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

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ClinicalTrials.gov Identifier: NCT03483948
Recruitment Status : Recruiting
First Posted : March 30, 2018
Last Update Posted : October 18, 2018
Sponsor:
Information provided by (Responsible Party):
Hutchison Medipharma Limited

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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: HMPL-523 Drug: Azacitidine Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 46 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 9, 2018
Estimated Primary Completion Date : August 1, 2020
Estimated Study Completion Date : November 1, 2020


Arm Intervention/treatment
Experimental: HMPL-523 & Azacitidine
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
HMPL-523 tablet

Drug: Azacitidine
Azacitidine Injection
Other Name: Vidaza




Primary Outcome Measures :
  1. Adverse Event (AE) monitoring of HMPL-523 in combination with azacitidine [ Time Frame: Measured from the first dose to within 30 days after the last dose. ]
    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.

  2. Overall response rate (ORR) [ 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 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 :
  1. Maximum plasma concentration (Cmax) of HMPL-523 [ Time Frame: Measured on the cycle 1 day 7, cycle 1 day 8, cycle 1 day 28 and cycle 2 day 1. ]
    Maximum concentration, occurring at Tmax.

  2. The time to Cmax (peak time, Tmax) of HMPL-523 [ Time Frame: Measured on the cycle 1 day 7, cycle 1 day 8, cycle 1 day 28 and cycle 2 day 1. ]
    The time at which maximum plasma concentration (Cmax) is observed.

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

  4. Half-life (t1/2) of HMPL-523 [ Time Frame: Measured on the cycle 1 day 7, cycle 1 day 8, cycle 1 day 28 and cycle 2 day 1. ]
    The time required for the concentration of the drug to reach half of its original value.

  5. Clearance (CL) of Azacitidine [ Time Frame: Measured on the cycle 1 day 7 and Cycle 1 day 8. ]
    Clearance is defined as the rate at which drug is cleared from the blood.

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

  7. Half-life (t1/2) of Azacitidine [ Time Frame: Measured on the cycle 1 day 7 and Cycle 1 day 8. ]
    The time required for the concentration of the drug to reach half of its original value.

  8. Steady-state concentration(Css) of Azacitidine [ Time Frame: Measured on the cycle 1 day 7 and Cycle 1 day 8. ]
    The average concentration of drug at steady state

  9. Complete Remission Rate of Minimal Residual Disease (MRD) Negativity (CR MRD- rate) [ 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. ]
    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.

  10. Event Free Survival (EFS) [ 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. ]
    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.

  11. Disease-free Survival (DFS) [ 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. ]
    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.

  12. Overall Survival (OS) [ 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. ]
    OS will be defined as the number of days from the date of enrollment to the date of death.

  13. Cumulative incidence of relapse (CIR) [ 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. ]
    CIR will be defined as the cumulative proportion of subjects who has relapsed after achieving a composite complete response (CR + CRi).



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Ages Eligible for Study:   65 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Subject must have confirmation of AML by WHO criteria, except for APL (M3)
  2. 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
  3. Subject must have received no prior treatment for AML with the exception of hydroxyurea
  4. ECOG performance status of 0-1. For dose-expansion stage, ECOG PS of 2 will also be eligible

Exclusion Criteria:

  1. Subject has received treatment of hypomethylating agent and/or chemo therapeutic agent for MDS or MPN
  2. Subject has known active CNS involvement or extramedullary sarcoma from AML
  3. 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)
  4. Subject has a white blood cell count > 25 × 109/L (Hydroxyurea is permitted to meet this criterion)
  5. Subject with serum amylase or lipase > the ULN
  6. Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load.
  7. Subject who don't have enough liver or renal function
  8. Subject with New York Heart Association (NYHA) Class III or greater congestive heart failure
  9. Subject received herbal therapy ≤ 1 week prior to initiation of study treatment
  10. Subject received prior treatment with any SYK inhibitors (Fostamatinib) or FLT3 inhibitor (Quizartinib) or multi-target inhibitor with SYK or FLT3 inhibition activity (Midostaurin)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03483948


Contacts
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Contact: Dan Yu +86 010-63365165 Dany@hmplglobal.com
Contact: Li Chen +86 021 20671801 ext 5801 Adac@hmplglobal.com

Locations
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China, Tianjin
Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences Recruiting
Tianjin, Tianjin, China, 300020
Contact: Jianxiang Wang, Prof.         
Sponsors and Collaborators
Hutchison Medipharma Limited
Investigators
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Principal Investigator: Jianxiang Wang, Prof. Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences

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Responsible Party: Hutchison Medipharma Limited
ClinicalTrials.gov Identifier: NCT03483948     History of Changes
Other Study ID Numbers: 2017-523-00CH3
First Posted: March 30, 2018    Key Record Dates
Last Update Posted: October 18, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors