A Study of HYML-122 and Cytarabine in Patients With FLT3 Positive Relapsed or Refractory Acute Myeloid Leukemia (AML)

Study Overview
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Brief Summary
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This is a single-arm, open, multicenter, phase 2 study to evaluate the efficacy, safety and pharmacokinetics of HYLM-122 in combination with cytarabine in Chinese subjects with FLT3 positive relapsed or refractory acute myeloid leukemia.

Detailed Description
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This study will have two phases. Phase 1: the escalation phase is to establish the recommended phase 2 dose (RP2D) of HYML-122 given in combination with cytarabine. Phase 2: the extension phase study will treat patients with FLT3 positive relapsed or refractory AML with HYML-122 in combination with cytarabine at the RP2D, and further evaluate efficacy and safety.

Official Title
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A Single-arm, Open, Multicenter, Phase II Study to Investigator the Efficacy and Safety of HYML-122 and Cytarabine in Patients With FLT3 Positive Relapsed or Refractory Acute Myeloid Leukemia (AML)

Conditions
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Relapsed or Refractory Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: HYML-122; cytarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Fully understand the procedures of the clinical study and participate voluntarily with signed and dated written informed consent form, comply with the requirements of the study protocol. Males and/or females at least 18 years old when signing the informed consent form. Histologically confirmed AML (defined using WHO criteria 2016) with one of the following: Refractory to at least 1 cycle of induction chemotherapy. Relapsed after achieving remission with a prior therapy. Subject is positive for FLT3 mutation in bone marrow or blood after completion of the subject's last interventional treatment. Eastern cooperative oncology group performance status (ECOG) ≤2 at screening. Life expectancy of at least 3 months. Women of childbearing potential have a negative pregnancy test at baseline and are willing to employ an effective method of contraception for the entire duration of study treatment and 6 months after the last dose. Exclusion Criteria: Known or suspected allergies to any of the investigational drug composition (HYML-122, lactose, hydroxypropyl cellulose, hyposubstituted hydroxypropyl cellulose, silicon dioxide, magnesium stearate, titanium dioxide and polyethylene glycol). Medical history and surgical history excluded according to the protocol. Any previous medical treatment history exclude from the protocol. Abnormal laboratory results exclude from the protocol. Combination of treatments and/or drugs required during the study period and cannot be discontinued that excluded from the protocol. Alcohol abuse within 6 months prior to screening, defined as long-term drinking history, generally more than 5 years, equivalent to alcohol quantity ≥40g/d for men, ≥20g/d for women, or heavy drinking history within 2 weeks, equivalent to alcohol quantity ≥80g/d. alcohol volume (g) conversion formula=alcohol consumption (mL)*alcohol content (%)*0.8. Abortion less than 30 days prior to screening, pregnant and lactating women (currently breast-feeding or less than one year after delivery although not breast-feeding), women of childbearing potential who are not guaranteed effective contraception during the study, planning pregnancy or donating eggs or sperm within 6 months after the last dose. History of drug abuse or drug addicts. Subjects may not be able to complete the study duo to poor compliance or other reasons, or unsuitable for the study by the investigator's judgment.

Ages Eligible for Study
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Minimum Age: 18 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: Sequential Assignment
Interventional Model Description: level 1: HYML-122 400mg bid (day1-day28) in combination with Cytarabine 100mg/m2 (day1-day7). each cycle is 28 days. level2: HYML-122 600mg bid (day1-day28) in combination with Cytarabine 100mg/m2 (day1-day7). each cycle is 28 days.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HYML-122 plus cytarabine<br>The first three eligible enrolled patients will be treated with initial dosing of HYML-122 400mg bid daily and cytarabine 100mg/m2 intravenously by using 3+3 escalating design to explore RP2D. the Data Monitoring Committee (DMC) will evaluate the safety, efficacy and PK data of the phase 1 subjects and establish the combined regimen recommended dose. Participants will be treated on continuous cycles until they no longer derive clinical benefit in the judgement of the investigator, have unacceptable toxicity, undergo hematopoietic stem cell transplantation (HSCT), or meet 1 of the discontinuation criteria, whichever occurs first. | Drug: HYML-122; cytarabine<br>* HYML-122 is administered orally consecutive with 400mg bid or 600mg bid or dose adjusted by DMC judgement in each 28-day treatment cycle. cytarabine is administered by intravenous infusion with 100mg/m2 or dose adjusted by DMC judgement once daily on the first to 7th day of each treatment cycle. Upon completion of each 28-day treatment cycle, patients may continue to receive HYML-122 and cytarabine if they are benefit from the treatment and the toxicity is tolerable.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR | overall remission rate, including complete remission without minimum residual disease (CRMRD-), complete remission (CR), complete remission with incomplete hematologic recovery (CRi), complete remission without platelet recovery (CRp), partial remission (PR). | up to 24 months | 
| composite complete remission (CRc) rate | CRc rate is defined as the rate of all complete and incomplete remission (CRMRD-+CR+CRp+CRi). | up to 24 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RFS | relapse-free survival, for patients achieving a complete remission, defined as the interval from the date of first documentation of a leukemia free state to date of recurrence, treatment failure, death due to any cause or last contact of the end-of-study follow up, which ever occurs first. | up to 24 months | 
| EFS | event-free survival, EFS is defined as the time from the date of enrollment until the date of documented relapse from CR, CRp or CRi, treatment failure, death from any cause or last contact of the end-of-study follow-up, whichever occurs first. | up to 24 months | 
| OS | overall survival, OS is defined as time from the date of enrollment until the date of death from any cause. For a subject who is not known to have died buy the end-of-study follow-up, OS is censored at the date of last contact. | up to 24 months | 
| DOR-CR | duration of CR remission, DOR-CR is defined as the time from the date of first CR, CRp, CRi until the date of documented relapse. | up to 24 months | 
| Incidence of treatment-emergent adverse events (TEAEs) | safety and tolerability of investigational product assessed as the number of participants experience adverse events (AEs, CTCAE 5.0) or abnormalities in vital signs, laboratory tests, or electrocardiograms. | up to 24 months | 
| Cmax,ss | Peak plasma concentration at steady state (Cmax,ss) | at the end of Cycle 1 (each cycle is 28 days) | 
| Cmin,ss | minimum observed plasma concentration at steady state (Cmin,ss) of drug in blood plasma | at the end of Cycle 1 (each cycle is 28 days) | 
| Cav,ss | the average steady-state plasma concentration | at the end of Cycle 1 (each cycle is 28 days) | 
| AUCss | the area under the plasma concentration at steady-state | at the end of Cycle 1 (each cycle is 28 days) |