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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)

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ClinicalTrials.gov Identifier: NCT02352948
Recruitment Status : Active, not recruiting
First Posted : February 2, 2015
Results First Posted : April 16, 2019
Last Update Posted : April 16, 2019
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

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®).

Condition or disease Intervention/treatment Phase
Non - Small Cell Lung Cancer NSCLC Drug: MEDI4736 (durvalumab) Drug: Vinorelbine Drug: Gemcitabine Drug: Erlotinib Drug: MEDI4736 (durvalumab) in combination with tremelimumab (anti-CTLA4) Drug: tremelimumab (anti-CTLA4) Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 597 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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).
Actual Study Start Date : January 13, 2015
Actual Primary Completion Date : February 9, 2018
Estimated Study Completion Date : June 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: MEDI4736 (durvalumab) monotherapy in Sub-study A
MEDI4736 (durvalumab) by intravenous infusion. Sub-study A for patients with PD-L1 positive tumors.
Drug: MEDI4736 (durvalumab)
MEDI4736 (durvalumab) treatment by intravenous infusion

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.
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

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.
Drug: MEDI4736 (durvalumab) in combination with tremelimumab (anti-CTLA4)
MEDI4736 (durvalumab) in combination with tremelimumab (anti-CTLA4) treatment by intravenous infusion

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.
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

Experimental: MEDI4736 (durvalumab) monotherapy in Sub-study B
MEDI4736 (durvalumab) by intravenous infusion. Sub-study B for patients with PD-L1 negative tumors.
Drug: MEDI4736 (durvalumab)
MEDI4736 (durvalumab) treatment by intravenous infusion

Experimental: tremelimumab in Sub-study B
tremelimumab by intravenous infusion. Sub-study B for patients with PD-L1 negative tumors.
Drug: tremelimumab (anti-CTLA4)
tremelimumab (anti-CTLA4) treatment by intravenous infusion




Primary Outcome Measures :
  1. 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.

  2. 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


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. 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

  6. 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

  7. 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

  8. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02352948


  Show 203 Study Locations
Sponsors and Collaborators
AstraZeneca
Investigators
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Study Director: Paul Stockman, MBChB, PhD AstraZeneca
  Study Documents (Full-Text)

Documents provided by AstraZeneca:
Statistical Analysis Plan  [PDF] January 24, 2018
Study Protocol  [PDF] January 8, 2018


Additional Information:
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02352948     History of Changes
Other Study ID Numbers: D4191C00004
First Posted: February 2, 2015    Key Record Dates
Results First Posted: April 16, 2019
Last Update Posted: April 16, 2019
Last Verified: March 2019

Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Small Cell Lung Carcinoma
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Gemcitabine
Erlotinib Hydrochloride
Durvalumab
Vinorelbine
Tremelimumab
Antibodies, Monoclonal
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors
Antineoplastic Agents, Immunological
Antineoplastic Agents, Phytogenic