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1 Clinical Trial Details (PDF Generation Date :- Fri, 02 Nov :52:50 GMT) CTRI Number Last Modified On 24/11/2016 Post Graduate Thesis Type of Trial Type of Study Study Design Public Title of Study Scientific Title of Study CTRI/2012/07/ [Registered on: 02/07/2012] - Trial Registered Prospectively No Interventional Biological Non-randomized, Active Controlled Trial Clinical Trial for metastatic melanoma patients. (skin cancer) Open-label, multicenter, multi-national, phase III study to assess the safety of RO in patients with BRAF V600 mutation-positive (identified by the cobas 4800 BRAF V600 Mutation Test) metastatic melanoma (surgically incurable and unresectable stage IIIC or stage IV; AJCC). Secondary IDs if Any Secondary ID Identifier Details of Principal Investigator or overall Trial Coordinator (multi-center study) MO25515 NCT Designation Affiliation Protocol Number ClinicalTrials.gov Details of Principal Investigator Details Contact Person (Scientific Query) Details Contact Person (Public Query) Phone Fax Designation Affiliation Details Contact Person (Scientific Query) Dr Rupesh Pophale Medical Manager Phone Fax Designation Affiliation Roche Products (India) Pvt.Ltd. "The View", 2nd Floor, 165, Dr. Annie Besant Road, Worli. Mumbai India rupesh.pophale@roche.com Details Contact Person (Public Query) Dr Rupesh Pophale Medical Manager Phone Roche Products (India) Pvt.Ltd. "The View", 2nd Floor, 165, Dr. Annie Besant Road, Worli. Mumbai India page 1 / 7

2 Source of Monetary or Material Support Primary Sponsor Details of Secondary Sponsor Countries of Recruitment Sites of Study Fax > Roche Products India Pvt. Ltd. Type of Sponsor NIL List of Countries Austria Brazil Canada Czech Republic Denmark Greece India Ireland Israel Malta New Zealand Portugal Slovakia Slovenia Switzerland United Kingdom United States of America of Principal Investigator Dr Senthil Rajappa Dr Vijay Kumar Dr Raju Chacko Dr Rajnish Nagarkar Source of Monetary or Material Support Primary Sponsor Details Roche Products India Pvt Ltd The View,2nd Floor, 165, Dr Annie Besant Road, Worli, Mumbai Pharmaceutical industry-global NIL of Site Site Phone/Fax/ Basavatarakam Indo-American Cancer Hospital & Research Institute Chhatrapati Shahuji Maharaj Medical University Christian Medical College Curie Manavata Cancer Centre Clinical Research Room, 4th floor, Road No 14, Banjara Hills, Hyderabad ANDHRA PRADESH Chowk Lucknow UTTAR PRADESH 3rd floor, Ida Schudder Road, Vellore TAMIL NADU 2nd Floor, Opp. Mahamarg Bus Stand, Mumbai Naka, Nashik om Dr Ullas Batra Rajiv Gandhi Cancer Room No. 2251, page 2 / 7

3 Details of Ethics Committee Regulatory Clearance Status from DCGI Health Condition / Problems Studied Intervention / Comparator Agent Dr P G Jayaprakash Institute and Research Centre Regional Cancer Centre Sector V, Rohini, New Delhi DELHI 2nd floor, Radiation Oncology Thiruvananthapuram KERALA Dr Sudeep Gupta Tata Memorial Hospital Research Room, Annex Bldg, Dr Ernest Borges Marg, Parel Mumbai ullasbatra@gmail.com pgjprakash@yahoo.co m sudeepgupta04@yahoo.com of Committee Approval Status Date of Approval Is Independent Ethics Committee? Chhatrapati Shahuji Maharaj Institutional Ethics Committee Institutional Ethics Committee, Tata Memorial Hospital Institutional Ethics Com mittee-basavatarakam Indo-American Cancer Hospital & Research Institute Institutional Review Board, Rajiv Gandhi Cancer Institute & Research Centre Approved 26/06/2012 No Approved 15/04/2014 No Approved 30/07/2012 No Approved 19/01/2012 No Institutional Review Approved 16/07/2012 No Board-Christian Medical College Manavata Clinical Research Institute Professional Ethics Committee Regional Cancer Centre Human Ethics Committee Status Approved 16/04/2012 No Approved 17/08/2012 No Date Approved/Obtained 18/04/2012 Health Type Patients Condition Patients with histologically confirmed metastatic melanoma harboring the BRAF V600 mutation as determined by the cobas 4800 BRAF V600 Mutation Test. Type Details Intervention Vemurafenib RO is a low molecular weight, orally available, selective inhibitor of the activated form of the BRAF serine-threonine kinase enzyme, which is commonly found in malignant melanoma. In vitro biochemical and cell-based assays have page 3 / 7

4 Inclusion Criteria Comparator Agent NA NA Age From Age To Gender Details Year(s) Year(s) Both Inclusion Criteria Inclusion Criteria: 1. Male or female patients? 16 years of age 2. Patients with histologically confirmed metastatic melanoma (surgically incurable and unresectable stage IIIC or stage IV; AJCC) with documented BRAF V600 mutation determined by the cobas 4800 BRAF V600 Mutation Test prior to administration of RO Unresectable stage IIIC disease must have confirmation from a surgical oncologist 3. Patients with either measurable or nonmeasurable disease(recist Version 1.1) 4. Patients may or may not have received prior systemic therapy for metastatic melanoma 5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of Patients must have recovered from all side effects of their most recent systemic or local treatment for metastatic melanoma 7. Adequate hematologic, renal and liver function as defined by the following laboratory values performed within 7 days prior to first dose of RO : Absolute neutrophil count (ANC)? 1.5 x 109/L Platelet count? 100 x 109/L Hemoglobin? 9 g/dl Serum creatinine? 1.5 times upper limit of normal (ULN) or creatine clearance (CrCl) > 50 ml/hr by Cockroft Gault formula confirmed a high degree of selectivity of RO for the oncogenic BRAF V600E kinase. It is equipotent against CRAF (44 nm) and 3-fold less potent against BRAF wild type (110 nm). In a panel of 58 kinases, RO had an IC50 1?M for only 1 kinase (BRK kinase) outside the BRAF family. RO was also screened against 63 receptors in 8 different families. At 10?M, RG7204 showed marginal activity (20 24% inhibition) against 4 receptors and was inactive against the other 59 targets. Dose: 960mg B.I.D Route of administration: Oral Frequency: every cycle wherein One cycle of therapy is defined as 28 days of treatment. Intotal 8 cycles. page 4 / 7

5 Exclusion Criteria Details Aspartate aminotransferase (AST [SGOT]) and alanine aminotransferase (ALT [SGPT])? 2.5 times ULN (? 5times ULN if considered due to tumor) Serum bilirubin? 1.5 times ULN Alkaline phosphatase? 2.5 times ULN (? 5times ULN if considered due to tumor) 8. Negative serum pregnancy test within 7 days prior to commencement of dosing in premenopausal women. Women of nonchildbearing potential may be included if they are either surgically sterile or have been postmenopausal for?1 year. 9. Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician. Effective methods of contraception are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly (for example implants, injectables, combined oral contraception or intra-uterine devices). At the discretion of the investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance.[periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.] 10.Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before trial entry 11.Signed informed consent must be obtained prior to performing any study-related procedures (including tumor testing for the V600 BRAF mutation) Exclusion Criteria 1. Evidence of symptomatic CNS lesions as determined by investigator (patients with radiographically stable, asymptomatic lesions previously irradiated or surgically resected are eligible) 2. Patients with a previous malignancy (other than melanoma) within the past 2 years are excluded except patients with treated and controlled basal or squamous cell carcinoma (SCC) of the skin or carcinoma in-situ of the cervix. Isolated elevation in prostatespecific antigen in absence of radiographic evidence of metastatic prostate cancer is allowed 3. Concurrent administration of any anti-cancer therapies (e.g. chemotherapy, other targeted therapy, experimental drug, etc) other than those administered in this study page 5 / 7

6 Method of Generating Random Sequence Method of Concealment Blinding/Masking Not Applicable Not Applicable Not Applicable 4. Known hypersensitivity to RO or another BRAF inhibitor 5. Pregnant or lactating women 6. Refractory nausea and vomiting,malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption. Patients must be able to swallow tablets 7. Any of the following within the 6 months prior to first RO administration: myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, hypertension not adequately controlled by current medications 8. History of congenital long QT syndrome, history or presence of clinically significant ventricular or atrial dysrhythmias? Grade 2 (NCI CTCAE Version 4.0) 9. Corrected QT (QTc) interval? 450 msec at baseline 10.Uncontrolled medical illness (such as infection requiring treatment with intravenous (IV) antibiotics) Primary Outcome Outcome Timepoints To evaluate the safety and tolerability of RO in patients with metastatic melanoma (surgically incurable and unresectable stage IIIC or stage IV; AJCC) harboring the BRAF V600 mutation. Secondary Outcome Outcome Timepoints Target Sample Size Phase of Trial Phase 3 Date of First Enrollment (India) Date of First Enrollment (Global) Estimated Duration of Trial Recruitment Status of Trial (Global) Recruitment Status of To evaluate the efficacy of RO as overall response rates (ORRs) determined by the investigator (RECIST, Version 1.1) as allowed by local regulatory requirements. Total Sample Size=900 Sample Size from India=12 02/07/ /03/2011 Years=1 Months=0 Days=0 Completed Completed N/A Screening, Cycle 3, Cycle 5 and End of the study. page 6 / 7

7 Powered by TCPDF ( PDF of Trial Trial (India) Publication Details Brief Summary NA Summary Metastatic melanoma represents a major clinical challenge as it is an essentially incurable disease with few satisfactory treatment options. Current first-line treatment options have yielded low response rates and no evidence of impact on survival. In the second-line setting, no treatment is considered effective and response rates to agents after first-line failure are very low (section 1.1.1). RO is a highly selective inhibitor of the oncogenic BRAF kinase which has been identified in a large number of malignant melanomas. Results from Phase I and II studies have shown that RO induces high response rates in patients with metastatic melanoma carrying the V600E BRAF mutation (section 1.1.3). Results from the phase 3 study show an OS and PFS benefit in patients with unresectable IIIC or stage IV metastatic melanoma. These data indicate that RO might be an effective treatment option in this patient population with no currently available satisfactory treatment options. The purpose of this multicenter, early access study is to make RO available to a larger number of patients than could otherwise be treated in registration trials and who are without satisfactory treatment options. The primary objective of this study will be to evaluate the safety of RO in patients with unresectable IIIC or stage IV metastatic melanoma positive for the V600 BRAF mutation (identified by the cobas 4800 BRAF V600 Mutation Test). Study Overview: This is an open-label, multicenter, multi-national, expanded access study of RO in patients with BRAF V600 mutation-positive (identified by the cobas 4800 BRAF V600 Mutation Test) metastatic melanoma who may or may not have received prior therapy for metastatic melanoma. The primary objective of this study is to assess the safety and tolerability of RO The study population will consist of patients at least 16 years of age with histological confirmed diagnoses of metastatic melanoma harboring the BRAF V600 mutation, as determined by cobas 4800 BRAF V600 Mutation Test. Patients with measurable and/or non-measurable disease (as defined by RECIST 1.1) are eligible for enrollment in this trial. Patients may or may not have received prior therapy for metastatic melanoma. The trial will consist of a screening period (Day 28 to Day 1), a treatment phase, and an end of study/follow up. Day 1 of the study will be defined as the first day a patient receives RO One cycle of therapy is defined as 28 days of treatment. page 7 / 7