Bioequivalence Study of Liposomal Doxorubicin 20 mg/10 mL (Doxopeg® vs Caelyx®) in Advanced Cancer Patients

Multicenter, Open Label, Balanced, Randomized, Two-Treatment, Two-Period, Two- Sequence, Single Dose, Crossover Bioequivalence Study Between Two Formulations of Doxorubicin Hydrochloride Liposome Injection 20 mg/10 mL (2 mg/mL) [Doxopeg® Manufactured by FAPASA - Farmaceutica Paraguay S.A. and Registered by Adium S.A., Formerly Zodiac Produtos Farmacêuticos S.A, (Test Formulation) and Caelyx® Manufactured by Janssen Pharmaceutica NV (Reference Formulation)] in Patients With Advanced Ovarian Cancer or Metastatic Breast Cancer

To characterize the pharmacokinetic profile of pegylated liposomal doxorubicin formulations, a multicenter, randomized, two-period crossover study was conducted in 74 patients with advanced ovarian cancer or metastatic breast cancer. Blood samples were collected up to 336 hours post-dose, and plasma concentrations of encapsulated and free doxorubicin were quantified using validated LC-MS/MS methods. Pharmacokinetic parameters (Cmax, AUC0-t, AUC0-inf, tmax, t1/2, Vd, and Cl) were calculated using noncompartmental analysis.

Inclusion Criteria:

1. Participant must sign an ICF indicating that the participant understands the purpose of, and procedures required for the study and is willing to participate in the study.

2. Female participant must be 18 to 75 years of age (both inclusive), at the time of signing the informed consent.

3. Participant meeting one of the following criteria:

   a Participant with documented advanced ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy AND who are already receiving or scheduled to start the monotherapy with liposomal doxorubicin (pegylated) at a dose of 50 mg/m2.

   b Participants with documented metastatic breast cancer AND who are already receiving or scheduled to start the monotherapy with liposomal doxorubicin (pegylated) at a dose of 50 mg/m2.

4. Life expectancy of ≥12 weeks at screening visit.

5. An Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2 at screening visit.

6. Participant should have recovered from any toxic effects of previous chemotherapy as judged by the Investigator. Participants who are already receiving liposomal doxorubicin (pegylated) at a dose of 50 mg/m2.should not require dose reduction(s) in next planned cycle in the study due to toxicity

7. A participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:

   a Is not a woman of childbearing potential (WOCBP) b Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency when used consistently and correctly, during the intervention period and for at least eight months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during the study and for at least eight months after the last dose of study intervention. The investigator should evaluate the effectiveness and the potential for contraceptive method failure (eg, noncompliance, recently initiated) of the contraceptive method in relationship to the first dose of study intervention.

   • A WOCBP must have a negative highly sensitive serum pregnancy test at screening; and urine pregnancy test within 24 hours before the first dose of study intervention.
   • If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

   The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.

8. Participant with adequate hematologic, renal and liver function at screening visit.

   a Absolute Neutrophil Count (ANC) with more, or equal than 1500/mm3 b Platelet count more, or equal than 75,000/mm3 c Hemoglobin ≥9.0 g/dL d Estimated Glomerular Filtration Rate (eGFR) of ≥30 mL/min/1.73 m2 by the CKD-EPI formula e Total Bilirubin <1.2 mg/dL f AST and ALT ≤2.5 × ULN (≤ 4 × ULN for liver metastasis)

9. Participant willing and able to adhere to the lifestyle restrictions specified in this protocol

Exclusion Criteria:

Any potential participant who meets any of the following criteria will be excluded from participating in the study:

1. Documented medical history of clinically significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric, or metabolic disturbances or any other medical condition(s) for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the wellbeing) or that could prevent, limit, or confound the protocol-specified assessments.

2. Known allergies, hypersensitivity, or intolerance to any of the study interventions, or components/ excipients thereof, or drug or other allergy that, in the opinion of the investigator, contraindicates participation in the study.

3. Prior doxorubicin exposure that would result in a total lifetime exposure of 450 mg/m2 or more after four cycles of treatment.

4. Current active systemic opportunistic infection based on clinical assessment.

5. Had major surgical procedure and will not have fully recovered from surgical procedure, or has surgical procedure planned during the time the participant is expected to participate in the study.

6. Presence of hepatitis B surface antigen (HBsAg) or IgM anti-HBC at screening or within 3 months prior to first dose of investigational intervention.

7. Positive hepatitis C antibody test result at screening or within 3 months prior to starting investigational intervention.

8. Has known human immunodeficiency virus (HIV) seropositive status, or positive HIV antibody test at screening.

9. History of drug or alcohol abuse according to medical history assessment by investigator within 1 year before screening.

10. History of malignancy except disease under study within the past 3 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years; carcinoma in situ of the cervix; or malignancy, which is considered cured with minimal risk of recurrence.

11. Known CNS disease, except for treated asymptomatic CNS metastases. Baseline brain imaging is not required for the eligibility assessment. Leptomeningeal disease is always an exclusion.

12. Participant with known history or current symptoms of any of the following clinically significant cardiac conditions:

    a Unstable angina or myocardial infarction within the past 6 months. b New York Heart Association (NYHA) cardiac disease (Class II or greater) within past 6 months c High-risk uncontrolled arrythmias within past 6 months d Clinically significant pericardial disease within past 6 months e Electrocardiographic evidence of acute ischemic or active conduction system abnormalities within past 6 months f Any other cardiac illness that could lead to a safety risk to the study participant within past 6 months g Participant with a known left ventricular ejection fraction (LVEF) < 50% by echocardiogram or multigated acquisition scan (MUGA) within last 28 days before randomization h Study participants with known coronary artery disease, congestive heart failure not meeting the above criteria, must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.

13. Received an investigational intervention or used an invasive investigational medical device within 6 months prior to baseline.

14. Intended use of prohibited medications within 14 days prior to dosing and during the study.

15. Positive Covid-19 RT-PCR test at the time of baseline within 72 hours before hospitalization.