A Randomized, Open-label, Single-dose, Two-preparation, Two-sequence, Two-cycle Crossover, Bioequivalence Study of Doxorubicin Hydrochloride Liposome Injection in Patients With Breast Cancer/Ovarian Cancer
Overview
- Phase
- Phase 1
- Intervention
- Doxorubicin Hydrochloride Liposome Injection
- Conditions
- Breast Cancer
- Sponsor
- Shenzhen Kangzhe Pharmaceutical Co., Ltd.
- Enrollment
- 80
- Locations
- 1
- Primary Endpoint
- Cmax
- Last Updated
- 4 years ago
Overview
Brief Summary
Bioequivalence study is proposed to be carried out on patients of breast cancer/ ovarian cancer, who are administrated for Doxorubicin Hydrochloride Liposomal Injection Lipodox® or Caelyx® in a dose of 50 mg/m2.
Detailed Description
This study is a randomized, open-label, single-dose, two-preparation, two-sequence, two-cycle crossover bioequivalence study. This study will be conducted in female subjects aged 18 to 75 years diagnosed with breast cancer/ ovarian cancer. Each subject will be randomized to two treatment sequences (RT or TR) with equal numbers of patients according to a randomization scheme prepared to start of the trial. The cleaning period was 28-42 days. Serial blood samples for determination of free and liposomal encapsulated doxorubicin plasma concentration for PK analysis will be obtained in each cycle. Blood samples to be obtained at 0 h (within 60 min) before infusion, 15 min, 30 min, 45 min, 60 min, 75 min, 90min after the beginning of infusion, 15 min, 30 min, 1.0 h, 3.0 h, 5.0 h, 8.0 h, 16.0 h, 24.0 h, 36.0 h, 48.0 h, 96.0 h, 168.0 h, 240.0 h, 336.0 h after infusion completed.
Investigators
Eligibility Criteria
Inclusion Criteria
- •The subjects fully understand the purpose, nature, methods and possible adverse reactions of the study, voluntarily participate in the study, and sign informed consent before the study procedure begins;
- •Adult female subjects between 18 to 75 years of age (both inclusive) at the time of screening visit. Body weight is greater than or equal to 40.0 kg. Body surface area (BSA) is less than 1.8 m2;
- •Subjects with histologically or cytological proven: 1) Advanced ovarian cancer patients who had previously failed first-line platinum-containing chemotherapy; Or 2) metastatic breast cancer;
- •ECOG performance status ≤ 2;
- •Life expectancy of at least 3 months;
- •Adequate renal, hepatic function:
- •Neutrophils ≥1.5×109/L;
- •Leukocyte≥3×109/L;
- •Platelet count ≥ 80×109/L;
- •Hemoglobin (Hb) ≥ 90g/L;
Exclusion Criteria
- •History of allergy to doxorubicin or any components of doxorubicin; or those with allergic constitution: such as those who are allergic to two or more drugs and food;
- •Previous treatment with Doxorubicin Liposome, and discontinue treatment due to treatment failure or severe adverse reactions;
- •Patients who have previously received more than 400 mg/m2 doxorubicin (Conversion of other anthracyclines and anthraquinone: 1 mg doxorubicin is equivalent to 2 mg epirubicin, or 2 mg pirarubicin, or 2 mg daunorubicin, or 0.5 mg dimethoxy-daunorubicin , or 0.45 mg mitoxantrone), or severe cardiotoxicity from prior exposure to anthracyclines;
- •Positive history of known spinal cord compression or brain metastases (unless asymptomatic, stable for more than 4 weeks, steroid treatment was discontinued at least 4 weeks prior to first administration of Lipodox®/ Caelyx®, and no radiographic evidence of significant edema around the tumor lesion). Untreated patients with disease progression due to brain metastases in the last treatment prior to screening;
- •Subjects with other known active malignancies that require treatment within 5 years;
- •Patients with abnormal cardiac function: ECG examination, QTc\>480ms; left ventricular ejection fraction(LVEF)\<55%；congestive heart failure, myocardial infraction, or uncontrolled angina pectoris of New York Heart Society≥2 within 6 months prior to enrollment; have undergone heart bypass surgery; Tropoin≥1.5 x ULN；N-terminal brain natriuretic peptide ≥1.5 x ULN; The investigator evaluated the overall cardiac function of the subjects by integrating all examination items.
- •Patients with poor control of hypertension (systolic≥160 mmHg, diastolic\>80 mmHg;
- •Diabetes blood glucose control is not up to standard, fasting blood glucose \>11.1 mol/L, or accompanied by diabetic complications (diabetic nephropathy, peripheral neuropathy);
- •Radiation therapy or chemotherapy drugs (paclitaxel, cyclosporine, dexrazoxane, cytarabine, streptozotocin, etc.) within 4 weeks before study administration prior to administration, or other anti-tumor therapies such as endocrine therapy, traditional Chinese medicine, and local radiation therapy to relieve pain;
- •Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug, or plan to undergo major surgery during the study period and those who have undergone surgery that may affect drug absorption, distribution, metabolism, and excretion;
Arms & Interventions
Reference product-R
Caelyx® (Janssen-Cilag International NV); 20 mg/10 mL (50 mg/m2 dose). As this is a crossover study, subjects receiving the Reference Product (Caelyx®) in Cycle 1, will receive the Test Product (Lipodox®) in Cycle 2. Cycle is defined as 28-42 days (RT).
Intervention: Doxorubicin Hydrochloride Liposome Injection
Test Product-T
Lipodox® (Sun Pharmaceutical Industries Ltd.); 20 mg/10 mL (50 mg/m2 dose). As this is a crossover study, subjects receiving the Test Product (Lipodox®) in Cycle 1, will receive the Reference Product (Caelyx®) in Cycle 2. Cycle is defined as 28-42 days (TR).
Intervention: Doxorubicin Hydrochloride Liposome Injection
Outcomes
Primary Outcomes
Cmax
Time Frame: Pre-dose (within 60 minutes), 15,30, 45,60,75,90minutes after the beginning of infusion, 15minutes, 30minutes, 1,3,5,8,16,24,36,48,96,168,240,336hours after infusion completed
Maximum observed plasma concentration
AUC[0-t]
Time Frame: Pre-dose (within 60 minutes), 15,30, 45,60,75,90minutes after the beginning of infusion, 15minutes, 30minutes, 1,3,5,8,16,24,36,48,96,168,240,336hours after infusion completed
Area under the plasma concentration-time curve from time 0 to last time of quantifiable concentration
AUC[0-∞]
Time Frame: Pre-dose (within 60 minutes), 15,30, 45,60,75,90minutes after the beginning of infusion, 15minutes, 30minutes, 1,3,5,8,16,24,36,48,96,168,240,336hours after infusion completed
Area under the plasma concentration-time curve from 0 extrapolated to infinite time
Secondary Outcomes
- AUC[0-48hours](Pre-dose (within 60 minutes) , 15, 30, 45, 60, 75, 90minutes after the beginning of infusion, 15 minutes, 30 minutes, 1, 3, 5, 8, 16, 24, 36, 48hours after infusion completed)
- AUC[48hours-t](48hours post-dose to the 336hours post-dose)
- Tmax(Pre-dose (within 60 minutes), 15,30, 45,60,75,90minutes after the beginning of infusion, 15minutes, 30minutes, 1,3,5,8,16,24,36,48,96,168,240,336hours after infusion completed)
- λz(Pre-dose (within 60 minutes), 15,30, 45,60,75,90minutes after the beginning of infusion, 15minutes, 30minutes, 1,3,5,8,16,24,36,48,96,168,240,336hours after infusion completed)
- t1/2z(Pre-dose (within 60 minutes), 15,30, 45,60,75,90minutes after the beginning of infusion, 15minutes, 30minutes, 1,3,5,8,16,24,36,48,96,168,240,336hours after infusion completed)
- AUC_%Extrap(Pre-dose (within 60 minutes), 15,30, 45,60,75,90minutes after the beginning of infusion, 15 minutes, 30 minutes, 1,3,5,8,16,24,36,48,96,168,240,336 hours after infusion completed)
- CL/F(Pre-dose (within 60 minutes), 15,30, 45,60,75,90 minutes after the beginning of infusion, 15 minutes, 30 minutes, 1,3,5,8,16,24,36,48,96,168,240,336 hours after infusion completed)
- Vd/F(Pre-dose (within 60 minutes), 15,30, 45,60,75,90 minutes after the beginning of infusion, 15 minutes, 30 minutes, 1,3,5,8,16,24,36,48,96,168,240,336 hours after infusion completed)