 2 cycles thereafter through peripheral blood tests, detection of bone marrow primitive cell ratio and other morphological changes by bone marrow aspiration/biopsy | 36 months | 
| Phase I/II efficacy assessment based on Event-free survival (EFS) | To assess the preliminary anti-tumor activity of BN104 based on Event-free survival (EFS) assessed by the Investigator at Cycle2. cycle3 and every 2 cycles thereafter through peripheral blood tests, detection of bone marrow primitive cell ratio and other morphological changes by bone marrow aspiration/biopsy | 36 months | 
| Phase I/II efficacy assessment based Relapse-free survival (RFS) | To assess the preliminary anti-tumor activity of BN104 based Relapse-free survival (RFS) assessed by the Investigator at Cycle2. cycle3 and every 2 cycles thereafter through peripheral blood tests, detection of bone marrow primitive cell ratio and other morphological changes by bone marrow aspiration/biopsy | 36 months | 
| Phase I/II efficacy assessment based on Overall survival (OS) | To assess the preliminary anti-tumor activity of BN104 based on Overall survival (OS) assessed by the Investigator at Cycle2. cycle3 and every 2 cycles thereafter through peripheral blood tests, detection of bone marrow primitive cell ratio and other morphological changes by bone marrow aspiration/biopsy | 36 months | 
| Phase I/II efficacy assessment Cumulative relapse rate (CIR) | To assess the preliminary anti-tumor activity of BN104 based on Cumulative relapse rate (CIR) assessed by the Investigator at Cycle2. cycle3 and every 2 cycles thereafter through peripheral blood tests, detection of bone marrow primitive cell ratio and other morphological changes by bone marrow aspiration/biopsy | 36 months | 
| PhaseI pharmacokinetic biomarkers | Changes in pharmacokinetic biomarkers (e.g., HOXA9, MEIS1, CD11b, etc.) before and after BN104 administration, and correlations with dosing and efficacy | 36 months | 
| correlation between specific gene alterations and clinical efficacy | The correlation between specific gene alterations (such as NPM1 mutation, KMT2A rearrangement) and other gene alterations (such as FLT3 mutation/fusion, TP53 mutation, NUP98 fusion, etc.), and clinical efficacy. | 36 months |