Bioequivalence Study of Doxorubicin Hydrochloride Liposome Injection

Study Overview
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Brief Summary
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Bioequivalence study is proposed to be carried out on patients of ovarian cancer, who are already receiving or who in the opinion of their treating physicians are candidates for Doxorubicin liposomal injection therapy .

Detailed Description
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This study has sequential two stage design. Bioequivalence based on encapsulated doxorubicin will be tested at the end of stage 1. Power analysis will be performed for the primary pharmacokinetic parameters of free Doxorubicin and liposome encapsulated Doxorubicin, for all completed patients before bioequivalence evaluation. If observed power will be >= 80% then two one-sided 90% CI will be calculated for bioequivalence assessment at stage I. If observed power will be < 80% then bioequivalence will be evaluated at stage I. If bioequivalence met then study will be stopped and if bioequivalence not met, then required additional patients will be enrolled in stage II. Each patient will be randomized to one of the 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 concentration for PK analysis will be obtained in each cycle . Bioequivalence Criteria : The 94.12% confidence intervals for the ratio of geometric least squares means of ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-inf should be within 80.00 to125.00% to conclude the test product is bioequivalent to the reference product.

Official Title
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A Multicenter, Open Label, Balanced, Randomized, Two-treatment, Two-period, Two-sequence, Single Dose, Cross-over Bioequivalence Study of Doxorubicin Hydrochloride Liposome Injection 20mg/10mL of Dr. Reddy's Laboratories Ltd, India, With That of Doxorubicin Hydrochloride Liposome Injection 20 mg/10mL , Manufactured by: Sun Pharmaceutical Ind. Ltd, India; in Ovarian Cancer Patients Whose Disease Has Progressed or Recurred After Platinum Based Chemotherapy and Who Are Already Receiving or Scheduled to Start Therapy With the Reference Listed Drug Under Fasting Condition.

Conditions
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Ovarian Epithelial Cancer Recurrent

Intervention / Treatment
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* Drug: Doxorubicin Hydrochloride Liposome Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female of Indian Nationality , between 18-60n years of age Able to understand investigational nature of this study and give written informed consent prior to the participation in the trial. Patients with ovarian cancer requiring Doxorubicin and whose disease has progressed or recurred after platinum-based chemotherapy and who are already receiving or scheduled to start therapy with reference listed drug ECOG performance status ≤ 2 Cardiac function ( LVEF) ≥ 50% patient with life expectancy of at least 3 months Adequate hematopoietic, renal and liver function Exclusion Criteria: Prior doxorubicin exposure that would result in a total lifetime exposure of 550mg/m2 or more after four cycles of treatment . Pregnant or breast-feeding female active opportunistic infection with mycobacteria , cytomegalovirus , toxoplasma Impaired cardiac function including any of the following conditions within past 6 months : Unstable angina QTc prolongation or other significant ECG abnormalities Coronary artery bypass graft surgery History of hypersensitivity reactions attributed to a conventional formulation of doxorubicin HCl or the components of Doxorubicin Hydrochloride liposome injection. known brain metastasis HIV positive antibody or syphilis Patients with significantly impaired hepatic function Clinically significant liver and kidney disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Female

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: Test Product - T<br>doxorubicin hydrochloride liposome ( Dr. Reddy's Lab ) Use the test drug (doxorubicin hydrochloride liposome Injection 20mg/10mL i.e. 2mg/mL from Dr.Reddy's Laboratories Ltd., India) ; then use the reference drug ( doxorubicin hydrochloride liposome Injection 20mg/10mL i.e. 2mg/mL from Sun Pharma ) after at least 4-weeks. | Drug: Doxorubicin Hydrochloride Liposome Injection<br>* 50mg/m2, IV on Day 1 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 upto 4 more cycles if tolerance permits under guidance of their attending physicians.<br>|
| Active Comparator: Reference Product - R<br>doxorubicin hydrochloride liposome ( Sun Pharma ) Use the reference drug (doxorubicin Hydrochloride Liposome Injection 20mg/10mL i.e. 2mg/mL; from Sun Pharma ) ; then use the test drug ( doxorubicin hydrochloride liposome Injection 20mg/10mL i.e. 2mg/mL from Dr.Reddy's Laboratories Ltd., India) after at least 4 weeks. | Drug: Doxorubicin Hydrochloride Liposome Injection<br>* 50mg/m2, IV on Day 1 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 upto 4 more cycles if tolerance permits under guidance of their attending physicians.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic ( PK ) parameter : the maximum plasma doxorubicin concentration ( Cmax ) [ Time frame : 2 cycles ] | The study end point will use PK parameter ( Cmax ) for free doxorubicin and liposome encapsulated doxorubicin | 58 days | 
| PK parameter : the areas under the plasma concentration versus time curve calculated from 0 to the last measurable observation ( AUC 0-t) | The study endpoint will use the PK parameter ( AUC 0-t) for free doxorubicin and liposome encapsulated doxorubicin ( AUC 0-t) | 58 days | 
| PK parameter : the areas under the plasma concentration versus time curve extrapolated from 0 to infinity ( AUC 0-inf) | The study endpoint will use the PK parameter ( AUC 0-Inf) for free doxorubicin and liposome encapsulated doxorubicin | 58 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events ( TEAEs) |  | 58 days |