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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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).

Conditions
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Non - Small Cell Lung Cancer NSCLC

Intervention / Treatment
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* Drug: MEDI4736 (durvalumab)
* Drug: Vinorelbine
* Drug: Gemcitabine
* Drug: Erlotinib
* Drug: MEDI4736 (durvalumab) in combination with tremelimumab (anti-CTLA4)
* Drug: tremelimumab (anti-CTLA4)


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MEDI4736 (durvalumab) monotherapy in Sub-study A<br>MEDI4736 (durvalumab) by intravenous infusion. Sub-study A for patients with PD-L1 positive tumors. | Drug: MEDI4736 (durvalumab)<br>* MEDI4736 (durvalumab) treatment by intravenous infusion<br>|
| Active Comparator: Standard of Care in Sub-study A<br>Investigator choice from Vinorelbine, Gemcitabine and Erlotinib. Sub-study A for patients with PD-L1 positive tumors. | Drug: Vinorelbine<br>* 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.<br>Drug: Gemcitabine<br>* 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.<br>Drug: Erlotinib<br>* Erlotinib administered at a dose of 150 mg once daily as a tablet for oral administration<br>|
| Experimental: MEDI4736 (durvalumab) + tremelimumab in Sub-study B<br>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)<br>* MEDI4736 (durvalumab) in combination with tremelimumab (anti-CTLA4) treatment by intravenous infusion<br>|
| Active Comparator: Standard of Care in Sub-study B<br>Investigator choice from Vinorelbine, Gemcitabine and Erlotinib. Sub-study B for patients with PD-L1 negative tumors. | Drug: Vinorelbine<br>* 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.<br>Drug: Gemcitabine<br>* 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.<br>Drug: Erlotinib<br>* Erlotinib administered at a dose of 150 mg once daily as a tablet for oral administration<br>|
| Experimental: MEDI4736 (durvalumab) monotherapy in Sub-study B<br>MEDI4736 (durvalumab) by intravenous infusion. Sub-study B for patients with PD-L1 negative tumors. | Drug: MEDI4736 (durvalumab)<br>* MEDI4736 (durvalumab) treatment by intravenous infusion<br>|
| Experimental: tremelimumab in Sub-study B<br>tremelimumab by intravenous infusion. Sub-study B for patients with PD-L1 negative tumors. | Drug: tremelimumab (anti-CTLA4)<br>* tremelimumab (anti-CTLA4) treatment by intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | The OS was defined as the time from the date of randomization until death due to any cause. | From randomization (Day 1) until death due to any cause, approximately 36 months | 
| Progression-Free Survival (PFS) | 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 | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OS, Contribution of the Components Analysis of Sub-study B | The OS was defined as the time from the date of randomization until death due to any cause. | From randomization (Day 1) until death due to any cause, approximately 36 months | 
| Percentage of Participants Alive at 12 Months (OS12) | 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. | From randomization (Day 1) up to 12 months | 
| PFS, Contribution of the Components Analysis of Sub-study B | 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 | 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. | 
| Objective Response Rate (ORR) | 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. | 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. | 
| Duration of Response (DoR) | 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 | 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. | 
| Percentage of Participants Alive and Progression Free at 6 Months (APF6) | 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 | Tumour scans performed at baseline then every  8 weeks up to 6 months | 
| Percentage of Participants Alive and Progression Free at 12 Months (APF12) | 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 | Tumour scans performed at baseline then every  8 weeks up to 12 months. | 
| Time From Randomisation to Second Progression (PFS2) of Sub-study B | 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. | 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. |