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1 Clinical Trial Details (PDF Generation Date :- Fri, 12 Apr :59:25 GMT) CTRI Number Last Modified On 10/07/2017 Post Graduate Thesis Type of Trial Type of Study Study Design Public Title of Study Scientific Title of Study CTRI/2016/08/ [Registered on: 18/08/2016] - Trial Registered Prospectively No Interventional Biological Randomized, Parallel Group Trial A clinical trial to study the efficacy of MEDI4736 in combination with Tremelimumab Therapy Versus Standard of Care Platinum-Based Chemotherapy in First-Line Treatment of Patients with Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC) A Phase III Randomized, Open-Label, Multi-Center, Global Study of MEDI4736 in Combination with Tremelimumab Therapy Versus Standard of Care Platinum-Based Chemotherapy in First-Line Treatment of Patients with Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC) (NEPTUNE) Secondary IDs if Any Secondary ID Identifier Details of Principal Investigator or overall Trial Coordinator (multi-center study) D419AC00003 Version 01, dated 21 March 2016 Protocol Number NCT Designation Affiliation 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) Mr Tapankumar M Shah Phone Fax Designation Affiliation Country Head - Site Management and Monitoring India AstraZeneca Pharma India Limited AstraZeneca Pharma India Limited Block N1, 12th Floor, Manyata Embassy Business Park, Rachenahalli, Outer Ring Road India tapankumar.shah@astrazeneca.com Details Contact Person (Public Query) Tapankumar M Shah Country Head - Site Management and Monitoring AstraZeneca Pharma India Limited AstraZeneca Pharma India Limited Block N1, 12th floor, Manyata Embassy Business Park, Rachenahalli, Outer Ring Road page 1 / 9

2 Source of Monetary or Material Support Primary Sponsor Details of Secondary Sponsor Countries of Recruitment Sites of Study India Phone Fax > AstraZeneca AB, Södertälje, Sweden Type of Sponsor NIL List of Countries Argentina Brazil Bulgaria Chile Denmark Finland Greece Hong Kong India Israel Japan Malaysia Mexico Peru Philippines Poland Portugal Qatar Republic of Korea Romania Saudi Arabia Singapore Sweden Turkey Ukraine United Arab Emirates United Kingdom United States of America of Principal Investigator Dr Sankar Srinivasan Source of Monetary or Material Support Primary Sponsor Details AstraZeneca AB Södertälje, Sweden Pharmaceutical industry-global NIL of Site Site Phone/Fax/ Apollo Speciality Hospital Padma Complex, No. 320, Anna Salai, Chennai Chennai com page 2 / 9

3 Details of Ethics TAMIL NADU Dr Hari Goyal Artemis HospitaL Sector- 51, Gurgaon , Haryana Gurgaon HARYANA Dr Shekhar Gowda Patil Dr Shah Pradeepkumar Ramanlal Dr Krishnakumar Rathnam Dr Amol Shankar Dongre Dr Dinesh Chandra Doval Dr Lokanatha Dasappa Dr K C Lakshmaiah Dr Harsha P Panchal HealthCare Global Enterprises Limited Manibhai Shivabhai Patel Cancer Centre, Shree Krishna Hospital and Medical Research Centre Meenakshi Mission Hospital and Research Centre Rahate Surgical Hospital Rajiv Gandhi Cancer Institute and Research Centre Sri Venkateshwara Hospital Srinivasam Cancer Care Multispeciality Hospitals India Private Limited The Gujarat Cancer & Research Institute, M.P Shah Cancer Hospital HCG Towers, #8, P. Kalinga Rao Road, Sampangi Ram Nagar, Gokal Nagar, Karamsad Anand GUJARAT Lake Area, Leur Road, Madurai Madurai TAMIL NADU 517, Kolbaswami Square, Juni Mangalwari, Central Avenue, Nagpur Nagpur MAHARASHTRA Sector-V, Rohini, New Delhi DELHI #86, Hosur Main Road, Madiwala, No. 36, 1st-A Main, 5th Cross, Maruthi Nagar, Nagarbhavi Main Road, New Civil Hospital Campus, Asarwa, Ahmedabad, Ahmadabad GUJARAT harig@artemishospitals.com spassociates6@gmail.c om pradeeps@charutarhea lth.org kkrathnam@gmail.com amolpgi@yahoo.co.in ddoval07@gmail.com drlok61@gmail.com kcluck@gmail.com drharshapanchal@gmai l.com of Approval Status Date of Approval Is Independent Ethics? Artemis Health Sciences Institutional Ethics Artemis Health Institute Ethics Rahate Surgical Hospital Approved 15/07/2016 No Approved 01/07/2016 No GCRI / GCS Ethics Approved 28/04/2016 No page 3 / 9

4 Regulatory Clearance Status from DCGI Health Condition / Problems Studied Intervention / Comparator Agent HCG Central Ethics Human Research Ethics, H M Patel Centre for Medical Care and Education Institutional Ethics, Meenakshi Mission Hospital and Research Centre Institutional Ethics Apollo Hospitals Enterprises Ltd Institutional Review Board, Rajiv Gandhi Cancer Institute and Research Centre Sri Venkateshwara Hospital Ethics Srinivasam Cancer Care Hospital- Institutional Ethics Status Approved 31/10/2015 No Approved 29/12/2015 No Approved 25/07/2016 No Approved 18/10/2016 No Approved 29/08/2016 No Approved 28/11/2015 No Approved 13/07/2016 No Date Approved/Obtained 08/08/2016 Health Type Patients Condition Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC) Type Details Intervention MEDI4736 plus tremelimumab combination therapy - MEDI mg/kg via intravenous (IV) infusion every 4 weeks (q4w), starting on Week 0, for up to a total of 4 doses/cycles, and then continue MEDI mg/kg via IV infusion q4w, starting on Week 16, for up to a total of 8 months (9 doses) - Tremelimumab 1 mg/kg via IV infusion q4w starting on Week 0, for up to 4 doses/cycles Comparator Agent Standard of Care therapy Patients randomized to SoC therapy will receive 1 of the following: - Paclitaxel + carboplatin: Paclitaxel 200 mg/m2 and carboplatin area under the curve (AUC) 5 or 6 via IV infusion on Day 1 of each until documented PD - Gemcitabine + cisplatin (squamous patients only): page 4 / 9

5 Inclusion Criteria Age From Age To Gender Details Year(s) Year(s) Both Inclusion Criteria Gemcitabine 1000 or 1250 mg/m2 via IV infusion on Days 1 and 8 of each 21-day cycle + cisplatin 75 or 80 mg/m2 via IV infusion on Day 1 of each until documented PD. - Gemcitabine + carboplatin (squamous patients only): Gemcitabine 1000 or 1250 mg/m2 via IV infusion on Days 1 and 8 of each 21-day cycle + carboplatin AUC 5 or 6 via IV infusion on Day 1 of each until documented PD. - Pemetrexed + cisplatin (non-squamous patients only): Pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 via IV infusion on Day 1 of each until documented PD - Pemetrexed + carboplatin (non-squamous patients only): Pemetrexed 500 mg/m2 and carboplatin AUC 5 or 6 via IV infusion on Day 1 of each until documented PD. 1. Age greater than or equal to 18 years at the time of screening 2. Written informed consent and any locally required authorization (eg, Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. 3. Histologically or cytologically documented Stage IV NSCLC not amendable to curative surgery or radiation (according to version 7 of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology; IASLC Staging Manual in Thoracic Oncology). 4. Patients must have tumors that lack activating EGFR mutation (eg, exon 19 deletion or exon 21 L858R, exon 21 L861, exon 18 G719, or exon 20 S7681 mutation) and ALK rearrangement. (If a patient has squamous histology or is known to have a tumor with a KRAS mutation, then EGFR and ALK testing is not required). 5. No prior chemotherapy or any other systemic therapy for advanced or metastatic NSCLC. Patients who have received prior platinum-containing adjuvant, neoadjuvant, or definitive chemoradiation for advanced disease are eligible, provided that progression has occurred >6 months from last therapy. page 5 / 9

6 6. Tumor PD-L1 status, confirmed by a reference laboratory using the Ventana IHC assay, must be known prior to randomization. As such, all patients must be able to undergo a fresh tumor biopsy during screening or to provide an available tumor sample taken 50 ml/min as determined by Cockcroft-Gault (using actual body weight) 11. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: - Women 1 year ago, had chemotherapy-induced menopause with >1 year interval since last menses, or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). Exclusion Criteria Details Exclusion Criteria Patients should not enter the study if any of the following exclusion criteria are fulfilled: 1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 2. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study 3. Mixed small-cell lung cancer and NSCLC histology or not otherwise specified (NSCLC NOS). 4. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable. 5. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of IP. Note: Local treatment of isolated lesions, excluding target lesions, for palliative intent is acceptable. 6. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable. 7. History of allogenic organ transplantation 8. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn s disease], diverticulitis with the exception of diverticulosis, celiac disease or other serious GI chronic conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis), Graves disease, rheumatoid arthritis, hypophysitis, uveitis, etc within the past 3 years prior to the start of treatment. The following are exceptions to this criterion: - Patients with vitiligo or alopecia - Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic page 6 / 9

7 treatment 9. Any condition that, in the opinion of the Investigator, would interfere with the evaluation of IP or interpretation of patient safety or study results, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, ILD, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs from MEDI4736 or tremelimumab, or compromise the ability of the patient to give written informed consent. 10. Medical contraindication to platinum (cisplatin or carboplatin)-based doublet chemotherapy. 11. History of another primary malignancy except for - Malignancy treated with curative intent and with no known active disease?5 years before the first dose of IP and of low potential risk for recurrence - Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease - Adequately treated carcinoma in situ without evidence of disease (eg, cervical cancer in situ) 12. History of leptomeningeal carcinomatosis 13. Brain metastases or spinal cord compression unless asymptomatic or treated and stable off steroids and anti-convulsants for at least 1 month prior to study treatment. Patients with suspected brain metastases at screening should have a CT/MRI of the brain prior to study entry. 14. Mean QT interval corrected for heart rate using Fridericia s formula (QTcF)?470 ms 15. History of active primary immunodeficiency 16. Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) 17. Current or prior use of immunosuppressive medication within 14 days before the first dose of MEDI4736 or tremelimumab. The following are exceptions to this criterion: - Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection). - Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent - Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) 18. Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IP. 19. Female patients who are pregnant or breastfeeding or male or page 7 / 9

8 female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of MEDI tremelimumab combination therapy or 90 days after the last dose of MEDI4736 monotherapy, whichever is the longer time period. 20. Known allergy or hypersensitivity to IP or any excipient or to other humanized mabs Method of Generating Random Sequence Method of Concealment Blinding/Masking Stratified randomization Not Applicable Open Label Primary Outcome Outcome Timepoints To assess the efficacy of MEDI tremelimumab combination therapy compared to Standard of Care (SoC) in terms of OS in patients with Non Small Cell Lung Cancer (NSCLC) Overall Survival (OS) (Time frame-approximately 4 years) Secondary Outcome Outcome Timepoints To assess the efficacy of MEDI4736 plus tremelimumab combination therapy compared to SoC in terms of Overall Survival in patients with PD-L1 negative NSCLC To further assess the efficacy of MEDI4736 plus tremelimumab combination therapy compared to SoC in terms of - Progression-free survival (PFS) - Objective response rate (ORR) - Duration of response (DoR) - Proportion of patients alive at 18 months (OS18) - Proportion of patients alive and progression free at 12 months (APF12) - Progression-free survival after subsequent anticancer therapy (PFS2) To assess the Pharmacokinetics (PK) of MEDI4736 plus tremelimumab combination therapy OS in patients with PD-L1 negative NSCLC (Time frame-approximately 4 years) - PFS, and ORR in patients with PD-L1 negative NSCLC - PFS, ORR, DoR, and APF12 using Investigator assessments according to RECIST 1.1 PFS2 using local standard clinical practice OS12 and OS18 (Time frame-approximately 4 years) Concentration of MEDI4736 and tremelimumab in blood and non-compartmental PK parameters, such as peak concentration and trough (as data allow; sparse sampling) (Time frame-approximately 4 years) To investigate the immunogenicity of MEDI4736 and tremelimumab Presence of ADAs for MEDI4736 and tremelimumab (confirmatory results: positive and negative; titers) (Time frame-approximately 4 years) Target Sample Size Phase of Trial Phase 3 Total Sample Size=800 Sample Size from India=60 page 8 / 9

9 Powered by TCPDF ( Date of First Enrollment (India) Date of First Enrollment (Global) Estimated Duration of Trial Recruitment Status of Trial (Global) Recruitment Status of Trial (India) Publication Details Brief Summary 19/08/ /11/2015 Years=4 Months=0 Days=0 Closed to Recruitment of Participants Closed to Recruitment of Participants This is a randomized, open-label, multi-center, global, Phase III study to determine the efficacy and safety of MEDI tremelimumab combination therapy versus platinum-based SoC chemotherapy in the first-line treatment of patients with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild-type advanced or metastatic NSCLC.Patients will provide a tumor tissue sample at screening to determine PD-L1 expression status (defined by an immunohistochemistry assay developed by Ventana in which?25% PD-L1 membrane expression in tumoral tissue is considered positive and <25% is considered negative; referred to hereafter as patients with PD-L1-positive or -negative tumors, respectively). Patients will be randomized in a 1:1 ratio in a stratified manner according to PD-L1 tumor expression status (as described above), histology (squamous versus non-squamous), and smoking status (never smoker versus ever smoker) to receive treatment with MEDI tremelimumab combination therapy or SoC therapy. Tumor assessments will be performed every 6 weeks for the first 48 weeks and then every 8 weeks until confirmed disease progression, with categorization of objective tumor response by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). The primary objective of this study is to assess the efficacy of MEDI tremelimumab combination therapy compared with SoC in terms of overall survival (OS) in patients with EGFR and ALK wild-type advanced or metastatic NSCLC. OS will be defined as the time from the date of randomization until death due to any cause. Secondary efficacy variables include OS in patients with PD-L1-negative tumors, as well as progression-free survival (PFS), PFS in patients with PD-L1-negative tumors, objective response rate (ORR), ORR in patients with PD-L1-negative tumors, duration of response (DoR), proportion of patients alive at 12 months from randomization (OS12), proportion of patients alive at 18 months from randomization (OS18), proportion of patients alive and progression free at 12 months from randomization (APF12), and time from randomization to second progression (PFS2). page 9 / 9