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

Primary Purpose

Acute Myeloid Leukemia

Status

Terminated

Phase

Phase 1

Locations

China

Study Type

Interventional

Intervention

HMPL-523

Azacitidine

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia

Eligibility Criteria

65 Years - undefined (Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

HMPL-523 & Azacitidine

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

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

Secondary Outcome Measures

Maximum plasma concentration (Cmax) of HMPL-523

Maximum concentration, occurring at Tmax.

The time to Cmax (peak time, Tmax) of HMPL-523

The time at which maximum plasma concentration (Cmax) is observed.

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.

Half-life (t1/2) of HMPL-523

The time required for the concentration of the drug to reach half of its original value.

Clearance (CL) of Azacitidine

Clearance is defined as the rate at which drug is cleared from the blood.

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.

Half-life (t1/2) of Azacitidine

The time required for the concentration of the drug to reach half of its original value.

Steady-state concentration(Css) of Azacitidine

The average concentration of drug at steady state

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.

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.

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.

Overall Survival (OS)

OS will be defined as the number of days from the date of enrollment to the date of death.

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).

Full Information

NCT ID

NCT03483948

First Posted

March 23, 2018

Last Updated

November 18, 2019

Sponsor

Hutchison Medipharma Limited

1. Study Identification

Unique Protocol Identification Number

NCT03483948

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2019

Overall Recruitment Status

Terminated

Why Stopped

Slow Enrollment

Study Start Date

October 9, 2018 (Actual)

Primary Completion Date

September 9, 2019 (Actual)

Study Completion Date

September 9, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Hutchison Medipharma Limited

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Myeloid Leukemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

7 (Actual)

8. Arms, Groups, and Interventions

Arm Title

HMPL-523 & Azacitidine

Arm Type

Experimental

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

HMPL-523

Intervention Description

HMPL-523 tablet

Intervention Type

Drug

Intervention Name(s)

Azacitidine

Other Intervention Name(s)

Vidaza

Intervention Description

Azacitidine Injection

Primary Outcome Measure Information:

Title

Adverse Event (AE) monitoring of HMPL-523 in combination with azacitidine

Description

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.

Title

Overall response rate (ORR)

Description

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.

Secondary Outcome Measure Information:

Title

Maximum plasma concentration (Cmax) of HMPL-523

Description

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.

Title

The time to Cmax (peak time, Tmax) of HMPL-523

Description

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.

Title

The area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) of HMPL-523

Description

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.

Title

Half-life (t1/2) of HMPL-523

Description

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, cycle 1 day 8, cycle 1 day 28 and cycle 2 day 1.

Title

Clearance (CL) of Azacitidine

Description

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.

Title

The area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) of Azacitidine

Description

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.

Title

Half-life (t1/2) of Azacitidine

Description

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.

Title

Steady-state concentration(Css) of Azacitidine

Description

The average concentration of drug at steady state

Time Frame

Measured on the cycle 1 day 7 and Cycle 1 day 8.

Title

Complete Remission Rate of Minimal Residual Disease (MRD) Negativity （CR MRD- rate）

Description

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.

Title

Event Free Survival (EFS)

Description

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.

Title

Disease-free Survival (DFS)

Description

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.

Title

Overall Survival (OS)

Description

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.

Title

Cumulative incidence of relapse (CIR)

Description

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.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

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)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jianxiang Wang, Prof.

Organizational Affiliation

Institute of Hematology ＆ Blood Diseases Hospital，Chinese Academy of Medical Sciences

Official's Role

Principal Investigator

Facility Information:

Facility Name

Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences

City

Tianjin

State/Province

Tianjin

ZIP/Postal Code

300020

Country

China

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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