A Multicenter, Double Blind, Randomized, Controlled Study of M7824 with Concurrent Chemoradiation Followed by M7824 versus Concurrent Chemoradiation Plus Placebo Followed by Durvalumab in Participants with Unresectable Stage III Non-small Cell Lung Cancer

Participants are eligible to be included in the study only if all the following
criteria apply:
Age
1. Are * 18 years of age at the time of signing the informed consent. In Japan,
if a patient is < 20 years, the written informed consent from his/her parent or
guardian will be required in addition to the patient*s written consent., Type
of Participant and Disease Characteristics
2. Participants must have measurable or non-measurable but evaluable disease
assessed by the Investigator. Participants must have histologically documented
NSCLC who present with Stage III locally advanced, unresectable disease
(International Association for the Study of Lung Cancer Staging Manual in
Thoracic Oncology [IASLC Staging Manual in Thoracic Oncology], v8).
3. Availability of tumor material (< 6 months old) adequate for biomarker
analysis is
Mandatory for all participants and central laboratory confirmation is required.
For participants enrolled in the safety run-in, PD-L1 expression will be tested
retrospectively by a central laboratory. For participants enrolled in the
expansion part of the study, PD-L1 expression must be tested by the central
laboratory and results available before randomization. Only results from the
central laboratory testing will be used for randomization and if PD-L1 status
is non-evaluable, the participant is not eligible for this study. Tumor samples
obtained by endoscopic biopsies, core needle biopsies, excisional biopsies,
punch biopsies, and surgical specimen that are < 6 months old and adequate for
biomarker analysis are acceptable. Biopsies obtained by fine needle aspiration
are not acceptable., 4. Participants with tumor harboring an EGFR sensitizing
(activating) mutation, ALK
translocation, ROS-1 rearrangement are eligible. These tests are not required
for enrollment in the study.
5. Participants with ongoing post-obstructive pneumonia due to the tumor are
eligible.
6. If a pleural effusion is present, the following criteria must be met to
exclude malignant
involvement (incurable T4 disease):
a. When pleural fluid is visible on both the CT scan and on a chest x-ray, a
thoracentesis is required to confirm that the pleural fluid is cytologically
negative.
b. Participants with exudative pleural effusions are excluded, regardless of
cytology.
c. Participants with effusions that are minimal, i.e., are too small to safely
tap are eligible.
7. Participants must be at least 3 weeks from prior thoracotomy (if performed).
8. Participants must have adequate pulmonary function defined as a forced
expiratory volume in 1 second (FEV1) * 1.2 liters or * 50% of predicted normal
volume measured within 3 weeks prior to randomization. If participants do not
meet the above criteria, treatment with inhaled steroids and bronchodilators
can be initiated if clinically indicated and eligibility can be reassessed
after 1-2 weeks.
9. ECOG performance status of 0 to 1 at Screening and on the day of first dose.
10. Life expectancy *12 weeks.
11. Have adequate organ function as indicated by the following laboratory values
a. Adequate hematological function defined by absolute neutrophil count (ANC) *
1.5
× 109/L, platelet count * 100 × 109/L, and hemoglobin * 9 g/dL.
b. Adequate hepatic function defined by a total bilirubin level * 1.5 × upper
limit of normal (ULN), an aspartate aminotransferase (AST) level * 3.0 × ULN,
an alanine
aminotransferase (ALT) level * 3.0 × ULN and alkaline phosphatase * 2.5 ULN.
c. Adequate renal function defined by creatine * 1.5x ULN or calculated
creatinine
clearance (CrCl) * 50 mL/min for participant with Cr > 1.5x ULN (GFR can also be
used). Note: CrCl should be calculated per institutional standard. If no local
guideline is
available, CrCl should be calculated using the Cockcroft-Gault Method:
CrCl <= ((140-age) * weight (kg) * (0.85 for females only)) / (72 * creatinine)
d. Adequate coagulation function defined as international normalized ratio
(INR) or
prothrombin time (PT) *1.5 X ULN unless the participant is receiving
anticoagulant
therapy and activated partial thromboplastin time (aPTT) *1.5 X ULN unless the
participant is receiving anticoagulant therapy.
Sex
12. Contraceptive use by males or females will be consistent with local
regulations on
contraception methods for those participating in clinical studies.
a. Male Participants:
Contraceptive measures should be continued as per guidance specified in labeling
document for approved chemotherapies. If not specified, continue measures
similar to
investigational agent i.e agree to the following during the study intervention
period and
for at least 6 months after the last dose of study intervention
- Refrain from donating sperm.
PLUS, either:
- Abstain from intercourse with a WOCBP.
OR
- Use a male condom: When having sexual intercourse with a WOCBP, who is not
currently pregnant, and advise her to use a highly effective contraceptive
method
with a failure rate of <1% per year, as described in Appendix 3, since a condom
may break or leak.
b. Female Participants:
- Are not pregnant or breastfeeding, and at least one of the following
conditions
applies:
- Not a WOCBP.
OR
- If a WOCBP, use a highly effective contraceptive method (i.e., with a failure
rate of <1% per year), preferably with low user dependency, as described in
Appendix 3 of the protocol for the following time periods:
- Before the first dose of the study intervention(s), if using hormonal
contraception:
- Has completed at least one 4-week cycle of an oral contraception pill and
either had or has begun her menses
OR
- Has used a depot contraceptive or extended-cycle oral contraceptive for least
28 days and has a documented negative pregnancy test using a highly sensitive
assay.
- During the intervention period.
- Contraceptive measures should be continued as per guidance specified in
labeling document for approved chemotherapies. If not specified, continue
measures similar to investigational agent i.e., after the study intervention
period (i.e., after the last dose of study intervention is administered) for at
least 4 months after the last dose of study
intervention and agree not to donate eggs (ova, oocytes) for reproduction
during this period.
- Have a negative pregnancy test, as required by local regulations, on W1D1
before the first dose of study intervention.
- Additional requirements for pregnancy testing during and after study
intervention
are in SoA.
- The Investigator reviews the medical history, menstrual history, and recent
sexual
activity to decrease the risk for inclusion of a female with an early
undetected pregnancy.
Informed Consent
13. Can give signed informed consent, as indicated in Appendix 2 of the
protocol, which includes compliance with the requirements and restrictions
listed in the informed consent form (ICF) and this protocol.

Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Mixed small cell with non-small cell lung cancer histology.
2. Greater than minimal, exudative, or cytologically positive pleural effusions.
3. Recent major surgery within 4 weeks prior to entry into the study (excluding
the placement
of vascular access) that would prevent administration of study drug.
4. Active or prior documented inflammatory bowel disease (e.g., Crohn*s
disease, ulcerative colitis).
5. History of organ transplant that requires therapeutic immunosuppression.
6. Significant acute or chronic infections including, among others:
a. Known history of positive test for human immunodeficiency virus (HIV) or
known
acquired immunodeficiency syndrome (testing at Screening is not required). If an
Investigator has a strong suspicion of HIV infection without known history for a
participant in Screening, however participant refuses testing, discuss with
Medical
Monitor to assess eligibility. (Note: HIV testing is not mandated for study
inclusion;
however, if it is performed at any point in Screening or while on study, a site
must
consent the participant for HIV testing as per local standard guidance.)
b. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (HBV
surface
antigen positive and HBV core antibody positive with reflex to positive HBV
DNA, or
HBV core antibody positive alone with reflex to positive HBV DNA, or positive
HCV
antibody with reflex to positive HCV RNA) at Baseline. Discuss with the Medical
Monitor if history of HBV or HCV infection is known. If medically indicated,
participants infected with HBV must be treated and on a stable dose of
antivirals (e.g,
entecavir, tenofovir, or lamivudine; adefovir or interferon are not allowed) at
study entry
and with planned monitoring and management according to appropriate labeling
guidance. Participants on active HCV therapy at study entry must be on a stable
dose
without documented clinically significant impaired liver function test or
hematologic
abnormalities (must meet criteria above) and with planned monitoring and
management
according to appropriate labeling guidance. HBV and/or HCV viral titers must be
monitored according to SoA in these participants.
c. Participants with active tuberculosis (history of exposure or history of
positive
tuberculosis test; plus presence of clinical symptoms, physical, or
radiographic findings).
7. Uncontrolled intercurrent illness including, but not limited to, symptomatic
congestive
heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac
arrhythmia,
active peptic ulcer disease or gastritis, active bleeding diatheses, or
psychiatric illness/social situations that would limit compliance with study
requirements or
compromise the ability of the patient to give written informed consent.
Participants with history of bleeding diathesis or recent major bleeding events
considered by the Investigator as high risk for investigational drug treatment
are also excluded.
8. Chronic Obstructive Pulmonary Disease exacerbation or other respiratory
illness requiring hospitalization or precluding study therapy within 30 days
before randomization.
9. Known clinical history of tuberculosis, lung sarcoidosis and Interstitial
Lung Diseases.
10. History of another primary malignancy within 3 years prior to starting
study drug, except for adequately treated basal or squamous cell carcinoma of
the skin, adequately treated carcinoma in situ, e.g., cancer of the cervix in
situ, or superficial bladder cancer. History of other localized malignancies
treated with curative intent needs to be discussed with the Medical Monitor.
11. Uncontrolled neuropathy Grade 2 or greater regardless of cause.
12. Significant hearing loss and participants unwilling to accept potential for
further hearing loss (Investigator should consider treating the participant
with carboplatin/paclitaxel)., Prior/Concomitant Therapy
13. Any prior systemic cytotoxic chemotherapy for their NSCLC or any antibody
or drug
targeting T-cell coregulatory proteins (immune checkpoints) such as
anti-PD-(L)1, or anti-CTLA-4 antibody.
14. Current or prior use of immunosuppressive medication within 28 days before
the first dose of study drug, 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.
Systemic steroid administration required to manage toxicities arising from
radiation therapy delivered as part of the cCRT for locally advanced NSCLC is
allowed.
15. Active autoimmune disease that has required systemic treatment in past 1
year (i.e., with use of disease-modifying agents, corticosteroids, or
immunosuppressive drugs), OR is receiving systemic steroid therapy < 3 days
prior to the first dose of study intervention or receiving any other form of
immunosuppressive medication. Participants requiring
hormone replacement with corticosteroids are eligible if the steroids are
administered only for the purpose of hormonal replacement and at low doses
(typically * 10 mg of prednisone or equivalent per day). Equivalent
hydrocortisone doses are also permitted if administered as a replacement
therapy. Corticosteroid use on study as a premedication for IV contrast
allergies/reactions (related to scans) is allowed and must be documented. This
must be discussed with Medical Monitors for clinical indications in which
articipants may require a higher dose. Active autoimmune disease that might
deteriorate when receiving an immunostimulatory agent. Participants with
diabetes Type I, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease
not requiring immunosuppressive treatment are eligible.
Consult Medical Monitor for other autoimmune diseases.
16. Receipt of live attenuated vaccination within 30 days of receiving study
drug.
17. Use of a prohibited concomitant drug, as defined in Section 6.5.2 of the
protocol within 4 weeks
randomization.
18. Known severe hypersensitivity (Grade * 3 National Cancer Institute [NCI]
Common
Terminology Criteria for Adverse Events [CTCAE] v5.0) to study interventions or
any
components in their formulations, or uncontrolled asthma (i.e., 3 or more
features of
partially controlled asthma).
Prior/Concurrent Clinical Study Experience
19. Participation in another clinical study with an investigational product
within the last
4 weeks.
20. Concurrent enrolment in another clinical study, unless it is an
observational
(non-interventional) clinical study or the follow-up period of an
interventional study.
Diagnostic Assessments
21. *10% weight loss within the past month.
22. 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.
Other Exclusions
23. Any condition that, in the opinion of the Investigator, would interfere
with evaluation of the study drug or interpretation of participant safety or
study results.