Assess Bioequivalence of Two Formulations of Doxorubicin Hydrochloride Liposome in Female Patients With Ovarian Cancer

Sponsor

Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd. (Industry)

Overall Status

Completed

CT.gov ID

NCT02237690

Collaborator

(none)

Enrollment

Locations

Arms

Actual Duration (Months)

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multi-center, single-dose, open-label, randomized, balanced, two-treatment, two-cycle, two-sequence crossover study to assess bioequivalence of test (T) and reference (R) formulations of doxorubicin hydrochloride liposome injection in female patients with ovarian cancer.

Each patient will be randomized to one of two treatment sequences (RT or TR) according to a randomization scheme prepared prior to the start of the trial.There will be at least 4-week apart between each single-dose administration. Serial blood samples for determination of free doxorubicin and liposomal encapsulated doxorubicin plasma concentrations for PK analysis will be obtained in each cycle.

The 90% confidence intervals on the GMR(geometric mean ratio) of test to reference products of free and liposome encapsulated doxorubicin for PK must be within 80-125% to demonstrate bioequivalence.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Cancer	Drug: Doxorubicin hydrochloride liposome	Phase 1

Detailed Description

This study has an adaptive 2-stage design. Bioequivalence based on encapsulated doxorubicin will be tested at the end of Stage 1 . An interim analysis of free doxorubicin will be performed at the end of Stage 1 . If needed, the study may continue into Stage 2 with additional number of ovarian cancer patients determined based on the interim analysis; and a final evaluation of bioequivalence for free doxorubicin will be performed at the end of Stage 2. Each patient will be randomized to one of two treatment sequences (RT or TR) according to a randomization scheme prepared prior to the start of the trial. Serial blood samples for determination of free doxorubicin and liposomal encapsulated doxorubicin plasma concentrations for PK analysis will be obtained in each cycle.

The 90% confidence intervals on the GMR（geometric mean ratio） of test to reference products of free and liposome encapsulated doxorubicin for PK must be within 80-125% to demonstrate bioequivalence.

Safety data will be summarized and listed. Adverse events will be coded and classified by system organ class and preferred term using Common Terminology Criteria for Adverse Events. A summary of all drug-related adverse events will also be generated. Clinical laboratory data will be summarized descriptively and listed by treatment group. The change from pre dose to the end of the study will also be summarized. Prior and concomitant medications will be coded with the World Health Organization Drug Dictionary and listed. Vital signs and electrocardiogram data will be summarized and listed by dose group and visit.

Study Design

Study Type:

Interventional

Actual Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized, Open Label, Single-Dose, Two-Cycle Crossover Study to Assess Bioequivalence of Test and Reference Formulations of Doxorubicin Hydrochloride Liposome Injection in Female Patients With Ovarian Cancer

Actual Study Start Date :

Sep 1, 2014

Actual Primary Completion Date :

Aug 1, 2015

Actual Study Completion Date :

Aug 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: doxorubicin hydrochloride liposome（Libaoduo） Use the test drug(doxorubicin hydrochloride liposome-Libaoduo,from Fudan-Zhangjiang ),then use the reference drug(doxorubicin hydrochloride liposome，from Sunpharma) after at least 4-weeks.	Drug: Doxorubicin hydrochloride liposome 50mg/m2,IV on day1 of each cycle,On Day 1 of Cycle 2, patients will crossover to the alternate reference or test formulation,After completion of Cycle 2 (Day 28), patients will be continued on the treatment of Doxorubicin Hydrochloride Liposome Injection up to 4 more cycles if tolerance permits under guidance of their attending physicians.
Active Comparator: doxorubicin hydrochloride liposome Use the reference drug(doxorubicin hydrochloride liposome，from Sunpharma),then use the test drug drug(doxorubicin hydrochloride liposome-Libaoduo,from Fudan-Zhangjiang) after at least 4-weeks.	Drug: Doxorubicin hydrochloride liposome 50mg/m2,IV on day1 of each cycle,On Day 1 of Cycle 2, patients will crossover to the alternate reference or test formulation,After completion of Cycle 2 (Day 28), patients will be continued on the treatment of Doxorubicin Hydrochloride Liposome Injection up to 4 more cycles if tolerance permits under guidance of their attending physicians.

Arm

Intervention/Treatment

Experimental: doxorubicin hydrochloride liposome（Libaoduo）

Use the test drug(doxorubicin hydrochloride liposome-Libaoduo,from Fudan-Zhangjiang ),then use the reference drug(doxorubicin hydrochloride liposome，from Sunpharma) after at least 4-weeks.

Drug: Doxorubicin hydrochloride liposome

50mg/m2,IV on day1 of each cycle,On Day 1 of Cycle 2, patients will crossover to the alternate reference or test formulation,After completion of Cycle 2 (Day 28), patients will be continued on the treatment of Doxorubicin Hydrochloride Liposome Injection up to 4 more cycles if tolerance permits under guidance of their attending physicians.

Active Comparator: doxorubicin hydrochloride liposome

Use the reference drug(doxorubicin hydrochloride liposome，from Sunpharma),then use the test drug drug(doxorubicin hydrochloride liposome-Libaoduo,from Fudan-Zhangjiang) after at least 4-weeks.

Drug: Doxorubicin hydrochloride liposome

Outcome Measures

Primary Outcome Measures

pharmacokinetic（PK） parameter:the maximum plasma doxorubicin concentrations(Cmax) [2 cycles]
The study endpoint will use the PK parameter(Cmax) for free doxorubicin and liposome encapsulated doxorubicin
PK parameter:the areas under the plasma concentration versus time curve calculated from 0 to the last measurable observation(AUC0-t) [2 cycles]
The study endpoint will use the PK parameter(AUC0-t) for free doxorubicin and liposome encapsulated doxorubicin(AUC0-t)
PK parameter:the areas under the plasma concentration versus time curve extrapolated from 0 to infinity(AUC0-inf) [2 cycles]
The study endpoint will use the PK parameter(AUC0-inf) for free doxorubicin and liposome encapsulated doxorubicin

Secondary Outcome Measures

incidence of treatment-emergent adverse events (TEAEs) [2 cycles]
study discontinuation information [2 cycles]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Able to give written informed consent for participation in the trial;
Females age 18 to 75 years, inclusive;
Histologically or cytologically proven ovarian cancer, which has progressed or recurred by CT/MRI confirmation after platinum-based chemotherapy;
ECOG (Eastern Cooperative Oncology Group) Performance Status 0 - 2;
Patient is expected to be able to receive both doses of Doxorubicin Hydrochloride Liposome Injection and participate in the trial for at least 56 days.
Urine pregnancy test before dosing of both cycle1 and cycle 2 must be negative (not including postmenopausal or surgically sterile women); Agree to use an approved method of birth control (condom with spermicide, diaphragm or cervical cap with spermicide, or intrauterine device); or patients of non-childbearing potential who are either surgically sterile (hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or >1 year postmenopausal with follicle-stimulating hormone in the postmenopausal range;
30days or 5 half-lives (whichever is longer) have elapsed from the completion of previous cancer therapy, and patients must have recovered to < Grade 2 or be at new stable baseline from any related toxicities;
Adequate renal, hepatic and bone marrow function without blood product or hematopoietic growth factor support:
Able to comply with study requirements in the opinion of the Principal Investigator

Exclusion Criteria:

Significant allergy, hypersensitivity or idiosyncratic reactions to doxorubicin and/or any related compounds;
History or presence of cardiac disease rated New York State Heart Association Classification class 2 or greater;
Uncontrolled cardiac arrhythmia or other findings on screening electrocardiogram (ECG) which could, in the judgment of the Principal Investigator, put the patient at undue risk for participation in the trial;
LVEF（left ventricular ejection fraction） below 50% or below institutional normal at screening;
Prior radiation therapy to mediastinum;
Concomitant use of other cytotoxic or cytostatic drugs or of radiotherapy;
Active, uncontrolled infection, including opportunistic infection with mycobacteria, cytomegalovirus, toxoplasma, or P. carinii;
Use of prescription or non-prescription herbal and dietary supplements, within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study medication.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cancer Institute& Hospital, Chinese Academy of Medical Sciences	Beijing	Beijing	China	100021
2	Sun Yat-sen University Cancer Center	Guangzhou	Guangdong	China	510060
3	QiLu Hospital of Shandong University	Jinan	Shandong	China	250012

Sponsors and Collaborators

Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd.

Investigators

Principal Investigator: Wu li ngying, Ph.D, Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Principal Investigator: Kong be ihua, Ph.D, Shandong University Qilu Hospital
Principal Investigator: Liu ji hong, Ph.D, Sun Yat-sen University