Nintedanib Compared With Placebo in Treating Against Radiation-Induced Pneumonitis in Patients With Non-small Cell Lung Cancer That Cannot Be Removed by Surgery and Are Undergoing Chemoradiation Therapy

PRIMARY OBJECTIVES:

I. To compare the rate of symptomatic radiation pneumonitis at 6 months after completion of
chemoradiation in patients with unresectable Stage II/III/ oligometastatic IV non-small cell
lung carcinoma (NSCLC) who completed chemoradiation followed by nintedanib versus placebo.

SECONDARY OBJECTIVES:

I. To compare the quality of life (QOL) in patients who received nintedanib versus placebo
during active treatment until 6 months after completion of treatment.

II. To compare the progression-free survival, overall survival and 1-year progression-free
survival rate in patients who received nintedanib versus placebo.

III. To compare pulmonary function test (PFT) results and radiation pneumonitis (RP) score in
patients who received nintedanib versus placebo.

IV. To compare the composite index (based on PFT, RP score and QOL) at the end of active
treatment and 6 months after completion of treatment between patients who received nintedanib
versus placebo.

V. To investigate blood-based biomarkers in evaluating risk of developing radiation
pneumonitis as well as the efficacy of nintedanib.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Beginning 4-6 weeks after completion of radiation therapy, patients receive nintedanib
orally (PO) twice daily (BID) on days 1-30. Treatment repeats every 30 days for up to 6
courses in the absence of disease progression or unacceptable toxicity.

ARM II: Beginning 4-6 weeks after completion of radiation therapy, patients receive placebo
capsules PO BID on days 1-30. Treatment repeats every 30 days for up to 6 courses in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, between 76-97 days,
between 166-187 days, and then between 2-2.5 years.

Inclusion Criteria:

- Histologically or cytologically-proven non squamous NSCLC; mixed histology with small
cell lung carcinoma (SCLC) component not allowed

- Patients with stage II - IV non squamous NSCLC who received at least 54 Gy of total
planned thoracic radiation dose will be eligible; patients must have received at least
one cycle of chemotherapy concurrently during the course of thoracic radiation;
regimens allowed are platinum combinations with either etoposide or a taxane
regardless of histology subtype; platinum with pemetrexed for patients with
nonsquamous NSCLC only; patients with oligometastatic stage IV cancer are eligible if
they have received only one line of systemic therapy for their stage IV cancer prior
to the concurrent chemoradiation phase

- Patient must have had a CR/PR/SD, 4-6 weeks after completing last fraction of
radiation therapy.

- Eastern Cooperative Oncology Group (ECOG) performance score 0-2 at the time of
randomization

- Absolute neutrophil count (ANC) >= 1,500/uL

- Platelet count >= 100,000/uL

- Hemoglobin >= 9 g/dL

- Total bilirubin =< 1.5 times upper limit of normal (ULN) OR direct bilirubin normal
(per institute standards)

- Aspartate aminotransferase (AST) =< 1.5 x ULN; alanine aminotransferase (ALT) and AST
=< 3 x ULN is acceptable if there is liver metastasis

- Fertile patients must use adequate contraception

Exclusion Criteria:

- Whole-brain radiotherapy (WBRT) < 14 days from the anticipated start of
nintedanib/placebo administration

- Squamous cell NSCLC

- Unable to start nintedanib/placebo treatment between 4 - 6 weeks after completing the
last dose of thoracic radiation

- Active untreated brain or leptomeningeal metastases; in patients with treated central
nervous system (CNS) metastases, eligible if symptoms controlled for at least 4 weeks;
dexamethasone allowed if total daily dose does not exceed 2 mg

- Major injuries or surgery (e.g., craniotomy) < 28 days from the start of
nintedanib/placebo administration; wound should be healed prior to starting therapy

- Second malignancies are allowed as long as the disease does not require active
treatment with concomitant systemic cytotoxic chemotherapy, investigational or
biologic therapy (e.g., anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA4] or
human epidermal growth factor receptor 2 [HER2] monoclonal antibodies);
hormone-related therapies (e.g., gonadotrophin releasing hormone (LHRH) agonists,
tamoxifen, etc.) are allowed

- Concurrent uncontrolled illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situation that would increase the risk
associated with study participation and/or limit compliance with study requirements

- Inability to swallow study medication

- Presence of active malabsorption disorder (e.g., flare episodes documented within the
preceding 3 months. Presence of symptoms requiring daily medications for control or
history of extensive small bowel resection

- Known bleeding or thrombotic diathesis

- History of arterial or venous thromboembolic event within 12 months prior to study
participation

- Active hemoptysis or history of clinically relevant hemoptysis as determined by the
treating physician; patients who had history of transient minor hemoptysis after
bronchoscopic biopsy are eligible unless deemed otherwise by the treating physician

- Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or higher proteinuria

- Systemic therapy or investigational agent administered < 28 days prior to treatment
with nintedanib

- Known chronic active hepatitis B or hepatitis C; human immunodeficiency virus
(HIV)-positive patients receiving or are candidates for antiretroviral therapy are
also excluded

- Pregnancy or breast feeding; female patients with child-bearing potential must have a
negative pregnancy test (beta-human chorionic gonadotropin [B-HCG] test in urine or
serum) prior to commencing study treatment

- Creatinine > 1.5 x ULN or creatinine clearance levels (CrCL) < 45 mL/min

- Centrally located tumors with radiographic evidence (computed tomography [CT] or
magnetic resonance imaging [MRI]) of local invasion of major blood vessels

- Therapeutic anticoagulation (except low-dose heparin and/or heparin flush as needed
for maintenance of an in-dwelling intravenous devise) or anti-platelet therapy (except
for low-dose therapy with acetylsalicylic acid < 325 mg per day)