A Phase II Study of TKI258 (Dovitinib Lactate) as Salvage Therapy in Patients With Stage IV HER2-negative Inflammatory Breast Cancer (IBC) and Local or Distant Relapse
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: M.D. Anderson Cancer Center

Protocol 2010-0296
Revised December 3, 2013
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Protocol Abstract Page
A Phase II Study of TKI258 (Dovitinib Lactate) as Salvage Therapy in 
Patients with Stage IV HER2-negative IBC and Local or Distant Relapse
2010-0296
Core Protocol Information
Study Chairman: 
Vicente Valero
Department:
Breast Medical Oncology
Phone:
713-563-3735
Unit:
1354
Full Title: 
A Phase II Study of TKI258 (Dovitinib Lactate) as Salvage Therapy in Patients with Stage IV 
HER2-negative IBC and Local or Distant Relapse
Protocol Phase:
Phase II
Version Status:
Terminated 06/08/2018
Version:
19
Document Status:
Final
Abstract
Objectives:
Primary
To determine an overall response (complete response [CR], partial response [PR] or stable 
disease [SD]) of dovitinib in patients with HER2-normal, local or distant relapse of metastatic 
inflammatory breast cancer
Secondary 

To evaluate safety analysis measures in terms of type, frequency and severity of adverse 
event reactions reported according to CTCAE v4.0
Exploratory Biomarkers:

To explore the predictive values of baseline FGFR-R1, and VEGF-R1, signaling in tumor 
tissue (primary tumor or metastasis) before and during treatment with dovitinib. 

To determine the effect of dovitinib on the presence of CTC and CTCs with epithelial 
and/or EMT gene expression in PB. 
To collect and archive biopsy tumor tissue, serum and plasma for later hypothesis generating 


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associations  
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.  Additional pathologic characteristics of IBC include high grade, negative 
hormone receptor status and overexpression of HER2 and E-cadherin; all of which are poor 
prognostic factors. Molecular features of IBC include mutation of the p53 suppressor gene, and 
an increased expression of proangiogenic factors (basic fibroblast growth factor [bFGF], 
vascular endothelial growth factor [VEGF], interleukin [IL]-6 and IL-8).
Receptor tyrosine kinases (RTKs) such as VEGF receptors, FGF receptors, and PDGF receptors 
have been shown to play an important role in tumor angiogenesis. VEGF is produced by both the 
host and the cancer cells and has a direct effect on endothelial cells, causing their proliferation, 
migration, invasion, and growth. FGFs are potent stimulators of angiogenesis in both normal and 
pathological tissues, having a direct effect on both vessel assembly and sprouting. A recent 
publication has demonstrated that a blockade of the FGF pathway can overcome resistance to 
VEGFR inhibitors, emphasizing the importance of FGFR and specifically the need for 
multi-targeted inhibitors. PDGF receptors are expressed on pericytes - smooth muscle cells that 
surround the vasculature and provide maintenance and support to the tumor neovasculature. 
Inhibition of these three growth factor receptor kinases should provide a powerful and broad 
inhibition of the angiogenesis process and provide potent antitumor effects. FGF family 
receptors play a critical role in tumorigenesis, morphogenesis, and inducers of angiogenesis. A 
study using tissue microarray comprised a cohort of 880 unselected breast tumors, FGF1 
amplification was observed in 8.7% using chromogenic in situ hybridization (CISH), and this 
amplification was an independent predictor of overall survival. A model of spontaneous, highly 
aggressive rat model with presentation and phenotype resembling IBC has been described. This 
model has peculiar characteristics and angiogenesis dependent on the expression of FGF3 and 
FGF-4.
IBC possesses an increase of VEGF, PDGF and other proangiogenic factors as compared with 
non-inflammatory breast cancer. VEGF and FGF inhibitors have low IC50s in in-vitro models. We expect 
that anti-VEGF drug, such as Dovitinib, may have a potential role in HER2 negative IBC setting. 
Dovitinib (dovitinib lactate) is an investigational new drug. Dovitinib inhibits receptor tyrosine 
kinases (RTKs) involved in solid and hematologic cancers, as well as tumor angiogenesis. Based 
upon its potency as an inhibitor of Class III/IV/V RTK signaling both in vitro and in vivo, and 
pharmaceutical properties including high oral bioavailability in three species, dovitinib is being 
studied in clinical trials as a cancer therapeutic.  
The dose limiting toxicity (DLT) of dovitinib as single agent in patients with advanced cancer is being 
evaluated in 7 Phase I dose escalation studies.  As of the 18 November 2009 cutoff date, 20 DLTs were 
observed in cycle 1 of dovitinib treatment.  The DLTs included grade 3 
anorexia/nausea/vomiting/diarrhea, grade 4 fatigue, grade 4 neutropenia, grade 3 hypokalemia,  grade 2 

Protocol 2010-0296
Revised December 3, 2013
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sinus bradycardia, and delayed recovery from AST/ALT elevation, increased GGT, hypertensive.  
Subsequently, dovitinib is being studies as a single agent in eight Phase I and one Phase II clinical trials 
designated to characterize safety, tolerability, pharmacokinetics (PK), phamacodynamics (PD) and 
anti-tumor activity. 
Additionally, in one study, 3 DLTs were reported by the investigators beyond cycle 1 treatment, including 
a grade 3 hypertension (occurred on cycle 2 day 8 in 1 patient at 100 mg/day), a grade 3 anorexia 
(occurred on cycle 2 day 9 in 1 patient at 175 mg/day), and a grade 3 alkaline phosphatase increase 
(occurred on cycle 2 day 29 in 1 patient at 175 mg/day). 
There are four studies that were terminated prior to reaching the maximum tolerated dose (MTD). The 
MTD for continuous daily dosing regimen was defined at 400 mg; the MTD for 5 days on/2 days off 
dosing regimen was defined at 500 mg. Based on previous phase I safety data, and ongoing study for 
metastatic breast cancer, we propose a 500 mg daily 5 days on/2 days off schedule for this study.
Eligibility: (List All Criteria)
Inclusion:
1)
Patients 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 for diagnosis.
2)
Patients have stage IV disease with local or distant relapse
3)
Patients have negative HER2 expression by IHC (defined as 0 or1+), or FISH. If HER2 is 2+, 
negative HER2 expression must be confirmed by FISH.
4)
Patients are able to swallow and retain oral medication.
5)
Patients have ECOG performance status 0-2.
6)
Patients have received two or more standard chemotherapies for metastatic disease and have 
relapsed.
7)
Patients have ability and willingness to sign written informed consent.
8)
Patients are 18 years of age or older.
9)
Female patients of childbearing potential (A female not free from menses > 2 years or not surgically 
sterilized) must be willing to use highly effective contraception to prevent pregnancy or agree to abstain 
from heterosexual activity throughout the study. Highly effective contraception, defined as male condom 
with spermicide, diaphragm with spermicide, intra-uterine device. Highly effective contraception must be 
used by both sexes during the study and must be continued for 8 weeks after the end of study treatment. 
Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are 
therefore not considered effective for this study.
10)
Female patients of childbearing potential must have negative serum pregnancy test </=14 days 
prior to starting study treatment.

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11)
If Patients have been treated with anti-VEGF agents, such as Bevacizumab, last dose must be > 4 
weeks.
12)
Patients have biopsy tissue of the metastatic disease (including chest wall or regional nodes) 
available (paraffin blocks or up to 20 unstained slides), if no biopsy tissue available, a biopsy (or 
thoracentesis if patient has pleural effusion only) of the metastatic disease will be performed to confirm 
the diagnoses.
13)
Serum total bilirubin must be within Upper Limited Normal (T. Bilirubin ULN=1.0 mg/dl)
14)
AST and ALT must be < 2.5 x ULN(with or without liver metastases).
Exclusion:
1)
Patients are receiving concurrent anti-cancer therapy (chemotherapy, immunotherapy, radiation 
therapy and biological therapy) while taking study medication.
2)
Cirrhosis of liver, or known hepatitis B or C infection have hepatic impairment Child-Pugh Score of 
B or worse.
3)
ANC < 1.5
4)
Patients have an active infection and require IV or oral antibiotics.
5)
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) < 50% or lower limit of normal (which ever is higher) or multiple gated 
acquisition scan (MUGA) < 45% or lower limit of normal (which ever is higher). d) 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), Cerebrovascular Accident (CVA), Transient 
Ischemic Attack (TIA), Pulmonary Embolism (PE); e) Uncontrolled hypertension defined by an SBP>150 
and/or a DBP>100 mm Hg with or without anti-hypertensive medication.
6)
History of gastrointestinal disorders (medical disorders or extensive surgery) which may interfere 
with the absorption of the study drug.
7)
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.
8)
Patients with only locally or regionally confined disease without evidence of metastatic disease.
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.)

Protocol 2010-0296
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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:
TKI258
Proposed Treatment/Study Plan:
Is treatment assignment randomized?
Yes
No
Is this a blinded or double-blinded study?
Yes
No
A complete treatment cycle is defined as 28 days or 4 weeks (+/- 2 days). Patients will receive a 
single daily oral dose of 500 mg of dovitinib for 5 consecutive days, followed by a 2-day rest 
period (5 days on/2 days off schedule). 
For patients who are unable to tolerate the protocol-specified dosing schedule of dovitinib, two 
steps of dose reduction are permitted. Dose reduction should be based on the worst toxicity 
demonstrated at the last dovitinib administration. A patient who requires a delay of treatment of 
>21 days must discontinue the study treatment. All dose modifications should be based on the 
worst preceding toxicity. Patients are only allowed two dose reductions to 400 mg and 300 mg. 
Dose reduction*  
 
Starting dose level - 0  
Dose level - 1  Dose level - 2  
Dovitinib  
500 mg  
400 mg  
300 mg**  
*Dose reduction should be based on the worst toxicity demonstrated at the last dose.  
**Dose reduction below 300 mg is not allowed.  
 

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Study Enrollment:
The study population for this research will consist of participants from:
Only at MDACC
Estimated Accrual:
Total Accrual at MDACC:
33
Estimated monthly accrual at MDACC:
0-1
Accrual Comments:
An average monthly accrual is about 0-1.
Is this an NCI-Cancer Therapy Evaluation Protocol (CTEP)?
No
Is this an NCI-Division of Cancer Prevention Protocol (DCP)?
No
Statistical Considerations:
This is a phase II study, single arm evaluating the efficacy and safety of dovitinib. The treatment 
plan consists in continuous treatment of dovitinib 500 mg PO daily 5 days on and 2 days off.
The primary endpoint is the six-month overall response rate (ORR) defined as the 
percentage of patients experiencing stable disease, complete or partial response (SD, CR 
or PR) as defined by RECIST. A response is anyone who experiences SD, CR or PR in the 
first 6 months.  In other words, any patient that has not achieved either SD, CR or PR in the first 
6 months will be considered a treatment non-responder. The trial will be conducted by the 
Simon’s two-stage design using the mini-max criterion and the response rate will be 
estimated accordingly.  
It is assumed that dovitinib will have a target ORR of 30%.  An ORR of 10% or lower is 
considered a failure based on the typical ORR with a second line regimen for IBC and the 
new regimen will be rejected under this circumstance.  When the probability of accepting 
a “bad” regimen (i.e. response rate  10%) is 0.05 and the probability of rejecting a “good” 
regimen (i.e. response rate  30%) is also 0.10, Simon’s design to minimize the maximum 
sample size requires 22 patients in the first stage.  If two or less patients respond to the 
treatment, the trial will be stopped and the regimen will be declared as ineffective.  If at 
least three of the first 22 patients respond to the treatment, 11 additional patients will be 
entered in the study to reach a total of 33 patients.  By the end of the study, the new 
regimen will be rejected if response rate is less than or equal to 6 out of 33 patients and 
will be accepted otherwise.  Patient accrual will be suspended in the case when there are 
not at least 3 responders in the first 22 patients and not all 22 patients have been 
evaluated for 6 months. The operating characteristics of the trial are given as follows.  
When the true response rate is 0.10, the probability of stopping the trial early is 62.0%.  
On the other hand, if the true response rate is 0.30, the probability to stop the trial early is 
2.1%.  The expected sample sizes are 26.18 and 32.77 when the true response rates are 
0.10 and 0.30, respectively.  At the end of the study, the overall response rate and the 

Protocol 2010-0296
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95% confidence interval will be reported and the toxicity profile of the regimen will be 
summarized.
As a secondary analysis we will evaluate safety by grading each adverse event (e.g., 
neutropenia, neurotoxicity, and CINV) according to CTCAE v4.0 and reporting the type, 
frequency and severity.  In order to understand the relationship of FGF R1, FGF9, FGF, 
and VEGF-R1 signaling in serum and those in the tumor tissue (primary tumor or 
metastasis) with tumor growth, a correlation analysis of the expression levels of the 
biomarkers and tumor size will be conducted.  For each biomarker, baseline expression 
level (EB) and post-treatment expression level (EP) will be determined by 
Immunohistochemistry (IHC).  Pearson product-moment correlation coefficient 
measuring the linear relationship between the percent change in expression level, 
[EB-EP]/EB, and the percent change in tumor size as measured by CT scan will be 
reported along with the associated 95% confidence interval and the p-value for testing 
that the true linear correlation coefficient is non-zero.  A linear model will be used to 
assess the joint impact of down regulation of FGFR-R1 and VEGF-R1 on tumor growth.  
The change in the number of circulating tumor cells (CTC) at baseline as compared to the 
number post-dovitinib will be investigated using a paired t-test.  If the change in CTC is 
not normally distributed based on Shapiro-Wilk test, we will consider a robust 
non-parametric procedure such as the Wilcoxon Rank-Sum test.  
Data Safety Monitoring Board / DSMB at MDACC:
Select the name of the data safety monitoring board (DSMB) monitoring this protocol:
Not Applicable
Please explain:
This is not a randomized and not blinded study.
Protocol Monitoring:
Does this protocol have a schedule for interim and final analysis?
Yes
Provide a summary or schedule of interim analysis.
We will conduct an interim analysis after the first 22 patients following Simon's 2 stage min-max design.
Protocol Monitoring Plan:
Adverse events will be assessed according to the CTCAE version 4.0. All study patients who 
have received any dose of dovitinib will be evaluable for safety.   Unexpected adverse events 
including laboratory adverse events deemed clinically significant by the investigator will be 
graded and recorded.
The ongoing review of safety data will include review of clinical AEs and SAEs. The NCI-CTC 
version 4.0 will be used to grade all AEs.  An AE is an undesirable medical occurrence (sign, 
symptom, or diagnosis) or worsening of a pre-existing medical condition (diabetes, congestive 

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heart failure, rheumatoid arthritis) that occurs after initiation of investigational product whether 
or not considered to be investigational product related. A worsening of an existing medical 
condition is one that was present at baseline (e.g., cancer, diabetes, migraine headaches, gout) 
and became more severe, more frequent, or increased in duration during investigational product 
treatment.
Reporting Procedures for AEs (>/=2 non-hematological and >/=3 hematological AEs) occurring 
after informed consent signing observed by the investigator or reported by the subject (whether 
or not attributed to investigational product), will be documented to the medical record then 
entered into the case report form. Abnormal laboratory values should not be reported as AEs; 
however, any clinical consequences of the abnormality should be reported as AEs. 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) need not be considered AEs and should not be recorded as 
an AE. Disease progression should not be recorded as an AE. The Investigator is responsible for 
verifying and providing source documentation for all adverse events and assigning attribution for 
each event for all subjects enrolled on the trial.
All patients will be followed for safety 30 days (+/- 10 days) after the last dose of dovitinib, and  
every 3 months for duration of up to one year or until death, whichever occurs first for response, 
PFS and OS. Patients will be followed a minimum of every 3 months by clinic visit (at MD 
Anderson or a local physician), telephone or e-mail correspondence.
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
Investigational New Drugs (IND):
Does this protocol require an IND?
Yes
Who is the IND Holder/Regulatory Sponsor?
MDA
IND Number:
Pending
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:

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Does the Study have a Sponsor, Supporter or Granting Agency?
Yes
Sponsor Name:
Novartis
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?
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).
HER2 status is the only one for determination of eligibility. IHC and FISH are both MDACC CLIA 
certified. 
Other biomarkers  FGFR-R1, VEGF-R1, Cytokines and Micro RNA, CTC, and EMT 
CTC are for research only. 
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:

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Is this research being conducted as a partial fulfillment for completion of a degree?
No