A Bioequivalence Study of (Cytarabine: Daunorubicin) Liposome for Injection

Study Overview
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Brief Summary
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The purpose of this study is to determine the bioequivalence of (cytarabine: daunorubicin) liposome for injection and Vyxeos in elderly acute myeloid leukemia (AML) subjects.

Detailed Description
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This is a multi-center, randomized, open-label, two-period, two-sequence, two-way crossover bioequivalence study of (cytarabine: daunorubicin) liposome for injection manufactured by CSPC Zhongnuo Pharmaceutical Technology Co., Ltd compared with Vyxeos manufactured by Jazz Pharmaceuticals, Inc. in elderly AML subjects. Patients who have achieved CR/CRi after induction treatment will be randomized to sequence A (T-R): (cytarabine: daunorubicin) liposome on C1D1 and C1D3/ Vyxeos on C2D1 and C2D3 or sequence B(R-T): Vyxeos on C1D1 and C1D3/ (cytarabine: daunorubicin) liposome on C2D1 and C2D3. Randomization will be in a 1:1 ratio. Forty to sixty subjects will be enrolled to ensure 36 evaluable subjects. Serial blood samples for determination of liposomal encapsulated cytarabine and liposomal encapsulated daunorubicin plasma concentration for PK analysis will be obtained in each cycle.

Official Title
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A Randomized, Open-label, Two-period, Two-way Crossover Bioequivalence Study of Two (Cytarabine: Daunorubicin) Liposome for Injection in Elderly AML Subjects

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: (cytarabine: daunorubicin) liposome for injection
* Drug: Vyxeos
* Drug: (cytarabine: daunorubicin) liposome for injection
* Drug: Vyxeos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to understand the study and voluntarily sign informed consent. Male or female between 55-75 years of age (inclusive). Subjects diagnosed with acute myeloid leukemia according to The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia who haven't been treated or who have achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi) after preceding induction therapy. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Adequate hematopoietic, renal and liver function. Cardiac function (LVEF) ≥ 50% and QTcF (Fridericia's) for male<450 ms, for female<470 ms at screening. Women of childbearing potential should agree to use contraceptive measures (such as IUD, contraceptive or condom) during the study and within 6 months after the end of the study. Exclusion Criteria: Subjects who are diagnosed as acute promyelocytic leukemia. Subjects with clinical evidence of active CNS leukemia. Subjects with any other active malignancy expect for those have been cured (basal cell carcinoma, superficial bladder cancer, cervical cancer in situ, carcinoma in situ of breast or prostate cancer with Gleason score <6). For subjects with induction remission who go directly to randomisation, their antitumour drug elution is required prior to the first dose in the consolidation phase for a minimum of 5 half-lives or 4 weeks, whichever is shorter. Subjects with a history of any major surgery or radiation therapy within 4 weeks prior to the first dose. Subjects with active cardiovascular disease within 6 months prior to the first dose. Subjects with severe hemorrhagic disorders or diseases may cause spontaneous bleeding. Subjects with active or history of cerebrovascular disease, such as stroke, cerebral hemorrhage within 6 months prior to the first dose. Subjects with severe pulmonary disease within 2 weeks prior to the first dose. Subjects with active or uncontrolled infection. Subjects with previous cumulative exposure to anthracyclines >302 mg/m^2 daunorubicin (or equivalent drug equivalent dose level). Subjects with hypersensitivity to liposomal products. Subjects with a history of Wilson's disease or other copper-metabolism disorder. Subjects with known HIV, hepatitis B or hepatitis C infection. Participation in another clinical trial or treatment with any investigational drug within 28 days of study start Female subjects who are pregnant, breast-feeding, or who are likely to become pregnant during the study. Any subject whom the Investigator believes will not be a good candidate for the study.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 75 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
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence A (T-R)<br>(cytarabine: daunorubicin) liposome for injection followed by Vyxeos | Drug: (cytarabine: daunorubicin) liposome for injection<br>* Be given intravenously at 65U/m^2 on days 1 and day3 of the first cycle of induction.<br>Drug: Vyxeos<br>* Be given intravenously at 65U/m^2 on days 1 and day3 of the second cycle of induction.<br>* Other names: CPX-351;|
| Experimental: Sequence B (R-T)<br>Vyxeos followed by (cytarabine: daunorubicin) liposome for injection | Drug: Vyxeos<br>* Be given intravenously at 65U/m^2 on days 1 and day3 of the first cycle of induction.<br>* Other names: CPX-351;Drug: (cytarabine: daunorubicin) liposome for injection<br>* Be given intravenously at 65U/m^2 on days 1 and day3 of the second cycle of induction.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum (peak) plasma drug concentration (Cmax) of daunorubicin cytarabine liposomes | Maximum (peak) plasma drug concentration is a Pharmacokinetic parameter | 30 minutes before administration and 1.5, 2, 5,9,24,48,72,120,168hours after administration of Day 1. | 
| Area under the plasma concentration versus time curve calculated from 0 to 48h post administration (AUC0-48h) of daunorubicin cytarabine liposomes | Area under the plasma concentration-time curve from time zero to time 48 hours is a Pharmacokinetic parameter | 30 minutes before administration and 1.5, 2, 5,9,24,48,72,120,168hours after administration of Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum (peak) plasma drug concentration (Cmax) of free daunorubicin and cytarabine | Maximum (peak) plasma drug concentration is a Pharmacokinetic parameter | 30 minutes before administration and 1.5, 2, 5,9,24,48,72,120,168hours after administration of Day 1. | 
| Area under the plasma concentration versus time curve calculated from 0 to 48h post administration (AUC0-48h) of free daunorubicin and cytarabine | Area under the plasma concentration-time curve from time zero to time 48 hours is a Pharmacokinetic parameterencapsulated and toal cytarabine and daunorubicin after Day 3 treatment of each period. | 30 minutes before administration and 1.5, 2, 5,9,24,48,72,120,168hours after administration of Day 1. | 
| Maximum (peak) plasma drug concentration (Cmax) of total daunorubicin and cytarabine | Maximum (peak) plasma drug concentration is a Pharmacokinetic parameter | 30 minutes before administration and 1.5, 2, 5,9,24,48,72,120,168hours after administration of Day 1. | 
| Area under the plasma concentration versus time curve calculated from 0 to 48h post administration (AUC0-48h) of total daunorubicin and cytarabine | Area under the plasma concentration-time curve from time zero to time 48 hours is a Pharmacokinetic parameterencapsulated and toal cytarabine and daunorubicin after Day 3 treatment of each period. | 30 minutes before administration and 1.5, 2, 5,9,24,48,72,120,168hours after administration of Day 1. | 
| Incidence of treatment-emergent adverse events (TEAEs) |  | Up to 35 calendar days after the last administration of the investigational product. | 
| Complete remission rate | Proportion of subjects with complete remission | Up to 1 year. | 
| Composite remission rate | Proportion of subjects with complete response (CR) or complete response with incomplete count recovery (CRi) | Up to 1 year. | 
| Relapse-free survival | From the date of remission to the date of relapse after CR/CRi, or death, whichever occurs first. | Up to 3 years. | 
| Proportion of subjects who achieve complete remission with MRD negativity |  | Up to 1 year. |