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1 Clinical Trial Details (PDF Generation Date :- Wed, 05 Dec :16:55 GMT) CTRI Number Last Modified On 24/01/2013 Post Graduate Thesis Type of Trial Type of Study Study Design Public Title of Study Scientific Title of Study CTRI/2012/01/ [Registered on: 31/01/2012] - Trial Registered Prospectively No Interventional Drug Single Arm Trial Phase II open label trial for Inflammatory Breast Cancer patients with Afatinib and/or Vinorelbine. An open label, phase II trial of afatinib with or without vinorelbine for the treatment of HER2-overexpressing Inflammatory Breast Cancer Secondary IDs if Any Secondary ID Identifier Details of Principal Investigator or overall Trial Coordinator (multi-center study) Details Contact Person (Scientific Query) ; Version 1.0 dated 03-Mar-2011 Protocol Number Designation Affiliation Details of Principal Investigator Shoma Das Phone Fax Designation Affiliation Project Manager-Clinical Operations Boehringer-Ingelheim Pvt Ltd 1102, 11th Floor, Hallmark business Plaza, Gurunanak Hospital Road, Bandra (East), Mumbai , Mumbai (Suburban) shoma.das@boehringer-ingelheim.com Details Contact Person (Scientific Query) Shoma Das Project Manager-Clinical Operations Boehringer-Ingelheim Pvt Ltd 1102, 11th Floor, Hallmark business Plaza, Gurunanak Hospital Road, Bandra (East), Mumbai , Details Contact Person (Public Query) Phone Fax Designation Affiliation shoma.das@boehringer-ingelheim.com Details Contact Person (Public Query) Shoma Das Project Manager-Clinical Operations Boehringer-Ingelheim Pvt Ltd 1102, 11th Floor, Hallmark business Plaza, Gurunanak Hospital Road, Bandra (East), Mumbai , Phone page 1 / 8

2 Source of Monetary or Material Support Primary Sponsor Details of Secondary Sponsor Countries of Recruitment Sites of Study Fax > Boehringer Ingelheim Pvt Ltd Type of Sponsor NIL List of Countries Australia Thailand Tunisia United Kingdom United States of America of Principal Investigator Dr Raju Titus Chacko Dr Chirag Desai Dr Nilesh Lokeshwar Source of Monetary or Material Support Primary Sponsor Details Boehringer Ingelheim Pvt Ltd 1102, 11th Floor, Hallmark business Plaza, Gurunanak Hospital Road, Bandra (East), Mumbai , Pharmaceutical industry-global NIL of Site Site Phone/Fax/ Christian Medical College, Hemato-Oncology Clinic Ahmedabad Pvt Ltd, Kashyap Nursing Home, Dept. of Medical Oncology, Ida Scudder Road, Vellore , Tamil Nadu, Vellore TAMIL NADU 1st Floor, Vedanta Institute of Medical Science, Stadium Commerce College Road, Nr. Samved Hosptial, Navrangpura, Ahmedabad , Gujarat,. Ahmadabad GUJARAT 3rd Floor, Imperial Mahal, Khodadad Circle, Dadar TT, Mumbai Mumbai Dr Minish Jain Ruby Hall Clinic New cancer Building, 3rd floor, 40,Sassoon Road, Pune , Maharashtra, Pune Dr Niti Raizada Narang Sri Venketeshwara Hospital #86, Hosur Main Road, Madiwala, Bangalore , Karnataka Bangalore rchacko@cmcvellore.ac.in chiragdesai.oncology@ gmail.com nilesh.lokeshwar@gmai l.com minishjain009@gmail.c om nitiraizada@yahoo.co.u k page 2 / 8

3 Details of Ethics Committee Regulatory Clearance Status from DCGI Health Condition / Problems Studied Intervention / Comparator Agent Inclusion Criteria Dr Rajendra Achyut Badwe KARNATAKA Tata Memorial Hospital, Main Building, 3rd Floor Dr. E. Borges Road, Parel, Mumbai, Maharashtra , Mumbai (Suburban) badwera@gmail.com of Committee Approval Status Date of Approval Is Independent Ethics Committee? Ethics Committee of CIMS (Care Institute of Medical Sciences), City- Ahmedabad, PI- Dr. Chirag Desai Human Ethics Committee, Tata Memorial Hospital, Mumbai Hyderabad Central Ethics Committee, Hyderabad, PI-Dr. Niti Narang ICON (n Cooperative Oncology Netwrok) - ARO, Mumbai, PI-Dr. Nilesh Lokeshwar Institutional Ethics Committee, Ruby Hall Clinic, Pune Institutional Board (Ethics Committee), Dr. Raju Chacko Status Yes No Yes Yes Approved 28/12/2011 No Date Approved/Obtained 19/12/2011 Health Type Patients Condition No Inflammatory Breast Cancer Type Details Intervention Afatinib 40 mg, po daily Continuous daily dosing until disease progression, Intervention Vinorelbine 25 mg/m2, IV weekly Weekly (Days 1, 8, 15 and 22) in a 4-weekly course for 2 years. Comparator Agent nil nil Age From Age To Gender Details Year(s) Year(s) Female Inclusion Criteria 1. Female patients?18 years. 2. Investigator-confirmed diagnosis of Inflammatory Breast Cancer defined as a clinico-pathologic entity that is characterized by diffuse page 3 / 8

4 Exclusion Criteria Details erythema and oedema (peau d orange). Pathological findings of dermal lymphatic emboli or palpable mass are supportive but not necessary for diagnosis. 3. Histologically confirmed breast cancer HER2-overexpressing disease (i.e. IHC 3+ or IHC 2+ with FISH/SISH positivity). (The central lab results of any analysis of archived tissue sample are not required to be available to confirm the eligibility of the patient to take part in the study). 4. Presence of locally advanced (in the opinion of the investigator) or metastatic disease. 5. For trastuzumab pre-treated patients, must have failed prior trastuzumab treatment in the investigator s opinion. 6. Must have biopsiable disease. 7. Must have disease that can be evaluated according to RECIST 1.1. NOTE: Patients with skin disease only may be included and their disease evaluated as non-target lesion(s) according to RECIST Eastern Cooperative Oncology Group (ECOG) score of 0, 1 or 2 (Ref: Appendix 2). 9. Life expectancy of at least six (6) months in the opinion of the investigator. 10. Written informed consent that is consistent with ICH-GCP guidelines and local legislation. 11. In addition for Part B (afatinib and vinorelbine combination therapy), patients must have progressed on afatinib monotherapy in Part A. Exclusion Criteria 1. Prior treatment with HER2-targeted small molecules or antibodies (other than trastuzumab which must have been given in the trastuzumab-failure study population). 2. Requirement for treatment with any of the prohibited concomitant medications listed in Section (restrictions). 3. Must not have received prior vinorelbine in any setting. 4. Known pre-existing interstitial lung disease (ILD). 5. Radiotherapy, chemotherapy, hormone therapy, immunotherapy, trastuzumab or surgery (other than biopsy) within 2 weeks prior to the first dose of afatinib in Part A. Patients must have recovered from previous lines of treatment in the investigator s opinion. Treatment with palliative radiotherapy (short course to non-target lesions) is allowed. 6. Active brain metastases (defined as stable for less than 4 weeks and/or symptomatic and/or requiring changes of treatment with anticonvulsants or steroids and/or leptomeningeal disease). 7. Any other current malignancy or malignancy diagnosed or relapsed within the past five (5) years (other than non-melanomatous skin cancer and in situ cervical cancer). 8. Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom e.g. Crohns disease, malabsorption or CTC grade?2 page 4 / 8

5 diarrhoea of any aetiology. 9. History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension (in the investigators opinion), congestive heart failure NYHA classification of 3 or higher, unstable angina or poorly controlled arrhythmia (in the investigators opinion). 10. Myocardial infarction within 6 months prior to the first dose of afatinib. 11. Cardiac left ventricular function with resting ejection fraction of less than 50%. 12. Any other concomitant serious illness or organ system dysfunction which in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the test drug. 13. Absolute neutrophil count (ANC) 1.5 x 109/L. 14. Platelet count 100 x 109/L for Part A (afatinib monotherapy). Platelet count 75 x 109/L for Part B (afatinib and vinorelbine combination therapy). 15. Calculated Creatinine clearance 60 ml / min (using Cr51-EDTA or Cockcroft-Gault formula Ref: Appendix 1) or serum creatinine 1.5 times upper limit of normal (ULN). 16. Bilirubin 1.5 times upper limit of normal. 17. Aspartate amino transferase (AST) or alanine amino transferase (ALT) 2.5 times ULN (if related to liver metastases 5 times ULN). 18. Women of childbearing potential, unwilling to use a medically acceptable method of contraception during the trial. Acceptable methods of contraception include: - Surgical sterilisation (tubal ligation/hysterectomy) - Hormonal contraception (if applicable) with one barrier method - Double barrier method. Double barrier method of contraception is defined as two barrier methods used simultaneously each time the patient has intercourse. Accepted barrier methods include diaphragm, female condom, cervical cap, male condom and intra-uterine device (IUD) (female and male condom, diaphragm and cervical cap must all be used in conjunction with spermicidal jelly/cream). Partner vasectomy, natural "rhythm" and spermicidal jelly/cream are not acceptable methods of contraception. NOTE: Women of child bearing potential, must also continue to use effective contraception for at least 1 month after ceasing afatinib monotherapy and for at least 3 months after ceasing vinorelbine. 19. Pregnancy or breast-feeding (lactation). 20. Patients unable to comply with the protocol in the investigator s opinion. 21. Known Hepatitis B or C infection, or known HIV infection. 22. Known or suspected active drug or alcohol abuse in the opinion page 5 / 8

6 Method of Generating Random Sequence Method of Concealment Blinding/Masking Not Applicable Not Applicable Open Label of the investigator. 23. Any contraindications for therapy with vinorelbine. 24. Known hypersensitivity to afatinib or the excipients of any of the trial drugs (including vinorelbine). 25. Use of any investigational drug within 4 weeks of the first dose of afatinib and during the study. 26. For Part B (afatinib and vinorelbine combination therapy), prior treatment with HER2-targeted small molecules or antibodies other than prior treatment with afatinib monotherapy in Part A If the screening blood results do not meet the eligibility criteria, they may be repeated within the protocol specified timeframe for the screening period. Primary Outcome Outcome Timepoints The primary endpoint of this study, defined separately for afatinib monotherapy and combination therapy with vinorelbine, is: Clinical Benefit (CB) assessed by Complete Response (CR), Partial Response (PR) and Stable Disease (SD) for at least 6 months using the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). 6 months Secondary Outcome Outcome Timepoints Target Sample Size Phase of Trial Phase 2 Date of First Enrollment () Date of First Enrollment (Global) Estimated Duration of Trial Recruitment Status of Trial (Global) Recruitment Status of Trial () Objective Response (OR) assessed by CR and PR (RECIST 1.1) Progression-Free Survival (PFS) will be defined for three time intervals: time from the date of the start of monotherapy to the date of 1st disease progression; time from the date of the start of combination therapy to the date of 2nd disease progression and the time from the date of the start of monotherapy to the date of 2nd disease progression. Total Sample Size=40 Sample Size from =12 01/03/ /09/2011 Years=1 Months=3 Days=0 Open to Recruitment Other (Terminated) First objective response to the time of progression or death. page 6 / 8

7 Publication Details Brief Summary This is a open label Phase II trial on Inflammatory Breast Cancer. R Piera JM, Alonso MC, Ojeda MB, Biete A. Locally advanced breast cancer with inflammatory component: a clinical entity with a poor prognosis. Radiother Oncol 1986;7: R Gonzalez-Angulo AM, Hennessy BT, Broglio K, Meric-Bernstam F, Cristofanilli M, Giordano SH, et al. Trends for inflammatory breast cancer: is survival improving? Oncologist 2007;12: R Kaptain S, Tan LK, Chen B. Her-2/neu and breast cancer. Diagn Mol Pathol 2001;10(3): R Kaufman B, Trudeau M, Awada A, Blackwell K, Bachelot T, Salazar V, et al. Lapatinib monotherapy in patients with HER2-overexpressing relapsed or refractory inflammatory breast cancer: final results and survival of the expanded HER2+ cohort in EGF103009, a phase II study. Lancet Oncol 2009;10: R Johnston S, Trudeau M, Kaufman B, Boussen H, Blackwell K, LoRusso P, et al. Phase II study of predictive biomarker profiles for response targeting page 7 / 8

8 Powered by TCPDF ( PDF of Trial human epidermal growth factor receptor 2 (HER-2) in advanced inflammatory breast cancer with lapatinib monotherapy. J Clin Oncol 2008;26(7): R Jones SF, Hainsworth JD, Spigel DR, Peacock NW, Willcutt NT, Pandite LN, et al. A phase I study of the dual kinase inhibitor GW in combination with paclitaxel (EGF10009). 40th Ann Mtg of the American Society of Clinical Oncology (ASCO), New Orleans, 5-8 Jun 2004 J Clin Oncol 2004;22(14S)(Suppl) Abstr 2083 R Cabioglu N, Gong Y, Islam R, Broglio KR, Sneige N, Sahin A, et al. Expression of growth factor and chemokine receptors: new insights in the biology of inflammatory breast cancer. Ann Oncol 2007;18: Reason for closure of the study: The trial did not recruit a single patient for 9 months after DCGI approval, because the approval provided was conditional and allowed n sites to recruit only trastuzumab-failed IBC cases. page 8 / 8