This is a Phase I, open-label, non-randomized, multicenter study to evaluate the safety, pharmacokinetics and preliminary efficacy of HMPL-523 in combination with Azacitidine in previously untreated elderly patients with AML who are not eligible for standard induction therapy.
There are two stages in this study: a dose-escalation stage (stage 1) and a dose-expansion stage (stage 2). Dose-escalation stage (stage 1): The conventional 3+3 design (3 patients per dose cohort, with the potential to add additional 3 patients to the same cohort to further evaluate toxicity) will be applied for dose escalation and maximum tolerated dosage determination. Approximately 12 to 18 dose limited toxicities evaluable patients will be enrolled. A dose of HMPL-523 up to 800mg will be taken orally once daily continuously through a 28-day Cycle of study treatment. Azacitidine will be administered subcutaneously, beginning on Day 1 through Day 7 of each Cycle. Dose-expansion stage (stage 2): This phase is to further evaluate the safety, pharmacokinetics and preliminary efficacy of HMPL-523 in combination with Azacitidine in approximately 28 previously untreated elderly patients with AML. Patients will receive HMPL-523 in combination with Azacitidine in a 28-day cycle continuously until disease progression/relapse, death, or intolerable toxicity, whichever comes first.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
7
HMPL-523 tablet
Azacitidine Injection
Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences
Tianjin, Tianjin Municipality, China
Adverse Event (AE) monitoring of HMPL-523 in combination with azacitidine
AE monitoring will be assessed by evaluation of study drug exposure, AEs , serious AEs, all deaths, as well as laboratory determinations and vital sign parameters.
Time frame: Measured from the first dose to within 30 days after the last dose.
Overall response rate (ORR)
Overall response rate will be defined as the proportion of subjects who achieve a complete remission (CR), complete remission incomplete (CRi), Morphologic leukemia-free state (MLFS), or partial remission(PR) per 2017 European Leukemia Net (ELN) recommendations
Time frame: Measured up to 1 year after the last subject has enrolled or all the subjects have finished their last EFS follow up, whichever comes first.
Maximum plasma concentration (Cmax) of HMPL-523
Maximum concentration, occurring at Tmax.
Time frame: Measured on the cycle 1 day 7, cycle 1 day 8, cycle 1 day 28 and cycle 2 day 1.
The time to Cmax (peak time, Tmax) of HMPL-523
The time at which maximum plasma concentration (Cmax) is observed.
Time frame: Measured on the cycle 1 day 7, cycle 1 day 8, cycle 1 day 28 and cycle 2 day 1.
The area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) of HMPL-523
The area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration.
Time frame: Measured on the cycle 1 day 7, cycle 1 day 8, cycle 1 day 28 and cycle 2 day 1.
Half-life (t1/2) of HMPL-523
The time required for the concentration of the drug to reach half of its original value.
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Time frame: Measured on the cycle 1 day 7, cycle 1 day 8, cycle 1 day 28 and cycle 2 day 1.
Clearance (CL) of Azacitidine
Clearance is defined as the rate at which drug is cleared from the blood.
Time frame: Measured on the cycle 1 day 7 and Cycle 1 day 8.
The area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) of Azacitidine
The area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration.
Time frame: Measured on the cycle 1 day 7 and Cycle 1 day 8.
Half-life (t1/2) of Azacitidine
The time required for the concentration of the drug to reach half of its original value.
Time frame: Measured on the cycle 1 day 7 and Cycle 1 day 8.
Steady-state concentration(Css) of Azacitidine
The average concentration of drug at steady state
Time frame: Measured on the cycle 1 day 7 and Cycle 1 day 8.
Complete Remission Rate of Minimal Residual Disease (MRD) Negativity （CR MRD- rate）
CR MRD- rate will be defined as the proportion of subjects who achieve a CR and has a negative RT-qPCR or MFC at the same time.
Time frame: Measured up to 1 year after the last subject has enrolled or all the subjects have finished their last EFS follow up, whichever comes first.
Event Free Survival (EFS)
EFS will be defined as the number of days from the date of first dose to the date of earliest recurrence or PD or death.
Time frame: Measured up to 1 year after the last subject has enrolled or all the subjects have finished their last EFS follow up, whichever comes first.
Disease-free Survival (DFS)
DFS will be defined as the number of days from the date of composite complete response (CR + CRi) to the date of earliest recurrence or death.
Time frame: Measured up to 1 year after the last subject has enrolled or all the subjects have finished their last EFS follow up, whichever comes first.
Overall Survival (OS)
OS will be defined as the number of days from the date of enrollment to the date of death.
Time frame: Measured up to 1 year after the last subject has enrolled or all the subjects have finished their last EFS follow up, whichever comes first.
Cumulative incidence of relapse (CIR)
CIR will be defined as the cumulative proportion of subjects who has relapsed after achieving a composite complete response (CR + CRi).
Time frame: Measured up to 1 year after the last subject has enrolled or all the subjects have finished their last EFS follow up, whichever comes first.