A Clinical Study of HMPL-506 in Patients With Hematological Malignancies

The study is divided into 2 Phases, Dose Escalation Phase &Dose Expansion Phase.

Dose Escalation Phase: In this phase, the accelerated titration design with the modified toxicity probability interval-2 (mTPI-2) design will be used for dose escalation and determination of the Maximum tolerated dose (MTD). Approximately 30 to 38 patients with MLL-rearranged and/or NPM1-mutant relapsed/refractory Acute Myeloid Leukemia (AML) and Acute Lymphocytic Leukemia (ALL) will be enrolled in this phase.

The determined starting dose of HMPL-506, i.e., 50 mg QD (orally once daily, approximately every 24 hours）, According to the Safety Monitoring Committee (SRC) safety, efficacy and PK/PD data of the first 4 patients in the 50 mg QD dose group of HMPL-506, it was decided to administer the pre dose + therapeutic dose, initially set the pre dose for one week (or duration based on SRC decision), and then continue the treatment at the therapeutic dose.

The Pre-dose is initially set as 25 mg QD (or the lead dose selected according to SRC decision), The preliminary set escalation gradient includes: a. QD dosing: 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, etc.; b. BID dosing: starting dose of 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, etc.; or refer to the SRC-determined incremental gradient.

According to the Safety Monitoring Committee (SRC) safety, efficacy and PK/PD data of the first 4 patients in the 50 mg QD dose group of HMPL-506, it was decided to administer the lead dose + therapeutic dose, initially set the lead dose for one week (or duration based on SRC decision), and then continue the treatment at the therapeutic dose.

The dose will be escalated based on available efficacy and safety data in conjunction with preclinical pharmacodynamics, PK data. safety review committee（SRC） meetings will be held to discuss the necessity of expanding the sample size of 1 or more selected dose groups, with approximately 6 to 10 patients in each dose group, to obtain a sufficient amount of safety and efficacy data.

Dose Expansion Phase: The dose expansion phase will be conducted after the determination of the recommended phase 2 dose(RP2D) and/or Maximum tolerated dose （MTD） and approximately 30 to 60 patients with hematological malignancies will be enrolled to further evaluate the safety, tolerability and preliminary efficacy of HMPL-506. Patients enrolled in this phase will be divided into three cohorts:

• MLL-rearranged and/or NPM1-mutant relapsed/refractory AML
• MLL-rearranged relapsed/refractory ALL
• Relapsed/refractory multiple myeloma (MM), and AML with genetic alterations such as NUP214 or NUP98 fusion

Approximately 10 to 20 patients are planned to be enrolled in each cohort. Enrolled patients will receive oral dose of HMPL-506 at the RP2D in 28-day cycles until disease progression/relapse (except for patients who are assessed by the investigator as continuing receiving benefit from treatment with the investigational product), death, intolerable toxicity, receiving another anti-tumor therapy, failure to further benefit from the treatment as judged by the investigator, patient withdrawal, loss to follow-up or end of the study, whichever comes first.

Inclusion criteria

• Subjects must meet all of the following criteria to be eligible for enrolment.

• Having understood this study adequately and being voluntary to sign the ICF;
• Age ≥18 years;
• 1) Dose escalation phase: patient with MLL-rearranged and/or NPM1-mutant relapsed/refractory AML or ALL (confirmed as per the 2022 World Health Organization (WHO) Classification of Myeloid Neoplasms and Acute Leukemia): 2) Dose expansion phase: approximately 10 to 20 patients will be enrolled in each of the following cohorts

• MLL-rearranged and/or NPM1-mutant relapsed/refractory AML
• MLL-rearranged relapsed/refractory ALL
• Relapsed/refractory MM (which can be screened and enrolled without biomarker testing), and AML harboring genetic alterations such as NUP214 or NUP98 fusion
• Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2;
• Agree to undergo bone marrow aspiration and/or biopsy before and during treatment;
• Women patients of childbearing potential must agree to use highly effective contraceptive methods from screening until 30 days after discontinuation of study treatment, and their male partners must use condoms. See Appendix 11 (Definition of Women of Childbearing Potential [WOCBP] and Acceptable and Unacceptable Contraceptive Methods) for more details. And women patients of childbearing potential should agree not to donate eggs (or oocytes) for reproductive purposes during this period.
• Male patients with a female partner of childbearing potential must agree to use condoms when having intercourse during the study and within 30 days after discontinuation of the investigational product. Patients should avoid sperm donation or freezing of sperm during the study and within 30 days after discontinuation of the investigational product.

Exclusion criteria

• Subjects will be excluded from this study project if they meet any of the following criteria:

• Patients who have previously received treatment with menin inhibitors and experienced progression during treatment;
• Patients with definite active central nervous system (CNS) leukemia (prior CNS leukemia has been treated and controlled, but a cerebrospinal fluid test through lumbar puncture is required at screening to confirm the absence of CNS involvement);
• Serum total bilirubin (TBIL) > 1.5 × the upper limit of normal (ULN), with the exception of the following patients:

• Patients with Gilbert's disease, with normal alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and serum TBIL ≤ 3 × ULN
• ALT or AST > 3 × ULN in the absence of liver involvement with leukemia or ALT or AST > 5 × ULN in the presence of liver involvement with leukemia (the latter criterion is not applicable in the dose escalation phase);
• Glomerular filtration rate or creatinine clearance estimated using Cockcroft-Gault formula < 50 mL/min.
• International normalized ratio (INR) > 1.5 × ULN or activated partial thromboplastin time (aPTT) > 1.5 × ULN; this criterion is not applicable in patients who are receiving anticoagulant therapy.
• Known history of clinically significant liver disease, including viral hepatitis or other types of hepatitis:

• Patients with hepatitis B (HBV) (HBsAg or HBcAb positive) can be enrolled if they test negative for HBV DNA by PCR, but the HBV DNA test should be performed every cycle
• Patients with hepatitis C (HCV) can be enrolled if they test negative for HCV RNA by PCR.
• Known human immunodeficiency virus (HIV) infection.
• Women who are pregnant (with a positive pregnancy test before administration) or breastfeeding.
• History of stroke or intracranial hemorrhage within 6 months prior to the first dose of the investigational product.
• Patients with other primary malignancies within the last 5 years, but patients with the following non-invasive tumors that have been treated with curative intent are exceptions: basal cell carcinoma of skin, squamous cell carcinoma of skin, in situ carcinoma of cervix and breast cancer in situ.
• Patients who meet any of the following cardiac function-related criteria:

• Any clinically significant abnormal heart rhythm or conduction requiring clinical intervention.
• Hereditary long QT syndrome or QTcF > 470 msec.
• Clinically significant cardiovascular diseases, including acute myocardial infarction, unstable angina pectoris, coronary artery bypass grafting within 6 months prior to enrollment, New York Heart Association (NYHA) Class III or above congestive heart failure, left ventricular ejection fraction (LVEF) < 50%, or uncontrolled hypertension (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg), or mean heart rate > 100 beats/min on triplicate electrocardiograms (ECGs) at screening.
• Receipt of systemic anti-tumor therapy or radiotherapy within 2 weeks prior to initiation of study treatment:

• For patients with increased peripheral white blood cell count (WBC > 25 × 109/L), use of hydroxycarbamide is allowed to control peripheral WBC before enrollment and during HMPL-506 treatment.
• Prophylactic intrathecal injection of chemotherapy drugs (cytarabine, dexamethasone and methotrexate) to prevent CNS leukemia is allowed.
• Patients who have received HSCT within 60 days before initiation of study treatment, or are receiving immunosuppressive therapy after HSCT at screening, or require medical intervention to control graft versus host disease (GVHD):

• Patients who use fixed-dose oral glucocorticoids and/or topical glucocorticoids for the treatment of skin GVHD can be enrolled.
• Patients who have received treatment with herbal and traditional medicines/their active ingredients with definite anti-tumor activity within 1 week before initiation of study treatment.
• Use of potent inducers or inhibitors of CYP3A4 within 2 weeks (3 weeks for St John's wort) or 5 half-lives (whichever is longer) before initiation of study treatment.
• An interval of less than 2 weeks from the last dose of any small molecular drug or of less than 4 weeks from the last dose of any macromolecular drug (e.g., antibody drugs) administered during previous participation in other drug clinical trials before treatment initiation in this study.
• Patients who have undergone major surgery within 4 weeks prior to the first dose of the investigational product.
• Toxicities from previous anti-tumor treatments have not yet recovered to Grade ≤ 1 (excluding alopecia).
• Patients with uncontrolled active infection requiring hospitalization or intravenous antibiotics (defined as persistent signs/symptoms related to the infection without improvement despite receipt of appropriate anti-infection therapy and/or other treatments); or unexplained pyrexia with a temperature above 38.5℃ during the screening period (only patients with tumor fever as judged by the investigator can be enrolled);

• Patients with neutropenia who, in the opinion of the investigator, require prophylactic intravenous antibiotics can be enrolled
• Presence of conditions that may affect the absorption of the investigational product as judged by the investigator, such as inability to take drugs orally, past surgery history or severe gastrointestinal diseases including dysphagia and active gastric ulcer.
• Patients with poor compliance who are judged by the investigator as not suitable for participation in this clinical study.
• Any other disease, metabolic abnormality, physical examination abnormality or clinically significant laboratory test abnormality, based on which the investigator has reason to suspect that the patient has certain disease or condition that is not suitable for treatment with the investigational product, or that will affect the interpretation of study results or will put the patient at high risk.