Phase I Study of HMPL-523+Azacitidine in Elderly Patients With Acute Myeloid Leukemia

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I Study of Safety, Pharmacokinetics and Efficacy of HMPL-523 With Azacitidine in Elderly Patients With Previously Untreated Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: HMPL-523
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must have confirmation of AML by WHO criteria, except for APL (M3) Subject must be ≥ 65 years of old and be ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to co-morbidity or other factors Subject must have received no prior treatment for AML with the exception of hydroxyurea ECOG performance status of 0-1. For dose-expansion stage, ECOG PS of 2 will also be eligible Exclusion Criteria: Subject has received treatment of hypomethylating agent and/or chemo therapeutic agent for MDS or MPN Subject has known active CNS involvement or extramedullary sarcoma from AML Subject has favorable risk cytogenetics as categorized by the NCCN Guidelines Version 1, 2018 for Acute Myeloid Leukemia, such as inv(16) or t(16;16) or t(8;21) or t(15;17) Subject has a white blood cell count > 25 × 109/L (Hydroxyurea is permitted to meet this criterion) Subject with serum amylase or lipase > the ULN Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load. Subject who don't have enough liver or renal function Subject with New York Heart Association (NYHA) Class III or greater congestive heart failure Subject received herbal therapy ≤ 1 week prior to initiation of study treatment Subject received prior treatment with any SYK inhibitors (Fostamatinib) or FLT3 inhibitor (Quizartinib) or multi-target inhibitor with SYK or FLT3 inhibition activity (Midostaurin)

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HMPL-523 & Azacitidine<br>HMPL-523 will be taken orally once daily continuously through a 28-days Cycle of study treatment. Azacitidine will be administered subcutaneously, beginning on Day 1 through Day 7 of each Cycle. | Drug: HMPL-523<br>* HMPL-523 tablet<br>Drug: Azacitidine<br>* Azacitidine Injection<br>* Other names: Vidaza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) of HMPL-523 | Maximum concentration, occurring at Tmax. | 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. | 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. | 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. | 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. | 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. | 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. | 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 | 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. | 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. | 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. | 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. | 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). | 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. |