Trial Title:
A Clinical Study of HMPL-506 in Patients With Hematological Malignancies
NCT ID:
NCT06387082
Condition:
Hematological Malignancies
Conditions: Official terms:
Neoplasms
Hematologic Neoplasms
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
HMPL-506
Description:
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.
Arm group label:
100mg QD
Arm group label:
200mg QD
Arm group label:
300mg QD
Arm group label:
400mg QD
Arm group label:
50mg QD
Other name:
Two strengths of HMPL-506 tablets (25 mg and 100 mg) will be used for this clinical study
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.
Detailed 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.
Criteria for eligibility:
Criteria:
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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Xiangya Hospital of Central South University
Address:
City:
Changsha
Country:
China
Status:
Recruiting
Contact:
Last name:
Yajing Xu
Investigator:
Last name:
Yajing Xu
Email:
Principal Investigator
Facility:
Name:
First Affiliated Hospital of Chongqing Medical University
Address:
City:
Chongqing
Country:
China
Status:
Recruiting
Contact:
Last name:
Lin Liu
Investigator:
Last name:
Lin Liu
Email:
Principal Investigator
Facility:
Name:
Nanfang Hospital, Southern Medical University
Address:
City:
Guangzhou
Country:
China
Status:
Recruiting
Contact:
Last name:
Yu Zhang
Investigator:
Last name:
Chongyuan Xu
Email:
Principal Investigator
Investigator:
Last name:
Yu Zhang
Email:
Principal Investigator
Facility:
Name:
The First Affiliated Hospital, Zhejiang University
Address:
City:
Hangzhou
Country:
China
Status:
Not yet recruiting
Contact:
Last name:
Jie Jin
Investigator:
Last name:
Jie Jin
Email:
Principal Investigator
Facility:
Name:
Anhui Provincial Hospital
Address:
City:
Hefei
Country:
China
Status:
Not yet recruiting
Contact:
Last name:
Xiaoyu Zhu
Investigator:
Last name:
Xiaoyu Zhu
Email:
Principal Investigator
Facility:
Name:
Qilu Hospital of Shandong University
Address:
City:
Jinan
Country:
China
Status:
Recruiting
Contact:
Last name:
Chunyan Ji
Investigator:
Last name:
Chunyan Ji
Email:
Principal Investigator
Facility:
Name:
The First Affiliated Hospital with Nanjing Medical University
Address:
City:
Nanjing
Country:
China
Status:
Not yet recruiting
Contact:
Last name:
Yu Zhu
Investigator:
Last name:
Yu Zhu
Email:
Principal Investigator
Facility:
Name:
Shengjing Hospital of China Medical University
Address:
City:
Shenyang
Country:
China
Status:
Not yet recruiting
Contact:
Last name:
Wei Yang
Investigator:
Last name:
Wei Yang
Email:
Principal Investigator
Facility:
Name:
Blood Diseases Hospital, Chinese Academy of medical Sciences
Address:
City:
Tianjin
Country:
China
Status:
Recruiting
Contact:
Last name:
Mingyuan Sun
Investigator:
Last name:
Mingyuan Sun
Email:
Principal Investigator
Facility:
Name:
Henan Cancer Hospital
Address:
City:
Zhengzhou
Country:
China
Status:
Not yet recruiting
Contact:
Last name:
Xudong Wei
Investigator:
Last name:
Xudong Wei
Email:
Principal Investigator
Start date:
May 27, 2024
Completion date:
December 8, 2027
Lead sponsor:
Agency:
Hutchmed
Agency class:
Industry
Source:
Hutchmed
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06387082
