A Study of Doxorubicin Hydrochloride Liposome Injection in Subjects With Ovarian Cancer.

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 .

This study is a randomized, open label, two arm, single dose, crossover bioequivalence study. This study will be conducted in female subjects aged 18 to 65 years diagnosed with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy and who are already receiving or scheduled to start therapy with Doxorubicin Hydrochloride Liposome Injection product. Each subject will be randomized to one of the two treatment sequences (RT or TR) according to a randomization scheme prepared prior to start of the trial. Serial blood samples for determination of free and liposomal encapsulated doxorubicin plasma concentration for PK analysis will be obtained in each cycle., This study has an adaptive 2-stage design. A sufficient number of subjects with ovarian cancer shall be recruited to have approximately 42 evaluable subjects completing all follow up procedures (Stage 1). An interim analysis of free and encapsulated doxorubicin will be performed at the end of Stage 1. If the bioequivalence of encapsulated and free doxorubicin has been established, then the study will be stopped. Otherwise, the study may continue into Stage 2 with additional number of ovarian cancer subjects. A final evaluation of bioequivalence based on free and encapsulated doxorubicin will be performed at the end of Stage 2 and will include all enrolled subjects completing the study. Bioequivalence criteria: the 94.12% confidence interval of the ratio of geometric means of TEST to REFERENCE for Cmax, AUC0-t, AUC0-∞, for free and encapsulated doxorubicin should be between 80.00% and 125.00%.

Eligibility Criteria:
Inclusion Criteria:

1. Adult female subjects between 18 to 65 years of age (both inclusive) at the time of screening visit.
2. Subjects with histologically or cytological proven ovarian cancer, whose disease has progressed or recurred after platinum-based chemotherapy and scheduled to start therapy with or who are already receiving an approved dose of 50 mg per meter square Doxorubicin Hydrochloride Liposome Injection product.
3. Subjects expected to be able to receive both doses of Doxorubicin Hydrochloride Liposome Injection.
4. Subjects eligible for receiving a dose of 50 mg per meter square of Doxorubicin Hydrochloride Liposome Injection.
5. Subjects with Performance less than or equal to 2 on the Eastern Cooperative Oncology Group (ECOG) performance scale
6. Cardiac function (LVEF) greater than or equal to 50 percentage.
7. Adequate renal, hepatic and bone marrow function without blood product or hematopoietic growth factor support.
8. Subjects able to understand the investigational nature of this study.
9. Availability of subject for the entire study period and willingness to adhere to protocol requirements.
10. For subjects of child-bearing potential, serum beta HCG pregnancy test at screening and urine pregnancy test prior to dosing must be negative and subjects agree to use an acceptable and effective approved method of contraception
11. Subjects of non-childbearing potential who are either surgically sterile (hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or greater than 1 year postmenopausal with follicle stimulating hormone in the postmenopausal range
12. Signed written informed consent.

Exclusion Criteria:

1. Subjects with history or presence of significant:

   * Allergy or significant history of hypersensitivity or idiosyncratic reactions to a conventional formulation of Doxorubicin Hydrochloride and/or any components of Doxorubicin Hydrochloride liposome injection.
   * Clinically significant pulmonary, hepatic, renal, bone marrow, gastrointestinal, endocrine, immunologic, dermatologic, musculoskeletal, neurological or psychiatric disease.
   * Impaired cardiac function
2. Alcohol dependence, alcohol abuse or drug abuse or addiction with any recreational drug within the past one year.
3. Active opportunistic infection with mycobacteria, cytomegalovirus, toxoplasma, p. carinii or other microorganism (bacterial, viral or fungal).
4. Clinically significant illness (except ovarian cancer) within four weeks prior to dosing.
5. Prior radiation therapy to mediastinum
6. Concomitant use of other cytotoxic or cytostatic drugs or of radiotherapy within four weeks prior to dosing
7. Subject under treatment of myelotoxic drugs, other than doxorubicin (liposomal).
8. Use of prescription or non-prescription herbal and dietary supplements, within 7 days prior to dosing.
9. Subjects with other known active malignancies requiring treatment within 3 years (except for ovarian and/or skin cancer).
10. Subjects with known brain metastasis and/or subjects considered for radiotherapy treatment.
11. Positive result to any of the following: HIV-1/2, hepatitis A, B and C; syphilis.
12. Use of CYP3A4 enzyme-modifying drugs in the previous 30 days prior to dosing and during the study
13. Subjects who have:

    * Systolic blood pressure less than 90 mmHg or more than 160 mmHg
    * Diastolic blood pressure less than 60 mmHg or more than 95 mmHg
    * Pulse rate below 55 per min. or above 100 per min14.
14. Subjects with abnormal laboratory parameters
15. Subject is currently enrolled in, or has not yet completed a period of at least 30 days since ending other investigational device or drug trial(s).
16. Subjects who are legally detained in an official institute.
17. Subjects with prior doxorubicin exposure that would result in a total lifetime exposure of 550 mg per meter square or more after four cycles of treatment.
18. Has any condition that, in the opinion of the investigator, would make participation not be in the best interest (e.g., compromise the well-being) of the subject or that could prevent, limit, or confound the protocol-specified assessments
19. Females of childbearing potential unwilling to use acceptable contraception (as identified in the protocol) throughout the trial and for 6 months after the last dose of study drug.
20. Pregnant or breast-feeding subjects.