Study of Durvalumab With Tremelimumab Versus SoC as 1st Line Therapy in Metastatic Non Small-Cell Lung Cancer (NSCLC) (NEPTUNE) (NEPTUNE)

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).

This is a randomized, open-label, multi-center, global, Phase III study to determine the efficacy and safety of durvalumab + 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.

Study Overview

• Status: Active, not recruiting
• Conditions: Non Small Cell Lung Carcinoma NSCLC
• Intervention / Treatment: Biological: Durvalumab +Tremelimumab; Drug: Paclitaxel + carboplatin; Drug: Gemcitabine + cisplatin; Drug: Gemcitabine + carboplatin; Drug: Pemetrexed + cisplatin; Drug: Pemetrexed + carboplatin

Detailed Description

Patients will be randomized in a 1:1 to receive treatment with durvalumab + tremelimumab combination therapy or SoC therapy. The primary objective of this study is to assess the efficacy of combination treatment compared with SoC in terms of Overall Survival (OS) in patients.

• Study Type: Interventional
• Enrollment (Actual): 953
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Berazategui, Argentina, B1884BBF
    • Research Site
  • Buenos Aires, Argentina, C1025ABI
    • Research Site
  • Caba, Argentina, C1426ANZ
    • Research Site
  • Córdoba, Argentina, 5000
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  • La Rioja, Argentina, 5300
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  • Rosario, Argentina, S2000KZE
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  • San Salvador de Jujuy, Argentina, 4600
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  • Santa Rosa, Argentina, 6300
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• Brazil
  • Barretos, Brazil, 14784-400
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  • Belo Horizonte, Brazil, 30110-022
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  • Belo Horizonte, Brazil, 30380-472
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  • Fortaleza, Brazil, 60336-045
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  • Ijui, Brazil, 98700-000
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  • Itajai, Brazil, 88310-110
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  • Porto Alegre, Brazil, 90035-003
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  • Porto Alegre, Brazil, 91350-200
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  • Porto Alegre, Brazil, 90160-093
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  • Sao Paulo, Brazil, 01246-000
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  • Sao Paulo, Brazil, 01221-020
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  • Sao Paulo, Brazil, 01323 900
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  • São José do Rio Preto, Brazil, 15090-000
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  • São Paulo, Brazil, 03102-002
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• Bulgaria
  • Plovdiv, Bulgaria, 4004
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  • Shumen, Bulgaria, 9700
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  • Sofia, Bulgaria, 1431
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  • Sofia, Bulgaria, 1784
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  • Sofia, Bulgaria, 1330
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  • Sofia, Bulgaria, 1303
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  • Varna, Bulgaria, 9010
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  • Vratza, Bulgaria, 3000
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• Chile
  • Santiago, Chile, 7520349
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  • Santiago, Chile, 7500713
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  • Santiago, Chile, 7500921
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  • Santiago, Chile, 8380456
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  • Santiago, Chile, 8420383
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  • Temuco, Chile, 4810297
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  • Viña del Mar, Chile, 2520612
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• China
  • Beijing, China, 100142
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  • Changchun, China, 130000
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  • Chongqing, China, 400030
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  • Guangzhou, China, 510100
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  • Hangzhou, China, 310022
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  • Shanghai, China, 200032
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  • Shanghai, China, 200030
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  • Urumqi, China, 830000
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  • Wuhan, China, 430022
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  • Wuhan, China, 430030
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• Denmark
  • Odense C, Denmark, 5000
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• Finland
  • Oulu, Finland, FI-90029
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  • Tampere, Finland, FI-33521
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• Greece
  • Athens, Greece, 11527
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  • Athens, Greece, 14564
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  • Athens, Greece, 115 22
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  • Heraklion, Greece, 711 11
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  • Holargos, Athens, Greece, 155 62
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  • Ioannina, Greece, 45000
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• Hong Kong
  • Hong Kong, Hong Kong
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  • King's Park, Hong Kong, 150001
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  • Shatin, Hong Kong, 00000
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• India
  • Ahmedabad, India, 380016
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  • Bangalore, India, 560068
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  • Bangalore, India, 560076
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  • Chennai, India, 600035
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  • Gurgaon, India, 122001
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  • Karamsad, India, 388325
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  • New Delhi, India, 110 085
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• Israel
  • Beer Sheva, Israel, 8410101
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  • Jerusalem, Israel, 91031
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  • Kfar Saba, Israel, 95847
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  • Nahariya, Israel, 22100
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  • Petah Tikva, Israel, 49100
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  • Ramat Gan, Israel, 5265601
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• Japan
  • Bunkyo-ku, Japan, 160-0023
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  • Fukushima-shi, Japan, 960-1295
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  • Habikino-shi, Japan, 583-8588
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  • Hirosaki-shi, Japan, 036-8545
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  • Iizuka-shi, Japan, 820-8505
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  • Iwakuni-shi, Japan, 740-8510
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  • Kanazawa, Japan, 920-8641
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  • Kishiwada-shi, Japan, 596-8501
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  • Kobe-shi, Japan, 650-0047
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  • Kurume-shi, Japan, 830-0011
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  • Kyoto-shi, Japan, 607-8062
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  • Mitaka-shi, Japan, 181-8611
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  • Nagaoka-shi, Japan, 940-2085
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  • Nagoya-shi, Japan, 466-8560
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  • Nagoya-shi, Japan, 460-0001
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  • Niigata-shi, Japan, 951-8566
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  • Okayama-shi, Japan, 700-8607
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  • Osaka-shi, Japan, 541-8567
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  • Saga-shi, Japan, 840-8571
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  • Sagamihara-shi, Japan, 252-0375
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  • Sakai-shi, Japan, 591-8555
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  • Sendai-shi, Japan, 980-0873
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  • Tokushima-shi, Japan, 770-8503
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  • Ube-shi, Japan, 755-0241
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  • Wakayama-shi, Japan, 641-8510
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  • Yokohama-shi, Japan, 241-8515
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  • Yokohama-shi, Japan, 236-0004
    • Research Site
• Korea, Republic of
  • Daegu, Korea, Republic of, 41404
    • Research Site
  • Hwasun-gun, Korea, Republic of, 58128
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  • Seoul, Korea, Republic of, 06273
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  • Seoul, Korea, Republic of, 08308
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  • Seoul, Korea, Republic of, 05030
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• Malaysia
  • Kuala Lumpur, Malaysia, 59100
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  • Kuantan, Malaysia, 25100
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  • Kuching, Malaysia, 93586
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• Mexico
  • Acapulco, Mexico, 39670
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  • Aguascalientes, Mexico, 20020
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  • Mexico, Mexico, 14080
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  • Monterrey, Mexico, 64710
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  • Mérida, Mexico, 97134
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  • México, Mexico, 06100
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• Peru
  • Arequipa, Peru, AREQUIPA01
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  • Bellavista, Peru, CALLAO 2
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  • Lima, Peru, 15033
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  • Lima, Peru, L27
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  • Lima, Peru, LIMA 34
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  • Lima, Peru, LIMA 41
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  • Lima, Peru, 41
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• Philippines
  • Baguio City, Philippines, 2600
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  • Cebu, Philippines, 6000
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  • Las Pinas City, Philippines, PH-1704
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  • Manila, Philippines, 1000
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  • Manila, Philippines, 1003
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  • Quezon City, Philippines, 1112
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• Poland
  • Bydgoszcz, Poland, 85-796
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  • Kielce, Poland, 25-734
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  • Kraków, Poland, 31-202
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  • Mrozy, Poland, 05-320
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  • Olsztyn, Poland, 10-357
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  • Poznan, Poland, 60-569
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  • Poznań, Poland, 60-569
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  • Warszawa, Poland, 02-781
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  • Warszawa, Poland, 01-138
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  • Wodzisław Śląski, Poland, 44-300
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  • Łódź, Poland, 93-513
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• Portugal
  • Amadora, Portugal, 2720-276
    • Research Site
  • Lisboa, Portugal, 1500-650
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  • Porto, Portugal, 4099-001
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  • Porto, Portugal, 4200-319
    • Research Site
  • Porto, Portugal, 4100-180
    • Research Site
• Qatar
  • Doha, Qatar, P.O. Box 3050
    • Research Site
• Romania
  • Suceava, Romania, 720237
    • Research Site
• Russian Federation
  • Moscow, Russian Federation, 125367
    • Research Site
  • Moscow, Russian Federation, 105229
    • Research Site
  • Moscow, Russian Federation, 115280
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  • Omsk, Russian Federation, 644013
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  • Saint Petersburg, Russian Federation, 197342
    • Research Site
  • Saint Petersburg, Russian Federation, 197022
    • Research Site
  • Saint-Petersburg, Russian Federation, 194291
    • Research Site
  • Saint-Petersburg, Russian Federation, 197183
    • Research Site
  • St. Petersburg, Russian Federation, 197758
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• Saudi Arabia
  • Dammam, Saudi Arabia, 31444
    • Research Site
  • Riyadh, Saudi Arabia, 11426
    • Research Site
  • Riyadh, Saudi Arabia, 12372
    • Research Site
• Singapore
  • Singapore, Singapore, 119228
    • Research Site
  • Singapore, Singapore, 308433
    • Research Site
  • Singapore, Singapore, 217562
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  • Singapore, Singapore, 258499
    • Research Site
• Sweden
  • Eskilstuna, Sweden, 63188
    • Research Site
  • Linköping, Sweden, 581 85
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  • Stockholm, Sweden, 171 64
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  • Uppsala, Sweden, 751 85
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• Turkey
  • Adana, Turkey, 01120
    • Research Site
  • Ankara, Turkey, 06230
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  • Ankara, Turkey, 06280
    • Research Site
  • Ankara, Turkey, 6500
    • Research Site
  • Ankara, Turkey, 06200
    • Research Site
  • Istanbul, Turkey, 34030
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  • Istanbul, Turkey, 31755
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  • Istanbul, Turkey, 34349
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  • Izmir, Turkey, 35100
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• Ukraine
  • Chernivtsі, Ukraine, 58013
    • Research Site
  • Dnipro, Ukraine, 49102
    • Research Site
  • Ivano-Frankivsk, Ukraine, 76018
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  • Kapitanivka Village, Ukraine, 08111
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  • Kharkiv Region, Ukraine, 61070
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  • Kirovohrad, Ukraine, 25006
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  • Kyiv, Ukraine, 04107
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  • Kyiv, Ukraine, 03115
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  • Lviv, Ukraine, 79031
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  • Lyutizh, Ukraine, 07352
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  • Odesa, Ukraine, 65055
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  • Sumy, Ukraine, 40022
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  • Uzhhorod, Ukraine, 88000
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  • Vinnytsia, Ukraine, 21029
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• United Kingdom
  • Guildford, United Kingdom
    • Research Site
  • London, United Kingdom, W6 8RF
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  • London, United Kingdom, NW1 2PG
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  • London, United Kingdom, EC1M 6BQ
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  • Manchester, United Kingdom, M20 4BX
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  • Nottingham, United Kingdom, NG5 1PB
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  • Taunton, United Kingdom, TA1 5DA
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  • Wirral, United Kingdom, CH63 4JY
    • Research Site
  • Wolverhampton, United Kingdom, WV10 0QP
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• United States
  • California
    • Anaheim, California, United States, 92801
      • Research Site
    • San Diego, California, United States, 92123
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    • Santa Rosa, California, United States, 95403
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  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Research Site
  • New Jersey
    • Florham Park, New Jersey, United States, 07932
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  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • Research Site
  • New York
    • East Setauket, New York, United States, 11733
      • Research Site
    • Fresh Meadows, New York, United States, 11366
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    • Poughkeepsie, New York, United States, 12601
      • Research Site
    • Stony Brook, New York, United States, 11794
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  • Ohio
    • Canton, Ohio, United States, 44710
      • Research Site
    • Columbus, Ohio, United States, 43219
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    • Zanesville, Ohio, United States, 43701
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  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
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  • Texas
    • Houston, Texas, United States, 77090
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

For inclusion in the study, patients should fulfill the following criteria:

• Aged at least 18 years
• Documented evidence of Stage IV NSCLC
• No activating EGFR mutation or ALK rearrangement
• No prior chemotherapy or any other systemic therapy for recurrent/metastatic NSCLC
• World Health Organization (WHO) Performance Status of 0 or 1
• No Prior exposure to Immune Mediated Therapy (IMT), including, but not limited to, other antiCTLA4, antiPD1, anti PDL1,or antiPDL2 antibodies, excluding therapeutic anticancer vaccines

Exclusion Criteria:

Patients should not enter the study if any of the following exclusion criteria are fulfilled:

• Mixed small cell lung cancer and NSCLC histology, sarcomatoid variant
• Brain metastases or spinal cord compression unless the patient is stable (asymptomatic; no evidence of new or emerging brain metastases) and off steroids for at least 14 days prior to start of study treatment.
• Active or prior documented autoimmune or inflammatory disorders (e.g., Crohn's disease, ulcerative colitis)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Combination Therapy; Durvalumab (PD-L1 monoclonal antibody) + Tremelimumab (monoclonal antibody directed against CTLA-4)	Biological: Durvalumab +Tremelimumab
Active Comparator: Standard of Care; Standard of Care chemotherapy treatment	Drug: Paclitaxel + carboplatin; Chemotherapy Agents; Other Names: Platinum based Standard of Care Chemotherapy; Drug: Gemcitabine + cisplatin; Chemotherapy Agents; Other Names: Platinum based Standard of Care Chemotherapy; Drug: Gemcitabine + carboplatin; Chemotherapy Agents; Other Names: Platinum based Standard of Care Chemotherapy; Drug: Pemetrexed + cisplatin; Chemotherapy Agent; Other Names: Platinum based Standard of Care Chemotherapy; Drug: Pemetrexed + carboplatin; Chemotherapy Agent; Other Names: Platinum based Standard of Care Chemotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS); Global Cohort: Blood Tumor Mutational Burden (bTMB) ≥20 Mutations Per Megabase (Mut/Mb) Analysis Set	The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.	From baseline (Day 1, Week 0) until death due to any cause, assessed up to the Global cohort DCO date (a maximum of approximately 44 months).
OS; China Cohort: China Programmed Cell Death Ligand 1 (PD-L1) Negative NSCLC Analysis Set	The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.	From baseline (Day 1, Week 0) until death due to any cause, assessed up to the China cohort DCO date (a maximum of approximately 44 months).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OS; Global Cohort: bTMB ≥16 Mut/Mb, bTMB ≥12 Mut/Mb, PD-L1-Negative NSCLC, bTMB <20 Mut/Mb, bTMB Non-Evaluable Population, tTMB ≥14 Mut/Mb, tTMB ≥12 Mut/Mb, tTMB ≥10 Mut/Mb, and tTMB ≥8 Mut/Mb Analysis Sets	OS was defined as time from date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at time of analysis was censored based on last recorded date on which participant was known to be alive. bTMB ≥16 mut/Mb, bTMB ≥12 mut/Mb and bTMB <20 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥16 mut/Mb, ≥12 mut/Mb and <20 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay. PD-L1-negative analysis set included the subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by the Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). bTMB non-evaluable analysis set included the subset of participants in FAS whose bTMB status at baseline could not be determined by the GuardantOMNI CDx assay or whose sample was not available. tTMB analysis sets are defined same as the bTMB analysis sets.	From baseline (Day 1, Week 0) until death due to any cause, assessed up to the Global cohort DCO date (a maximum of approximately 44 months).
OS; Global and China Cohorts: FAS, PD-L1 Tumor Cell (TC) ≥25%, and PD-L1 TC ≥50% Analysis Sets	The OS was defined as time from date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis was censored based on last recorded date on which participant was known to be alive. Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. Any participants recruited in China, after global recruitment had ended, were not included in the FAS. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses. PD-L1 TC ≥25% and PD-L1 TC ≥50% analysis sets included the subset of participants in the FAS whose PD-L1 status was TC ≥25% and TC ≥50% membrane expression in tumoral tissue, respectively at baseline as defined by the Ventana SP263 PD-L1 Assay.	From baseline (Day 1, Week 0) until death due to any cause, assessed up to the Global or China cohort DCO dates, as applicable (a maximum of approximately 44 months) for each cohort.
Progression-Free Survival (PFS); Global Cohort: bTMB ≥20 Mut/Mb, bTMB ≥16 Mut/Mb, bTMB ≥12 Mut/Mb, tTMB ≥14 Mut/Mb, tTMB ≥12 Mut/Mb, tTMB ≥10 Mut/Mb, and tTMB ≥8 Mut/Mb Analysis Sets	The PFS (per Response Evaluation Criteria in Solid Tumors, version 1.1 [RECIST 1.1] using Investigator assessments) was defined as the time from the date of randomization until the date of objective PD or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anticancer therapy prior to progression (ie, date of PFS event or censoring - date of randomization + 1). bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb and bTMB ≥12 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥20 mut/Mb, ≥16 mut/Mb and ≥12 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay. tTMB ≥14 mut/Mb, tTMB ≥12 mut/Mb, tTMB ≥10 mut/Mb and tTMB ≥8 mut/Mb analysis sets included the subset of participants in FAS whose tTMB status was ≥14 mut/Mb, ≥12 mut/Mb, ≥10 mut/Mb and ≥8 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay.	Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global cohort DCO date (approximately 44 months).
PFS; Global and China Cohorts: PD-L1-Negative NSCLC, FAS, PD-L1 TC ≥25%, and PD-L1 TC ≥50% Analysis Sets	PFS (per RECIST 1.1 using Investigator assessments) was defined as time from date of randomization until date of objective PD or death regardless of whether participant withdrew from randomized therapy or received another anticancer therapy prior to progression (ie, date of PFS event or censoring - date of randomization + 1). PD-L1-negative analysis set included subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). Global Cohort: FAS included all randomized participants prior to end of global recruitment. China Cohort: China FAS included all randomized participants in China cohort and were used for all China only efficacy analyses. PD-L1 TC ≥25% and PD-L1 TC ≥50% analysis sets included subset of participants in FAS whose PD-L1 status was TC ≥25% and TC ≥50% membrane expression in tumoral tissue, respectively at baseline as defined by the Ventana SP263 PD-L1 Assay.	Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global or China cohort DCO dates, as applicable (approximately 44 months) for each cohort.
Objective Response Rate (ORR); Global Cohort: bTMB ≥20 Mut/Mb, bTMB ≥16 Mut/Mb, bTMB ≥12 Mut/Mb, tTMB ≥14 Mut/Mb, tTMB ≥12 Mut/Mb, tTMB ≥10 Mut/Mb, and tTMB ≥8 Mut/Mb Analysis Sets	The ORR (per RECIST 1.1 using Investigator assessments) was defined as the percentage of participants with at least 1 visit response of complete response (CR) or partial response (PR) prior to PD. bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb and bTMB ≥12 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥20 mut/Mb, ≥16 mut/Mb and ≥12 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay. tTMB ≥14 mut/Mb, tTMB ≥12 mut/Mb, tTMB ≥10 mut/Mb and tTMB ≥8 mut/Mb analysis sets included the subset of participants in FAS whose tTMB status was ≥14 mut/Mb, ≥12 mut/Mb, ≥10 mut/Mb and ≥8 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay.	Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global cohort DCO date (approximately 44 months).
ORR; Global and China Cohorts: PD-L1-Negative NSCLC, FAS, PD-L1 TC ≥25%, and PD-L1 TC ≥50% Analysis Sets	The ORR (per RECIST 1.1 using Investigator assessments) was defined as the percentage of participants with at least 1 visit response of CR or PR prior to PD. PD-L1-negative analysis set included the subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by the Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses. PD-L1 TC ≥25% and PD-L1 TC ≥50% analysis sets included the subset of participants in the FAS whose PD-L1 status was TC ≥25% and TC ≥50% membrane expression in tumoral tissue, respectively at baseline as defined by the Ventana SP263 PD-L1 Assay.	Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global or China cohort DCO dates, as applicable (approximately 44 months) for each cohort.
Duration of Response (DoR); Global Cohort: bTMB ≥20 Mut/Mb, bTMB ≥16 Mut/Mb, and bTMB ≥12 Mut/Mb Analysis Sets	DoR (per RECIST 1.1 using Investigator assessments) was defined as the time from the date of first documented response (CR or PR) until the first date of documented progression or death in the absence of PD (ie, date of PFS event or censoring - date of first response + 1). bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb and bTMB ≥12 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥20 mut/Mb, ≥16 mut/Mb and ≥12 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay.	Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global cohort DCO date (approximately 44 months).
DoR; Global and China Cohorts: PD-L1-Negative NSCLC and FAS Analysis Sets	DoR (per RECIST 1.1 using Investigator assessments) was defined as the time from the date of first documented response (CR or PR) until the first date of documented progression or death in the absence of PD (ie, date of PFS event or censoring - date of first response + 1). PD-L1-negative analysis set included the subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by the Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses.	Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global or China cohort DCO dates, as applicable (approximately 44 months) for each cohort.
Alive and Progression-Free at 12 Months (APF12); Global Cohort: bTMB ≥20 Mut/Mb, bTMB ≥16 Mut/Mb, and bTMB ≥12 Mut/Mb Analysis Sets	The APF12 was defined as the percentage of participants who were alive and progression free at 12 months from randomization (ie, PFS rate at 12 months). bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb and bTMB ≥12 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥20 mut/Mb, ≥16 mut/Mb and ≥12 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay.	Tumour scans performed at baseline then every 6 weeks up to 12 months.
APF12; Global and China Cohorts: PD-L1-Negative NSCLC and FAS Analysis Sets	The APF12 was defined as the percentage of patients who were alive and progression free at 12 months from randomization (ie, PFS rate at 12 months). PD-L1-negative analysis set included the subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by the Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses.	Tumour scans performed at baseline then every 6 weeks up to 12 months.
Time From Randomization to Second Progression or Death (PFS2); Global Cohort: bTMB ≥20 Mut/Mb, bTMB ≥16 Mut/Mb, and bTMB ≥12 Mut/Mb Analysis Sets	The PFS2 was defined as the time from the date of randomization to the earliest of the progression events subsequent to that used for the primary variable PFS, or death (ie, date of PFS2 event or censoring - date of randomization + 1). bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb and bTMB ≥12 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥20 mut/Mb, ≥16 mut/Mb and ≥12 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay.	Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global cohort DCO date (approximately 44 months).
PFS2; Global and China Cohorts: PD-L1-Negative NSCLC and FAS Analysis Sets	The PFS2 was defined as the time from the date of randomization to the earliest of the progression events subsequent to that used for the primary variable PFS, or death (ie, date of PFS2 event or censoring - date of randomization + 1). PD-L1-negative analysis set included the subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by the Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses.	Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global or China cohort DCO dates, as applicable (approximately 44 months) for each cohort.
OS at Months 12, 18 and 24; Global Cohort: bTMB ≥20 Mut/Mb, bTMB ≥16 Mut/Mb, and bTMB ≥12 Mut/Mb Analysis Sets	The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb and bTMB ≥12 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥20 mut/Mb, ≥16 mut/Mb and ≥12 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay.	Months 12, 18 and 24
OS at Months 12, 18 and 24; Global and China Cohorts: PD-L1-Negative NSCLC and FAS Analysis Sets	The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). PD-L1-negative analysis set included the subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by the Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses.	Months 12, 18 and 24
Serum Concentrations of Durvalumab	Blood samples were collected to determine the serum concentration of durvalumab.	Pre-dose and within 1 hour after end of infusion at Week 0 and 12; pre-dose on Week 24 and at follow-up Month 3
Serum Concentrations of Tremelimumab	Blood samples were collected to determine the serum concentration of tremelimumab.	Pre-dose and within 1 hour after end of infusion at Week 0 and 12, and at follow-up Month 3
Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab	Blood samples were measured for the presence of ADAs and ADA-neutralizing antibodies (nAb) for durvalumab using validated assays. ADA prevalence is defined as the percentage of participants with positive ADA result at any time, baseline or post-baseline. Treatment-emergent ADA is defined as the sum of treatment-induced ADA and treatment-boosted ADA. ADA incidence is the percentage of participants who were treatment-emergent ADA-positive. Treatment-boosted ADA is defined as baseline positive ADA titer that was boosted to >=4 fold during the study period. Persistently positive is defined as having at least 2 post baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least 1 post baseline ADA positive measurement and not fulfilling the conditions for persistently positive.	At Weeks 0, 12, and 24; 3 and 6 months after last dose of study treatment.
Number of Participants With ADA Response to Tremelimumab	Blood samples were measured for the presence of ADAs and ADA-nAb for tremelimumab using validated assays. ADA prevalence is defined as the percentage of participants with positive ADA result at any time, baseline or post-baseline. Treatment-emergent ADA is defined as the sum of treatment-induced ADA and treatment-boosted ADA. ADA incidence is the percentage of participants who were treatment-emergent ADA-positive. Treatment-boosted ADA is defined as baseline positive ADA titer that was boosted to >=4 fold during the study period. Persistently positive is defined as having at least 2 post baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least 1 post baseline ADA positive measurement and not fulfilling the conditions for persistently positive.	At Weeks 0 and 12; 3 and 6 months after last dose of study treatment.

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Gilberto de Castro, Faculdade de Medicina da Universidade de Sao Paulo

Publications and helpful links

Helpful Links

• Related Info
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Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2015
• Primary Completion (Actual): September 21, 2020
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: August 26, 2015
• First Submitted That Met QC Criteria: September 3, 2015
• First Posted (Estimated): September 7, 2015

Study Record Updates

• Last Update Posted (Actual): February 14, 2024
• Last Update Submitted That Met QC Criteria: February 13, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: NSCLC; PDL1; OS; Durvalumab; Tremelimumab; MEDI4736; TMB
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Folic Acid Antagonists; Carboplatin; Paclitaxel; Cisplatin; Durvalumab; Tremelimumab; Pemetrexed; Gemcitabine
• Other Study ID Numbers: D419AC00003; 2015-002197-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP