Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Sub-study A (PD-L1-positive population) To assess the efficacy of MEDI4736 monotherapy compared with Standard of Care in terms of OS and PFS Sub-study B (PD-L1-negative population) To assess the efficacy of MEDI4736+tremelimumab treatment compared with Standard of Care in terms of OS and PFS To further assess the efficacy in terms of: OS12, ORR, DoR, APF6, APF12 and PFS2 To assess the safety and tolerability profile To assess the PK of MEDI4736 and tremelimumab To investigate the immunogenicity of MEDI4736 and tremelimumab To assess symptoms and health-related QoL using EORTC QLQ-C30 v3 and LC13

MEDI4736; Tremelimumab

MEDI4736; Tremelimumab

concentrate for solution for infusion
concentrate for solution for infusion

50 mg/mL, 500 mg/vial
20 mg/mL, 400 mg/vial

OSa
PFS using investigator assessments according to
RECIST 1.1a,b
OS12
ORR using investigator assessments according to
RECIST 1.1a
DoR using investigator assessments according to
RECIST 1.1a
APF6 and APF12 using investigator assessments
according to RECIST 1.1a
PFS2 as defined by local standard clinical practice

OS12
ORR using investigator assessments according to
RECIST 1.1a
DoR using investigator assessments according to
RECIST 1.1a
APF6 and APF12 using investigator assessments
according to RECIST 1.1a
PFS2 as defined by local standard clinical practice
Adverse events, physical examinations, vital signs
including blood pressure, pulse, electrocardiograms,
and laboratory findings including clinical chemistry,
haematology and urinalysis
Concentration of PK in blood and non-compartmental
PK parameters (such as peak concentration and trough,
as data allow) (sparse sampling)
ADA (confirmatory results: positive or negative; titres
[ADA neutralising antibodies will also be assessed])
EORTC QLQ-C30: Time to symptom deterioration
(fatigue, pain, nausea/vomiting, dyspnoea, loss of
appetite, insomnia, constipation, and diarrhoea). Time
to QoL/function deterioration (physical function, role
function, emotional function, cognitive function, social
function and global health status/QoL)
LC13: Time to symptom deterioration (dyspnoea,
cough, haemoptysis, chest pain, arm/shoulder pain,
other pain)
Changes in World Health Organisation Performance
Status will also be assessed

1.Provision of signed, written and dated informed consent prior to any study specific procedures
2.Male or female aged 18 years or older
3.Patients must have EITHER
•Histologically- or cytologically-documented NSCLC who present with Stage IIIB/ Stage IV disease (according to Version 7 of the IASLC Staging Manual in Thoracic Oncology [IASLC Staging Manual in Thoracic Oncology]), OR
•Recurrent or progressive disease following multimodal therapy (radiation therapy, surgical resection, or definitive chemoradiation therapy for locally advanced disease)
4.Patients must have received at least 2 prior systemic treatment regimens for NSCLC
5.Patients must have experienced disease progression or recurrence after both a platinum-based chemotherapy regimen and at least 1 additional systemic therapy
•Maintenance therapy following platinum doublet-based chemotherapy is not considered a separate regimen of therapy
•Prior platinum-containing adjuvant, neoadjuvant or definitive chemoradiation therapy given for locally advanced disease is considered first-line therapy only if recurrent (local or metastatic) disease developed within 6 months of completing therapy. Patients with recurrent disease >6 months must have received a subsequent platinum-based therapy regimen, which counts as their first –line of therapy.

6. Patient’s tumour sample must be assessed as PD-L1-positive (where positive is defined as ≥25% of tumour cells with membrane staining [proprietary PD-L1 immunohistochemistry assay; Ventana Medical Systems, Inc]) (for Sub-study A) or PD-L1-negative (ie, those with <25% of tumour cells with membrane staining) (for Sub-study B) (either recent or archival sample) based on central assessment. Sample requirements as follows:
• Patients must be able and willing to give valid written consent to provide newly acquired tumor tissue (preferred) or archival tissue (≤3 years old) for the purpose of establishing PD-L1 status.(for collection and processing procedures, refer to Section 6.7.1 and the Laboratory Manual). Tumour lesions planned for biopsy must not be used as index lesions for assessment of disease, unless there are no other lesions suitable for biopsy. Fine needle aspirate specimens are not acceptable. Specimens from metastatic bone lesions are typically unacceptable unless there is a significant soft tissue component. 
•If the patient’s PD-L1 status has already been assessed using the analytically validated Ventana assay as a part of the screening process for another AstraZeneca/MedImmune study, this test result can be used for the determination of eligibility.
•In addition to the samples used for determining PD-L1 status, patients are required to provide an archived tumour tissue block (or at least 10 newly cut unstained slides) where such samples exist in a quantity sufficient to allow for analysis (refer to Section 6.7.1 and the Laboratory Manual for details).

7.Patients must have measurable disease, at least 1 lesion, not previously irradiated or, which can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes that must have short axis ≥15 mm) with CT or MRI and which is suitable for accurate repeated measurements per RECIST v1.1 guidelines
8.Life expectancy ≥12 weeks at Day 1
9.WHO Performance Status of 0 or 1
10.Evidence of post-menopausal status, or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered postmenopausal if they are amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
•Women <50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution
•Women ≥50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, radiation-induced oophorectomy with last menses >1 year ago, chemotherapy-induced menopause with >1 year interval since last menses, or surgical sterilisation (bilateral oophorectomy or hysterectomy).
11.Adequate organ and marrow function as defined below:
•Absolute neutrophil count >1.5 x 109/L (1500 per mm3)
•Platelets >100 x 109/L (100,000 per mm3)
•Haemoglobin ≥9.0 g/dL (5.59 mmol/L)
•Serum creatinine clearance (CL) >40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.
•Serum bilirubin ≤1.5 x upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinaemia that is predominantly unconjugated in the absence of evidence of haemolysis or hepatic pathology) who will be allowed in consultation with their physician.
•In patients with no liver metastasis: AST and ALT ≤2.5 x ULN
•In patients with liver metastasis: AST or ALT ≤5 x ULN.
•For patients receiving Standard of care, patients should fulfil the relevant requirements in the local prescribing information.

1.Involvement in the planning and/or conduct of the study (applies to both AstraZeneca/MedImmune staff and/or staff at the study site)
2. Either:
•Previous drug assignment in the present study
•Prior treatment in a previous durvalumab (MEDI4736) clinical study
3.Participation in another clinical study with an investigational product during the last 4 weeks
4.Concurrent enrolment in another clinical study, unless it is an observational (non interventional) clinical study or the follow-up period of an interventional study
5.Mixed small cell and non-small cell lung cancer histology
6.Patients with known EGFR TK activating mutations or ALK rearrangements. Patients with EGFR TK inactivating mutations eg, exon 20, are eligible (Yasuda et al 2012). Note: Prospective testing is not planned within this study.
7.Receipt of any investigational drug within 4 weeks prior to the first dose of study drug.
8.Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumour embolisation, mAbs) ≤21 days prior to the first dose of study drug (≤14 days prior to the first dose of study drug for patients who have received prior TKIs [eg, erlotinib, gefitinib and crizotinib] and within 6 weeks for nitrosourea or mitomycin C). If sufficient wash out time has not occurred due to the schedule or PK properties of an agent, a longer wash-out period will be required, as agreed by AstraZeneca/MedImmune and the investigator.
9.Current or prior use of immunosuppressive medication within 28 days before the first dose of study treatment, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
10.Prior exposure to any anti-PD-1 or anti-PD-L1 antibody
11.Any unresolved toxicity CTCAE >Grade 2 from previous anti-cancer therapy. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by study treatment may be included (eg, hearing loss) after consultation with the AstraZeneca/MedImmune medical monitor.
12.Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1
13.Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment. Note: Local treatment of isolated lesions, excluding target lesions, for palliative intent is acceptable (eg, by local surgery or radiotherapy).
14.Receipt of radiation therapy within 4 weeks prior to starting study treatment. Limited field of radiation for palliation within 2 weeks of the first dose of study treatment is allowed:
•Provided the lung is not in the radiation field
•Provided irradiated lesion(s) cannot be used as target lesions.
15.Recent major surgery within 4 weeks prior to entry into the study (excluding the placement of vascular access) that would prevent administration of study treatment
16.Active or prior documented autoimmune disease within the past 2 years. Note: Patients with vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
17.Active or prior documented inflammatory bowel disease (eg, Crohn’s disease, ulcerative colitis)
18.History of primary immunodeficiency
19.History of allogeneic organ transplant
20.History of hypersensitivity to MEDI4736, or the active comparators (erlotinib gemcitabine or vinorelbine), or any excipient of these agents
21.Brain metastases or spinal cord compression unless asymptomatic, treated and stable off steroids and anti-convulsants for at least 1 month prior to entry into the study
22.History of leptomeningeal carcinomatosis
23.Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Bazett’s Correction
24.Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any patient known to have acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent
25.Active infection of tuberculosis, as determined by clinical signs and symptoms
26.Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving study treatment
27.History of another primary malignancy within 5 years prior to starting study treatment, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ, and the disease under study, except for:
•Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study drug 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
28.Female patients who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control
29.Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
30.Absence of a tumour sample (archival and recent).
Additional exclusion criteria for Sub-study B
31.Receipt of any prior mAb against CTLA-4.
32.History of chronic inflammatory or autoimmune disease (eg, Addison’s disease,multiple sclerosis, Grave’s disease, Hashimoto’s thyroiditis, rheumatoid arthritis,hypophysitis, uveitis) with symptomatic disease within the last 3 years prior to enrollment. Note: Active vitiligo or alopecia or a history of vitiligo will not be a basis for exclusion.
33.Active or history of diverticulitis. Note: Diverticulosis is permitted.Active or history of inflammatory bowel disease (eg, colitis, Crohn’s disease), irritable bowel disease, celiac disease, or other serious GI chronic conditionsassociated with diarrhoea. Active or history of systemic lupus erythematosus or Wegener’s granulomatosis.
34.History of sarcoidosis syndrome.
35.History of hypersensitivity to compounds of similar biologic composition to tremelimumab or any constituent of the product