CTRI/2016/12/007543 [Registered on: 07/12/2016] Trial Registered Prospectively
Last Modified On:
08/08/2017
Post Graduate Thesis
No
Type of Trial
BA/BE
Type of Study
Study Design
Randomized, Crossover Trial
Public Title of Study
Bioequivalence study of Doxorubicin Hydrochloride in Subjects with Epithelial Ovarian Carcinoma Who Have Failed Platinum-Based Chemotherapy
Scientific Title of Study
A Multicenter, randomized, single-blind, 2-way crossover, Pivotal Pharmacokinetic Bioequivalence Study Comparing Generic to Reference Liposome-Encapsulated Doxorubicin Hydrochloride in Subjects with Epithelial Ovarian Carcinoma Who Have Failed Platinum-Based Chemotherapy
Trial Acronym
Secondary IDs if Any
Secondary ID
Identifier
TOL2649G Version No. 4.1 Date 10-MAY-2016
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study) Modification(s)
Name
Dr Bina Naik
Designation
Director
Affiliation
CBCC-Vibgyor Research Pvt. Ltd.
Address
Second floor, Skoda house, Opp. LJ campus, S.G. Highway Sarkhej,
Ahmedabad – 382210,
Gujarat, India
A standardized dose of 50 mg/m2 of TOLMAR formulation or DOXOrubicin will be administered as a 1 hour i.v. infusion. Each subject will receive a total of 2 infusions (1 dose of TOLMAR formulation and 1 dose of DOXOrubicin), the second infusion being given 28 to 42 days after the first infusion.
A standardized dose of 50 mg/m2 of TOLMAR formulation or DOXOrubicin will be administered as a 1 hour i.v. infusion. Each subject will receive a total of 2 infusions (1 dose of TOLMAR formulation and 1 dose of DOXOrubicin), the second infusion being given 28 to 42 days after the first infusion.
Inclusion Criteria
Age From
18.00 Year(s)
Age To
75.00 Year(s)
Gender
Female
Details
1. Female between 18 and 75 years of age, inclusive.
2. Histologically proven epithelial ovarian carcinoma.
3. Documented progressive or recurrent disease after treatment with platinum based chemotherapy.
4. Able and clinically indicated to receive liposomal doxorubicin HCl, as specified in the DOXOrubicin Package Insert for subjects with ovarian cancer, without exceeding a lifetime cumulative dosage of 450 mg/m2 (See Section 7.3.1 for rationale). Prior use of conventional or liposomal doxorubicin formulations, in addition to the use of other anthracyclines or anthracenediones should be included in calculations of total lifetime cumulative dose.
5. Able and clinically indicated to receive the recommended minimum 4 courses of liposomal doxorubicin HCl either during participation in this study, including infusions prior to enrolling in this study or after completing study participation
6. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 (See Appendix 14.1). Any subject who experiences deterioration in ECOG status to 4 during the study should discontinue participation in the study.
7. Life expectancy of > 180 days.
8. Acceptable hematology status:
a. Hemoglobin ≥ 9 g/dL
b. Absolute neutrophil count (ANC) ≥ 1500 cells/µL
c. Platelet count ≥ 75,000 cells/µL
9. Acceptable liver function:
a. Alanine aminotransferase (ALT) ≤ 2X upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≤ 2X ULN
c. Bilirubin < 1.2 mg/dL
d. Alkaline phosphatase ≤ 2X ULN
10. Acceptable kidney function
a. Creatinine ≤ 2X ULN or
b. Creatinine clearance ≥ 60 mL/minute
11. Cardiac ejection fraction ≥ 50% by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan within 14 days prior to first dose of Investigational Product.
12. If of childbearing potential, must agree to use adequate contraception (eg, hormonal, chemical, double-barrier, or abstinence) while on study and for 3 months after study participation is discontinued.
13. Willing and able to provide written informed consent prior to any study-related activities being performed.
ExclusionCriteria
Details
Exclusion Criteria:
1. Received liposomal doxorubicin HCl in the past and had a required dose reduction to below 50 mg/m2, or whose disease has progressed or recurred after treatment with liposomal doxorubicin.
2. Received previous chemotherapy less than 4 weeks prior to dosing of Investigational Product.
3. Recent (6 month) history of myocardial infarction or severe arrhythmias prior to dosing of Investigational Product (See DOXOrubicin Package Insert).
4. History of major cardiac (New York Heart Association [NYHA] Type III or IV), liver, or kidney disease.
5. Received any prior mediastinal irradiation (as cardiac toxicity may occur at lower cumulative doses).
6. Receipt of trastuzumab within 24 weeks prior to dosing of Investigational Product and during the study (DOXOrubicin Hydrochloride Injection Package Insert).
7. Receipt of cyclophosphamide, calcium channel blockers, and other potential cardiotoxic drugs for 2 weeks prior to dosing of Investigational Product, and during the study (See DOXOrubicin Package Insert and anthracycline package insert).
8. Receipt of phenytoin for 2 weeks prior to dosing of Investigational Product, and during the study as phenytoin levels may be decreased by doxorubicin (See DOXOrubicin Hydrochloride Injection Package Insert).
9. Known hypersensitivity, idiosyncratic, or allergic reactions to conventional or liposomal formulations of doxorubicin, anthracycline therapy or to any of their components.
10. Pregnant or breastfeeding.
11. Active opportunistic infection with mycobacteria, cytomegalovirus, toxoplasma, Pneumocystis carinii, or other microorganism.
12. Presence or recent history (within the last 2 months) of clinically significant ascites requiring intervention (eg, paracentesis).
Note: stable dose of diuretics will be permitted.
13. Known central nervous system metastasis.
14. Major surgical procedure (including periodontal) within 28 days of first dose of Investigational Product.
15. Surgical or other non-healing wounds.
16. Exposure to any investigational agent within 28 days prior to first dose of Investigational Product.
17. History of other malignancies in the last 5 years. Potential subjects with prior history of in situ cancer or basal or squamous cell skin cancer are eligible. Potential subjects with other malignancies that were cured with definitive primary therapy alone (eg, surgery) and who have been continuously free of the previous disease for 1 year are also eligible upon Sponsor approval.
18. Severe or life-threatening infection, including known past medical history of human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS).
19. Has not recovered to Grade 0 or 1 toxicity from previous anticancer treatments or previous investigational agents. Exceptions are alopecia (any grade is acceptable), fatigue (Grade 2 is acceptable), and peripheral neuropathy (stable Grade 2 is acceptable) (Per National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], v4.03).
20. Uncontrolled diabetes mellitus.
21. Any other medical condition or serious intercurrent illness that, in the opinion of the Investigator, may make it undesirable for the subject to participate in the study including but not limited to cirrhosis or psychiatric illness/social situations that would limit adherence to study requirements.
22. Any other condition(s) which could significantly interfere with Protocol compliance including, but not limited to, dementia, psychosis, cognitive impairment, altered mental status, or other major psychiatric disorder.
23. Participation in any clinical study within 28 days before the first dose of Investigational Product.
24. (INDIA) Donation and/or loss of 350 ml (1 unit) of blood within 90 days of Cycle 1 Day 0.
25. (INDIA) Positive hepatitis screening laboratory tests for hepatitis A, hepatitis B, and/or hepatitis C.
26. (INDIA) Presence identified during screening laboratory tests of malaria, syphilis or HIV.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Blinding/Masking
Participant and Outcome Assessor Blinded
Primary Outcome
Outcome
TimePoints
To compare the PK parameters of DOXOrubicin and TOLMAR
formulation in subjects with progressive or recurrent epithelial ovarian cancer.
Up to 30 minutes prior dosing, During infusion: 0.50 hr; end of infusion: 1.00 hr and after end of infusion: 2.00, 3.00, 4.00, 8.00, 24.00, 48.00, 96.00, 168.00, 240.00, 336.00 hr
Secondary Outcome
Outcome
TimePoints
To assess safety and tolerability of DOXOrubicin and TOLMAR
Formulation.
NA
Target Sample Size
Total Sample Size="60" Sample Size from India="30" Final Enrollment numbers achieved (Total)= "97" Final Enrollment numbers achieved (India)="17"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Brief Summary
This is a multicenter,
randomized, single-blind, 2-way crossover, PK BE study in subjects with epithelial
ovarian carcinoma whose disease has progressed or recurred after platinum-based
chemotherapy.
This study is designed
to evaluate the PK parameters and safety of DOXOrubicin and TOLMAR formulation
at the standard 50 mg/m2 dose for patients with ovarian cancer. Cohort
1 will receive DOXOrubicin on Cycle 1/Day 0 and TOLMAR formulation on Cycle
2/Day 0. Cohort 2 will receive TOLMAR formulation on Cycle 1/Day 0 and DOXOrubicin
on Cycle 2/Day 0.
Subjects, the
bioanalytical laboratory personnel, and TOLMAR personnel performing data analysis
will remain blinded throughout the study with regard to subject treatment (ie,
cohort assignment). Investigators will have knowledge of subject treatment
assignment to verify that subjects received their correct treatment as per
their randomized assignment.
The dose of Doxorubicin
Hydrochloride for individual subject will be calculated according to body
surface area (Calculated by Mosteller formula).
A total of twenty-six
(26) blood samples, each of 10 mL from each patient will be collected during
study for PK assessment.
On Day 0 of Dosing
cycles 1 and 2:
The pre-dose blood
sample of 10 mL will be drawn at up to 30 minutes prior to start of infusion.
The post-dose blood
samples of 10 mL each will be drawn at 0.50, 1.00 (i.e. at end of infusion),
2.00, 3.00, 4.00, 8.00, 24.00, 48.00, 96.00, 168.00, 240.00 and 336.00 hours
after start time of intravenous Infusion.