CTRI/2021/03/032185 [Registered on: 22/03/2021] Trial Registered Prospectively
Last Modified On:
22/01/2022
Post Graduate Thesis
No
Type of Trial
BA/BE
Type of Study
Study Design
Randomized, Crossover Trial
Public Title of Study
multicenter, open label, three periods, three sequence single dose bioequivalence study of Doxorubicin Injection in female patients with ovarian cancer
Scientific Title of Study
A multicenter, open label, randomized, balanced, two treatment, three
periods, three sequence, reference replicate, crossover, single dose,
bioequivalence study of Doxorubicin Hydrochloride Liposome Injection 2
mg/mL of ForDoz Pharma Corp., USA with Doxorubicin Hydrochloride
Liposome Injection for intravenous infusion 2 mg/mL Manufactured By: Sun
Pharmaceutical Industries Ltd., India, administered in female patients 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 under fasting conditions.
Bhaktivedanta Swami Marg, Sector 6, Sector 1, Srishti Complex, Mira Road, Mira Bhayandar, Thane-401107 Maharashtra,India Thane MAHARASHTRA
9930398156 2228459885 drnirmalraut@gmail.com
Dr Mukesh Bhavsing Chandre
Dhadiwal Hospital,
Opp. New CBS, Trimbak Road,
Nashik - 422002,Maharashtra, India Nashik MAHARASHTRA
9595160424
mukeshchandre@gmail.com
Dr Ashok k Diwan
Government Medical College & Hospital, Nagpur
Department of Rediation Therapy & Oncology, Medical Square Road, Nagpur-440003, Maharashtra, India Nagpur MAHARASHTRA
9822816608
tinuad76@gmail.com
Dr L P Bhaskar Bhuvan
HCG Cancer Centre
A unit of Health Care Global Enterprises Ltd, Plot No. 10,11 & 12, Survey No. 13P, APIIC Health City, Arilova, Chinnagadili, Visakhapatnam-530040, Andhra Pradesh, India. Visakhapatnam ANDHRA PRADESH
9154144100
bhaskarlp60@gmail.com
Dr K Lakshmi Priyadarshini
HCG City Cancer Centre
33-25-33, Ch Venkata Krishayya street, Suryaraopet, Vijayawada-520002, Andhra Pradesh, India West Godavari ANDHRA PRADESH
9502945399 8662435901 priyadarshini006@gmail.com
Dr Rajnish Nagarkar
HCG Manavata Cancer Centre,
Behind Shivang Auto, Mumbai Naka
Nashik-422002, Maharashtra, India. Nashik MAHARASHTRA
9823061929
drraj@manavatacancercentre.com
Dr Guruprasad Mohanty
Kailash Cancer Hospital & Research Center
Muni Seva Ashram, Goraj, Waghodia,
Vadodara - 391760 Gujarat, India. Vadodara GUJARAT
9427432383
guruprasad.mohanty@greenasharm.com
Dr Ashish Agrawal
Kiran Hospital Multi Super Speciality Hospital
Vasta Devdi Road, Near Sumul Dairy Road, Katargam, Surat-395004,Gujarat, India Surat GUJARAT
(1) ICD-10 Condition: C569||Malignant neoplasm of unspecifiedovary,
Intervention / Comparator Agent
Type
Name
Details
Intervention
Doxorubicin Hydrochloride Liposome Injection 2
mg/mL of ForDoz Pharma Corp., USA
Single dose of Doxorubicin
Hydrochloride as per
randomization schedule
Comparator Agent
Doxorubicin Hydrochloride Liposome Injection for
intravenous infusion 2 mg/mL Manufactured By: Sun Pharmaceutical Industries
Ltd., India,
Single dose of Doxorubicin
Hydrochloride as per
randomization schedule
Inclusion Criteria
Age From
18.00 Year(s)
Age To
70.00 Year(s)
Gender
Female
Details
1.Non-smoker, female patient 18 to 70 years of age (both inclusive).
2.Patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy and who are already receiving or scheduled to start Doxorubicin Hydrochloride liposomal injection 50 mg per m2 dose as monotherapy as confirmed by treatment and medical history.
3.Patients should have recovered from any toxic effects of previous chemotherapy as judged by the investigator.
4.Patients with life expectancy of at least 3 months.
5.ECOG performance status of less than or equal to 2.
6.Adequate hemopoeitic, renal and liver function.
Body system Parameters
Bone marrow function ANC more than or equal 1500/mm
Platelet count more than or equal to 100,000/mm
Haemoglobin more than or equal to 9.0 g/dL Renal function
Serum Creatinine less than or equal to 1.5 times ULN Hepatic function AST and ALT less than 3 times ULN (less than or equal to 5× ULN for liver metastasis) Alkaline phosphatase less than equal 3 times ULN less than or equal to 5 × ULN for bone metastasis) Bilirubin less than to 1.2 mg/dL
7.Sexually active women, unless surgically sterile (with documented evidence of hysterectomy / bilateral salpingectomy / bilateral oophorectomy at least 6 months prior to study drug administration) or postmenopausal for at least 12 consecutive months of spontaneous amenorrhea, must agree to use an effective method of avoiding pregnancy [including oral, transdermal, or implanted contraceptives (any hormonal method in conjunction with a secondary method), intrauterine device, female condom with spermicide, diaphragm with spermicide, absolute sexual abstinence, use of condom with spermicide by sexual partner or sterile (at least 6 months prior to study drug administration) sexual partner] for at least 4 weeks prior to study drug administration, during study and up to 6 months after the last dose of study drug. Cessation of birth control after this point should be discussed with a responsible physician. It is investigator‘s responsibility to ensure that above points regarding an effective methods of avoiding pregnancy are discussed with patient in detail and patient agreed for this and it is documented in source document. The investigator should ensure that the patient is using an effective method of avoiding pregnancy as per protocol.
8.Patient should able to understand and sign the written informed consent form and willing to follow the study requirements as per protocol.
9.Cancer patients receiving stable concomitant medications are allowed to participate, provided:
a. The concomitant medication and their dosing regimen is expected to remain same for all the study periods and clearly documented.
b. The concomitant medications do not interfere with the study drug.
ExclusionCriteria
Details
Patients will be excluded from the study, if they meet any of the following
criteria:
1.History of allergy or hypersensitivity reactions to a conventional product of
Doxorubicin Hydrochloride or the components of Doxorubicin Hydrochloride Liposome Injection or any related compound at any dose or other anthracycline drugs, or granisetron or dexamethasone.
2.Patients who require a dose reduction to below 50 mg/m2.
3.Prior history of significant infusion-related reaction.
4.Concurrent use of calcium channel blockers or other cardiotoxic Medications such as cyclophosphamide.
5.Have received radiotherapy to mediastinal area or who are prone to radiation recall reaction due to recent radiotherapy.
6.For female of child bearing potential, positive pregnancy test at screening serum) and prior to dosing urine in period I.
7.Prior Doxorubicin exposure that would result in a total lifetime exposure of
550 mg per m2 or more after four cycles of treatment as confirmed by patient s
treatment history. (Prior use of other anthracyclines or anthracenodiones
should be included in calculations of total cumulative dosage
8.Patient having active opportunistic infection with mycobacteria,
cytomegalovirus, toxoplasma, P. carinii or other clinically significant
infection at screening or within 7 days prior to receiving the study drug.
9.Abnormal baseline findings considered by the investigator to indicate
conditions that might affect study endpoints.
10.Patients with history of other clinically significant concomitant disease
including gastrointestinal, pulmonary, endocrine, immunologic,
dermatologic, neurologic, psychological, musculoskeletal, cardiac, liver or
renal disease.
11.Alcohol or drug abuse or drug dependence within the preceding year.
12.The receipt of an investigational product (other than doxorubicin
hydrochloride liposome injection) or participation in a drug research
study within a period of 30 days or 5 half-lives (whichever is greater)
prior to receiving the first dose of investigational medicinal product in
the study.
13.Pregnant or breastfeeding female.
14.Patients with any of the below mentioned cardiac risks. Patients will
undergo evaluation by a cardiologist prior to study enrollment as applicable:
• Resting LVEF of less than or equal 50%
Note: Based on clinical suspicion of subclinical LV systolic dysfunction
by a Cardiologist/Investigator if required, patients may be referred to other
cardiac imaging methods such as strain, strain rate, cardiac MRI or nuclear
medicine etc. for further assessment of the cardiac risk.
• History of angina or coronary artery disease
• History of myocardial infarction
• NYHA (New York State Heart Association) class II-IV heart failure
• Clinically significant ventricular arrhythmia or tachyarrhythmia
• Clinically significant pericardial disease
• Electrocardiographic evidence of acute ischemic or significant
conduction system abnormalities
• Significant QTc prolongation or other significant ECG abnormalities.
• Any other cardiac illness that could lead to a safety risk to the patient in
case of enrollment in the study
Known symptomatic or untreated or recently treated less than or equal to 6 months of
screening central nervous system CNS metastases. Patients with
previously treated more than 6 months of screening CNS metastases and are
now stable and asymptomatic are allowed. Pre-existing motor or sensory
neurotoxicity of a severity more than or equal to grade 2 by NCI CTCAE criteria.
16. A positive HIV and hepatitis screen including hepatitis B surface antigen
and HCV antibodies, syphilis (VDRL or RPR test).
17. Donation of blood (1 unit or 350 mL) within 90 days prior to receiving the
first dose of Investigational Medicinal Product for the current study.
18. Known, existing uncontrolled coagulopathy.
19. Physiological, familial, sociological, or geographical conditions that do not
permit compliance with the protocol.
20. Uncontrolled hypertension (systolic blood pressure [BP] >160 or
diastolic BP >100 mm Hg) with or without antihypertensive treatment.
21. Presence of uncontrolled diabetes mellitus (HbA1c ≥ 8 %).
22. Patients who have taken any potent CYP3A4 inhibitors including but not
limited to: ketoconazole, itraconazole, troleandomycin, clarithromycin,
erythromycin, ritonavir, indinavir, nelfinavir, saquinavir, amprenavir,
nefazodone, fluvoxamine, diltiazem, verapamil, mibefradil, cimetidine and
cyclosporine during the study and within 14 days prior to day of first dosing
and/or use of drug metabolism enzymes inducers such as phenytoin,
carbamazepine, phenobarbital, etc. and any medications that can cause
significant myelosuppression (other than liposomal doxorubicin), during the
study and within 14 days prior to day of first dosing or 5 half-lives
(whichever is greater) have not elapsed prior to receiving the first dose of
investigational medicinal product.
23. Past or current history of neoplasm other than the entry diagnosis with the
exception of treated non-melanoma skin cancer or carcinoma in situ of the
cervix, or other cancers cured by local therapy alone and a
disease free survival ≥ 5 years
24. Any other condition, that in the investigator‘s judgment, might increase the
risk to the patient or decrease the chance of obtaining satisfactory data
needed to achieve the objectives of the study.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Other
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
To characterize the pharmacokinetic profile and to assess the Bioequivalence of the test product [Doxorubicin Hydrochloride Liposome Injection for intravenous infusion 2 mg/mL of ForDoz Pharma Corp., USA] to that of reference product [Doxorubicin Hydrochloride Liposome
Injection for intravenous infusion 2 mg/mL by Sun Pharmaceutical Industries Ltd., India] in female patients with ovarian cancer
A total of 22 blood samples each of 3.5 mL will be collected during each
period. The pre-infusion blood sample (0.00) will be collected within one hour
prior to the dosing.
After start of intravenous infusion, blood samples (1 x 3.5 ml each) will be
collected at 0.25, 0.50, 0.75, 1.00 (at the end of infusion), 1.25, 1.50, 2.00, 2.50,
3.00, 3.50, 4.00, 5.00, 6.00, 9.00, 12.00, 24.00, 48.00, 96.00, 168.00, 240.00
and 336.00 hours
Secondary Outcome
Outcome
TimePoints
To monitor the adverse events and to ensure the safety of patients.
Physical examination,vital signs,ECG,laboratory
evaluations and adverse event monitoring at period I(On Day 0), period II(On Day 28,29,30,31) & period III (day 56,57,58,59)
Target Sample Size
Total Sample Size="51" Sample Size from India="51" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - YES
What data in particular will be shared? Response - All of the individual participant data collected during the trial, after de-identification.
What additional supporting information will be shared? Response - None of the above
Who will be able to view these files? Response - Anyone
For what types of analyses will this data be available? Response - Any purpose.
By what mechanism will data be made available? Response (Others) -
For how long will this data be available start date provided 03-06-2021 and end date provided 31-12-2021? Response (Others) -
Any URL or additional information regarding plan/policy for sharing IPD? Additional Information - NIL
Brief Summary
The study is designed as a multicenter, open label, randomized, balanced, two treatment, three periods, three sequence, reference replicate, crossover, single dose, bioequivalence study under fasting conditions. Patient 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 2 mg/mL will be screened for eligibility assessment. Screening will be done within 10 days preceding first Investigational Medicinal Product (IMP) administration on day 1 of period I. Treatments will be allocated to patient as consecutive three treatment cycles by carrying out randomization using statistical techniques. During the study period, each patient will receive the reference product in any of the two study periods and the test product in remaining one study period. Patients will be randomly allocated to the sequence in which they receive study drug (i.e., either TRR or RTR or RRT).