Nintedanib in Treating Patients With Recurrent or Persistent Endometrial Cancer

PRIMARY OBJECTIVES:

I. To estimate the proportion of patients with persistent or recurrent endometrial cancer,
who survive progression-free without going on a subsequent therapy against the disease for at
least 6 months and the proportion of patients who have objective tumor response (complete or
partial), treated with BIBF 1120 (nintedanib).

II. To determine the nature and degree of toxicity of BIBF 1120 in this cohort of patients.

SECONDARY OBJECTIVES:

I. To estimate the progression-free survival (PFS) and overall survival (OS) of patients with
persistent or recurrent endometrial cancer treated with BIBF 1120.

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 every 3 months for 2 years and
then every 6 months for 3 years.

Inclusion Criteria:

- Patients must have recurrent or persistent endometrial carcinoma, which is refractory
to curative therapy or established treatments; histologic confirmation of the original
primary tumor is required; patients with the following histologic epithelial cell
types are eligible: endometrioid adenocarcinoma, serous adenocarcinoma,
undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma,
adenocarcinoma not otherwise specified (N.O.S.), mucinous adenocarcinoma, squamous
cell carcinoma, and transitional cell carcinoma

- All patients must have measurable disease as defined by Response Evaluation Criteria
in Solid Tumors (RECIST) 1.1; measurable disease is defined as at least one lesion
that can be accurately measured in at least one dimension (longest diameter to be
recorded); each lesion must be >= 10 mm when measured by computed tomography (CT),
magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or >= 20 mm
when measured by chest x-ray; lymph nodes must be >= 15 mm in short axis when measured
by CT or MRI

- Patient must have at least one "target lesion" to be used to assess response on this
protocol as defined by RECIST 1.1; tumors within a previously irradiated field will be
designated as "non-target" lesions unless progression is documented or a biopsy is
obtained to confirm persistence at least 90 days following completion of radiation
therapy

- Patients must not be eligible for a higher priority Gynecologic Oncology Group (GOG)
protocol, if one exists; in general, this would refer to any active GOG Phase III
protocol or Rare Tumor protocol for the same patient population

- Patients must have a GOG performance status of 0, 1, or 2

- Patients must have normal thyroid function; patients with a history of hypothyroidism
are eligible, provided it is well controlled on medication

- Recovery from effects of recent surgery, radiotherapy, or chemotherapy

- Patients should be free of active infection requiring antibiotics (with the exception
of uncomplicated urinary tract infection)

- Any hormonal therapy directed at the malignant tumor must be discontinued at least one
week prior to registration

- Any other prior therapy directed at the malignant tumor, including chemotherapy and
immunologic agents, must be discontinued at least three weeks prior to registration

- Any prior radiation therapy must be completed at least 4 weeks prior to registration

- Patients must have had one prior chemotherapeutic regimen for management of
endometrial carcinoma; chemotherapy administered in conjunction with primary radiation
as a radio-sensitizer will be counted as a systemic chemotherapy regimen

- Patients are allowed to receive, but are not required to receive, one additional
cytotoxic regimen for management of recurrent or persistent disease

- Patients must have NOT received any non-cytotoxic (biologic or targeted) agents, as
part of their primary treatment or for management of recurrent or persistent disease;
non-cytotoxic (biologic or targeted) agents include (but are not limited to)
monoclonal antibodies, cytokines, and small-molecule inhibitors of signal
transduction; prior hormonal therapy is allowed; there is no limit on the number of
prior hormonal therapies allowed

- Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl

- Platelets greater than or equal to 100,000/mcl

- Creatinine less than or equal to 1.5 x institutional upper limit normal (ULN)

- Urine protein creatinine (UPC) ratio must be < 1.0 gm; if UPC ratio >= 1, collection
of 24-hour urine measurement of urine protein is recommended

- Bilirubin must be less than 1.5 X ULN

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be less than
3 X ULN

- Alkaline phosphatase must be less than 2.5 X ULN

- Prothrombin time (PT) such that international normalized ratio (INR) is =< 1.5 x ULN
(or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of
therapeutic warfarin) and a partial thromboplastin time (PTT) =< 1.5 times the
institutional upper limit of normal

- Electrocardiogram (EKG) must have corrected QT interval (QTc) < 450 msec without
evidence of serious ventricular arrhythmia (ventricular tachycardia lasting more than
3 beats or ventricular fibrillation)

- Patients must have signed an approved informed consent and authorization permitting
release of personal health information

- Patients must meet pre-entry requirements

- Patients of childbearing potential must have a negative serum pregnancy test prior to
the study entry; women of child-bearing potential must agree to use adequate
contraception (two barrier methods of birth control) prior to study entry and for the
duration of study participation; should a woman become pregnant or suspect she is
pregnant while participating in this study, she is to inform her treating physician
immediately; all patients must be willing to take contraception up to three months
after the final dose of BIBF 1120

Exclusion Criteria:

- Patients who have had prior therapy with BIBF 1120

- Patients with a history of other invasive malignancies, with the exception of
non-melanoma skin cancer and other specific malignancies, are excluded if there is any
evidence of other malignancy being present within the last three years; patients are
also excluded if their previous cancer treatment contraindicates this protocol therapy

- Patients who have received prior radiotherapy to any portion of the abdominal cavity
or pelvis OTHER THAN for the treatment of endometrial cancer within the last three
years are excluded; prior radiation for localized cancer of the breast, head and neck,
or skin is permitted, provided that it was completed more than three years prior to
registration, and the patient remains free of recurrent or metastatic disease

- Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER
THAN for the treatment of endometrial cancer within the last three years are excluded;
patients may have received prior adjuvant chemotherapy for localized breast cancer,
provided that it was completed more than three years prior to registration, and that
the patient remains free of recurrent or metastatic disease

- Patients with serious, non-healing wound, ulcer, or bone fracture; this includes
history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
within 28 days prior to the start date of treatment; patients with underlying lesions
that caused the fistula or perforation in the past that have not been corrected

- Patients with active bleeding or pathologic conditions that carry high risk of
bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major
vessels

- Patients with history of brain metastases, or evidence upon physical examination of
active central nervous system (CNS) disease, including primary brain tumor, seizures
not controlled with standard medical therapy or any brain metastases

- Uncontrolled hypertension, defined as systolic >= 150 mm Hg or diastolic >= 90 mm Hg

- Myocardial infarction or unstable angina within 6 months of study treatment

- New York Heart Association (NYHA) class II or greater congestive heart failure

- Women with an ejection fraction < institutional lower limit of normal (LLN)

- History of serious ventricular arrhythmia (i.e., ventricular tachycardia or
ventricular fibrillation) or cardiac arrhythmias requiring anti-arrhythmic medications
(except for atrial fibrillation that is well controlled with anti-arrhythmic
medication)

- Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or greater peripheral
vascular disease

- History of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or
subarachnoid hemorrhage within six months of study treatment

- Patients undergoing invasive procedures as defined below: major surgical procedure,
open biopsy or significant traumatic injury within 28 days prior to the first date of
treatment; major surgical procedure anticipated during the course of the study; minor
surgical procedures, fine needle aspirates, or core biopsies within 7 days prior to
the first date of therapy

- Patients who are pregnant or nursing

- Patients with a history of major thromboembolic event defined as: symptomatic
pulmonary embolism (PE), recurrent asymptomatic PE, or recurrent deep venous
thrombosis

- Prior thrombosis or thromboembolic event due to a known inherited coagulopathy (i.e.,
antithrombin-III deficiency, protein C or protein S deficiency, factor V Leiden
mutation presence, prothrombin G20210A mutation)

- Serious infections requiring systemic antibiotics or antiviral therapy including:
known active hepatitis B or C infection; known human immunodeficiency virus (HIV)
infection

- Gastrointestinal (GI) or other medical disorders that would impact ingestion or
absorption of the drug

- Patients with a history of photosensitivity or who must take agents which increase
photosensitivity, e.g. topical retinoids and doxycycline

- Patients who are unable to swallow capsules