A Study to Evaluate HMPL-306 in Patients With IDH1- and IDH2-mutated Acute Myeloid Leukemia

An open-label design is adopted in this study. All patients will first undergo pre-screening to determine the mutation status of IDH, and all patients will be assigned to the registry study of the corresponding cohorts of IDH1 and IDH2 based on the pre-screening results. Patients with both IDH1 and IDH2 mutations will be enrolled in the IDH2 cohort. This study is divided into two cohorts. Cohort 1 includes R/R AML patients with IDH1-R132 mutations; Cohort 2 includes R/R AML patients with IDH2-R140 and R172 mutations. The two cohorts are designed independently and will be analyzed separately for statistical hypothesis testing. Patients in both cohorts will be randomized in a 1:1 ratio according to the central Interactive Web Response System (IWRS) into the test or control group, patients in the test group will receive HMPL-306 monotherapy at a dose of 250 mg once daily (QD) (Cycle 1, C1) + 150 mg QD \[starting from Cycle 2 (C2)\]. Patients in the control group will receive salvage chemotherapy (one of four options) consisting of two intensive chemotherapy regimens (MEC regimen and FLAG ± Ida regimen) and two non-intensive chemotherapy regimens (azacitidine and LoDAC)

Study overview This is a multicenter, randomized, open-label phase III clinical study to evaluate the efficacy, safety, and pharmacokinetic (PK) of HMPL-306 vs. salvage chemotherapy in patients with IDH1- and IDH2-mutated R/R AML.

An open-label design is adopted in this study. All patients will first undergo pre-screening to determine the mutation status of IDH, and all patients will be assigned to the registry study of the corresponding cohorts of IDH1 and IDH2 based on the pre-screening results. Patients with both IDH1 and IDH2 mutations will be enrolled in the IDH2 cohort. This study is divided into two cohorts. Cohort 1 includes R/R AML patients with IDH1-R132 mutations; Cohort 2 includes R/R AML patients with IDH2-R140 and R172 mutations. The two cohorts are designed independently and will be analyzed separately for statistical hypothesis testing. Patients in both cohorts will be randomized in a 1:1 ratio according to the central Interactive Web Response System (IWRS) into the test or control group, patients in the test group will receive HMPL-306 monotherapy at a dose of 250 mg once daily (QD) (Cycle 1, C1) + 150 mg QD \[starting from Cycle 2 (C2)\]. Patients in the control group will receive salvage chemotherapy (one of four options) consisting of two intensive chemotherapy regimens (MEC regimen and FLAG ± Ida regimen) and two non-intensive chemotherapy regimens (azacitidine and LoDAC). Before randomization, the investigator will preselect a salvage chemotherapy regimen based on the patient's condition. Patients will then be stratified and randomized based on their prior first-line treatment response (recurrence within 6 months after allogeneic Hematopoietic stem cell transplantation (HSCT), recurrence beyond 6 months after allogeneic HSCT, primary refractory disease without HSCT, recurrence within 6 months after achieving CR/CRh without HSCT, recurrence beyond 6 months after achieving complete response (CR)/CR with partial hematologic recovery (CRh) without HSCT) and the intensity of preselected chemotherapy regimen (intensive chemotherapy, non-intensive chemotherapy).

After the patient signs the pre-screening informed consent form (ICF), pre-screening (genetic testing) will be performed to determine the mutation status of IDH, so as to clarify the subsequent enrollment of the cohorts. Patients who meet the inclusion criteria will receive treatment in the test group or the control group. Each treatment cycle lasts for 28 days. Treatment will continue until progression of disease (PD)/recurrence, death, intolerable toxicity, initiation of a new anti-tumor therapy, the patient no longer benefits from the treatment as judged by the investigator, the patient or his/her legal representative requests to withdraw from the study, loss to follow-up, or end of study, whichever occurs first (the treatment cycle of MEC regimen and FLAG ± Ida regimen in the chemotherapy group will be adjusted based on the actual dosing, and a maximum of two treatment cycles is allowed).

Patients with PD in the control group should not be crossed over to the test group, and patients in the control group should not be crossed over to other salvage treatment regimens.

The information of treatment groups is as follows (consistent between the two cohorts):

* Test group: Patients will receive HMPL-306 monotherapy:

  - HMPL-306 PO at 250 mg QD (C1) + 150 mg QD (starting from C2), 28 days as a cycle.
* Control group: Patients will receive treatment with one of the following regimens, and the regimen will be selected by the investigator based on the patient's condition:

  * MEC regimen: etoposide injection 100 mg/m2, cytarabine injection 1000 mg/m2, mitoxantrone injection 8 mg/m2 QD IV for 5 consecutive days (Days 1-5).
  * FLAG ± Ida regimen: granulocyte colony stimulating factor (G-CSF) injection 300 mcg/m2 QD subcutaneous injection（SC） for 5 consecutive days (Days 1-5); fludarabine injection 30 mg/m2 QD IV for 5 consecutive days (Days 2-6); cytarabine injection 2000 mg/m2 QD IV for 5 consecutive days (Days 2-6); idarubicin injection 10 mg/m2 QD IV for 3 consecutive days (Days 2-4). This regimen can be given with or without Ida, which will be determined by the investigator based on the actual condition of the patient. After the completion of chemotherapy, the investigator will determine whether it is necessary to continue G-CSF administration. If necessary, G-CSF may be administered again until absolute neutrophil count (ANC) \> 0.5 × 109/L.
  * LoDAC: cytarabine injection 20 mg q12h SC or IV for 10 consecutive days (Days 1-10).
  * Azacitidine: azacitidine injection 75 mg/m2 QD SC or IV for 7 consecutive days (Days 1-7).

Phase of study:

The study phase includes a pre-screening period, a screening period, a treatment period, and a follow-up period \[including end-of-treatment (EOT) follow-up, EFS follow-up, and OS follow-up\].

Pre-screening period: The pre-screening period is defined as the period from signing the pre-screening ICF to obtaining test reports on IDH1 and IDH2 mutations. For patients without a previous report of IDH1 or IDH2 testing, specimens can be sent to the central laboratory for IDH1 and IDH2 mutation and other concomitant gene testing before screening and after signing the pre-screening ICF. Patients previously reported to be positive for IDH1/IDH2 mutation test can enter the screening period directly without pre-screening, if permitted by the investigator. Patients should not be enrolled until the test results are confirmed by the central laboratory.

The screening period is defined as the time from signing the main screening ICF until pre-dose on C1D1.

The treatment period is defined as the time from the first dose to EOT. EOT visit: Patients at EOT are required to return to the study site for an EOT follow-up visit within 30 (±7) days after the last dose of investigational product or before starting any other anti-tumor therapy, whichever occurs first.

EFS follow-up: Patients at EOT (except for PD/recurrence and lack of efficacy) will be retained in the study and enter the EFS follow-up stage. EFS follow-up will be conducted every 8 weeks from the day of entering the EFS follow-up stage until progression of disease/recurrence, death, withdrawal by the patient or his/her legal representative, loss to follow-up, or end of study (whichever occurs first). Subsequent new transplant conditioning regimens or new anti-tumor regimens should be recorded during the EFS follow-up period. \[According to the "Guidelines for Clinical Development of New Drugs for Acute Myeloid Leukemia" issued by the Center for Drug Evaluation (CDE), "lack of efficacy" is defined as failure to achieve CR or CRh/CR with incomplete hematologic recovery (CRi)/morphological leukemia-free status (MLFS)/partial response (PR) after 2 cycles of treatment under the protocol of the intensive chemotherapy group. In the reduced intensity chemotherapy group, if CR or CRh/CRi/MLFS/PR is not achieved after 180 days of treatment, it will be judged as lack of efficacy. "Lack of efficacy" in the test group is defined as failure to achieve CR or CRh/CRi/MLFS/PR from the day of HMPL-306 treatment until C5D1 (including C5D1 visit). Whether patients are considered "lack of efficacy" during the study will be determined by the investigator based on the actual clinical condition. For patients who are deemed as having experienced an event-free survival (EFS) event due to meeting the definition of "lack of efficacy" among EFS events, but who could still potentially benefit from continued treatment as judged by the investigator, they may continue to receive treatment after being fully informed (without changing the conclusion that an EFS event has occurred)\].

OS follow-up: After the end of EFS follow-up, patients will enter the overall survival (OS) follow-up stage. OS follow-ups will be conducted every 8 weeks from the day of OS follow-up until death, request for withdrawal from the study by the patient or her/his legal representative, loss to follow-up, or end of study (whichever occurs first).

End of study The two cohorts may vary in the time of end of study. The end of study for each cohort is defined as the number of target OS events for which the final analysis is observed in that cohort. The actual study duration for each cohort depends on the actual enrollment rate, dropout rate, and median OS of each group.

Efficacy assessment Efficacy assessment will be based on the European Leukemia Collaboration (ELN) 2022 criteria. Efficacy assessment will be conducted once every cycle during the first 6 treatment cycles (i.e., C2D1, C3D1, C4D1, C5D1, C6D1, and C7D1) and once every 2 cycles thereafter (i.e., C9D1, C11D1, C13D1,... ); efficacy evaluation will also be conducted at EOT follow-up and at each EFS follow-up.

Safety assessment All adverse events (AEs) will be graded as per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), V5.0. AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The number and frequency of treatment emergent adverse events (TEAEs) will be summarized by system organ class (SOC) and preferred term (PT).

In this study, all serious adverse events (SAEs) related to study procedures reported from the date of signing the informed consent form for pre-screening to the date of signing the master informed consent form will be collected; all SAEs need to be collected from the date of signing the master informed consent form to the date of the first dose; all AE/SAEs need to be collected from the first dose to 30 days after the last dose or the initiation of a new anti-tumor therapy, whichever occurs first; SAEs confirmed by investigators as having a reasonable possibility of correlation with the investigational product need to be collected 30 days after the last dose or after the initiation of a new anti-tumor therapy, whichever occurs earliest.

Eligibility Criteria:
Inclusion Criteria:

1. Have signed the ICF;
2. Be able to follow the requirements of the protocol;
3. Aged ≥18 years;
4. Eastern Cooperative Oncology Group (ECOG) Performance Status score: 0 or 2;
5. Cohort 1: Patients with R/R AML harboring IDH1-R132 site mutations (WHO 2022 Classification of Myeloid Neoplasms and Acute Leukemias); Cohort 2: Patients with R/R AML harboring IDH2-R140/R172 mutations (WHO 2022 Classification of Myeloid Neoplasms and Acute Leukemias). A patient with both IDH1 and IDH2 mutations is recommended to be included in Cohort 2 (IDH2 mutation group).
6. Agree to undergo bone marrow aspiration and/or biopsy before and during treatment;
7. Be willing to complete QoL assessments at specified time points during study treatment and after treatment discontinuation;
8. Female patients of childbearing potential must agree to use highly effective contraceptive methods during the study and within 30 days after discontinuation of the investigational product (the time limit of contraception for the chemotherapy group needs to be extended to 6 months after the last dose), as detailed in Appendix 9 (contraceptive requirements), and agree not to donate eggs (oocytes) for reproductive purposes during this period; patients must not be lactating and must have a negative pregnancy test (if of childbearing potential);
9. Male patients with female partners of childbearing potential must use condoms during intercourse and avoid donating or freezing sperm during the study and within 30 days after discontinuation of the investigational product (the time limit of contraception for the chemotherapy group needs to be extended to 6 months after the last dose).

Exclusion Criteria:

1. Patients who received prior treatment with an IDH1 inhibitor, IDH2 inhibitor, or IDH1/IDH2 dual-target inhibitor;
2. Patients with known RAS or FLT3(FMS-like tyrosine kinase 3) hotspot mutations;
3. Inadequate organ function, as defined below:

   * Serum total bilirubin (TBIL) higher than 1.5 times the upper limit of normal (ULN), excluding the following patients:

     - Patients with Gilbert's disease, with normal alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and serum TBIL ≤ 3 × ULN.
   * AST or ALT \> 2.5 × ULN (if leukemia invades the liver, patients with AST and ALT levels ≤ 5 × ULN can be enrolled);
   * Glomerular filtration rate or creatinine clearance estimated using Cockcroft-Gault formula \< 50 mL/min;
4. International normalized ratio (INR) \> 1.5 × ULN or activated partial thromboplastin time (aPTT) \> 1.5 × ULN, except for patients who are receiving anticoagulant therapy;
5. Blood amylase or blood lipase \> 1.5 × ULN and assessed to be clinically significant by the investigator;
6. Current known history of liver disease, including cirrhosis, alcoholic liver disease, active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV):

   * Chronic hepatitis B is defined as positive serum hepatitis B surface antigen (HBsAg). Patients with occult or previous HBV infection \[defined as positive hepatitis B core antibody (HBcAb) and negative HBsAg\] but negative HBV DNA test can be enrolled; such patients need to be tested for HBV DNA monthly;
   * Patients with positive HCV serology may be enrolled only if they test negative for HCV RNA;
7. Known human immunodeficiency virus (HIV) infection;
8. Meet any of the following cardiac function-related criteria:

   * Any clinically significant cardiac rhythm or conduction abnormality requiring clinical intervention;
   * Clinically significant cardiovascular diseases that require clinical intervention as judged by the investigator, including but not limited to: acute myocardial infarction, unstable angina pectoris, coronary artery bypass grafting within 6 months prior to enrollment, New York Heart Association (NYHA) Class II (inclusive) or above congestive heart failure, left ventricular ejection fraction (LVEF) \< 45%, or uncontrolled hypertension (systolic blood pressure \> 160 mmHg or diastolic blood pressure \> 100 mmHg);
   * Congenital long QT syndrome or QTcF \> 470 msec in females/QTcF \> 450 msec in males; Note: QTcF = QT/∛RR
   * Current use of medicines known to cause QT prolongation or Torsades de Pointes (See full list at http://www.crediblemeds.org)
9. Patients with other primary malignancies within the last 5 years, except for patients who have been cured and patients with the following non-invasive tumors that have been treated with definitive therapy:

   * Basal cell carcinoma of skin
   * Cutaneous cervical squamous cell carcinoma
   * Carcinoma in situ of cervix
   * Breast cancer in situ
10. Pregnant (positive pregnancy test prior to treatment) or lactating women;
11. Males with childbearing requirements;
12. History of stroke or intracranial hemorrhage within 6 months prior to the first dose of investigational product;
13. Patients who have undergone major surgery within 4 weeks prior to the first dose of investigational product;
14. Patients who have received any monoclonal antibody for anti-tumor therapy within 4 weeks or 2 half-lives prior to the first dose of investigational product, whichever is longer;
15. Patients who have received treatment with the investigational product or investigational device in a clinical study within 4 weeks prior to the first dose of investigational product;
16. Patients who have received anti-tumor treatment (chemotherapy, targeted therapy, immunotherapy, or anti-tumor vaccine) within 4 weeks prior to initial study treatment or received radiotherapy within 3 months prior to initial study treatment; patients who have received HSCT within 60 days prior to the start of study treatment, or are receiving immunosuppressive therapy after HSCT at screening, or are accompanied by graft-versus-host disease (GVHD) requiring drug control; patients undergoing treatment for skin graft-versus-host disease (GVHD) with fixed oral doses of and/or topical corticosteroids may be enrolled only if they can benefit from the study treatment as assessed by the investigator.
17. Central nervous system leukemia: patients with clinical symptoms suggesting active central nervous system (CNS) leukemia or confirmed CNS leukemia invasion;
18. Patients who have received live vaccines within 4 weeks prior to the first dose of investigational product;
19. Patients with uncontrolled active systemic fungal, bacterial, or viral infection (defined as persistent signs/symptoms related to the infection without improvement despite appropriate antibiotic or antiviral therapy and/or other treatments), or unexplained pyrexia (\> 38.5℃) during the screening period (only patients with tumor fever as judged by the investigator can be enrolled);
20. The presence of conditions that may affect the absorption of 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;
21. Insufficient compliance in participating in this clinical study as judged by the investigator;
22. Toxicities from previous anti-tumor treatments have not yet recovered to ≤ Grade 1 levels (excluding alopecia).
23. Patients with 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.