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

Hematological Malignancies Clinical Trial

Official title:

A Multicenter, Open-Label Phase I Clinical Study to Evaluate the Safety, Pharmacokinetics and Efficacy of HMPL-506 in Patients With Hematological Malignancies

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06387082
• Other study ID #: 2023-506-00CH1
• Status: Recruiting
• Phase: Phase 1
• Start date: May 27, 2024
• Est. completion date: December 8, 2027

Study information

• Verified date: June 2024
• Source: Hutchmed
• Contact: Jian Chen, Doctor
• Phone: +86 21 2067 1942
• Email: jianc2[@]hutch-med.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase 1, multicenter, open-label clinical study of HMPL-506 administered orally in the treatment of hematological malignancies. Only eligible patients who provide the signed informed consent form (ICF) can be enrolled in this study. The study consists of two phases, i.e., a dose escalation phase and a dose expansion phase. The study is expected to enroll approximately 60 to 98 patients, including approximately 30 to 38 patients in the dose escalation phase and approximately 30 to 60 patients in the dose expansion phase.

Description:

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）, will be subsequently escalated to 100 mg QD (100%), 200 mg QD (100%), 300 mg QD (50%), and finally 400 mg QD (33%) (this is an assumed dose gradient, and the percentage in brackets corresponds to the dose increment from the previous dose level). A modified Fibonacci design will be used for dose escalation.

The dose will be escalated based on available efficacy and safety data in conjunction with preclinical pharmacodynamics, PK data. safety review committees（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. In addition, the SRC will determine the necessity of exploring a dose above 400 mg QD or an intermediate dose between two dose groups or other administration methods.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 98
• Est. completion date: December 8, 2027
• Est. primary completion date: October 8, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

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

1. Having understood this study adequately and being voluntary to sign the ICF;

2. Age =18 years;

3. 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

4. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2;

5. Agree to undergo bone marrow aspiration and/or biopsy before and during treatment;

6. 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.

7. 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:

1. Patients who have previously received treatment with menin inhibitors and experienced progression during treatment;

2. 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);

3. 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

4. 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);

5. Glomerular filtration rate or creatinine clearance estimated using Cockcroft-Gault formula < 50 mL/min.

6. 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.

7. 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.

8. Known human immunodeficiency virus (HIV) infection.

9. Women who are pregnant (with a positive pregnancy test before administration) or breastfeeding.

10. History of stroke or intracranial hemorrhage within 6 months prior to the first dose of the investigational product.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. Patients who have undergone major surgery within 4 weeks prior to the first dose of the investigational product.

19. Toxicities from previous anti-tumor treatments have not yet recovered to Grade = 1 (excluding alopecia).

20. 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

21. 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.

22. Patients with poor compliance who are judged by the investigator as not suitable for participation in this clinical study.

23. 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.

Related Conditions & MeSH terms

• Hematologic Neoplasms
• Hematological Malignancies
• Neoplasms

Intervention

Drug:
• HMPL-506
HMPL-506 will be administered orally in 28-day cycles, until disease progression/relapse , death, intolerable toxicity, receipt of another anti-tumor therapy (including HSCT), failure to further benefit , patient withdrawal, loss to follow-up or end of the study, whichever comes first.

Locations

Country	Name	City	State
China	Xiangya Hospital of Central South University	Changsha
China	First Affiliated Hospital of Chongqing Medical University	Chongqing
China	Nanfang Hospital, Southern Medical University	Guangzhou
China	The First Affiliated Hospital, Zhejiang University	Hangzhou
China	Anhui Provincial Hospital	Hefei
China	Qilu Hospital of Shandong University	Jinan
China	The First Affiliated Hospital with Nanjing Medical University	Nanjing
China	Shengjing Hospital of China Medical University	Shenyang
China	Blood Diseases Hospital, Chinese Academy of medical Sciences	Tianjin
China	Henan Cancer Hospital	Zhengzhou

Sponsors (1)

Lead Sponsor	Collaborator
Hutchmed

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Evaluate the changes of the Pharmacodynamic Biomarker	Changes in Pharmacodynamic biomarkers (e.g., MEIS3, HOXA9, CD11b etc.) before and after HMPL506 administration, and correlations with dosing and efficacy	the time before the first dose of HMPL-506 to 30 days after last dose or Disease progression.Maybe assessed up to 42 Months.
Primary	Safety evaluation: Safety Incidence of Dose-limiting Toxicity (DLTs)	Incidence of serious Dose-limiting Toxicity evaluated using the NCI CTCAE V5.0.	The DLT assessment window is Cycle 1 + 3 days (starting from dosing on Day -3, i.e., 28 + 3 days) in the first two dose groups (50 mg and 100 mg), and Cycle 1 (starting from Day 1 of each cycle, i.e., 28 days) in other dose groups.
Primary	Safety evaluation: Incidence of serious adverse events (SAEs) and Relationship to Study Drug	Incidence of serious adverse events (SAEs) evaluated using the NCI CTCAE V5.0 and the relationship of DLTs and SAEs with the investigational product.; The assessment window is from the first dose of HMPL-506 to 30 days after last dose, or initiation of a new anti-tumor therapy, whichever comes first.	The time from the first dose of HMPL-506 to 30 days after last dose, or initiation of a new anti-tumor therapy, whichever comes first. Maybe assessed up to 42 months
Primary	Efficacy evaluation: Anti-tumor efficacy evaluation.	Performing anti-tumor efficacy evaluation of HMPL-506 based on Complete response (CR), Complete response with partial recovery of hematology (CRh), Complete response with incomplete hematological recovery (CRi) assessed by the Investigator.; Response evaluation in AML will be conducted based on the European LeukmiaNet (ELN) 2022 criteria; response evaluation in ALL will be conducted based on the National Comprehensive Cancer Network (NCCN) Guidelines for the Diagnosis and Treatment of ALL (2023 Version 3).	To assess at every cycle during the first 6 cycles of treatment (each cycle is 28 days) and once every 2 cycles thereafter; response evaluation will also be conducted at each Event-free survival (EFS) follow-up visit.Maybe assessed up to 42 Months.
Secondary	Incidence of adverse events (AEs) and Relationship to Study Drug	Incidence of each type of adverse event evaluated by NCI CTCAE V5.0 and its relationship to study drug	The time from the first dose of HMPL-506 to 30 days after last dose, or initiation of a new anti-tumor therapy, whichever comes first. Maybe assessed up to 42 Months.
Secondary	Adverse Events Associated with Dose Modifications	Incidence of adverse events leading to dose interruption, reduction, or treatment discontinuation	The time from the first dose of HMPL-506 to 30 days after last dose, or initiation of a new anti-tumor therapy, whichever comes first. Maybe assessed up to 42 Months.
Secondary	Evaluate electrocardiogram (ECG) assessments.	Observe QT interval changes before and after treatment.	The time from the first dose of HMPL-506 to 30 days after last dose, or initiation of a new anti-tumor therapy, whichever comes first. Maybe assessed up to 42 Months.
Secondary	Complete response rate (CR rate)	Defined as the proportion of subjects achieving CR as assessed by the investigator.Response evaluation in AML will be conducted based on the European LeukmiaNet (ELN) 2022 criteria; response evaluation in ALL will be conducted based on the National Comprehensive Cancer Network (NCCN) Guidelines for the Diagnosis and Treatment of ALL (2023 Version 3).	To assess at every cycle during the first 6 cycles of treatment (each cycle is 28 days) and once every 2 cycles thereafter; response evaluation will also be conducted at each EFS follow-up visit.Maybe assessed up to 42 Months.
Secondary	Complete response (CR)+ Complete response with partial recovery of hematology (CRh) rate	Defined as the proportion of subjects achieving CR or CRh as assessed by the investigator. Response evaluation in AML will be conducted based on the European LeukmiaNet (ELN) 2022 criteria; response evaluation in ALL will be conducted based on the National Comprehensive Cancer Network (NCCN) Guidelines for the Diagnosis and Treatment of ALL (2023 Version 3)	To assess at every cycle during the first 6 cycles of treatment (each cycle is 28 days) and once every 2 cycles thereafter; response evaluation will also be conducted at each EFS follow-up visit.Maybe assessed up to 42 Months.
Secondary	Composite complete response (CRc) rate	Defined as the proportion of subjects achieving CR, CRh, or CRi(incomplete hematological recovery) as assessed by the investigator.; Response evaluation in AML will be conducted based on the European LeukmiaNet (ELN) 2022 criteria; response evaluation in ALL will be conducted based on the National Comprehensive Cancer Network (NCCN) Guidelines for the Diagnosis and Treatment of ALL (2023 Version 3)	To assess at every cycle during the first 6 cycles of treatment (each cycle is 28 days) and once every 2 cycles thereafter; response evaluation will also be conducted at each EFS follow-up visit.Maybe assessed up to 42 Months.
Secondary	Objective response rate (ORR)	defined as the proportion of patients with CR, CRh, CRi, morphologic leukemia-free status (MLFS), and partial response (PR) as judged by the investigator.; Response evaluation in AML will be conducted based on the European LeukmiaNet (ELN) 2022 criteria; response evaluation in ALL will be conducted based on the National Comprehensive Cancer Network (NCCN) Guidelines for the Diagnosis and Treatment of ALL (2023 Version 3)	To assess at every cycle during the first 6 cycles of treatment (each cycle is 28 days) and once every 2 cycles thereafter; response evaluation will also be conducted at each EFS follow-up visit.Maybe assessed up to 42 Months.
Secondary	Time to Complete response (CR)+Complete response with partial recovery of hematology (CRh)	Defined as the time from the first administration of HMPL-506 to the first occurrence of CR/CRh.; Response evaluation in AML will be conducted based on the European LeukmiaNet (ELN) 2022 criteria; response evaluation in ALL will be conducted based on the National Comprehensive Cancer Network (NCCN) Guidelines for the Diagnosis and Treatment of ALL (2023 Version 3)	To assess at every cycle during the first 6 cycles of treatment (each cycle is 28 days) and once every 2 cycles thereafter; response evaluation will also be conducted at each EFS follow-up visit.Maybe assessed up to 42 Months.
Secondary	Time to Complete response (CR)+Complete response with partial recovery of hematology (CRh) +incomplete hematological recovery (CRi)	Defined as the time from the first administration of HMPL-506 to the first occurrence of CR/CRh/CRi.; Response evaluation in AML will be conducted based on the European LeukmiaNet (ELN) 2022 criteria; response evaluation in ALL will be conducted based on the National Comprehensive Cancer Network (NCCN) Guidelines for the Diagnosis and Treatment of ALL (2023 Version 3)	To assess at every cycle during the first 6 cycles of treatment (each cycle is 28 days) and once every 2 cycles thereafter; response evaluation will also be conducted at each EFS follow-up visit.Maybe assessed up to 42 Months.
Secondary	Time to disease response (TTR)	Defined as the time from the first administration of HMPL-506 to the first achievement of CR/CRh/CRi/MLFS/PR.; Response evaluation in AML will be conducted based on the European LeukmiaNet (ELN) 2022 criteria; response evaluation in ALL will be conducted based on the National Comprehensive Cancer Network (NCCN) Guidelines for the Diagnosis and Treatment of ALL (2023 Version 3)	To assess at every cycle during the first 6 cycles of treatment (each cycle is 28 days) and once every 2 cycles thereafter; response evaluation will also be conducted at each EFS follow-up visit.Maybe assessed up to 42 Months.
Secondary	Duration of Complete response (CR)+Complete response with partial recovery of hematology (CRh)	Defined as the time from first achievement of CR/CRh until disease recurrence, progression, or death from any cause, whichever occurs first.; Response evaluation in AML will be conducted based on the European LeukmiaNet (ELN) 2022 criteria; response evaluation in ALL will be conducted based on the National Comprehensive Cancer Network (NCCN) Guidelines for the Diagnosis and Treatment of ALL (2023 Version 3)	To assess at every cycle during the first 6 cycles of treatment (each cycle is 28 days) and once every 2 cycles thereafter; response evaluation will also be conducted at each EFS follow-up visit.Maybe assessed up to 42 Months.
Secondary	Duration of response (DOR)	Defined as the time from the patient 's first achievement of CR/CRh/CRi/MLFS/PR until disease recurrence, progression, or death from any cause, whichever came first.; Response evaluation in AML will be conducted based on the European LeukmiaNet (ELN) 2022 criteria; response evaluation in ALL will be conducted based on the National Comprehensive Cancer Network (NCCN) Guidelines for the Diagnosis and Treatment of ALL (2023 Version 3).	To assess at every cycle during the first 6 cycles of treatment (each cycle is 28 days) and once every 2 cycles thereafter; response evaluation will also be conducted at each EFS follow-up visit.Maybe assessed up to 42 Months.
Secondary	Event-free survival (EFS)	Defined as the time from the start of treatment to the date of loss of response, hematologic relapse after CR/CRh/CRi, or death from any cause, whichever came first.; Response evaluation in AML will be conducted based on the European LeukmiaNet (ELN) 2022 criteria; response evaluation in ALL will be conducted based on the National Comprehensive Cancer Network (NCCN) Guidelines for the Diagnosis and Treatment of ALL (2023 Version 3).	To assess at every cycle during the first 6 cycles of treatment (each cycle is 28 days) and once every 2 cycles thereafter; response evaluation will also be conducted at each EFS follow-up visit.Maybe assessed up to 42 Months.
Secondary	Relapse-free survival (RFS)	(For patients who achieved CR/CRh/CRi only) Defined as the time from achievement of response (CR/CRh/CRi) to hematologic relapse, death from any cause, whichever came first. hematologic relapse after CR/CRh/CRi, or death from any cause, whichever came first.; Response evaluation in AML will be conducted based on the European LeukmiaNet (ELN) 2022 criteria; response evaluation in ALL will be conducted based on the National Comprehensive Cancer Network (NCCN) Guidelines for the Diagnosis and Treatment of ALL (2023 Version 3).	To assess at every cycle during the first 6 cycles of treatment (each cycle is 28 days) and once every 2 cycles thereafter; response evaluation will also be conducted at each EFS follow-up visit.Maybe assessed up to 42 Months.
Secondary	Overall survival (OS)	Defined as the time from the start of study drug until death from any cause. Response evaluation in AML will be conducted based on the European LeukmiaNet (ELN) 2022 criteria; response evaluation in ALL will be conducted based on the National Comprehensive Cancer Network (NCCN) Guidelines for the Diagnosis and Treatment of ALL (2023 Version 3).	Until to disease progression/relapse or initiate new anti-tumor therapies will continue to attend OS follow-up visits every 2 months until death, patient withdrawal, loss to follow-up or end of study, whichever comes first, Maybe assessed up to 42 Months
Secondary	Pharmacokinetic analysis-Maximum concentration (Cmax)	To characterized Maximum concentration (Cmax) of HMPL-506 and metabolite M7 in plasma and bone marrow were measured before and after treatment.	The window is before the first dose of HMPL-506 to Cycle 3 Day1(each cycle is 28 days).
Secondary	Pharmacokinetic analysis: Peak time (Tmax)	To characterized Peak time (Tmax)of HMPL-506 and metabolite M7 in plasma and bone marrow were measured before and after treatment.	The access window is before the first dose of HMPL-506 to Cycle 3 Day1(each cycle is 28 days).12 Weeks.
Secondary	Pharmacokinetic analysis: Clearance half-life (T1/2)	To characterized Clearance half-life (T1/2) of HMPL-506 and metabolite M7 in plasma and bone marrow were measured before and after treatment.	The access window is before the first dose of HMPL-506 to Cycle 3 Day1(each cycle is 28 days).12 Weeks.
Secondary	Pharmacokinetic analysis: area under the plasma concentration-time curve (AUC0-t)	To characterized area under the plasma concentration-time curve (AUC0-t) of HMPL-506 and metabolite M7 in plasma and bone marrow were measured before and after treatment.	The access window is before the first dose of HMPL-506 to Cycle 3 Day1(each cycle is 28 days).12 Weeks.