A Global Study to Assess the Effects of MEDI4736 (Durvalumab), Given as Monotherapy or in Combination With Tremelimumab Determined by PD-L1 Expression Versus Standard of Care in Patients With Locally Advanced or Metastatic Non Small Cell Lung Cancer (ARCTIC)

• ClinicalTrials.gov Identifier: NCT02352948
• Recruitment Status: Completed
• First Posted: February 2, 2015
• Results First Posted: April 16, 2019
• Last Update Posted: October 11, 2023
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: January 28, 2015
• First Posted Date: February 2, 2015
• Results First Submitted Date: February 7, 2019
• Results First Posted Date: April 16, 2019
• Last Update Posted Date: October 11, 2023
• Actual Study Start Date: January 13, 2015
• Actual Primary Completion Date: February 9, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 25, 2019)

• Overall Survival (OS) [ Time Frame: From randomization (Day 1) until death due to any cause, approximately 36 months ]
  The OS was defined as the time from the date of randomization until death due to any cause.
• Progression-Free Survival (PFS) [ Time Frame: Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until confirmed disease progression. Assessed up to a maximum of approximately 3 years. ]
  The PFS was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression. The PFS was determined by Investigator assessments according to response evaluation criteria in solid tumours (RECIST) version 1.1. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 millimeter (mm) or progression of non-target lesions or the appearance of a new lesion

Original Primary Outcome Measures (submitted: January 28, 2015)

• Overall Survival (OS) [ Time Frame: up to 3 years after first patient randomized ]
• Progression Free Survival (PFS) [ Time Frame: up to 3 years after the first patient randomized ]

Current Secondary Outcome Measures (submitted: March 25, 2019)

• OS, Contribution of the Components Analysis of Sub-study B [ Time Frame: From randomization (Day 1) until death due to any cause, approximately 36 months ]
  The OS was defined as the time from the date of randomization until death due to any cause.
• Percentage of Participants Alive at 12 Months (OS12) [ Time Frame: From randomization (Day 1) up to 12 months ]
  The OS12 was defined as the percentage of participants who were alive at 12 months after randomisation per Kaplan-Meier estimate of OS at 12 months.
• PFS, Contribution of the Components Analysis of Sub-study B [ Time Frame: Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until confirmed disease progression. Assessed up to a maximum of approximately 3 years. ]
  The PFS was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression. The PFS was determined by Investigator assessments according to RECIST v1.1. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 millimeter (mm) or progression of non-target lesions or the appearance of a new lesion
• Objective Response Rate (ORR) [ Time Frame: Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until confirmed disease progression. Assessed up to a maximum of approximately 3 years. ]
  The ORR was defined as the percentage of participants with at least 1 visit response of complete response (CR) or partial response (PR) among ITT participants who had measurable disease at baseline. CR was defined as disappearance of all target lesions (any pathological lymph nodes selected as target lesions must have a reduction in short axis to <10 mm) and PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum of diameters as long as criteria for PD are not met). The ORR was measured using Investigator assessments according to RECIST v1.1.
• Duration of Response (DoR) [ Time Frame: Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until confirmed disease progression. Assessed up to a maximum of approximately 3 years. ]
  The DoR was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression. The DoR was determined by Investigator assessments according to RECIST v1.1. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 millimeter (mm) or progression of non-target lesions or the appearance of a new lesion
• Percentage of Participants Alive and Progression Free at 6 Months (APF6) [ Time Frame: Tumour scans performed at baseline then every ~8 weeks up to 6 months ]
  The APF6 was defined as the percentage of participants who were alive and progression free per RECIST v1.1 at 6 months after randomization per Kaplan-Meier estimate of PFS at 6 months. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 millimeter (mm) or progression of non-target lesions or the appearance of a new lesion
• Percentage of Participants Alive and Progression Free at 12 Months (APF12) [ Time Frame: Tumour scans performed at baseline then every ~8 weeks up to 12 months. ]
  The APF12 was defined as the percentage of participants who were alive and progression free per RECIST v1.1 at 12 months after randomization per Kaplan-Meier estimate of PFS at 12 months. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 millimeter (mm) or progression of non-target lesions or the appearance of a new lesion
• Time From Randomisation to Second Progression (PFS2) of Sub-study B [ Time Frame: Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until first progression. Disease then assessed per local practice until 2nd progression. Assessed up to a maximum of approximately 3 years. ]
  The PFS2 was defined as the time from the date of randomization to the earliest of the progression event subsequent to that used for the PFS endpoint or death and determined by local standard clinical practice and have included any of the following: objective radiological, symptomatic progression, or death. PFS2 was reported for sub-study B only.

Original Secondary Outcome Measures (submitted: January 28, 2015)

• Proportion of patients alive at 12 months from randomization (OS12) [ Time Frame: up to 1 year after last patient randomized ]
• Objective Response Rate (ORR) [ Time Frame: up to 3 years after the first patient randomized ]
• Duration of Response (DoR) [ Time Frame: up to 3 years after the first patient randomized ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Global Study to Assess the Effects of MEDI4736 (Durvalumab), Given as Monotherapy or in Combination With Tremelimumab Determined by PD-L1 Expression Versus Standard of Care in Patients With Locally Advanced or Metastatic Non Small Cell Lung Cancer
• Official Title: A Phase III, Open Label, Randomised, Multi-centre, International Study of MEDI4736, Given as Monotherapy or in Combination With Tremelimumab Determined by PD-L1 Expression Versus Standard of Care in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer (Stage IIIB-IV) Who Have Received at Least Two Prior Systemic Treatment Regimens Including One Platinum Based Chemotherapy Regimen and Do Not Have Known EGFR TK Activating Mutations or ALK Rearrangements (ARCTIC).
• Brief Summary: This study is a Phase III, randomised, open label, multi-centre study assessing the efficacy and safety of MEDI4736 (durvalumab) versus Standard of Care in NSCLC patients with PD-L1 positive tumours and the combination of MEDI4736 (durvalumab) plus tremelimumab (MEDI4736+treme) versus Standard of Care in NSCLC patients with PD-L1-negative tumours in the treatment of male and female patients with locally advanced or metastatic NSCLC (Stage IIIB-IV), who have received at least 2 prior systemic treatment regimens including 1 platinum-based chemotherapy regimen for NSCLC. Patients with known EGFR (Epidermal growth factor receptor) tyrosine kinase (TK) activating mutations and anaplastic lymphoma kinase (ALK) rearrangements are not eligible for the study (prospective testing is not planned within this study). The Standard of Care options are: an EGFR tyrosine kinase inhibitor (erlotinib [TARCEVA®]), gemcitabine or vinorelbine (NAVELBINE®)
• Detailed Description: The study has an umbrella design with 2 sub-studies: sub-study A (randomizing patients with PD-L1 positive tumours 1:1 into MEDI4736 (durvalumab) vs. Standard of Care) and sub-study B (randomizing patients with PD-L1 negative tumours 2:3:1:2 into MEDI4736 (durvalumab) vs. MEDI4736 (durvalumab) plus tremelimumab vs. tremelimumab vs. Standard of Care. The two substudies may have different durations of recruitment periods due to differences in patient population (PD-L1 expression). They may not run concurrently with start and completion of recruitment potentially occurring at different time points.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non - Small Cell Lung Cancer NSCLC

Intervention

• Drug: MEDI4736 (durvalumab)
  MEDI4736 (durvalumab) treatment by intravenous infusion
• Drug: Vinorelbine
  Vinorelbine by intravenous infusion. Administered at a dose of 30 mg/m2 iv on Days 1, 8, 15 and 22 of a 28-day cycle.
• Drug: Gemcitabine
  Gemcitabine by intravenous infusion. Administered at a dose of 1000 mg/m2 iv over 30 minutes on Days 1, 8, and 15 of a 28-day cycle.
• Drug: Erlotinib
  Erlotinib administered at a dose of 150 mg once daily as a tablet for oral administration
• Drug: MEDI4736 (durvalumab) in combination with tremelimumab (anti-CTLA4)
  MEDI4736 (durvalumab) in combination with tremelimumab (anti-CTLA4) treatment by intravenous infusion
• Drug: tremelimumab (anti-CTLA4)
  tremelimumab (anti-CTLA4) treatment by intravenous infusion

Study Arms

• Experimental: MEDI4736 (durvalumab) monotherapy in Sub-study A
  MEDI4736 (durvalumab) by intravenous infusion. Sub-study A for patients with PD-L1 positive tumors.
  Intervention: Drug: MEDI4736 (durvalumab)
• Active Comparator: Standard of Care in Sub-study A
  Investigator choice from Vinorelbine, Gemcitabine and Erlotinib. Sub-study A for patients with PD-L1 positive tumors.
  Interventions:

  • Drug: Vinorelbine
  • Drug: Gemcitabine
  • Drug: Erlotinib
• Experimental: MEDI4736 (durvalumab) + tremelimumab in Sub-study B
  MEDI4736 (durvalumab) by intravenous infusion and tremelimumab by intravenous infusion. Sub-study B for patients with PD-L1 negative tumors.
  Intervention: Drug: MEDI4736 (durvalumab) in combination with tremelimumab (anti-CTLA4)
• Active Comparator: Standard of Care in Sub-study B
  Investigator choice from Vinorelbine, Gemcitabine and Erlotinib. Sub-study B for patients with PD-L1 negative tumors.
  Interventions:

  • Drug: Vinorelbine
  • Drug: Gemcitabine
  • Drug: Erlotinib
• Experimental: MEDI4736 (durvalumab) monotherapy in Sub-study B
  MEDI4736 (durvalumab) by intravenous infusion. Sub-study B for patients with PD-L1 negative tumors.
  Intervention: Drug: MEDI4736 (durvalumab)
• Experimental: tremelimumab in Sub-study B
  tremelimumab by intravenous infusion. Sub-study B for patients with PD-L1 negative tumors.
  Intervention: Drug: tremelimumab (anti-CTLA4)

Publications *

• Martin ML, Correll J, Walding A, Ryden A. How patients being treated for non-small cell lung cancer value treatment benefit despite side effects. Qual Life Res. 2022 Jan;31(1):135-146. doi: 10.1007/s11136-021-02882-6. Epub 2021 May 31.
• Planchard D, Reinmuth N, Orlov S, Fischer JR, Sugawara S, Mandziuk S, Marquez-Medina D, Novello S, Takeda Y, Soo R, Park K, McCleod M, Geater SL, Powell M, May R, Scheuring U, Stockman P, Kowalski D. ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer. Ann Oncol. 2020 May;31(5):609-618. doi: 10.1016/j.annonc.2020.02.006. Epub 2020 Feb 20.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 1, 2017): 597
• Original Estimated Enrollment (submitted: January 28, 2015): 900
• Actual Study Completion Date: August 30, 2023
• Actual Primary Completion Date: February 9, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Aged at least 18 years
• Documented evidence of NSCLC (Stage IIIB/ IV disease)
• Disease progression or recurrence after both a platinum-based chemotherapy regimen and at least 1 additional regimen for treatment of NSCLC
• World Health Organization (WHO) Performance Status of 0 or 1
• Estimated life expectancy more than 12 weeks

Exclusion Criteria:

• Prior exposure to any anti-PD-1 or anti-PD-L1 antibody or anti-CTLA4
• Brain metastases or spinal cord compression unless asymptomatic, treated and stable (not requiring steroids)
• Active or prior documented autoimmune disease within the past 2 years
• Evidence of severe or uncontrolled systemic disease, including active bleeding diatheses or active infections including hepatitis B, C and HIV
• Any unresolved toxicity CTCAE (Common Terminology Criteria of Adverse Events) >Grade 2 from previous anti-cancer therapy
• Known EGFR TK activating mutations or ALK rearrangements
• Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1
• Active or prior documented inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Bulgaria, Canada, Chile, Czechia, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Japan, Korea, Republic of, Netherlands, Poland, Romania, Russian Federation, Serbia, Singapore, Spain, Taiwan, Thailand, United Kingdom, United States
• Removed Location Countries: Argentina, Czech Republic, Philippines, South Africa, Turkey

Administrative Information

• NCT Number: NCT02352948
• Other Study ID Numbers: D4191C00004; 2014-000338-46 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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 request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• 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
• 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
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Paul Stockman, MBChB, PhD; AstraZeneca

• PRS Account: AstraZeneca
• Verification Date: September 2023