Nintedanib in Molecularly Selected Patients With Advanced Non-Small Cell Lung Cancer

Inclusion Criteria:

- Histologically confirmed diagnosis of advanced (metastatic or unresectable) NSCLC with
mutations, rearrangement and fusion involving RET oncogene, or abnormalities
(non-synonymous SNV or amplification) in the nintedanib target genes VEGFR1-3, TP53,
PDGFR-A, PDGFR-B, and FGFR1-3. CLIA certified lab testing for nintedanib target genes
using cell free DNA from peripheral blood and/or assays performed on tumor tissues are
acceptable.

- Patients with EGFR mutations or ALK rearrangements must have disease progression on
appropriate FDA-approved therapy for these genomic aberrations prior to enrollment.

- Disease progression on platinum-doublet chemotherapy prior to enrollment.

- At least one measurable lesion or evaluable disease. Measurable disease is defined as
lesions that can be accurately measured in at least one dimension (longest diameter to
be recorded) as ≥10 mm with CT scan, as ≥20 mm by chest x-ray, or ≥10 mm with calipers
by clinical exam.

- Prior treatment of cancer (chemotherapy, radiation therapy, and surgery) is allowed if
completed at least 3 weeks prior to start of treatment with nintedanib and if all
treatment-related toxicities are resolved.

- At least 18 years of age.

- ECOG performance status 0-1

- Normal bone marrow and organ function as defined below:

- Leukocytes ≥ 3,000/mcL

- Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 100,000/mcL

- Hemoglobin ≥ 9.0 g/dL

- INR < 2.0

- PT and PTT < 50% of deviation from IULN

- Total bilirubin ≤ 1.5 x IULN

- AST(SGOT)/ALT(SGPT) ≤ 1.5 x IULN for patients without liver metastases and ≤ 2.5
x IULN for patients with liver metastases

- Urine protein < 2+

- Creatinine within normal institutional limits OR Creatinine clearance > 45 mL/min
for patients with creatinine levels above institutional normal

- Women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control, abstinence) prior to study entry, for
the duration of study participation, and for 3 months after the end of treatment.
Should a woman become pregnant or suspect she is pregnant while participating in this
study, she must inform her treating physician immediately.

- Able to understand and willing to sign an IRB approved written informed consent
document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

- Prior treatment with VEGFR tyrosine kinase inhibitors.

- A history of other malignancy ≤ 5 years previous with the exception of basal cell or
squamous cell carcinoma of the skin which were treated with local resection only or
carcinoma in situ of the cervix.

- Currently receiving any other investigational agents, or received an investigational
agent within 3 weeks of the first dose of nintedanib.

- Radiotherapy to the target lesion within the past 3 months prior to baseline imaging.

- Symptomatic brain metastases. Patients with known brain metastases are eligible if the
metastases are asymptomatic and previously treated.

- Leptomeningeal disease.

- Radiographic evidence of cavitary or necrotic tumors.

- Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of
major blood vessels.

- A history of allergic reactions attributed to compounds of similar chemical or
biologic composition to nintedanib or other agents used in the study.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure > NYHA II, active coronary artery
disease, unstable angina pectoris, serious cardiac arrhythmia, uncontrolled
hypertension (defined as systolic pressures > 150 mmHg or diastolic pressure > 90
mmHg), pericardial effusion, uncontrolled seizure disorder, or psychiatric
illness/social situations that would limit compliance with study requirements.

- Major injuries and/or surgery with then past 4 weeks prior to the start of study
treatment with incomplete wound healing and/or planned surgery during the on-treatment
study period.

- History of clinically significant hemorrhagic or thromboembolic event in the past 6
months.

- Known inherited predisposition to bleeding or thrombosis.

- History of cardiac infarction within the past 12 months prior to the start of study
treatment.

- Receiving therapeutic anticoagulation (except low-dose heparin and/or heparin flush as
needed for maintenance of an in-dwelling intravenous device) or anti-platelet therapy
(except for low-dose therapy with acetylsalicylic acid < 325 mg QD).

- Pregnant and/or breastfeeding. Patients of childbearing potential must have a negative
pregnancy test within 14 days of study entry.

- Significant weight loss (> 10% of BW) within past 6 months prior to inclusion into the
trial.

- Known active or chronic hepatitis B or C infection.

- Active alcohol or drug abuse.

- Gastrointestinal disorder or abnormality that would interfere with absorption of the
study drug.

- Known HIV-positivity on combination antiretroviral therapy because of the potential
for pharmacokinetic interactions with nintedanib. In addition, these patients are at
increased risk of lethal infections when treated with marrow-suppressive therapy.
Appropriate studies will be undertaken in patients receiving combination
antiretroviral therapy when indicated.