Nintedanib in Treating Patients With Locally Advanced or Metastatic Neuroendocrine Tumors

PRIMARY OBJECTIVES:

I. To assess progression free survival (PFS), defined as the time interval from initiation of
therapy, to its cessation for documentation of progressive disease (PD) or death.

SECONDARY OBJECTIVES:

I. To assess the clinical response (complete response + partial response) in all patients
with measurable disease (using standard Response Evaluation Criteria in Solid Tumors [RECIST]
version [v]1.1 criteria).

II. To assess overall survival (OS) in all patients. III. Assess changes in quality of life
(QOL) throughout treatment using the European Organization for Research and Treatment of
Cancer (EORTC) quality of life questionnaire (QLQ) - Gastrointestinal Neuroendocrine Tumors
(NET) 21 (GI.NET21) questionnaire for carcinoid patients with gastrointestinal neuroendocrine
tumors, in all patients who have filled out at least two QOL questionnaires and, will be
reported by groups based on response (response, stable disease or progressive disease).

IV. Steady-state pharmacokinetics (PK) of nintedanib, biomarkers, regulatory T cell (Treg)
and cytokine expression and growth factors will be analyzed for all patients and reported in
groups based on response.

V. Gene mutations and copy number alterations analysis in the mammalian target of rapamycin
(mTOR) pathway (will be performed only on the first 10 patients), protein expression of
activation of protein kinase B (Akt) (as well as other downstream targets).

VI. Toxicity (graded using the National Cancer Institute [NCI] Common Terminology Criteria
for Adverse Events [CTCAE] version 4.0) will be closely monitored and all toxicities will be
tabulated.

OUTLINE:

Patients receive nintedanib orally (PO) twice daily (BID) on days 1-28. Courses repeat every
28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3
months for 2 years.

Inclusion Criteria:

- Patient must be on a stable dose of octreotide (Sandostatin®) long-acting release
(LAR) or lanreotide for 3 months prior to study enrollment

- Patient must have histologically or cytologically confirmed well differentiated or
moderately differentiated (low grade or intermediate grade) neuroendocrine tumor that
is locally advanced or metastatic and not of pancreatic origin

- Measurable disease determined by computed tomography (CT) or magnetic resonance
imaging (MRI)

- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

- Life expectancy greater than 3 months

- Leukocytes >= 3,000/uL

- Absolute neutrophil count >= 1,500/uL

- Total bilirubin =< 2 mg/dL

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 1.5 x upper limit
of normal (ULN) and bilirubin =< ULN for patients without liver metastases

- AST/ALT =< 2.5 x ULN and bilirubin =< ULN for patients with liver metastases

- Patients with Gilbert syndrome and bilirubin < 2 x ULN and normal AST/ALT

- Creatinine =< 1.5 mg/dl

- Prior treatment will be permitted including surgery (>= 4 weeks), cytotoxic
chemotherapy (maximum of 2 prior regimens); radiation, interferon, targeted growth
factors (>= 4 weeks); and prior treatment with octreotide, will be allowed

- Ability to swallow and retain oral medication

- Participants of child-bearing potential (both male and female) must agree to use
adequate contraceptive methods (e.g., hormonal or barrier method of birth control;
abstinence) prior to study entry; should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately

- Participant or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure

- Archival tissue of carcinoid biopsy must be available

Exclusion Criteria:

- Uncontrolled hypertension, unstable angina, New York Heart Association grade II or
greater congestive heart failure, unstable symptomatic arrhythmia requiring
medication, or clinically significant peripheral vascular disease (grade II or
greater)

- Presence of brain metastases

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to day 0, or anticipated need for major surgical procedure during the course of
the study, or fine needle aspirations or core biopsies within 7 days prior to day 0

- Significant proteinuria at baseline (>= 500 mg/24 hours [h])

- Serious non-healing wound, ulcer or bone fracture

- Evidence of bleeding diathesis or coagulopathy

- Recent (=< 6 months) arterial thromboembolic events, including transient ischemic
attack, cerebrovascular accident, unstable angina, or myocardial infarction

- Poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma,
adenocarcinoid, goblet cell carcinoma, or small cell carcinoma

- Hepatic artery embolization or ablation of hepatic metastasis within 3 months of
enrollment, prior peptide receptor radionuclide therapy (PRRT) within 4 months or any
other cancer therapy within 4 weeks (as long as all toxicities are resolved)

- Intolerance or hypersensitivity to octreotide

- Severe or uncontrolled medical conditions

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant or nursing female participants

- Unwilling or unable to follow protocol requirements

- Any condition which in the investigator's opinion deems the participant an unsuitable
candidate to receive study drug