Nintedanib in Treating Patients With Recurrent or Persistent Endometrial Cancer

Study Overview
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Brief Summary
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This phase II trial studies the side effects and how well nintedanib works in treating patients with endometrial cancer that has come back. Nintedanib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the tumor.

Detailed Description
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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.

Official Title
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A Phase II Evaluation of BIBF 1120 in the Treatment of Recurrent or Persistent Endometrial Carcinoma

Conditions
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Endometrial Adenocarcinoma, Endometrial Clear Cell Adenocarcinoma, Endometrial Mucinous Adenocarcinoma, Endometrial Serous Adenocarcinoma, Endometrial Squamous Cell Carcinoma, Endometrial Transitional Cell Carcinoma, Endometrial Undifferentiated Carcinoma, Malignant Uterine Corpus Mixed Epithelial and Mesenchymal Neoplasm, Recurrent Uterine Corpus Carcinoma

Intervention / Treatment
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* Drug: Nintedanib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (nintedanib)<br>Patients receive nintedanib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Nintedanib<br>* Given PO<br>* Other names: Vargatef;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | The incidence of adverse events (grade 3 or higher) as assessed by the National Cancer Institute CTCAE version 4.0 | Up to 5 years | 
| Objective Tumor Response | Complete and Partial Tumor Response by RECIST 1.1 | For disease that can be evaluated by physical exam,response was assessed prior to each cycle CT scan or MRI if used to follow lesion for measurable disease every other cycle up to 5 years. | 
| Progression-free Survival > 6 Months | Whether or not the patient survived progression-free for at least 6 months. | for disease that can be evaluated by physical exam, progression was assessed prior to each cycle. CT scan or MRI if used to follow lesion for measurable disease every other cycle up to 5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | The observed length of life from entry into the study to death or the date of last contact. | From study entry to death or last contact, up to 5 years | 
| Progression Free Survival | the period of progression free survival for patients with persistent or recurrent endometrial cancer treated with study drug. | The duration of time from study entry to time of progression or death, whichever occurs first, assessed up to 5 years |