Clinical Trial Details (PDF Generation Date :- Mon, 27 Sep 2021 22:34:38 GMT)

PDF of Trial CTRI Website URL - http://ctri.nic.in

CTRI Number CTRI/2017/10/010010 [Registered on: 05/10/2017] - Trial Registered Prospectively Last Modified On 26/04/2021 Post Graduate Thesis No Type of Trial Interventional Type of Study Drug Study Design Randomized, Parallel Group, Placebo Controlled Trial Public Title of Study A Study of Atezolizumab and Paclitaxel Versus Placebo and Paclitaxel in Participants With Previously Untreated Locally Advanced or Metastatic Triple Negative Breast Cancer (TNBC) (IMpassion131) Scientific Title of A Phase III, Multicenter, Randomised, Double-Blind, Placebo-Controlled Study of Atezolizumab Study (Anti-Pd-L1 Antibody) in Combination With Paclitaxel Compared With Placebo With Paclitaxel for Patients With Previously Untreated Inoperable Locally Advanced or Metastatic Triple Negative Breast Cancer Secondary IDs if Any Secondary ID Identifier MO39196, Protocol Version 1.0 dated 14 Feb Protocol Number 2017 Details of Principal Details of Principal Investigator Investigator or overall Name Dr Sudeep Gupta Trial Coordinator (multi-center study) Designation Professor of Medical Oncology, Deputy Director (CRC), ACTREC Affiliation Tata Memorial Centre Address Department of Medical Oncology, Dr. E.Borges Road, Parel Mumbai MAHARASHTRA 400012 India Phone 912224177201 Fax 912224177201 Email [email protected] Details Contact Details Contact Person (Scientific Query) Person (Scientific Name Dr Raeesuddin Syed Query) Designation Medical Chapter Lead - Medical Affairs Affiliation Roche Products (India) Pvt. Ltd. Address Roche Products (India) Pvt. Ltd., 146-B, 166 A, Unit No. 7, 8, 9 8th Floor, R City Office, R City Mall, Lal Bahadur Shastri Marg, Ghatkopar, Mumbai - 400 086, Maharashtra, India Mumbai MAHARASHTRA 400051 India Phone 91-22-33941414 Fax 91-22-33941054 Email [email protected] Details Contact Details Contact Person (Public Query) Person (Public Query) Name Priyanka Bhattacharya Designation Lead – Clinical Operations Affiliation Roche Products (India) Pvt. Ltd. Address Roche Products (India) Pvt. Ltd., 146-B, 166 A, Unit No. 7, 8, 9 8th Floor, R City Office, R City Mall, Lal Bahadur Shastri Marg, Ghatkopar, Mumbai - 400 086, Maharashtra, India

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Mumbai MAHARASHTRA 400051 India Phone 022-33941476 Fax 022-33941054 Email [email protected] Source of Monetary or Source of Monetary or Material Support Material Support > F. Hoffmann-La Roche Ltd. CH-4070, Basel, Switzerland > Roche Products (India) Pvt. Ltd., 146-B, 166 A, Unit No. 7, 8, 9 8th Floor, R City Office, R City Mall, Lal Bahadur Shastri Marg, Ghatkopar, Mumbai - 400 086, Maharashtra, India Primary Sponsor Primary Sponsor Details Name F HoffmannLa Roche Ltd Address CH-4070, Basel, Switzerland Type of Sponsor Pharmaceutical industry-Global Details of Secondary Name Address Sponsor Roche Products India Pvt Ltd 146-B, 166 A, Unit No. 7, 8, 9, 8th Floor, R City Office, R City Mall, Lal Bahadur Shastri Marg, Ghatkopar, Mumbai - 400 086, Maharashtra, India Countries of List of Countries Recruitment Algeria Argentina Brazil Canada China Croatia Czech Republic Egypt France Germany Greece India Israel Italy Morocco Romania Russian Federation Saudi Arabia Slovakia Turkey United Kingdom United States of America Viet Nam Sites of Study Name of Principal Name of Site Site Address Phone/Fax/Email Investigator Dr Prabrajya Narayan Apollo Gleneagles Department of Medical 919674311610 Mohapatra Hospitals, Kolkata Oncology, 58, Canal 913323201739 Circular Road, prabrajya.mohapatra@r

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Kolkata-700 054, West ediffmail.com Bengal, India Kolkata WEST BENGAL Dr Sankar Srinivasan Apollo Specialty Department of Medical 919940080233 Hospital Oncology, No. 320, 914424362424 Anna Salai, Teynampet, srinivasangirija@gmail. Nandanam, Chennai, com Tamil Nadu 600035, India Chennai TAMIL NADU Dr Amit Agarwal BLK Cancer Centre, 5, Pusa Road, New 9971611311 BLK Super Speciality Delhi 110005 Hospital New Delhi [email protected] DELHI m Dr Ashish Singh Christian Medical Department of Medical 914162283040 College Oncology, Christian Medical College, Ida ashishsingh@cmcvellor Scudder Road, Vellore - e.ac.in 632 004 Vellore TAMIL NADU Dr Ashish Kaushal HealthCare Global Sola-Science City 7940410227 Cancer Centre Road, Off S.G. Highway, Sola, ashish_critical@yahoo. Ahmedabad co.in Ahmadabad GUJARAT Dr Shekar Patil HealthCare Global 8, Bangalore Institute of 918026589762 Enterprises Limited Oncology, Kalinga Rao Rd, Sampangiram [email protected] Nagar, nBengaluru, om Karnataka 560027, India Bangalore KARNATAKA Dr Manish Kumar Indraprastha Apollo Sarita Vihar, 9818736533 Singhal Hospitals Delhi-Mathura Road, New Delhi 110076 singhaloncocare@yaho New Delhi o.co.in DELHI Dr Shona Nag Jehangir Clinical Department of Medical 919371072441 Development Centre Oncology, Jehangir 912026059319 Private Limited Hospital Premises, 32 [email protected] Sasson Road, Pune 411001 Pune MAHARASHTRA Dr Poonam Patil Manipal Hospital Department of Medical 919945687185 Oncology, #98, HAL 918025207181 Airport Road, [email protected] Bengaluru 560017 m Bangalore KARNATAKA Dr Waseem Abbas Max Super Speciality FC 50, C & D Block, 9810619717 Hospital Shalimar Bagh, New Delhi 110088 Waseem.Abbas@maxh New Delhi ealthcare.com

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DELHI Dr Meenu Walia Max Super Speciality 108-A, Indraprastha 9818994001 Hospital, Patparganj (A Ext., Patparganj, Delhi - Unit of Balaji Medical & 110092 Meenu.Walia@maxheal Diagnostic Research New Delhi thcare.com Centre) DELHI Dr DC Doval Rajiv Gandhi Cancer Department of Medical 911147022428 Institute and Research Oncology, Sector-5, 911127051037 Center Rohini, New Delhi - [email protected] 110085 North West DELHI Dr Minish Jain Ruby Hall Clinic 40 SASSOON ROAD 912066455604 Pune MAHARASHTRA [email protected] om Dr Sanjoy Chatterjee Tata Medical Centre 14 Major Arterial Road 9038161825 (EW), New Town, Rajarhat, Kolkata - sanjoy.chatterjee@tmck 700160, West Bengal olkata.com Kolkata WEST BENGAL Dr Sudeep Gupta Tata Memorial Centre Department of Medical 912224177201 Oncology, Room No. 912224177201 1109, 11th Floor, Homi sudeepgupta04@yahoo Bhabha Block, Dr. .com E.Borges Road, Parel, Mumbai-400012, India. Mumbai MAHARASHTRA Dr Nikhil Ghadyalpatil Yashoda Hospital Department of Medical 918008037474 Oncology, Raj Bhavan 914023414613 Rd, Somajiguda, nikhilghadyalpatil@gma Hyderabad, Andhra il.com Pradesh 500082, India. Hyderabad ANDHRA PRADESH Details of Ethics Name of Committee Approval Status Date of Approval Is Independent Ethics Committee Committee? Dr. B.L. Kapur Approved 13/09/2018 No Memorial Hospital Ethics Committee Ethics Committee of Approved 21/02/2018 No Manipal Hospitals, Bangalore Ethics Committee Submittted/Under No Date Specified No Silver, Christian Review Medical College Ethics Committee, Approved 18/12/2017 No JCDC Institutional Ethics Submittted/Under No Date Specified No Committee - Clinical Review Studies Institutional Ethics Approved 28/12/2018 No Committee - MAX Super Speciality Hospital, Patparganj

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Institutional Ethics Approved 05/08/2017 No Committee, Apollo Gleneagles Hospital, Kolkata Institutional Ethics Approved 18/04/2018 No Committee, Tata Memorial Centre Institutional Ethics Approved 13/12/2017 No Committee, Yashoda Academy of Medical Education & Research, Yashoda Group of Hospitals Institutional Ethics Approved 17/01/2018 No Committee-Clinical Studies, Apollo Hospitals, Chennai Institutional Ethics Approved 11/01/2019 No Committee-Poona Medical Research Foundation Institutional Review Approved 08/12/2017 No Board, Rajiv Gandhi Cancer Institute & Research Center Institutional Review Approved 27/07/2018 No Board, Tata Medical Center, Kolkata Max Healthcare Ethics Approved 01/06/2018 No Committee Poona Medical Approved 11/01/2019 No Research Foundation Regulatory Clearance Status Date Status from DCGI Approved/Obtained 18/09/2017 Health Condition / Health Type Condition Problems Studied Patients Locally advanced or Metastatic Triple Negative Breast Cancer Patients Malignant neoplasm of breast Intervention / Type Name Details Comparator Agent Intervention Placebo Placebo will consist of the vehicle without the antibody. Placebo will be supplied in a single-use, 20cc glass vials containing 20 mL of solution. Placebo will be given by IV infusion administered on Day 1 and Day 15 (± 3 days) of every 28-day cycle Intervention Atezolizumab The dose of atezolizumab in this study will be 840 mg administered by intravenous infusion on Day 1 and Day 15 (± 3 days) of every 28-day cycle. Comparator Agent Paclitaxel Paclitaxel will be administered at the 90 mg/m2 dose via

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1-hour IV infusion on Days 1, 8, and 15 of every 28-day cycle. Inclusion Criteria Inclusion Criteria Age From 18.00 Year(s) Age To 99.00 Year(s) Gender Both Details 1. Signed Informed Consent Form
2. Women or men aged ?18 years
3. Patients with locally advanced or metastatic, histologically documented TNBC by central testing (HER2, ER and PR expression), not amenable to
surgical therapy.
4. Eligible for taxane monotherapy.
5. No prior chemotherapy or targeted systemic therapy (including endocrine therapy) for inoperable locally advanced or metastatic TNBC.
6. ECOG performance status of 0 or 1
7. Life expectancy ?12 weeks
8. Measurable disease, as defined by RECIST v1.1.
9. Women of child bearing potential must agree to either use a contraceptive method with a failure rate of ?1% per year or to remain abstinent during the treatment period and for at least 5 months after the last dose of atezolizumab/placebo, or for at least 6 months after the last dose of paclitaxel
Exclusion Criteria Exclusion Criteria Details 1. Spinal cord compression 2. Known CNS disease, except for treated asymptomatic CNS metastases. 3. Leptomeningeal disease 4. Uncontrolled pleural effusion, pericardial effusion, or ascites 5. Uncontrolled tumour-related pain 6. Pregnant or lactating women, or intending to become pregnant during the study. 7. Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), MI within 3 months prior to randomisation, unstable arrhythmias, or unstable angina. 8. Major surgical procedure within 4 weeks prior to randomisation or anticipation of the need for a major surgical procedure during the study other than for diagnosis. 9. History of autoimmune disease. 10. Prior allogeneic stem cell or solid organ transplantation 11. Positive test for HIV 12. Active hepatitis B or hepatitis C 13. Active tuberculosis 14. Poor peripheral venous access

Method of Generating Permuted block randomization, fixed Random Sequence Method of Centralized Concealment Blinding/Masking Participant and Investigator Blinded Primary Outcome Outcome Timepoints To evaluate the efficacy of atezolizumab plus Progression-Free Survival (PFS) Assessed paclitaxel compared with placebo plus paclitaxel Using Response Evaluation Criteria in Solid as measured by progression-free survival (PFS) Tumors Version 1.1 (RECIST v1.1) [ Time Frame: From Day 1 to disease progression (PD) or death from any cause, assessed up to end of study (up to approximately 45 months) ] Secondary Outcome

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Outcome Timepoints Secondary Efficacy Objectives - OS [up to approximately 45 months] To evaluate the efficacy of atezolizumab plus 12-month and 18-month OS rates paclitaxel compared with placebo plus paclitaxel Time to deterioration (TTD) in Global Health as measured by overall survival (OS), 12-month Status/HRQoL [up to approximately 45 months] and 18-month OS rates, health-related quality of PFS rate at 12 months life (HRQoL), 12-month PFS rate, second line PFS2 [up to approximately 45 months] PFS (PFS2), objective response rate (ORR), ORR [up to approximately 45 months] duration of objective response (DoR), and DoR [up to approximately 45 months] clinical benefit rate (CBR) CBR [up to approximately 45 months]

Exploratory Efficacy Objectives- Mean changes from baseline score in patient To evaluate PROs of function & function & disease/treatment-related symptoms disease/treatment-related symptoms as assessed by EORTC QLQ-C30 and To evaluate PROs of Global Health QLQ-BR23. Status/HRQoL scale To evaluate & compare between treatment arms Mean and mean changes from baseline score in patient’s health utility HRQoL as assessed by the EORTC QLQ-C30. To evaluate the burden of treatment associated with the addition of atezolizumab to paclitaxel Health utility scores of the EQ-5D-5L questionnaire.

GP5 item ("I am bothered by side effects of treatment") from the physical wellbeing subscale of the FACT-G Quality of Life instrument.

Pharmacokinetic Objective- Cmin and Cmax of Atezolizumab [ Pre-dose (0 a) To characterize the PK of atezolizumab when hours) on Day 1 of Cycles 1(only for Cmin), 2, 3, administered concomitantly with paclitaxel 4, 8, 12, 16, and at every 8 cycles thereafter until b) To characterize the PK of paclitaxel when treatment discontinuation (TD), and at 90-150 administered concomitantly with atezolizumab days after TD (maximum up to 45 months) ]

Cmin of Paclitaxel [ Pre-dose (0 hours) on Day 1 of Cycles 1 and 3]

Cmax of Paclitaxel [ Pre-dose (0 hours), 5-10 min before and after paclitaxel infusion, 60 min after paclitaxel infusion on Day 1 of Cycles 1 and 3]

Safety Objective- Percentage of Participants With Adverse Events To evaluate the safety of atezolizumab plus (AEs) and Serious AEs (SAEs) [ Time Frame: paclitaxel compared with placebo plus paclitaxel From Day 1 to 90 days after last dose of study drug, assessed up to end of study (up to approximately 45 months) ] Immunogenicity Objective- Incidence of anti-therapeutic antibodies (ATAs) To evaluate the immunogenicity of atezolizumab during the study relative to the prevalence of ATAs at baseline. For patients who show evidence of immune-mediated toxicity, samples will be collected and tested for anti-nuclear antibody (ANA), anti-double-stranded DNA antibody, circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil cytoplasmic antibody.

Exploratory Immunogenicity Objective- Relationship between ATA status and efficacy, To evaluate potential effects of ATAs safety, or pharmacokinetic endpoints Biomarker Objective- Relationship between PD-L1 by

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To assess the activity and safety of atezolizumab immunohistochemistry in recently obtained according to programmed death?ligand 1 tumour tissues, and clinical outcomes (PD-L1) status Target Sample Size Total Sample Size=495 Sample Size from India=35 Final Enrollment numbers achieved (Total)=Applicable only for Completed/Terminated trials Final Enrollment numbers achieved (India)=Applicable only for Completed/Terminated trials Phase of Trial Phase 3 Date of First 25/12/2017 Enrollment (India) Date of First 25/08/2017 Enrollment (Global) Estimated Duration of Years=5 Trial Months=0 Days=0 Recruitment Status of Completed Trial (Global) Recruitment Status of Closed to Recruitment of Participants Trial (India) Publication Details None yet Brief Summary This is a Phase III, global, multicentre, randomised, double-blind, two-arm, placebo controlled study designed to evaluate the efficacy and safety of atezolizumab (an anti-PD-L1 antibody) administered in combination with paclitaxel compared with placebo in combination with paclitaxel in patients with previously untreated, inoperable locally advanced or metastatic, centrally confirmed TNBC.

A total of approximately 495 patients are planned to be randomised at approximately 200 sites globally. Patients will be randomised centrally, using an interactive voice or web response system (IxRS), in a 2:1 randomization ratio to receive atezolizumab (840 mg) or placebo IV infusions on Days 1 and 15 of every 28-day cycle, plus paclitaxel (90 mg/m2) administered via IV infusion on Days 1, 8, and 15 of every 28-day cycle. Randomisation will be stratified by the following factors: tumour PD-L1 status (PD-L1 expression on tumour-infiltrating immune cells [ICs] assessed by immunohistochemistry [IHC]) (IC0 vs. IC1/2/3), prior taxane treatment (yes vs. no), presence of liver metastases (yes vs. no), and region (North America vs. Western Europe/Australia; vs. Eastern Europe/Asia Pacific vs. South America). Randomised patients will not be replaced.

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