Nintedanib For HER2-Negative Metastatic Inflammatory Breast Cancer (MIBC)

Study Overview
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Brief Summary
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The goal of this clinical research study is to learn if Ofev® (nintedanib, also called BIBF1120) can help to control IBC. The safety of this drug will also be studied. This is an investigational study. Nintedanib is commercially available and FDA approved for the treatment of certain types of lung disease. Its use in this study is investigational. The study doctor can explain how the study drug is designed to work. Up to 44 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed Description
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Study Drug Administration: Each study cycle is 4 weeks. If you are found to be eligible to take part in this study, you will take nintedanib capsules by mouth 2 times each day. Each dose should be about 12 hours apart, at about the same times every day. The capsules should be swallowed whole with about a cup (8 ounces) of water within 30 minutes after eating a meal. If you forget to take the capsules and it has been more than 2 hours since you were scheduled to take the dose, you should skip that dose and take the next dose as scheduled. Do not double the next dose to make up the missed one. You will be given a study drug diary to write down when you took each dose of study drug. You will need to bring back any empty or partially used bottles of study drug, along with any leftover study drug, with you to the clinic at each cycle. If you experience side effects, you will be given standard drugs to help decrease the symptoms of the side effects. You may ask the study staff for information about how the drugs are given and their risks. Study Visits: All tests and procedures below will be performed before your dose of study drug. On Day 1 of every cycle: You will have a physical exam. Blood (about 2 tablespoons) will be drawn for routine tests. On Day 1 of Cycles 1-7 and then every odd-numbered cycle after that (Cycles 9,11, 13, and so on), the physical exam and blood draw will be performed at MD Anderson . On Day 1 of Cycles 8 and then every even-numbered cycle after that (Cycles 10, 12, 14, and so on), the physical exam and blood draw may be performed at a local clinic or doctor's office and the results will be sent to the study doctor for review. The study doctor will discuss this option with you. On Day 1 of Cycle 3, blood (about 2 tablespoons) will also be drawn for biomarker testing. On Day 1 of Cycles 3, 5, 7, and then every odd numbered cycle after that (Cycles 9, 11, 13, and so on): If the doctor thinks it is needed, photographs will be taken of any areas affected by the disease. If the doctor thinks it is needed, you will have an x-ray, ultrasound, CT scan, PET/CT scan, and/or a bone scan to check the status of the disease. At any point that the doctor thinks it is needed, you will have an EKG, ECHO, and/or MUGA scan. You may have any of the above tests/procedures repeated as well, if the doctor thinks it is needed, to check on your health. Length of Study: You may continue taking the study drug for up to 2 years. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions. Your participation on the study will be over after you have completed the follow-up period. End-of-Treatment Visit: Within 14 days after the last study visit: You will have a physical exam. Blood (about 1 tablespoon) will be drawn for routine tests. If the doctor thinks it is needed, photographs will be taken of your skin and any areas affected by the disease. If the doctor thinks it is needed, you will have an x-ray, ultrasound, CT scan, PET/CT scan, and/or a bone scan to check the status of the disease. If the doctor thinks it is needed, you will have an EKG and either an ECHO or MUGA scan. Follow-up Visits: You will be called by a member of the study staff every 3 months for up to 1 year after your end-of-treatment visit and asked how you are doing. These calls should last about 2 minutes.

Official Title
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A Phase II Study of BIBF1120 (Nintedanib) for Patients With Metastatic HER2-Negative Inflammatory Breast Cancer (IBC)

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: BIBF 1120
* Behavioral: Phone Call


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients are 18 years of age or older Patients are female or male. Have histological confirmation of breast carcinoma with a clinical diagnosis of IBC based on presence of inflammatory changes in the involved breast, including diffuse erythema and edema (peau d'orange), with or without an underlying palpable mass involving the majority of the skin of the breast. Pathological evidence of dermal lymphatic invasion should be noted but is not required at diagnosis. Have confirmed distant metastasis with or without local recurrence. Have negative HER2 expression by IHC (defined as 0 or1+), or FISH. If HER2 is 2+, negative HER2 expression must be confirmed by FISH. Patients may undergo an optional biopsy of the metastatic disease at baseline and after 2 cycles of BIBF-1120. Estimated life expectancy of at least 3 months Have ECOG performance status score 0-2 Have received at least one any prior treatment for local recurrence or metastatic disease and have relapsed. Signed and dated written informed consent prior to admission to the study If Patients have been treated with anti-VEGF agents, such as Bevacizumab, last dose must be >/= 4 weeks. Have tissues from a biopsy, or have up to 20 unstained slides available from archived metastatic tissue block for biomarker evaluation Patients are able to swallow and retain oral medication Exclusion Criteria: Patients have an active infection and require IV or oral antibiotics. Patients have impaired cardiac function or clinically significant cardiac diseases, including any of the following: a) History or presence of serious uncontrolled ventricular arrhythmias or presence of atrial fibrillation; b) Clinically significant resting bradycardia (< 50 beats per minute); c) LVEF assessed by 2-D echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) < 45%; d). pericardial effusion Any of the following within 6 months prior to study entry: myocardial infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), Congestive Heart Failure (CHF) > NYHA II, Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA), Pulmonary Embolism (PE), Uncontrolled hypertension defined by an SBP>150 and/or a DBP>100 mm Hg with or without anti-hypertensive medication History of gastrointestinal disorders (medical disorders or extensive surgery) which may interfere with the absorption of the study drug as determined by the investigator. Patients have a concurrent disease or condition that would make them inappropriate for study participation, or any serious medical disorder that would interfere with patients' safety as determined by the investigator. Patients with only locally or regionally confined disease without evidence of metastatic disease Prior treatment with BIBF 1120 or any other VEGFR inhibitor within 4 weeks Known hypersensitivity to the trial drugs , to their excipients or to contrast media Chemotherapy, hormonal therapy, radiotherapy (except for brain and extremities) or immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 4 weeks prior to treatment with the trial drug Persistence of toxicity from previous chemo and/or radiotherapy > grade 2. Active brain metastases (e.g. stable for <4 weeks, no adequate previous treatment with radiotherapy, symptomatic, requiring treatment with anti-convulsants; dexamethasone therapy will be allowed if administered as stable dose for at least one month before randomisation). Radiographic evidence of cavitary or necrotic tumors Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of major blood vessels Treatment with other investigational drugs or treatment in another clinical trial within the past 4 weeks before start of therapy or concomitantly with the trial 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 < 325mg per day Major injuries within the past 10 days prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period History of clinically significant haemorrhagic or thromboembolic event in the past 6 months Known inherited predisposition to bleeding or thrombosis Proteinuria CTCAE grade 2 or greater Creatinine >/= 1.5 x ULN or GFR < 45 ml/min Hepatic function: total bilirubin outside of normal limits; ALT or AST >1.5 x ULN in pts without liver metastasis. For Pts with liver metastasis: total bilirubin outside of normal limits, ALT or AST >2.5 x ULN Coagulation parameters: International normalised ratio ( INR) > 2, prothrombin time (PT) and partial thromboplastin time (PTT) > 50% of deviation of institutional ULN Absolute neutrophil count ( ANC) < 1500/ml, platelets < 100000/ml, Haemoglobin < 9.0 g/dl Other malignancies within the past 5 years other than basal cell skin cancer or carcinoma in situ of the cervix Known history of active or chronic hepatitis C and/or B infection Serious illness or concomitant non-oncological disease such as neurologic, psychiatric, infectious disease or active ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk associated with study participation or study drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the study. Patients who are sexually active and unwilling to use a medically acceptable method of contraception (e.g. such as implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner for participating females) during the trial and for at least three months after end of active therapy (Contraception in patients with preserved reproductive capacity, patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two years.) Patients with child bearing potential must have a negative pregnancy test (urine or serum) prior to study treatment Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule Active alcohol or drug abuse Significant weight loss (> 10% of BW) within past 6 months prior to inclusion into the trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: BIBF 1120<br>Initial dose of BIBF 1120 is 200 mg twice daily orally for a 28 day cycle. Participant called by a member of the study staff every 3 months for up to 1 year after end-of-treatment visit. Participant called by a member of the study staff every 3 months for up to 1 year after end-of-treatment visit. | Drug: BIBF 1120<br>* Initial dose is 200 mg twice daily orally for a 28 day cycle.<br>* Other names: Nintedanib;Behavioral: Phone Call<br>* Participant called by a member of the study staff every 3 months for up to 1 year after end-of-treatment visit. These calls should last about 2 minutes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (Complete Response [CR], Partial Response [PR] or Stable Disease [SD] Date) of BIBF 1120 (Nintedanib) in Patients With HER2-negative Metastatic Inflammatory Breast Cancer (IBC). | Clinical benefit defined as participants who achieve CR or PR within 3 months post-treatment, or participants who experience SD for at least three months post-treatment. Clinical benefit rate determined by RECIST 1.1 version. PATHOLOGICAL CR: No evidence of residual invasive tumor, including no residual tumor in the axillary lymph nodes. PR is defined as 30% or greater decrease for a minimum of 4 weeks in the measurable lesion as determined by the product of the perpendicular diameters of the lesion. Every lesion should not regress to qualify as a PR. However, if any lesion progresses or if new lesions appear, the response cannot be classified as a (PR). Minor Response [MR] Decreases in tumor masses insufficient to qualify as a partial remission, i.e. <50%. SD between MR and PD. PD increase in the size by 25% of any measured lesion from baseline. Appearance of new lesions will also constitute increasing disease. Mixed responses will be considered PD. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Measures of BIBF 1120 in Terms of Type, Frequency and Severity of Adverse Event According to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 in Patients With Metastatic IBC. | An adverse event (AE) is defined as any untoward medical occurrence, including an exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a pharmaceutical product. The event does not necessarily have to have a causal relationship with this treatment. All adverse events (grade 3 or higher for hematological toxicity, grade 2 or higher for non-hematological toxicity) | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast cancer, Metastatic inflammatory breast cancer, MIBC, HER2-negative, Breast carcinoma, BIBF 1120, Nintedanib, Phone call