Clinical trial NCT03483948: 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
Overall status: TERMINATED
Phase: PHASE1
Conditions: Acute Myeloid Leukemia
Lead sponsor: Hutchmed
Sponsor class: INDUSTRY
First posted: 2018-03-30
Enrollment: 7
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility 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)

Primary outcomes:
measure: Adverse Event (AE) monitoring of HMPL-523 in combination with azacitidine
timeFrame: Measured from the first dose to within 30 days after the last dose.
measure: Overall response rate (ORR)
timeFrame: 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 outcomes:
measure: Maximum plasma concentration (Cmax) of HMPL-523
timeFrame: Measured on the cycle 1 day 7, cycle 1 day 8, cycle 1 day 28 and cycle 2 day 1.
measure: The time to Cmax (peak time, Tmax) of HMPL-523
timeFrame: Measured on the cycle 1 day 7, cycle 1 day 8, cycle 1 day 28 and cycle 2 day 1.
measure: The area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) of HMPL-523
timeFrame: Measured on the cycle 1 day 7, cycle 1 day 8, cycle 1 day 28 and cycle 2 day 1.
measure: Half-life (t1/2) of HMPL-523
timeFrame: Measured on the cycle 1 day 7, cycle 1 day 8, cycle 1 day 28 and cycle 2 day 1.
measure: Clearance (CL) of Azacitidine
timeFrame: Measured on the cycle 1 day 7 and Cycle 1 day 8.
measure: The area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) of Azacitidine
timeFrame: Measured on the cycle 1 day 7 and Cycle 1 day 8.
measure: Half-life (t1/2) of Azacitidine
timeFrame: Measured on the cycle 1 day 7 and Cycle 1 day 8.
measure: Steady-state concentration(Css) of Azacitidine
timeFrame: Measured on the cycle 1 day 7 and Cycle 1 day 8.
measure: Complete Remission Rate of Minimal Residual Disease (MRD) Negativity （CR MRD- rate）
timeFrame: 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.
measure: Event Free Survival (EFS)
timeFrame: 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.
measure: Disease-free Survival (DFS)
timeFrame: 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.
measure: Overall Survival (OS)
timeFrame: 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.
measure: Cumulative incidence of relapse (CIR)
timeFrame: 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.
Other outcomes:
Locations:
city: Tianjin
country: China
facility: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences
state: Tianjin
Study officials:
affiliation: Chinese Academy of Medical Sciences
name: Jianxiang Wang, Prof.
role: PRINCIPAL_INVESTIGATOR
References: