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CTRI Number  CTRI/2018/08/015335 [Registered on: 14/08/2018] Trial Registered Prospectively
Last Modified On: 21/11/2019
Post Graduate Thesis  No 
Type of Trial  BA/BE 
Type of Study    
Study Design  Randomized, Crossover Trial 
Public Title of Study   Study of Everolimus 10 mg tablets in advanced renal cell carcinoma patients under fasting conditions 
Scientific Title of Study   A Multicentric Open Label Randomized Two Treatment Two-sequence Two period Cross-over Multiple dose, Steady-state Clinical Bioequivalence Study of Everolimus 10 mg tablets of Eugia Pharma Specialities Limited India A Joint venture of Aurobindo Pharma Limited and Celon Laboratories Limited Test with Afinitor® Everolimus 10 mg tablets of Novartis Pharmaceuticals Corporation USA Reference in advanced renal cell carcinoma patients under fasting conditions 
Trial Acronym  RCC 
Secondary IDs if Any  
Secondary ID  Identifier 
CR178-17  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr Subhra Lahiri 
Designation  Associate Vice President 
Affiliation  Axis Clinicals Ltd 
Address  1 121 1 Miyapur

Hyderabad
ANDHRA PRADESH
500049
India 
Phone  8886221089  
Fax  40408060  
Email  subhra.l@axisclinicals.com  
 
Details of Contact Person
Scientific Query  
Name  Dr Subhra Lahiri 
Designation  Associate Vice President 
Affiliation  Axis Clinicals Ltd 
Address  1 121 1 Miyapur


ANDHRA PRADESH
500049
India 
Phone  8886221089  
Fax  40408060  
Email  subhra.l@axisclinicals.com  
 
Details of Contact Person
Public Query  
Name  Dr Subhra Lahiri 
Designation  Associate Vice President 
Affiliation  Axis Clinicals Ltd 
Address  1 121 1 Miyapur


ANDHRA PRADESH
500049
India 
Phone  8886221089  
Fax  40408060  
Email  subhra.l@axisclinicals.com  
 
Source of Monetary or Material Support  
Eugia Pharma Specialities Limited A Joint venture of Aurobindo Pharma Limited and Celon Laboratories Limited 
 
Primary Sponsor  
Name  Eugia Pharma Specialities Limited 
Address  Survey Numbers 550 551 and 552 Kolthur Village Shameerpet Mandal Ranga Reddy District Telengana State India 500 078  
Type of Sponsor  Pharmaceutical industry-Indian 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 15  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Shailesh Shah  Bodyline Hospital  Room 01 First Floor Opposite Annapurna HallNear Dev Status New Vikas Gruh Road Paldi Ahmedabad 380007
Ahmadabad
GUJARAT 		 9824035673

shaileshsahuro58@gmail.com 
Dr Arun Shesachalam  GVN Hospital  Room No 4 Ground Floor No 46 Singarathope Trichy 620008
Tiruchirappalli
TAMIL NADU 		 9047991191

arunonco@gmail.com 
Dr M Gopichand  HCG City Cancer Centre  Room 1 Ground floor 33 25 33 Ch Venkata Krishnayya street suryaraopeta vijayawada
Krishna
ANDHRA PRADESH 		 9885256059

mgopichand@yahoo.com 
Dr Rajinish Nagarkar  HCG Manavata Cancer Centre  Room No 01 Basement Behind Shivang Auto Mumbai Naka Nashik
Nashik
MAHARASHTRA 		 9823061929

drraj@cmccnasik.in 
Dr Anindya Chakraborty  Health Point Hospital  Room No 12 First Floor Prannath Pandit Street Kolkatta 700025
Kolkata
WEST BENGAL 		 9830242758

dr.anindyachakraborty@yahoo.in 
Dr Jitendra Kumar Verma  J K Cancer Institute  Room No 10 Ground floor Near Rawatpur Crossing Kanpur 208002
Kanpur Nagar
UTTAR PRADESH 		 9936151385

drjitendrakgmc@yahoo.com 
Dr S N Sankhwar  King Geroge Medical University  Room No 01 Ground Floor Department of Urology Lucknow 226003
Lucknow
UTTAR PRADESH 		 9415007703

sankhwarsn_sn@yahoo.co.in 
Dr Mahesh Kalloli  KLES Dr Prabhakar Kore Hospital  Room No 02 Second Floor Nehru Nagar Belagavi 590 010
Belgaum
KARNATAKA 		 9945014996

mahesh.kalloli@gmail.com 
Dr Ravi Kumar Wateganokar  Lokmanya Medical Research Centre  Room No 124 First Floor Lokamanya Hospital 314 13 Telco Roads Chinchwad Pune 411 033
Pune
MAHARASHTRA 		 9823602626

rnwategaonkar@gmail.com 
Dr K S Kirushna Kumar  Meenakshi Mission Hospital and Research Centre  Room No 01 Ground Floor Department of Oncology Lake Area Melur Road Near Mattuthavani Bus Stand Madurai 625107
Madurai
TAMIL NADU 		 9787713004

drkskk@yahoo.com 
Dr R R Srikanth  MNJ Institute of Oncology and regional cancer Centre  Room No 08 Ground Floor Red Hills Hyderabad
Hyderabad
ANDHRA PRADESH 		 9849009958

srikanthsapthagiri@yahoo.com 
Dr Irfan Shaik  Noble Hospital  Room No 3 First Floor Magarpotta City Road Pune 411013
Pune
MAHARASHTRA 		 727637538

irfanurologist@gmail.com 
Dr Rachan Shetty  Omega Hospital  D13 Basement Mahaveer Circle kankanady Mangalore 575002
Dakshina Kannada
KARNATAKA 		 9008753317

drrachanshetty.medoncology@gmail.com 
Dr A Rajeshwar  Srikara Hospitals  Room No 1 Ground Floor Plot No 50 LB Nagar Ring Road Hyderabad
Hyderabad
ANDHRA PRADESH 		 9848750915

Rajeshavanch@gmail.com 
Dr Venkata Krishna Reddy  Vijaya Super Speciality Hospital  Room No 2 First Floor S2 Complex road Pogathota Nellore 524001
Nellore
ANDHRA PRADESH 		 9849048222

projectspcr@gmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 15  
Name of Committee  Approval Status 
Dr GVN Cancer Institute Institutional Ethics Committee  Approved 
Ethics Committee J K Cancer institute   Approved 
Ethics committee Lokmanya Medical Research Centre  Approved 
Health Point Ethics Committe   Approved 
Institutional Ethics Committee Body Line Hospital  Approved 
Institutional Ethics Committee City Cancer Centre  Approved 
Institutional Ethics Committee King Georges Medical University  Approved 
Institutional Ethics Committee KLE university  Approved 
Institutional Ethics Committee Meenakshi mission Hospital and Research centre   Approved 
Institutional Ethics committee MNJ Institute of Onclogy and Regional Cancer Centre  Approved 
Institutional Ethics Committee Noble Hospital Pvt Ltd  Approved 
Manavata clinical Research Institute Ethics Committee   Approved 
Omega Ethical Committee  Approved 
SNR Galaxy Hospital and Ethics Committee  Approved 
Vijaya Ethics Committee   Approved 
 
Regulatory Clearance Status from DCGI  
Status 
No Objection Certificate 
 
Health Condition / Problems Studied
Modification(s)  
Health Type  Condition 
Patients  (1) ICD-10 Condition: C649||Malignant neoplasm of unspecifiedkidney, except renal pelvis,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Comparator Agent  Afinitor Everolimus 10 mg manufactured by Novartis Pharmaceuticals Corporation USA  The study will consist of two periods on Day 1 period I or Day 15 Period II patients will be administered one tablet of investigational medicinal product as per randomization schedule. 
Intervention  Everolimus 10 mg manufactured by Eugia Pharma Specialities Limited  The study will consist of two periods on Day 1 period I or day 15 period II based on randomization schedule patients will be administered one tablet of investigational medicinal product as per randomization schedule 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  65.00 Year(s)
Gender  Both 
Details  1. Male and females of age in between 18 years to 65 years (both inclusive).
2. Ability to provide informed consent prior to participation in the study by patient/LAR
3. Confirmed diagnosis of advanced renal cell carcinoma.
4. Who are already receiving a stable dose of Everolimus tablets, 10 mg tablet once daily as per investigator’s discretion for at least 14 days at first dosing of study drug.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
6. Estimated life expectancy ≥ 3 months.
7. No persistent toxicities from prior medications [Recovery to baseline or ≤ Grade 1 CTCAE v.4.03 (or) higher and/or stable on supportive therapy at screening visit if any toxicities had occurred unless the toxicities were clinically insignificant]
8. Adequate organ and bone marrow function based upon the following laboratory criteria within 7 days before randomization:
a. Hemoglobin ≥9.0 g/dL
b. Absolute neutrophil count ≥1500/uL
c. Platelet count ≥100,000/uL
d. Creatinine < 1.5 x ULN
e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 × upper limit of normal.
f. Total bilirubin within ≤ 1.5 × upper limit of normal.
g. Clinically insignificant fasting serum glucose levels, S. blood urea nitrogen (BUN) and Urine protein levels.
9. Patient having negative urine screen for drugs of abuse
10. Patient having negative breath alcohol test
11. Sexually active women, unless surgically sterile (at least 6 months prior to study drug administration) or postmenopausal for at least 12 consecutive months, must agree to use effective methods of avoiding pregnancy from screening, during study and up to 8 weeks after the last dose of study drug.
12. Females must use acceptable and effective methods of contraception such as the following:
• Tubal sterilization (tubal ligation performed more than one month before Study Day1 transcervical tubal occlusion procedure performed more than six months before Study Day 1)
• Intrauterine Device (IUD)
• Progestin Implant (i.e. Implanon or its equivalent)
• Progestin injection or progestin oral contraceptive pill + one barrier method (cervical cap, diaphragm, contraceptive sponge, or vaginal spermicide + a male or female condom)
• Two barrier methods used together (cervical cap, diaphragm contraceptive sponge, or vaginal spermicide + a male or female condom)
• Absolute sexual abstinence (no sexual intercourse or genital contact with a male partner)
13. Male patient must agree to use an effective method of contraception from screening, during study and up to 8 weeks after the last dose of study drug.
14. Clinically insignificant laboratory values at screening
15. Patients willing to and able to comply with the protocol
 
 
ExclusionCriteria 
Details  1. Known hypersensitivity to rapamycin, temsirolimus, everolimus or any excipient of everolimus.
2. Any prior treatment with everolimus resulting in unacceptable toxicity.
3. Receipt of any type of small molecule kinase inhibitors (i.e. axitinib, pazopanib, sorafenib, sunitinib etc) within 2 weeks before randomization.
4. Patients with renal failure, hepatic failure or for whom the need for dose change during the study can be anticipated.
5. Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before randomization.
6. Patients on active treatment with strong, moderate inhibitors or strong inducers of P-glycoprotein and CYP3A4[a minimal of 2 weeks or 5 half- lives wash-out period(whichever is earlier) recommended after stopping such medications].
7. History of brain metastasis, spinal cord compression
8. Systemic treatment with radionuclides within 6 weeks before randomization or with clinically relevant persistent complications from prior radiation therapy.
9. Concomitant anticoagulation at therapeutic doses with oral anticoagulants or platelet inhibitors [Low-dose aspirin and low-dose warfarin (< 1 mg/day), are permitted]. Anticoagulation with low molecular weight heparin (LMWH) is allowed if on a stable dose for at least 2 weeks before randomization.
10. Uncontrolled, significant inter-current or recent illness including, but not limited to
a. Cardiovascular disorders:
i. Symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmias.
ii. Uncontrolled hypertension defined as sustained BP 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment.
iii. Stroke (including TIA), myocardial infarction, within 6 months before randomization.
b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
i. Active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction.
ii. Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 6 months before randomization. Clinically significant hematuria, hematemesis, or hemoptysis of half teaspoon (2.5 ml) of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage) within 3 months before randomization.
c. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.
d. Patient with active infection and symptoms of Non-infectious pneumonitis as judged by the investigator.
e. Malabsorption syndrome.
f. Serious non-healing wound/ulcer/bone fracture.
g. Lesions invading major pulmonary blood vessels.
11. In the past 5 years, other prior malignancy (except basal cell carcinoma, squamous cell carcinoma of the skin, or cervical carcinoma in situ).
12. Pregnant and lactating females.
13. Chronic treatment with corticosteroids or other immunosuppressive agents (with the exception of inhaled or topical corticosteroids or corticosteroids with a daily dosage equivalent ≤ 10 mg prednisone if given for disorders other than renal cell cancer).
14. Positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus (HIV) 1 and 2 serological test at screening or has been previously treated for hepatitis B, hepatitis C or HIV infection.
15. Local or systemic clinically significant infection within 28 days of screening as determined by the investigator.
16. Patients within 4 weeks post-major surgery, open biopsy, or significant traumatic injury to avoid wound healing complications within 4 weeks prior to study or who have not recovered from prior major surgery or patient is anticipated to require major surgery during the course of the study.
17. Participation in another clinical trial in the last 60 days.
18. Clinically significant abnormal finding on the physical examination, medical history, ECG, Chest X ray or clinical laboratory results at screening according to the Principal Investigator precluding everolimus administration.
19. History of noncompliance to medical regimens.
20. History of alcoholism / alcohol abuse.
21. History of difficulty with donating blood or difficulty in accessibility of veins.
22. Patients for whom oral administration of drug is not possible.
23. An unusual or abnormal diet, for whatever reason within 48 hours prior to check-in. e.g. religious fasting.
24. Consumption of grape fruit/mosumbi/sweet lime juice within 48 hours prior to study check-in and for the entire period of study
25. Donation of blood (1 unit or 350 ml) within 90 days prior to receiving the first dose of investigational medicinal product in the study.
26. Females of child bearing potential unwilling to use acceptable contraception throughout the trial and for 8 weeks after the last dose of study drug
 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Centralized 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
Cmax AUC0-Ï„ Area under the blood concentration time curve over the steady state dosing interval

Cmax ss Maximum concentration over the steady state dosing interval
 		 Venous blood samples 3mL will be withdrawn within 5 minutes prior to dosing on Day 1 12 13 and 14 Period I and Day 15 26 27 and 28 Period II to confirm steady state condition
Venous blood samples 3mL will be withdrawn on Day 14 and 28 at 0.17 0.25 0.50 0.75 1 1.25 1.50 1.75 2.00 2.25 2.50 3.00 4.00 6.00 8.00 12.00 16.00 and 24.00 hours post drug administration.
 
 
Secondary Outcome  
Outcome  TimePoints 
Minimum concentration over the steady state dosing interval
Average concentration over the steady state dosing interval
Percentage fluctuation
Time of maximum measured blood concentration over the steady state dosing interval
Pre dose concentrations determined before a dose at steady state
Swing
Safety and tolerability 		 Venous blood samples 3mL will be withdrawn within 5 minutes prior to dosing on Day 1 12 13 and 14 Period I and Day 15 26 27 and 28 Period II to confirm steady state condition
Venous blood samples 3mL will be withdrawn on Day 14 and 28 at 0.17 0.25 0.50 0.75 1 1.25 1.50 1.75 2.00 2.25 2.50 3.00 4.00 6.00 8.00 12.00 16.00 and 24.00 hours post drug administration. 
 
Target Sample Size   Total Sample Size="42"
Sample Size from India="42" 
Final Enrollment numbers achieved (Total)= "0"
Final Enrollment numbers achieved (India)="45" 
Phase of Trial   Phase 1 
Date of First Enrollment (India)
Modification(s)  		 10/09/2018 
Date of Study Completion (India) 14/03/2019 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Date Missing 
Estimated Duration of Trial   Years="0"
Months="8"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  		 Not Applicable 
Recruitment Status of Trial (India)  Completed 
Publication Details
Modification(s)  		 None Yet 
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Brief Summary
Modification(s)  		 There was allowed screening period of 21 days. This was a two period study without washout. Period I was from Day 1 to Day 14 and Period II was from Day 15 to Day 28. Patients were administered one tablet of investigational medicinal product as per randomization schedule  from Day 1 to Day 28. 

Complete PK sampling was done on Day 14 and Day 28. Pre-dose blood sample of 3 mL was collected within 5 minutes before dosing on Day 1, 12, 13, 14, 15, 26, 27 and 28 to confirm steady state.

On Day 14 and 28, venous blood samples of 3 mL was collected at 0.17, 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 3.00, 4.00, 6.00, 8.00, 12.00, 16.00 and 24.00 hours post drug administration.


 

  

 
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