A Phase IB, Open-Label, Multi-Center Study to Determine the Efficacy and Safety of Durvalumab in Combination With Novel Oncology Therapies, With or Without Chemotherapy, for First-Line Stage IV Non-Small Cell Lung Cancer (NSCLC) (MAGELLAN)

1) Age >=18 years at the time of screening.
2) Written informed consent.
3)Histologically or cytologically documented Stage IV NSCLC not amenable to
curative surgery or radiation.
4)Tumours that lack activating EGFR mutations and ALK fusions.  If a patient
has squamous histology or is known to have a tumor with a KRAS mutation, then
EGFR and ALK testing is not required.
5) WHO/ECOG performance status of 0 or 1 at enrolment and treatment assignment.
6) No prior chemotherapy or any other systemic therapy for metastatic NSCLC.
Prior platinum-containing adjuvant, neoadjuvant, or definitive chemoradiation
for non-metastatic disease is allowed, provided that progression has occurred
>12 months from end of last therapy.
7) No prior exposure to immune-mediated therapy (anti-CTLA-4, anti-PD-1,
anti-PD-L1, and anti-PD-L2 antibodies)
8) At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1
target lesion at Baseline.
9) Known tumor PD-L1 status, confirmed by a central reference laboratory using
a validated Ventana SP263 PD-L1 IHC assay (fresh biopsy or sample taken <=3
years prior to enrollment). 
10)Adequate organ and marrow function as defined below:
- Hemoglobin >=9 g/dL
- Absolute neutrophil count >=1.5 × 109/L
- Platelet count >=100 × 109/L
- Serum bilirubin <=1.5 × the ULN, unless due to Gilbert*s syndrome, who will be
allowed in consultation with their physician and AZ.
- ALT and AST <=2.5 × ULN; for patients with hepatic metastases, ALT, and AST <=5
× ULN
- Creatinine Clearance >=60 mL/min calculated by Cockcroft-Gault equation (using
actual body weight) or by measured 24-hour urine collection
Males:
Creatinine clearance (mL/min) = Weight (kg) × (140 - Age)
72 × Serum creatinine (mg/dL)
Females:
Creatinine clearance (mL/min) = Weight (kg) × (140 - Age) × 0.85
72 × Serum creatinine (mg/dL)
- Albumin >=3 g/dL
11) Life expectancy of at least 12 weeks.
12) Body weight >35kg.
13) Postmenopausal or negative pregnancy test

1) History of allogeneic organ transplantation
2) Active or prior documented autoimmune or inflammatory disorders, including
inflammatory bowel disease, diverticulitis, systemic lupus erythematosus,
Sarcoidosis syndrome, or
Wegener syndrome, Graves* disease, rheumatoid arthritis, hypophysitis, uveitis,
etc).
3) Uncontrolled intercurrent illness, including but not limited to, ongoing or
active infection,
symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, uncontrolled cardiac arrhythmia, active ILD, serious chronic
gastrointestinal conditions associated with diarrhea, or psychiatric
illness/social situations that would limit compliance with study requirement,
substantially increase risk of incurring AEs or compromise the ability of the
patient to give written informed consent
4) Prior history of myocardial infarction, stroke, or transient ischemic attack
in the past 6 months
5) History of venous thromboembolism within the past 3 months
6) History of another primary malignancy except for
- Malignancy treated with curative intent and with no known active disease >=5
years before the first dose of study treatment 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
7) History of leptomeningeal carcinomatosis
8) History of active primary immunodeficiency
9) Active infection including tuberculosis, hepatitis B, hepatitis C, or human
immunodeficiency virus (positive HIV 1/2 antibodies).
10) Untreated CNS metastases identified either on the baseline brain imaging
obtained during the
screening period or identified prior to signing the ICF.
11) Known allergy or hypersensitivity to any of the study treatments or any of
the study treatment excipients
12) Mean QT interval corrected for heart rate using Fridericia*s formula (QTcF)
>=470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart).
13) Any clinically important abnormalities in rhythm, conduction, or morphology
of resting ECG (eg, complete left bundle branch block, third-degree heart
block).
14) Any factors that increase the risk of QTc prolongation or risk of
arrhythmic events, such as heart failure, hypokalemia, potential for torsades
de pointes, congenital long QT syndrome, family history of long QT syndrome or
unexplained sudden death under 40 years of age, or any concomitant medication
known to prolong the QT interval.
15) Any prior chemotherapy or any other systemic therapy for Stage IV NSCLC
16) Any concurrent chemotherapy, study treatment, biologic, or hormonal therapy
for cancer
treatment. Concurrent use of hormonal therapy for non-cancer-related conditions
(eg, hormone replacement therapy) is acceptable.
17) Radiation therapy, unless it is (1) definitive radiation that had been
administered at least
12 months prior to the date of progression to Stage IV disease (see also
inclusion
criterion 8), (2) palliative radiation to brain, with associated criteria for
stability or lack of
symptoms, at least 4 weeks prior to the first study treatment dose (see also
exclusion
criterion 10), or (3) palliative radiation to painful bony lesions (this must
comprise less
than 30% of the bone marrow) at least 4 weeks prior to the first study
treatment dose.
18) Receipt of live attenuated vaccine within 30 days prior to the first dose
of study treatment.
19) Major surgical procedure (as defined by the Investigator) within 28 days
prior to the first
dose or still recovering from prior surgery. Local procedures (eg, placement of
a
systemic port, core needle biopsy, and prostate biopsy) are allowed if
completed at least
24 hours prior to the administration of the first dose of study treatment.
20) Current or prior use of immunosuppressive medication within 28 days before
the first
dose of durvalumab.
21) Participation in another clinical study with a study treatment administered
in the last 12 months
22) Previous study treatment assignment in the present study
23) Concurrent enrollment in another clinical study, unless it is an
observational (non-interventional) clinical study or during the follow-up
period of an interventional study
24) Prior randomization or treatment in a previous durvalumab clinical study
regardless of
treatment arm assignment
25) Mixed SCLC and NSCLC histology, sarcomatoid variant
26) Female patients who are pregnant or breastfeeding or male or female
patients of reproductive potential who are not willing to employ effective
birth control from screening to 180 days after the last dose of durvalumab +
novel oncology therapy ± chemotherapy or 90 days after the last dose of
durvalumab monotherapy, whichever is later.
27) Judgment by the Investigator that the patient should not participate in the
study if the patient is unlikely to comply with study procedures, restrictions,
and requirements
28) Medical contraindication to platinum-based doublet chemotherapy if tumor is
PD-L1 low
29) Exclusion criteria for participation in the optional (DNA) genetics
research component of
the study include:
- Previous allogeneic bone marrow transplant
- Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample
collection