Clinical trial NCT02389764
Conditions: Breast Cancer
Keywords: Breast cancer Metastatic inflammatory breast cancer MIBC HER2-negative Breast carcinoma BIBF 1120 Nintedanib Phone call
Sponsor: M.D. Anderson Cancer Center
Start date: 2015-06-22; Completion date: 2019-06-08
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
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:
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.

Arms: arm 1: 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.
Interventions: intervention 1: BIBF 1120 intervention 2: Phone Call
Intervention descriptions: intervention 1: Initial dose is 200 mg twice daily orally for a 28 day cycle. intervention 2: 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.

Protocol documents:
Prot_SAP_000.pdf: 
2014-0464
January 12, 2018
Abstract Page 1  
Protocol Abstract Page
A phase II study of BIBF1120 (Nintedanib) for patients with metastatic 
HER2-negative inflammatory breast cancer (IBC)
2014-0464
Core Protocol Information
Study Chairman: 
Naoto Ueno
Department:
Breast Medical Oncology
Phone:
713-792-2817
Unit:
1354
Full Title: 
A phase II study of BIBF1120 (Nintedanib) for patients with metastatic HER2-negative 
inflammatory breast cancer (IBC)
Protocol Phase:
Phase II
Version Status:
Terminated 06/08/2018
Version:
11
Document Status:
Final
Abstract
Objectives:
1. Primary Objectives: To determine the clinical benefit rate (complete response [CR], partial response 
[PR] or stable disease [SD] rate) of BIBF 1120 (Nintedanib) in patients with HER2-negative, metastatic 
inflammatory breast cancer.
2. Secondary Objectives: To analyse the safety measures of BIBF1120 in terms of type, frequency and 
severity of adverse event according to CTCAE v4.0 in patients with metastatic IBC.
3. Exploratory Biomarkers: 
3.1 Pharmacodynamic analysis of BIBF-1120: to evaluate the changes in the levels of pVEGF-R2, 
pPDGF-Rß, and pFGF-R1 in tumor tissues at pretreatment and 8 weeks post treatment, and to 
determine the correlates with clinical outcomes.
3.2 Determine the effects of BIBF 1120 on the presence of CTC and CTCs with epithelial and/or EMT 
gene expression in peripheral blood. 
3.3. Explore the utilization of the ViSion Reporting System to accurately measure tumor response to 
BIBF1120.
Rationale: (Be as concise as possible)
Inflammatory breast carcinoma (IBC) is one of the most aggressive forms of primary breast carcinoma 
that accounts for 1-6% of all invasive breast tumors in the United States and Western Europe. IBC is 
distinguished from other types of breast cancer by clinical, pathologic and molecular features and is 
classified by the American Joint Committee on Cancer (AJCC) as a separate clinic pathological entity 
(T4d). Unfortunately, there is no current standard treatment for those patients with HER2-negative 
disease that recur after the multidisciplinary management. Vascular lymphatic processes include 


2014-0464
January 12, 2018
Abstract Page 2  
angiogenesis, lymphangiogenesis, and vasculogenesis have more prominent roles in IBC than in 
non-IBC. Treatment strategies that target angiogenic pathways have shown effective results in IBC. 
Several clinical studies have demonstrated the role of antiangiogenesis treatment in patients with IBC. 
The rationale for measuring CTCs is due to the number of CTC in metastatic BC has been shown to be 
a prognostic indicator for treatment response, progression free survival, and overall survival. The 
presence of circulating tumor cells (CTCs), detected using CellSearch, in women with metastatic breast 
cancer (MBC) is predictive of early recurrence and poor survival. However, there is discrepancy in a 
study with this technique. Thus, in a prospective study conducted in our institution we isolated epithelial 
and non-epithelial cells from patients with MBC and characterized their epithelial differentiation, 
transcript levels of transcription factors known to induce EMT (EMT-TF), and stem cell features to better 
understand circulating tumor cell seeding.  
 
BIBF 1120 is a potent, orally available triple kinase inhibitor targeting VEGFRs, PDGFRs, and FGFRs. 
The specific and simultaneous abrogation of these pathways results in effective growth inhibition of both 
endothelial and, via PDGF- and FGF-receptors of perivascular cells, which may be more effective than 
inhibition of endothelial cell growth via the VEGF pathway alone. Furthermore, signalling by 
FGF-receptors has been identified as a possible escape mechanism for tumour angiogenesis when the 
VEGF pathway is disrupted.  Preclinical models show that BIBF 1120 may have a direct anti-tumour 
effect on those malignant cells which overexpress PDGFR and/or FGFR. 
Clinical trials revealed BIBF 1120 is generally well tolerated with mild to moderate adverse effects, and 
has anti-tumor efficacy; the maximum tolerated dose was defined to be 250 mg for twice daily dosing in 
Caucasians and 200 mg twice daily in Japanese patients with a manageable safety profile in advanced 
cancer patients. The maximum tolerated dose for combination therapy of BIBF 1120 and other 
anti-cancer drugs (such as docetaxel, paclitaxel, pemetrexed, carboplatin, 5-FU, oxaliplatin) was 
determined to be 200 mg twice daily. BIBF 1120 is non-mutagenic, even at high doses. 
The purpose of the study is to collect data and define the efficacy and safety of BIBF1120 in patients 
with HER-2 negative metastatic IBC. Antiangiogenic treatment with the orally available triple angiokinase 
inhibitor BIBF 1120 with inhibition of VEGFR, PDGFR and FGFR offers the chance to control both locally 
recurrent and distant metastatic disease on an outpatient basis. 
Eligibility: (List All Criteria)
Inclusion:
1)
Patients are 18 years of age or older
2)
Patients are female or male.
3)
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.
4)
Have confirmed distant metastasis with or without local recurrence.
5)
Have negative HER2 expression by IHC (defined as 0 or1+), or FISH. If HER2 is 2+, negative 
HER2 expression must be confirmed by FISH.
6)
Patients may undergo an optional biopsy of the metastatic disease at baseline and after 2 cycles of 
BIBF-1120.
7)
Estimated life expectancy of at least 3 months


2014-0464
January 12, 2018
Abstract Page 3  
8)
Have ECOG performance status score 0-2
9)
Have received at least one any prior treatment for local recurrence or metastatic disease and have 
relapsed.
10)
Signed and dated written informed consent prior to admission to the study
11)
If Patients have been treated with anti-VEGF agents, such as Bevacizumab, last dose must be >/= 
4 weeks.
12)
Have tissues from a biopsy, or have up to 20 unstained slides available from archived metastatic 
tissue block for biomarker evaluation
13)
Patients are able to swallow and retain oral medication
Exclusion:
1)
Patients have an active infection and require IV or oral antibiotics.
2)
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
3)
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),
4)
Uncontrolled hypertension defined by an SBP>150 and/or a DBP>100 mm Hg with or without 
anti-hypertensive medication
5)
History of gastrointestinal disorders (medical disorders or extensive surgery) which may interfere 
with the absorption of the study drug as determined by the investigator.
6)
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.
7)
Patients with only locally or regionally confined disease without evidence of metastatic disease
8)
Prior treatment with BIBF 1120 or any other VEGFR inhibitor within 4 weeks
9)
Known hypersensitivity to the trial drugs , to their excipients or to contrast media
10)
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
11)
Persistence of toxicity from previous chemo and/or radiotherapy > grade 2.
12)
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).
13)
Radiographic evidence of cavitary or necrotic tumors


2014-0464
January 12, 2018
Abstract Page 4  
14)
Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of major blood 
vessels
15)
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
16)
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
17)
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
18)
History of clinically significant haemorrhagic or thromboembolic event in the past 6 months
19)
Known inherited predisposition to bleeding or thrombosis
20)
Proteinuria CTCAE grade 2 or greater
21)
Creatinine >/= 1.5 x ULN or GFR < 45 ml/min
22)
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
23)
Coagulation parameters: International normalised ratio ( INR) > 2, prothrombin time (PT) and partial 
thromboplastin time (PTT) > 50% of deviation of institutional ULN
24)
Absolute neutrophil count ( ANC) < 1500/ml, platelets < 100000/ml, Haemoglobin < 9.0 g/dl
25)
Other malignancies within the past 5 years other than basal cell skin cancer or carcinoma in situ of 
the cervix
26)
Known history of active or chronic hepatitis C and/or B infection
27)
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.
28)
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.)
29)
Patients with child bearing potential must have a negative pregnancy test (urine or serum) prior to 
study treatment
30)
Psychological, familial, sociological or geographical factors potentially hampering compliance with 
the study protocol and follow-up schedule
31)
Active alcohol or drug abuse
32)
Significant weight loss (> 10% of BW) within past 6 months prior to inclusion into the trial


2014-0464
January 12, 2018
Abstract Page 5  
Are patients <18 years of age eligible to participate in this study?  
Yes
No
Studies that include children must meet the criteria for inclusion.
http://www.fda.gov/ohrms/dockets/AC/04/briefing/4028B1_05_NIH-Inclusion%20of%20Children.doc
http://www.hhs.gov/ohrp/policy/populations/children.html
Studies that exclude children must have appropriate justification.  Please select all that 
apply:
Phase I or Phase II study targeting cancer that is very unusual in pediatrics (e.g., prostate, lung, 
breast, chronic lymphocytic leukemia, etc.)
Are participants >65 years of age eligible to participate in this study?  
Yes
No
Are pregnant women eligible to participate in this study?
Yes
No
Will the recruitment population at M. D. Anderson include persons who are incarcerated at time of 
enrollment (e.g., prisoners) or likely to become incarcerated during the study?
Yes
No
Disease Group:
Breast
Treatment Agents/Devices/Interventions:
BIBF 1120 nintedanib
Proposed Treatment/Study Plan:
Is treatment assignment randomized?
Yes
No
Is this a blinded or double-blinded study?
Yes
No
Initial dose is BIBF 1120 200 mg twice daily orally.  The capsules of the defined dose should be 
swallowed unchewed with 8 ounces of water (240ml). If taken twice daily the dose interval should be 
of around 12 hours at the same times every day, usually in the morning and the evening within 30 
minutes after food intake. Each cycle/course will be 28 days.
Study Calender


2014-0464
January 12, 2018
Abstract Page 6  


2014-0464
January 12, 2018
Abstract Page 7  
Study Enrollment:
The study population for this research will consist of participants from:
Only at MDACC
Estimated Accrual:
Total Accrual at MDACC:
up to 44
Estimated monthly accrual at MDACC:
0-2
Accrual Comments:
An average monthly accrual is about 0-2.
Is this an NCI-Cancer Therapy Evaluation Protocol (CTEP)?
No
Is this an NCI-Division of Cancer Prevention Protocol (DCP)?
No
Statistical Considerations:
Up to 44 patients will be enrolled in this phase II study to assess the efficacy of 
BIBF-1120 (Nintedanib).  The primary endpoint of this study is the clinical benefit rate 
(CR, PR, and SD as determined by RECIST 1.1) of BIBF-1120 as single agent in 
metastatic IBC. Patients receiving clinical benefit is defined as patients who achieve 
complete response or partial response within 3 months after the initiation of treatment 
or patients who experience stable disease for at least three months after the initiation 
of treatment. 
The purpose of this trial is to determine the clinical benefit rate (complete response [CR], 
partial response [PR] or stable disease [SD] rate) of BIBF 1120 (Nintedanib) in patients with 
HER2-negative, metastatic inflammatory breast cancer.  Given a planned maximum number 
of patients, N=44, we would like to implement futility monitoring at 15, 30 and 44 patients and 
stop the trial when Bayesian Predictive Probability (PP) = å= Sumi=0,1,2,3,…, m  {P(Y=i | x, 
n) ´ (P(p > 1%| x, n, Y=i)>= 95%)}<= 10%, where x represents current number response or 
stable disease in n treated patients,  m represents the future number of patients.  This means 
that given what are observed, there is a less than 10% chance that the clinical benefit rate is 
better than 1% if the trial continues to the end.  With this rule, and assuming that the prior of 
response rate follows a beta distribution, beta (0.01, 0.99), we have the boundaries and the 
operating characteristics as listed below.
Futility Monitoring Boundaries
Cohort
Stop if # CR, PR or SD <=
15
0
 30
1
 44
2


2014-0464
January 12, 2018
Abstract Page 8  
 Operating Characteristics
True Rate
PET
EN
Prob(Non-Negative)
1%
0.972
17.5
0.006
5%
0.633
28.2
0.272
10%
0.277
37.0
0.684
20%
0.040
42.9
0.959
30%
0.005
43.9
0.995
40%
0.000
44.0
1.000
At the end of the study, we will estimate the clinical benefit rate with 95% credible interval.  
Toxicity data, pharmacodynamic data, CTC and EMT gene expression in peripheral blood will 
be summarized using descriptive statistics.  For the exploratory objective, we will correlate 
the number of CTC with EMT gene expression in peripheral blood using Spearman 
correlation, or estimate EMT gene expression in peripheral blood in patients with or without 
the presence of CTC, separately. Similarly we will evaluate if there are differential the 
pharmacodynamics biomarkers change in different groups by response status.
Data Safety Monitoring Board / DSMB at MDACC:
Select the name of the data safety monitoring board (DSMB) monitoring this protocol:
Not Applicable
Please explain:
The study is not randomized and not blinded.
Protocol Monitoring:
Does this protocol have a schedule for interim and final analysis?
Yes
Provide a summary or schedule of interim analysis.
The study design requires 25 patients in the first stage.  If no patients respond to the treatment, the trial 
will be stopped and the regimen will be declared as ineffective.  If at least one of the first 25 patients 
achieve clinical benefit (PR or CR) to the treatment, 19 additional patients will be enrolled onto the study 
to reach a total of 44 patients. 
Protocol Monitoring Plan:
This study will be monitored by the MD Anderson IND office and a protocol-specofic monitoring plan will 
be followed.
Intellectual Property:
1.
Does this study include any agents, devices, or radioactive compound (or 
drug) manufactured at  MD Anderson Cancer Center or by a contract 
manufacturer?
No


2014-0464
January 12, 2018
Abstract Page 9  
Investigational New Drugs (IND):
Does this protocol require an IND?
Yes
Who is the IND Holder/Regulatory Sponsor?
MD Anderson
IND Number:
125610
Please "Compose" an Investigator’s Brochure Cover Letter.  For technical assistance, contact the PDOL 
Help Desk, 713-745-7365.
Investigational Device (IDE):
Does this study utilize an Investigational Device?
No
Sponsorship and Support Information:
Does the Study have a Sponsor, Supporter or Granting Agency?
Yes
Sponsor Name:
Boehringer Ingelheim
Support Type:
Industry Funding
This Sponsor/Supporter/Granting Agency will receive data.
Radioactive Material:
Does this study involve the administration of radioisotopes or a
radioisotope labeled agent?
Click here  for help
No
Biosafety:
Does this study involve the use of Recombinant DNA Technology? 
No
Does this study involve the use of organisms that are infectious to humans?
No
Does this study involve human/animal tissue other than blood derived 
hematopoietic stem cells?
No
Questions should be addressed to the Transfusion Medicine Tissue Coordinator at 713-792-8630.
Laboratory Tests:
Is there any biomarker testing in this study being used to determine patient/participant eligibility, 
treatment assignment, or management of patient/participant care?


2014-0464
January 12, 2018
Abstract Page 10  
Yes
No
Not Applicable For This Protocol
Please provide the name of the test(s), the purpose of the test, the performing laboratory identification 
and contact information, and confirm that the testing lab is CLIA certified (may attach a certificate or 
provide a certificate number).
HER-2/neu need to be negative to qulify for this study.
Manufacturing:
Will you manufacture in full or in part (split manufacturing) a drug or biological 
product at the M. D. Anderson Cancer Center for the proposed clinical study?
No
Student/Trainee Information:
Is this research being conducted as a partial fulfillment for completion of a degree?
No