Clinical trial NCT00831792
Conditions: Prostate Cancer
Keywords: Prostate Cancer Advanced Prostate Cancer Castrate Resistant Prostate Cancer Prostate Specific Antigen PSA Castration-Resistant Prostate Cancer Patients TK1258 CHIR-258
Sponsor: M.D. Anderson Cancer Center
Start date: 2010-04-07; Completion date: 2017-06-12
Enrollment: 46 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if a decrease in the levels of prostate specific antigen (PSA) may be linked with the status of prostate cancer that has spread to the bones. Researchers also want to learn how changes in your blood PSA level might affect the rebuilding of healthy bones while you are being treated with TKI258 for prostate cancer.

Detailed description:
The Study Drug:

TKI258 is designed to perform several anti-tumor functions, including cutting off the blood supply to tumors. Researchers think this may help slow or stop the growth of prostate cancer.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will take 4 capsules of TKI258 1 time each day for 5 days in a row followed by 2 days of rest (Days 1-5, 8-12, 15-19, and 22-26 of each 28-day study "cycle"). You should take the TKI258 capsules with about 8 ounces of water and at least 1 hour before a meal (breakfast) or at least 2 hours following a meal (breakfast). If you want, you may take the drug with a meal that has fewer than 500 calories and 20 grams of fat.

Study Visits:

Every 28 days makes up 1 study "cycle."

On Day 1 of Cycle 1 and all cycles after that, the following tests and procedures will be performed:

* Your complete medical history will be recorded.
* You will be asked about any drugs or treatments you may be receiving.
* You will be asked about any side effects you may have experienced.
* You will have a physical exam, including measurement of your vital signs and weight.
* Your performance status will be evaluated.
* Blood (about 2 tablespoons) will be collected for routine tests. This blood will also be tested to measure your PSA.
* You will have a triplicate ECG (3 ECGs in a row) before you take the study drug. You will also have 1 ECG about 6 hours after you take the study drug.

On Day 12 (+/- 3 days) of Cycles 1 and 2, and day 26 of Cycle 1 (+/- 3 days) blood (about 1 tablespoon) will be collected for routine tests. Part of the Cycle 2 blood draw will be used to measure the amount of TKI258 in your system. Note that the Day 26 of Cycle 1 visit could end up being scheduled on the same day as the Day 1 of Cycle 2 visit described above.

On Day 1 of Cycle 2 and every odd numbered Cycle after this (Cycles 3, 5, 7and so on), the following tests and procedures will be performed:

* Blood (about 2 teaspoons) will be collected for routine tests.
* Urine will be collected to test for markers relating to your bone.

At the end of every cycle (about Day 26), you will have an ECG.

Every 3 Cycles (about every 12 weeks), the following tests and procedures will be performed:

* Blood (about 1 teaspoon) will be drawn to measure your levels of heart enzymes
* You will have an echocardiogram or MUGA scan like the one you had at the screening visit to check your heart function.

About 7-10 weeks after your first dose of study drug, you will have another bone marrow biopsy and aspiration performed to check the status of the disease and for biomarker testing.

CT and/or bone scans will be performed every 8 weeks for the first 6 months and every 3 months after that to check the status of the disease.

Length of Study:

You may remain on study for as long as you are benefiting. You will be taken off study if intolerable side effects occur or if the disease gets worse.

End-of-Study Visit:

Within 4 weeks after your last dose of the study drug, you will return to the clinic for an end-of-study visit. The following tests and procedures will be performed:

* You will have a physical exam, including measurement of your vital signs, and weight.
* Your performance status will be evaluated.
* You will be asked about any drugs or treatments you may be receiving.
* You will be asked about any side effects you have experienced since you last visit.
* Blood (about 3 tablespoons) and urine will be collected for routine tests. This blood will also be tested to measure certain hormones, heart enzymes, and PSA.
* You will have a chest x-ray, bone scan, and either a computed tomography (CT) or magnetic resonance imaging (MRI) scan of your abdomen and pelvis to check the status of the disease.
* You will have an ECG and either an echocardiogram or a MUGA scan.
* You will have a bone marrow biopsy and aspiration performed to check the status of the disease and for biomarker testing.

Long-Term Follow-up:

Once you are no longer on this study, the research staff will check up on you about every 3 months. This update will consist of a phone call, an e-mail, or a review of your medical and/or other records. You will not have any extra tests, procedures, or study visits. If contacted by phone, the call would only last about 5 minutes.

This is an investigational study. TKI258 is not FDA approved or commercially available. It is being used in this study for research purposes only.

Up to 40 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: 4 capsules (100 mg/capsules) of TKI 258 by mouth once daily (total of 400 mg of TKI258 per day). Following an initial 4-week cycle at a starting dose of 400 mg 5 days- on and 2 days off, TKI258 may be escalated to 500 mg/day 5 days-on/2 days off if no significant Grade3/4 AEs or laboratory abnormalities are observed.
Interventions: intervention 1: TK1258
Intervention descriptions: intervention 1: 4 capsules (100 mg/capsules) of TKI 258 by mouth once daily (total of 400 mg of TKI258 per day).

Protocol documents:
Prot_SAP_000.pdf: 
Protocol 2008-0510 
May 8, 2013 
Page 1 
 
Study Title: 
An Observational Study of TKI258 in Castration-Resistant Prostate 
Cancer Patients Evaluating Markers of FGF signaling in Bone Marrow 
Plasma. 
Study Phase: 
Phase II Exploratory 
Product Name: 
TKI 258 
IND Number: 
104,602 
Indication: 
Castration-Resistant Prostate Cancer 
Investigators: 
Single Center: U.T. M. D. Anderson Cancer Center 
 
Principal Investigator: 
Name:  Paul Corn, M.D., Ph.D. 
Address:  1155 Pressler Street, Unit 1374 
City, State, Zip: Houston, TX 77030 
Phone: (713) 563-7208 
Fax: (713) 563-0099 
Email: pcorn@mdanderson.org 
 
Co-PI 
Christopher J. Logothetis, M.D. 
Address: 1155 Pressler Street, Unit 1374 
City, State, Zip: Houston, TX 77030 
Phone: (713) 792-2830 
Fax: (713) 745-1625 
Email: clogothe@mdanderson.org 
 
Co-PI 
Name:  Nora Navone, M.D., Ph.D. 
Address:  P.O. Box 301439, Unit 1374 
City, State, Zip: Houston, TX 77030 
Phone: (713) 563-7273 
Fax: (713) 745-9880 
Email: nnavone@mdanderson.org 
 
Supporter: 
Novartis 


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SYNOPSIS 
Name of Finished Product: 
TKI 258 
Study Title:  
An Observational Study of TKI258 in Castration-Resistant Prostate Cancer Patients 
Evaluating Markers of FGF signaling in Bone Marrow Plasma. 
Study Phase: Phase II Exploratory 
Primary Objective:  
 To estimate overall survival and early response as characterized by a drop in PSA 
 To identify the PSA modulation in 40 selected patients with advanced prostate 
cancer, and correlate PSA Modulation with changes in bone remodeling markers  
Secondary Objective(s): 
 
 To estimate the objective tumor response rate by RECIST criteria for subjects with 
measurable disease at baseline. 
 To explore the potential association between serum PSA and bone turnover 
markers with bone marrow FGF R1 and FGF9 while on TKI 258 
 To explore the predictive values of baseline FGF R1, FGF9, and FGF signaling in 
serum and those in the bone marrow before and during treatment with TKI258. 
 To identify candidate mRNA gene expression changes in bone marrow biopsy 
aspirates  following treatment with TKI258 
 To collect and archive bone marrow biopsies and aspirates, serum and plasma in 
study patients for later hypothesis generating associations 
 To explore FGF R expression following eight weeks of TKI 258 
Study Design:  
This is an observational study to explore the effect of TKI258 therapy on bone turnover 
markers (serum bone specific alkaline phosphatase and urinary N-telopeptides), and 
expression of FGF R 1, on both tumor and host cell compartments in bone marrow. 
Study Population:  
Approximately 40 patients are planned for enrollment. 
Test Product, Dose, and Mode of Administration:  
TKI258 500mg PO daily for 5 days, followed by a 2 day rest period. Each cycle is 28 days.  
Duration of Treatment:  
Patients will continue to receive TKI 258 until progression, unacceptable toxicity or 
withdrawal of consent 
Statistical Methods:  
This is a phase IIA activity trial of TKI 258 for treatment of castrate resistant prostate 
cancer with skeletal metastases. The two primary outcomes are survival time and early 
response as characterized by a drop in PSA as defined by Prostate Cancer Working Group 
2 criteria. Based on a historical mean survival of time 8 months, a mean survival time on 
average > 10 months with TKI258 would be considered promising evidence of anti-disease 
activity.  The planned sample size is 40 patients, with an anticipated accrual rate of 3 


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patients per month. Based on historical experience using carefully selected candidates with 
evidence for iliac involvement on bone scan, we anticipate that ~60% of patients will have 
positive biopsies. No early stopping rule in terms of the probability of PSA response will 
be employed because blocking the stromal-epithelial interactive pathway (SE-pathway) 
may produce clinical benefit independent of PSA modulation.  Consequently, it may be the 
case that TKI258 does not cause significant reductions in PSA, but survival time is 
prolonged due to inhibition of disease progression. Given the short survival time of these 
patients and anticipated accrual rate of 3 patients per month, it also will not be feasible to 
implement an early stopping rule in terms of observed survival times.  Based on an 
historical rate of 20% grade 3 or 4 toxicity with standard therapies the method of Thall and 
Sung (1998) will be used to monitor toxicity.  
 
Unadjusted survival time will be estimated using the method of Kaplan and Meier (1958) 
and  the effects of the following four potential prognostic covariates Inhibition of FGF 
signaling by bone marrow biopsy at 8 weeks, modulation of the bone markers (a) urinary 
NTX and (b) bone specific alkaline phosphatase, and  baseline signature of FGF signaling 
in terms of FGF R-1, FGF R-3 and FGF 9 on Prob(PSA response) will be estimated using 
logistic regression, and on survival time will be estimated using the Cox model or an 
appropriate time-to-event regression model. 
 
Preliminaries: This is a phase IIA activity trial of TKI258 for treatment of castrate resistant 
prostate cancer with skeletal metastases. The two primary outcomes are survival time and 
early response as characterized by a drop in PSA as defined by Prostate Cancer Working 
Group criteria (25).   
 
Historical Experience and Goals: Based on the historical experience in which the mean 
survival time was 8 months, under a Bayesian model we assume that the unadjusted mean 
survival time with TKI258 follows an uninformative inverse gamma with mean 8 and 
variance 1000, equivalently with scale parameter 2.064 and shape parameter 8.512, 
denoted mE ~ IG(2.064, 8.512).  A mean survival time on average > 10 months would be 
considered promising evidence of anti-disease activity.  Formally, assuming that the 
historical mean survival mH ~ IG(52, 400),  TKI258 will be considered promising if, 
based on the data from the trial,  Pr(mE >  mH | data ) > .95. The planned sample size is 40 
patients, with an anticipated accrual rate of 3 patients per month.  In addition, the 
relationships between several potential prognostic covariates and the above clinical 
outcomes will be explored, as described below. 
 
Monitoring Rules: No early stopping rule in terms of the probability of PSA response will 
be employed because it is not known whether blocking the stromal-epithelial interactive 
pathway (SE-pathway) will be related to clinical benefit.  Consequently, it may be the case 
that PSA does not drop but survival time is prolonged due to inhibition of disease 
progression by TKI258. Given the short survival time of these patients and anticipated 
accrual rate of 3 patients per month, it will not be feasible to implement an early stopping 
rule in terms of observed survival times.  However, based on an historical rate of 20% 
grade 3 or 4 toxicity with standard therapies, it will be assumed that p = Prob(grade 3 or 4 


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with TKI258) follows a beta prior with parameters (.20, .80).  Using the method of Thall 
and Suung (26), based on the observed toxicity data, accrual to the trial will be stopped 
early if Pr(p > .20 | data)  > .95, with this rule applied after successive cohorts f size 5.  
This rule says to stop the trial if [# patients with a grade 3 or 4 toxicity]/[# patients 
evaluated] is greater than or equal to 3/5, 5/10, 7/15, 8/20, 9/25, 11/30, 12/35.  


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
ALT 
Alanine aminotransferase (SGPT) 
ANOVA 
Analysis of variance 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase (SGOT) 
bid 
Twice daily 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CBC 
Cell blood count 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case report form  
CRPC 
Castration-resistant prostate cancer 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
DHA 
Directions for Handling and Administration 
DHEA 
Dihydroepiandrosterone 
DHT 
Dihydrotestosterone 
FDA 
Food and Drug Administration 
FGF 
Fibroblast Growth Factor 
FGF R 
Fibroblast Growth Factor Receptor 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
Hct 
Hematocrit 
HEENT 
Head, Eyes, Ears, Nose, Throat 
Hgb 
Hemoglobin 


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HIPAA 
Health Information Portability and Accountability Act 
ICH 
International Conference on Harmonisation  
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
LDH 
Lactic dehydrogenase 
LHRH 
Luteinizing hormone-releasing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NDA 
New Drug Application 
PSA 
Prostate Specific Antigen 
qd 
Once daily 
qid 
Four times daily 
RBBB 
Right bundle branch block 
RBC 
Red blood cell (count) 
RH 
Relative humidity 
RTK 
Receptor Tyrosine Kinase 
SAE 
Serious adverse event 
SD 
Standard deviation 
SE 
Standard error  
SGOT 
Serum glutamic oxaloacetic transaminase (AST) 
SGPT 
Serum glutamic pyruvic transaminase (ALT) 
SSRIs 
Serotinin reuptake inhibitors 
tid 
Three times daily 
US 
United States 
WBC 
White blood cell (count) 


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1.0 INTRODUCTION 
1.1 
Receptor Tyrosine Kinsases (RTKs) are involved in both the growth of different types 
of tumors as well as in the initiation, growth, and maintenance of blood vessels 
supplying the tumor with blood, oxygen, and nutrients (Schlessinger 2000, Arteaga 
2001, and Cohen 2002). Several members of the RTKs are expressed on solid tumors 
and are involved in cancer cell growth and survival (Collett and Erikson 1978; 
Takahaski, et al 1995). In some cases, mutations of these RTKs and their subsequent 
aberrant signaling are directly linked to the abnormal growth (Mizuki, et al 2000; 
Deininger, et al 2000). In many other cases, expression and/or overexpression of 
these RTKs have been demonstrated; however, the exact role of these kinases in 
driving most cancerous growth is still unknown. Some tumors, however, are known 
to have their growth driven by a single mutation in a growth factor receptor kinase. 
These include FLT3 mutations in 20% to 30% of patients with AML (Gilliland and 
Griffin 2002); FGFR3 ectopic expression/mutation in 15% to 20% of patients with 
multiple myeloma (Rasmussen, et al. 2003; Li, et al 2001); c-KIT in gastrointestinal 
stromal tumors (GIST), a rare form of stomach cancer (DeMatteo 2002), and the 
Philadelphia chromosome fused gene translocation mutation (Bcr abl) in nearly all 
patients with CML (Druker, et al 2001). 
 
RTKs such as VEGF receptors, FGF receptors, and PDGF receptors have been shown 
to play an important role in tumor angiogenesis (Dvorak 2003). 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 (Nagy, et al 2002). FGFs 
are potent stimulators of angiogenesis in both normal and pathological tissues, having 
a direct effect on both vessel assembly and sprouting (Auguste, et al 2003). 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 (Casanovas, et al 2005). PDGF 
receptors are expressed on pericytes - smooth muscle cells that surround the 
vasculature and provide maintenance and support to the tumor neovasculature 
(Bergers, et al 2003). Inhibition of these three growth factor receptor kinases should 
provide a powerful and broad inhibition of the angiogenesis process and provide 
potent antitumor effects. TKI258 is a potent inhibitor of these three RTKs as well as 
other RTKs directly involved in tumor cell growth, particularly activating mutations 
of c-KIT and FLT3. Nonclinical studies were conducted with TKI258 free base or its 
lactate, mesylate, or hydrochloride salts. For consistency, these forms are collectively 
referred to as TKI258 in this document.  
 
As mentioned above, the pathways and growth factors involved in angiogenesis and 
tumor cell growth are very complex and in many cases redundant. The first 
generation receptor kinase inhibitors to undergo clinical trials were in many cases 
specific inhibitors of a single receptor kinase. Compounds such as gefitinib (Iressa®) 
(EGFR), SU5416 (VEGF), and PTK787 (VEGF) are examples of some of the earlier, 
single targeted kinase inhibitors (Arteaga 2003; Dancey and Sausville 2003). A 
second generation kinase inhibitor, SU6668, hits a variety of kinase targets, including 
PDGFR, VEGFR, and FGFR. Other drug candidates such as ZD6474 (vandetanib), 


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SU11248 (sunitinib), and BAY43-9006 (sorafenib) were later developed to have 
activity against a variety of growth factor receptor kinases. Sunitinib (Sutent®) and 
sorafenib (Nexavar®) have recently been approved for the treatment of advanced 
renal cell carcinoma, an indication with a high level of VEGF-induced angiogenesis. 
Sunitinib was also approved in refractory GIST, a tumor type driven by activating 
mutations in c-KIT. The approval of these drugs provides clinical rationale for the 
development of additional multi-targeted receptor tyrosine kinase inhibitors with 
different target profiles. TKI258 is from a novel chemical series, inhibits multiple 
cancer or angiogenesis related kinases, and has favorable physicochemical and PK 
properties. TKI258 has potent activity in a variety of nonclinical tumor xenograft and 
targeted-tumor or angiogenesis animal models. 
 
1.2 
Background /Rationale 
Androgen deprivation (AD) therapy induces a remission in 80% to 90% of patients 
with advanced prostate cancer and results in a median progression-free survival of 12 
to 33 months, at which time; an androgen-independent phenotype usually emerges. 
 
Androgen deprivation can be achieved surgically with orchiectomy, or medically 
using some form of drug treatment that lowers serum testosterone.  Medical castration 
is commonly achieved with luteinizing hormone - releasing hormone (LHRH) 
agonists (for example, Lupron).  The conventionally accepted definition of castration 
is a serum concentration of testosterone to less then 50 ng/dl. Additional anti-
androgen therapies include classes of agents that: (1) block testosterone activity (for 
example, bicalutimide), (2) block adrenal synthesis of testosterone (for example, 
ketoconazole); or (3) synthetic estrogens (for example, DES). These agents are 
generally used to treat patients who demonstrate PSA and/or clinical progression 
while on Lupron monotherapy. Because many cancers continue to respond to these 
“second-line” hormonal strategies (given either singly or in combination) despite 
castrate levels of testosterone, this clinical state is referred to “castrate-resistant” 
disease (as opposed to “hormone-refractory” disease).  
 
After failure of anti-androgen therapy, patients with castrate-resistant prostate cancer 
are routinely treated with cytotoxic chemotherapies. Two randomized trials testing 
docetaxel based regimens demonstrated PSA responses ranging from 40 to 50% but 
only a modest survival benefit of ~ 2 to 3 months. Chemotherapy was also associated 
with significant toxicities, including grade 3/4 neutropenia (~30%), infections (~6%), 
anemia (~5%), fatigue (~5%), dyspnea (~3%), nausea (~3%), diarrhea (~2%) and 
neuropathy (~1.5%). Based on these data, docetaxel-based chemotherapy is an option 
for patients with castrate-resistant disease but is not considered “standard of care”.   
Current research efforts are now focused on identifying novel molecularly targeted 
therapies that will reduce morbidity and mortality from castrate-resistant disease and 
obviate (or at least delay) the use of cytotoxic chemotherapy.  
 
The propensity for prostate cancer to metastasize to the skeleton has led investigates 
to speculate that the tumor microenvironment and the stromal-epithelial interactions 
within bone are critical for prostate cancer progression. Furthermore, the development 


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of castrate resistant disease is almost invariably associated with some extent of tumor 
infiltration into the bone marrow.  There is evidence of increased expression of 
androgen converting genes in the castrate-resistant bone marrow tumor 
microenvironment.  
 
MD Anderson Experimental observation: 
We recently discovered that prostate cancer cells, especially those that had 
metastasized to bone, overexpress fibroblast growth factor 9 (FGF9), a discovery that 
prompted us to study how FGF9 participates in prostate cancer progression and 
metastasis.  FGF9 (also known as glial activating factor) is a secreted, glycosylated 
26-kDa protein that has mitogenic effects on a variety of different cell types. In the 
normal prostate, FGF9 is not expressed by prostate epithelial cells, but is expressed 
by prostate stroma cells [21]. We have recently found positive staining for FGF9 in 
prostate cancer cells in 24 of 56 primary tumors derived from organ-confined prostate 
cancer and in all the bone metastases cases studied (25 of 25) (Table 1 and Figure 1). 
Findings were confirmed by RT-PCR analysis of RNA obtained by laser capture 
microdissection of normal prostate epithelial cells and prostate cancer epithelial cells 
derived from two bone metastases (Figure 1a). This switch in the source of FGF9 
from the stroma to the cancer cells could increase the availability of FGF9, thereby 
favoring prostate cancer growth or survival at metastatic sites (Li, et al. 2008).   
 
Figure 1a. Fibroblast growth factor 9 (FGF9) expression in a normal prostate and 
prostate cancer.  Upper panels and lower left and middle panels, 
immunohistochemical staining with antibody to FGF9 in normal prostate, two cases 
of organ confined primary prostate cancer (one positive and one negative for FGF9 
expression) and two cases of bone metastases of prostate cancer. Original 
magnification 200x. Lower right panel, reverse-transcription polymerase chain 
reaction analysis of FGF9 expression in normal prostate (NP) and two case of bone 
metastases of prostate cancer (BM). gapdh - glyceraldehyde-3-phosphate 
dehydrogenase. 
 


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To obtain preclinical evidence of the role of FGF9 in the osteoblastic progression of 
prostate cancer cells in bone, we used a new prostate cancer xenograft (MDA PCa 
118b) derived from a bone metastases in a man with castrate resistant prostate cancer. 
MDA PCa 118b cells, which express high FGF9 levels, induce the proliferation of 
cocultured osteoblasts in vitro and can grow and induce a strong osteoblastic reaction 
in the bone of immunodeficient mice. We found that MDA PCa 118b–induced 
osteoblast proliferation in vitro was blocked by FGF9 antibody and that FGF9 
induced the formation of new bone in an organ-culture assay. To assess in vivo the 
relevance of FGF9 in the osteoblastic bone growth of this model, we examined the 
effect of blocking FGF9 signals in mice injected with MDA PCa 118b cells into their 
femurs. We injected MDA PCa 118b (1X106) cells into the femurs of 20 SCID male 
mice. Ten mice were treated with neutralizing antibody against FGF9 (R&D (Clone 
36912), 250 µg/mouse) i.v. twice weekly and another 10 mice were treated with IgG 
isotype (R&D, 250 µg/mouse) i.v. twice weekly. Treatment started the same day of 
cell injection and was performed for five consecutive weeks at which time tumor 
volumes in the femurs were determined by MRI analysis following established 
procedures [22].  MRI analysis of MDA PCa 118b tumors five weeks after cell 
injection demonstrated that the mice treated with FGF9 neutralizing antibody 
developed significant smaller tumors than controls did (P=0.011, Figure 1b). In order 
to assess whether the MDA PCa 118 induced bone reaction was also affected by 
FGF9 blockade, we subsequently monitor the tumor associated bone mass by weekly 
X-ray analysis and terminated the experiment 7 weeks after cell injection (2 weeks 
post end of treatment).  We then performed specimen micro CT analysis (20 µm 
resolution) of tumor bearing bones and found a significantly lower bone volume in 
the femur of treated than in control mice (P=0.0057). Accordingly, histological 
analysis of tumor bearing bones demonstrated areas of woven bone in control but not 
in treated femurs (Figure 2).   Taken together, these results suggest that FGF9 plays 
an important role in the osteoblastic progression of prostate cancer cells in bone (Li et 
al. 2008).  


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Figure 1b. Effects of FGF9 blockade on MDA PCa 118b bone growth and 
osteoblastic reaction in vivo. (A) Tumor volume. MDA PCa 118b tumor visualized 
and quantified by T2-weighted, fat suppressed MR. Left and middle panels: 
Representative axial MR images of mice injected with MDA PCa 118b cells in the 
femur and obtained after five weeks of treatment with FGF9 neutralizing antibody or 
IgG isotype. Arrows indicate tumor. Tumors were confined to the bone, spreading 
throughout the femur area in the IgG treated mice (control) and scattered in the bone 
area in the mice treated with FGF9 neutralizing antibody. Right panel: Volumes of 
regions of increased signal in the MDA PCa 118b injected femur measured by MR 
after five weeks of treatment were significantly higher in the control than in the 
treated mice (P=0,011).  (B) Bone mass.  X-Ray - Radiographs show mouse pelvis 
and rear limbs of mice 7 weeks after intrafemoral injection of MDA PCa 118b cells in 
the control and treatment groups. Arrows indicate area illustrated in the lower panels 
(H&E). H&E. H&E–stained sections of MDA PCa 118b bearing femurs. Note that 
the marrow cavity is fill with new bone (NB) in the femurs of the control but not the 
treated mice M, bone matrix; NB, new bone.  
 
µCT - Effect of FGF9 blockade on bone volume fraction.  Lower panel, cross-
sectional views of both control and tumor-bearing bones.   
 
Prostate cancer is a characterized by a unique bone marrow. Castrate resistance is 
almost invariably associated with some extent of infiltration of the bone marrow.   
 


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1.3 
Drug and Dosing Information 
TKI258 (dovitinib lactate) is an investigational new drug initially discovered and 
developed under the name of CHIR-258 by Chiron Corporation, now part of Novartis. 
TKI258 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, TKI258 is being studied in clinical 
trials as a cancer therapeutic.  
 
TKI258 has in vitro inhibitory activity against vascular endothelial growth factor 
(VEGF), basic fibroblast growth factor (bFGF), and platelet derived growth factor 
(PDGF) receptor kinases with IC50 values of approximately 10 nM. These 
structurally related receptors are important for the growth and survival of endothelial 
cells during tumor angiogenesis; PDGFR and FGFR are also believed to play a role in 
the proliferation of certain tumor cells and supporting stromal cells. Based on growth 
factor specific cell based assays and kinase assays, additional kinases such as stem 
cell factor receptor (c-KIT), FMS like tyrosine kinase 3 (FLT3), colony stimulating 
factor 1 (CSF 1R), tyrosine receptor kinase A (TrkA) and the Ret oncogene are also 
inhibited in vitro with IC50s below 10 nM (for c-KIT, FLT3, TrkA and RET) and 
below 40 nM (for CSF 1R). c-KIT and FLT3 have been implicated to play a role in 
leukemias; CSF 1R has been implicated in the activation of osteoclast progenitor 
cells, initiating bone resorption in multiple myeloma, and other cancers that are 
associated with bone metastasis. Distantly related RTKs and most serine/threonine 
kinases were not inhibited by TKI258. 
 
As a result of inhibition of RTKs by TKI258, cellular functions are blocked, 
including activation of downstream-signaling molecules, cellular proliferation, and 
survival. In cultured human endothelial cells expressing VEGFR, TKI258 inhibits 
VEGF stimulated mitogenesis.  In a FGF2 dependent model of angiogenesis, TKI258 
potently inhibited neovascularization of Matrigel plugs in vivo with an average ED50 
of 3 mg/kg. The effects on endothelial cells suggest that TKI258 may have potent 
antiangiogenic activity. Additionally, direct antiproliferative effects were observed in 
cell lines; those cells that expressed an RTK inhibited by TKI258 were most sensitive 
to the drug (MV4;11: an acute myeloid leukemia [AML] cell line driven by 
constitutively active FLT3; TF 1: a AML cell line driven by c-KIT; KMS11: a 
multiple myeloma line driven by an activating mutation in FGFR3; RT112 and RT4 
bladder cancer cell lines overexpressing FGFR3; and the colon cancer cell line 
KM12L4a, driven by TPM3-TRKA translocation). Antitumor effects for this agent 
may therefore be conferred by antiangiogenesis, antistromal activity, and 
antiproliferative activity directed against tumor cells that directly express TKI258 
targets. 
 
The antitumor activity of TKI258 was evaluated in a variety of tumor xenograft 
models in athymic mice. In all models tested, TKI258 administered orally caused 
anti-tumor responses, ranging from growth inhibition and stasis to regression in tumor 
models driven by activating mutations of TKI258 targets. Furthermore, in a model of 


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disseminated disease, colonization of breast cancer cells in the livers of mice from a 
subcutaneous (SC) xenograft primary was significantly reduced by oral treatment 
with TKI258. To demonstrate that direct inhibition of RTKs in tumors was a primary 
mechanism of xenograft growth inhibition by TKI258, tyrosine phosphorylation of 
VEGFR2, PDGFRβ, FGFR3 and the downstream-signaling proteins AKT (also 
known as protein kinase B) and ERK (also known as MAPK) was shown to be 
inhibited following a single oral dose of TKI258. Inhibition was observed up to 24 
hours (h) in some models. These results indicate that TKI258 may be useful in the 
treatment of disseminated disease and leukemia, as well as solid tumors and 
myeloma. The broad target profile of TKI258 is likely to contribute to its efficacy in 
many different types of tumor models by acting on endothelial cells and tumor cells. 
 
The safety of TKI258 was evaluated on a daily dosing schedule in rats, dogs, and 
monkeys.  The dose-limiting toxicity in all animal species tested was gastrointestinal 
irritation reflected in emesis, diarrhea, severely decreased food consumption, and 
severe body weight loss. There were no target organs identified for clinical 
monitoring other than GI irritation. At severely toxic doses, morbidity was attributed 
to emaciation. Comparison of plasma exposure between species for assessment of a 
safety margin was confounded by the time-dependent reduction in plasma exposure 
of TKI258 (as assessed by maximum plasma concentration [Cmax] and area under 
the concentration time curve [AUC] values) following repeated oral administration. 
Therefore, body surface area-normalized dosing between species provided the most 
accurate prediction of safety. 
 
TKI258 is manufactured for use in clinical trials as a 100mg hard gelatin capsule. As 
of 10 September 2010, there were a total of 420 patients enrolled in the nine Phase I 
and three Phase II single agent clinical studies: CTKI258A1101 (1101) (advanced 
solid tumors), CTKI258A2101 (2101) (advanced solid tumors), CTKI258A2102 
(2102) (acute myeloid leukemia [AML]), CTKI258A2103 (2103) and 
CTKI258A2104 (2104) (multiple myeloma [MM]), CTKI258A2105 (2105) (locally 
advanced or metastatic melanoma), CTKI258A2106 (2106) (advanced solid 
malignancies,) CTKI258A2107 (2107) advanced/ metastatic renal cell cancer (RCC), 
CTKI258A2112 (2112) (Phase 1, Bioavailability - FMI capsules), CTKI258A2116 
(2116) (Phase I, Bioavailability - FMI tablets), CTKI258A2202 (2202) (Phase II, 
metastatic breast cancer) and CTKI258A2204 (2204) (Phase II, multiple myleoma). 
Clinical studies 2101, 2102, 2103, 2104, 2105 and 2106 have been discontinued and 
the 1101, 2107, 2112, 2116, 2201, 2202 and 2204 studies are ongoing. The maximum 
tolerated dose (MTD) of TKI258 for the continuous daily dosing regimen was defined 
at 400 mg/day (study 2105); the MTD for the intermittent dosing regimen of 5 days 
on/2 days off was defined at 500 mg/day (study 2107). The MTD has not been 
established in Japanese population (dose escalation is still ongoing for study 1101). 
 
 
Adverse events (AEs) and laboratory data (hematology and chemistry) were available 
from 382 patients as of 10 September 2010. The five most commonly reported non-
laboratory AEs were nausea, fatigue/asthenia, diarrhea, vomiting and 


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anorexia/decreased appetite for both continuous daily dosing and 5 days on/2 days off 
dosing regimens. Commonly reported AEs were reversible and manageable; most 
were mild or moderate in severity (CTCAE grade 1 or 2). 
 
The majority of the hematology laboratory abnormalities were grade 1 or 2 events 
across all dosing regimens. In continuous dosing regimen studies, five patients (3.5%) 
had grade 4 hemoglobin values, 7 patients (7.4%) had grade 4 absolute neutrophil 
count (ANC) values, 19 patients (14.6%) had grade 4 platelet counts, and 9 patients 
(6.9%) had grade 4 WBC values during study participation. The relatively higher 
incidence rate of grade 3/4 hematology abnormalities in the continuous daily dosing 
regimen was mainly due to acute myeloid leukemia (study 2102) and multiple 
myeloma (studies 2103 and 2104) patients. In global 5 days on/2 days off dosing 
regimen studies, 2 patients (1.3%) had grade 4 ANC values, 1 patient (0.5%) had 
grade 4 platelet counts, and no patients had grade 4 hemoglobin or white blood counts 
during study participation. Also, one patient (4.5%) had grade 4 hemoglobin in the 
Japanese 5 days on/2 days off dosing regimen study and no patients had grade 4 
ANC, platelet or white blood cell counts. 
 
Regarding biochemisty laboratory abnormailities, the most frquent lab test 
abnormalities observed were liver function test elevations (aspartate aminotransferase 
[AST], alanine aminotransferase [ALT], alkatine phoshatase, and total bilirubin). In 
most cases these changes were CTC grades 1 or 2. Overall CTC grade 3 or 4 liver 
function test abnormailites were seen in < 10% of patients treated with dovitinib. 
There was one fatal case of hepatoxicity (cholestatic liver injury); both the death and 
the heaptotoxicity were deemed related to dovitinib treatment by the investigator. 
As of the 10 September 2010 cutoff date, data from a total of 5196 ECGs (of which 
3432 were post-treatment) were obtained from 360 patients across ten studies (2101, 
2102, 2103, 2104, 2105, 2107, 2112, 2201, 2202, and 2204). The time-averaged 
changes from baseline ECG for each patient across different study days and dose 
groups were investigated. Outlier analyses were performed according to the ICH E14 
guidance. The results of the analyses of  the available ECG data do not reveal any 
effect of TKI258 on cardiac repolarization across days and doses of therapy, nor is 
there any specific outlier signal observed consistent with the central tendency finding. 
 
In September 2009, an exposure ECG analysis was conducted through a mixed effect 
linear model using 546 matching ECG-TKI258 concentration data from 61 patients 
(studies 2105 and 2107 in which more timepoints with ECG monitoring and PK 
sample collection were availabe). The exposure-ECG analysis confirmed the 
conclusion of no-QTc prolonging signal from central tendency and outlier analyses. 
 
Left ventricular ejection fraction (LVEF) data were available from 200 patients who 
had both pre- and post-treatment data from studies 2101, 2102, 2103, 2104, 2105, 
2107, 2112, 2201, 2202 and 2204. Of these patients, 21 had ≥ 20% post-treatment 
LVEF decrease on ECHO or MUGA. Among the 21 patients, 11 patients had LVEF 
decrease to a value that was below 50%. The LVEF data were reviewed by an 


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independent cardiologist consultant. According to his assessment, based on the 
available data, TKI258 had no effect on the LVEF. 
 
In summary, based on the available data, no consistent pattern of cardiac events 
related to TKI258 administration has been observed to date. More data will be 
collected to further assess the cardiac safety in relationship to TKI258 treatment. 
Although efficacy was not the primary end point for the dose escalation portion of the 
Phase I trials, preliminary efficacy data were obtained from some of the studies. Two 
metastatic renal cell cancer patients treated at 500 mg on a 5-day on/ 2-days off 
dosing regimen in study 2107 achieved confirmed partial response (PR). A FLT3-ITD 
acute myeloid leukemia (AML) patient who was treated at 100 mg/day in study 2102 
achieved a morphologic complete remission with incomplete blood count recovery. 
Unfortunately the patient’s peripheral blood count did not recover and the patient died 
unexpectedly due to a fungal infection, secondary to diseae progression. This patient 
stayed on the study for 69 days. A metastatic melanoma patient who was treated at 
175 mg/day in study 2101 achieved a partial response at the end of cycle 11 and 
remained on treatment for 3.3 years (1217 days) before discontinued due to disease 
progression.  
 
As of March 2010, pharmacokinetic data were available from 178 patients in studies 
CTKI258A2101, CTKI258A2102, CTK2582103/2104, CTKI258A2105, 
CTKI258A2106 and CTKI258A2107. Noncompartmental analysis was conducted on 
full plasma PK profiles of TKI258. Coefficients of variation in the PK parameters 
(Cmax and AUC24hr) were between 16 and 111%. Cmax was observed at 
approximately 4 - 8 hours after dosing, and the concentration of TKI258 declined 
monoexponentially thereafter. Within the tested dose levels ranging from 25 to 600 
mg/day, linear absorption of TKI258 was observed. TKI258 was extensively 
distributed to tissues.  
 
Time-dependent PK of TKI258 was observed across all tested dose levels ranging 
from 25 to 600 mg/day. Following daily administration at dose below 400 mg, the 
auto-induction of CYP1A1/A2 resulted in lower plasma exposure of TKI258 on day 7 
(steady state) than that observed on day 1. However, after increasing the daily dose to 
400 - 600 mg, TKI258 plasma concentration on day 7 was found to be similar to or 
greater than that on day 1, suggesting a more pronounced accumulation of TKI258 at 
higher doses. In addition, an over-proportional increase in TKI258 plasma exposure 
was observed with doses from 400 to 600 mg/day. The maximum tolerated dose of 
TKI258 for the continuous daily dosing schedule was 400 mg (CTKI258A2105). 
 
The time-dependent PK and the nonlinear PK resulted in dose-dependent time to 
reach steady state, as well as dose-dependent accumulation at steady state. To prevent 
the prolonged and over-proportional accumulation in TKI258 exposure with dose 
escalation, an intermittent dosing schedule of 5 days on/2 days off was proposed for 
study CTKI258A2107. At tested dose levels of 500 mg and 600 mg, no accumulation 
was observed on day 15 (steady state). 
 


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The MTD for the 5 days on/2 days off dosing schdule was 500 mg (CTKI258A2107). 
The human ADME study identified the major metabolites as C-hydroxyl metabolites 
(in feces) and N-oxide (in plasma). The ADME study demonstrated that majority of 
the total dose administered was recovered from feces, and less than 21% of the dose 
was recovered in urine.  
 
No formal drug-drug interaction studies have been conducted. Available data from 
human as well as in vitro studies demonstrated that TKI258 has low or no inhibition 
potential for CYP450s. Therefore, TKI258 is not expected to cause inhibitory 
metabolic drug-drug interactions when co-administered with drugs metabolized by 
CYP450s. TKI258 induces CYP1A2, CYP2C9 and CYP2C19; hence co-
administration with substrates of CYP1A2/2C9/2C19 could reduce the exposure of 
these substrates.  
 
A relative bioavailability study (CTKI258A2112) was conducted to compare the final 
market image (FMI) capsule of TKI258 (monohydrate salt) with the clinical service 
form (CSF) capsule of TKI258 (anhydrate salt). PK data from 16 evaluable patients 
demonstrated that FMI capsule and the CSF capsule have comparable bioavailability. 
Therefore, FMI capsules will replace CSF capsules to be used in the new clinical 
studies moving forward. . 
 
The effect of food on the bioavailability of TKI258 was studied in 19 patients with 
advanced solid tumors (CTKI258A2112 Arm 2;  FMI capsule formulation).  The PK 
of TKI258 following administration with no meal (i.e. at least 1 hour prior to a light 
meal or at least 2 hours following a light meal) (NM), with a low-fat meal (LF) or 
with a high-fat meal (HF) were compared to determine the relative bioavailability of 
drug administered with LF and HF compared to NM.  The results demonstrated that 
there was no clinically relevant effect on the AUC or Cmax of TKI258 when 
administered with either LF or HF meal relative to NM (please refer to the current IB 
for additional information).  However, the study design did not allow an assessment 
of the impact of consistently taking the daily TKI258 dose with HF in the multiple-
dosing condition, compared to no effect expected when consistently taking the drug 
with LF and NM, or occasionally with HF.  Based on the results of the food effect 
test, TKI258 may be taken, as previously, without food, or with an amount of food up 
to the level tested, i.e. low-fat meal of ≤ 500 calories with ≤ 20 grams fat. 
 
Examples of a low-fat meal of approximately 500 calories and 20 grams of fat  
include: (1) 6 ounces (approximately 177 mL) of orange juice (except Seville), 8 
ounces (approximately 237 mL) of 2% milk, 1 banana, ¾ cups of cereal, a slice of 
toast and 2 teaspoons (approximately 10 ml) of butter; (2) 1 cup of plain 
congee/porridge (approximately 240-250mL), 1 cooked salted duck egg or 1 
preserved duck egg and 1 steamed pork bun; (3) 1 cup of steamed rice (186 g), 1 cup 
of miso soup (approximately 240-250mL), fried soybean curd (30 g) and 1 fried egg. 
If taken without food,  
 


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Plasma VEGF levels have been reported as a pharmacodynamic (PD) biomarker for 
drugs of anti-VEGF/VEGFR pathways such as bevacizumab (Avastin®), sunitinib 
(Sutent®) and PTK787/ZK222584. The preliminary PD data from study 2102 (AML) 
indicated that VEGF levels were increased in patients treated with TKI258 at 400 mg 
dose but not at lower doses. 
 
In the melanoma trial (study 2105), plasma VEGF level were increased 2-5 fold at 
cycle 1 day 26 in 3 patients treated at 400 mg and 4 out of 5 patients at 500 mg. 
Patients at all dose levels had 20-30% reduction of soluble VEGFR2 in plasma, which 
is consistent with other VEGFR2 inhibitor such as sunitinib and sorafenib 
(Nexavar®).  
 
Reduction of leukemic blasts either in bone marrow or in peripheral blood has proven 
to be a robust marker of tumor burden in clinical trials of FLT3 inhibitors and has 
been routinely monitored as a primary response marker. In study 2102, a total of 32 
patients were enrolled at doses ranging from 50 - 600 mg. Of these 32 patients, 26 
had measurable blasts. Of the 26 patients who had measurable blasts, 4 had blast 
increases without any reduction while on the study; 22 showed > 50% blast cell count 
reduction at some point during the study and 16 of these 22 patients sustained this 
level of reduction over the course of the study. The median duration of blast reduction 
for these 16 patients was 21 days (range 2 - 82). Of the 22 patients who had > 50% 
blast cell count reduction, 7 patients were FLT3-ITD and 15 patients were FLT3-WT. 
 
 
 
1.3.1 Physical, chemical and pharmaceutical properties 
TKI258 lactate salt (TKI258 or TKI258LC) is designated chemically as (4 Amino 5 
fluoro 3 [6 (4 methyl 1 piperazinyl) 1H benzimidazol 2 yl] 2(1H) quinolinone mono 
DL lactate) and its structural formula is: 
 
 
 
TKI258 is a yellow to orange and/or brownish tinged, nonhygroscopic solid that 
dissociates into TKI258 free base and lactic acid between 125 to 250oC. Its molecular 
formula is C21H21FN6O • C3H6O3 (molecular weight 482.5). TKI258 is freely 
soluble in water, DMSO, 1 methy 2 pyrrolidone, and acetic acid. In buffered aqueous 
solutions, depending on the prevailing pH, TKI258 reverts back to the appropriate 


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ionized species or free base. Since the degree of ionization is pH dependent, the 
solubility of TKI258 varies with pH (e.g., 6 μg/mL at pH 7 and 13.6 mg/mL at pH 2). 
 
1.3.2 Clinical formulations 
TKI258 is available in a capsule form. Each hard gelatin capsule contains TKI258 
equivalent to 100 mg of TKI258 free base. The inactive ingredients for the TKI258 
capsules are pregelatanized starch, colloidal silicon dioxide, microcrystalline 
cellulose, and magnesium stearate. The capsules are stored in a high-density 
polyethylene bottle. Each bottle will contain 30 capsules. The capsules should be 
stored between 15 to 30 °C (59 to 86 °F) in a secured, limited access area until 
required. 
 
1.4  
Pre-clinical studies 
TKI258 was evaluated in a number of in vitro and in vivo nonclinical models to 
characterize its pharmacology, antitumor efficacy, pharmacokinetics, metabolism, 
and toxicology. TKI258 is an RTK inhibitor with potent antiangiogenic and 
antiproliferative activity. It targets type III, IV, and V RTKs, which include PDGFRβ, 
CSF 1R, KIT, FLT3, VEGFR, TrkA, RET and FGFRs. The biochemical and cell 
based potency against these receptors is in the nanomolar range. As a result of 
inhibition of target RTKs by TKI258, cellular functions are blocked, including 
activation of downstream-signaling molecules, cellular proliferation, and survival. 
Additionally, in vivo antitumor effects have been observed in a variety of nonclinical 
models representing solid and hematological cancers. The in vivo effects of TKI258 
were shown to be a result of its dual mechanisms of action: antiangiogenesis and 
direct antitumor activity. Inhibition of angiogenesis (through inactivation of VEGFR, 
PDGFRβ, and FGFR on stroma and endothelium) was demonstrated by a reduction in 
hemoglobin concentration in subcutaneous Matrigel plugs, as well as reduced 
microvessel density in tumor xenografts after administration of TKI258. Direct 
inhibition of RTK activation on tumor cells (PDGFRβ, FLT3, and FGFR 1 & 3) was 
confirmed by a reduction in phosphorylation of these target RTKs, as well as 
signaling pathway components (ERK, STAT5, and AKT) in tumor xenografts (Chase 
et al. 2007). Target inhibition was observed for as long as 24 h after a single high 
dose of TKI258. A decrease in tumor cell proliferation and induction of apoptosis, in 
combination with the antiangiogenic effect of TKI258, resulted in significant 
antitumor efficacy. The target profile of TKI258 is likely to confer activity in many 
different types of solid and hematologic tumor models by acting on both endothelial 
cells and tumor cells. In all human tumor xenograft models tested, including colon, 
prostate, myeloma, AML, breast, and ovarian, TKI258 had anti-tumor effects on both 
small and large established tumor xenografts. 
 
TKI258 has high oral bioavailability in mice, rats, and monkeys, and moderate 
bioavailability in dogs. The agent clears rapidly from plasma with an elimination t1/2 
of about 3 hours in mice, rats, dogs, and monkeys. TKI258 distributes widely to 
tissues, including tumor xenografts (in mice). After multiple dosing, TKI258 
demonstrates a time dependent reduction in plasma exposure in rats, dogs, and 
monkeys, but not mice. Two major metabolites were identified in vitro and in vivo in 


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plasma from mice, rats, and monkeys. The N desmethyl TKI258 metabolite 
(generated by CYP3A4) has in vitro potency similar to that of TKI258, whereas the N 
oxide TKI258 metabolite (generated by FMO) is 5 to 10 fold less active.  
 
TKI258 is metabolized by a number of enzymes, including CYP2C8, CYP2D6, 
CYP3A4, CYP1A1/2, FMO1, FMO3, and FMO5.  Though no drug interactions have 
been studied clinically, drugs that inhibit or induce such enzymes may interact with 
TKI258. TKI258 demonstrated low inhibition potential (IC50 greater than 25 µM) in 
five major human hepatic cDNA derived CYP450 isozymes and in pooled human 
hepatic microsomes (CYP 3A4, 2D6, 2C19, 2C9, 1A2), suggesting that TKI258 is 
unlikely to cause significant inhibitory metabolic drug drug interactions when 
coadministered with drugs metabolized by the major CYP450s. The induction 
potential of TKI258 was evaluated in primary cultures of rat, dog, monkey and 
human hepatocytes.  TKI258 treatment was not associated with the induction of 
CYP2B or CYP3A protein or enzyme activity in these species.   
However, TKI258 treatment was associated with the induction of CYP1A1 and 
CYP1A2 protein and activity, as well as with the induction of UGT protein in dog, 
monkey and human hepatocytes. Therefore potent inhibitors/inducers of these 
enzymes, such as quinidine (a CYP2D6 inhibitor), fluvoxamine (CYP1A inhibitor), 
omeprazole (a CYP1A inducer), ketoconazole, itraconazole, erythromycin and 
glibenclamide (CYP3A4 inhibitors), as well as phenobarbital, phenytoin, 
carbamazepine and rifampicin (all CYP3A4 inducers), should be used with caution. 
 
The safety of TKI258 was evaluated on a daily dosing schedule in rats, dogs, and 
monkeys for up to 28 consecutive days to determine target organ toxicity and the safe 
starting dose in clinical trials, and to provide information for clinical monitoring. A 
no- to minimal-effect level was approximately 60 mg/m², and 180 mg/m² approached 
the MTD after 28 days of daily dosing. The dose-limiting toxicity in all animal 
species tested was gastrointestinal irritation reflected in emesis, diarrhea, severely 
decreased food consumption, and severe body weight loss. There were no target 
organs identified for clinical monitoring other than GI irritation. At severely toxic 
doses, morbidity was attributed to emaciation. Comparison of plasma exposure 
between species for assessment of a safety margin was confounded by time-
dependent reduction in plasma exposure of TKI258 (as assessed by Cmax and AUC 
values) following repeated oral administration. Therefore, body surface area-
normalized dosing between species provided the most accurate prediction of safety. 
 
1.5 
Pharmacology 
TKI258 demonstrated activity in a number of in vitro and in vivo models. It potently 
inhibits the activity of multiple RTKs including PDGFRβ, CSF 1R, KIT, FLT3, 
VEGFR, TrKA, RET, and FGFR. Inhibition of these RTKs impedes tumor growth 
and progression through different mechanisms, including both direct antitumor effects 
and effects on host tissues, such as endothelial cells and supporting stromal cells. 
Antiangiogenic effects are due to the pivotal role of these receptors and their growth 
factors in growth and maintenance of new blood vessels supplying the tumor. In 


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addition, inhibition of these receptors results in modulation of important downstream-
signaling pathways that are essential for tumor cell proliferation and metastasis. 
 
TKI258 inhibited angiogenesis in an FGF driven murine model of neovascularization 
with a minimum effective dose (MED) of 3 mg/kg/day (9 mg/m2). Considerable 
antitumor activity (MED 4 to 10 mg/kg/day; 12 to 30 mg/m2) was demonstrated in 
target driven tumor models. These included an AML xenograft model (MV4;11) with 
an FLT3 internal tandem duplication (ITD) mutation and an FGFR3 mutated multiple 
myeloma model (KMS11), both cell lines with constitutively active receptor tyrosine 
kinases known to be essential for tumor cell proliferation. Tumor regressions, 
including complete responses, were observed with doses of at least 10 mg/kg/day (30 
mg/m2) against established (300 mm3) and very large tumors MV4;11 tumors (500 to 
1000 mm3). TKI258 also demonstrated tumor stasis at 50 mg/kg/day in the orthotopic 
RT112 bladder cancer model and regression at 60 mg/kg/day in the KMS11 multiple 
myeloma xenograft. 
 
TKI258 treatment in additional oncology models of diverse tumor origin, including 
colon, myeloma, prostate, ovarian, lung, renal cell carcinoma and hepatocellular 
carcinoma, also resulted in tumor regression, stabilization, or growth inhibition. 
Spontaneous liver metastases were inhibited in a murine breast tumor model. Several 
dose scheduling studies have demonstrated similar efficacy with twice-daily, 
intermittent, or cyclic regimens compared with daily dosing in several models. 
 
The biological activities of TKI258 have been determined in vivo. Inhibition of 
activity of downstream-signaling components of the target RTKs and reduced 
receptor phosphorylation have been demonstrated. Durable inhibition of kinase 
activity was demonstrated for 24hr after a high single dose of TKI258.  
 
1.5.1  In Vitro pharmacology 
TKI258 is an inhibitor of type III, IV, and V receptor tyrosine kinases (RTKs) that 
mediate both endothelial and tumor cell proliferation and survival. These growth 
factor receptors include FGFR subtypes 1, 2 and 3, three VEGFR subtypes (VEGFR 
1, 2, and 3), PDGFRβ, CSF 1R, c-KIT, RET, TrkA, and FLT3. The biochemical 
activity against these receptors is in the low nanomolar range (IC50 = 1 to 40 nM) 
(Table 1-1). 
 


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Table 1-1 - In Vitro activity of TKI258       
 
 
 
RTKs belonging to other classes are either not inhibited or are much less responsive 
to inhibition by TKI258 (Table 1-2). For example, EGFR1, HER2, or Insulin 
Receptor (INSR) were inhibited in biochemical assays at IC50 values greater than 2.1 
μM. TKI258 exhibited limited inhibitory activity against other intracellular kinases 
(IC50 values greater than 1 μM). Four additional tyrosine and serine threonine 
kinases (Fyn, Lck, RSK2, and Nek2) had IC50 values of less than 100 nM. Fyn and 
Lck have roles in T-cell signaling and proliferation, RSK2 is implicated in the 
activation of the mitogen activated kinase (MAPK) cascade and the stimulation of 
cell proliferation and differentiation, and Nek2 is a regulator of centrosome structure 
and function. 
 
 
 
 


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Table 1-2 - Kinase selectivity of TKI258 determined by in vitro kinase assays 
 
      
 
 
TKI258 was further profiled in a panel of enzyme, receptor, and transporter assays 
and did not demonstrate any effect on enzymes, excluding kinases, at concentrations 
below 10 μM. The antiproliferative activities of TKI258 were tested against a large 
number of cancer cell lines and primary nonmalignant cell lines in vitro (Table 1-3). 
In a subset of cancer cell lines and in endothelial cells, proliferation was inhibited 
with an EC50 value less than 60 nM, consistent with their dependence on an RTK 
targeted by TKI258; for example, t(4;14) translocation and FGFR3 activation in 
KMS11 cell line; expression of constitutively active FLT3 in MV4;11 cell line; 
VEGFR2 mediated proliferation in HMVEC; and c-KIT mediated proliferation in the 
TF 1 cell line). The EC50s for proliferation inhibition in primary normal cell lines 
were all greater than 1 μM. 
 
Table 1-3 - Antiproliferative effects of TKI258 on cancer and normal cells 
      
 
 
 


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The inhibitory activity of TKI258 on VEGF-mediated signaling pathways was 
evaluated in human microvascular endothelial cells (HMVEC). Immunoprecipitation 
and Western blot analysis demonstrated greater than 50% inhibition of 
phosphorylation of VEGFR2 after 1 hour of incubation with 100 nM TKI258. There 
was no change in total VEGFR2 levels. Consistent with inhibition of VEGFR2, the 
phosphorylation of the downstream-signaling molecule ERK/MAPK was also 
inhibited significantly after 1 hour with 100 nM TKI258 (Figure 1-4). Equivalent 
protein loading was confirmed by blotting for an abundant cellular protein, 14-3-3. 
 
Figure 1-4 - Dose-dependent inhibition of ERK phosphorylation by TKI258 (CHIR-
258) in VEGF-stimulated endothelial cells (HMVEC) 
 
 
 
Inhibition of receptor activation (PDGFR, FGFR, FLT3) and reduced 
phosphorylation of downstream-signaling proteins (MEK, ERK, STAT5, and AKT) 
was demonstrated in several tumor cell lines expressing RTK targets of TKI258, 
including KMS;11 (mutant FGFR3 multiple myeloma) and KM12L4a (TPM3-TrkA 
expressing colon cancer cell line). 
 
1.5.1.1  IN VITRO ACTIVITY OF TKI258 IN PROSTATE TUMOR CELLS 
Prostate cancer epithelial cells express all four types of FGF receptors (FGFR1 to 4) 
at variable frequencies. Expression of FGFR1 and FGFR4 is most closely linked to 
prostate cancer progression, while the role of FGFR2 remains controversial. 
Expression of FGFRs and other TKI258 targets were assessed by expression profiling 
of prostate tumor derived cell lines (not shown). FGFR1, 2, 3 and 4 were expressed at 
varying levels in prostate cell lines, with marked high expression of FGFR3 in 22RV1 
cells and FGFR4 in MRI-HI-579 tumor xenograft samples. The cognate FGF ligands 
were also expressed, suggesting the possibility of autocrine activation of FGFR 
signaling. Prostate tumor cell lines and tumor xenograft samples also expressed other 
TKI258 targets such as VEGFR1 and 2, PDGFRβ, and FLT3. 
 
Inhibition of FGF stimulated signaling was analyzed by western blot in several 
prostate cell lines (Figure 1-5). Concentrations of 2 uM TKI258 were able to 
completely inhibit the ligand induced phosphorylation of the adaptor protein FRS2 


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and signaling in the MAPK pathway (pERK) in 22RV1 and PC3 cells. DU145 cells 
showed pERK phosphorylation that did not increase after FGF stimulation but was 
reduced by TKI258. 
 
Figure 1-5 - Inhibition of FRS2 and ERK phosphorylation in human prostate cell-
lines by TKI258 
 
 
Proliferation and/or survival of these established prostate tumor-derived cell lines and 
the patient derived prostate cell line PRXF1369 from Oncotest GmBH were inhibited 
by TKI258 in soft agar clonogenic assays. Table 1-6 shows the EC50 values for 
TKI258 inhibition in the clonogenic growth assay. Comparison of cell line sensitivity 
with expression profiling of FGFR1-4 showed that tumor cell sensitivity did not 
correlate with expression of a particular FGFR. The degree to which inhibition of 
FGFR contributes to the in vitro block in cell proliferation and how much of the 
proliferation effect is contributed by inhibition of other prostate tumor cell TKI258 
targets, such as PDGFRβ, remains to be determined. 
 
Table 1-6 - Inhibition of cell proliferation of human prostate cell lines by TKI258 
 
 
 
1.5.2  In vivo pharmacology 
The in vivo activity of TKI258 in nonclinical tumor models and an FGF murine 
Matrigel model was evaluated at multiple dose levels using daily administration 
(Table 1-7). Mice were randomized to treatment groups, and treatment began when 


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mean tumor volume was 100 to 200 mm3. TKI258 was formulated as a solution in 
water and was administered daily by oral gavage. Statistically significant tumor 
growth inhibition was observed in each study, and a minimum effective dose (MED) 
was determined from the dose response curve. TKI258 was also evaluated in an in 
vivo angiogenesis model in which Matrigel-containing FGF2 was placed 
subcutaneously in mice. TKI258 was administered daily for 8 days after which the 
Matrigel plugs were removed and the hemoglobin content measured. 
 
Table 1-7 - In Vivo efficacy of TKI258 in mouse models 
      
 
 
The most potent antitumor activity of TKI258 (MED of 3 to 10 mg/kg/day; 9 to 30 
mg/m2/day) was observed in RTK target-driven tumor models (e.g., KMS11 FGFR3 
mutant multiple myeloma and MV4;11 FLT3-ITD mutant AML). In these cases, the 
mutations in the target RTK are known to drive disease progression and to be 
associated with poor clinical prognosis. 
 
For in vivo studies mentioned in Section 1.4.2, tumor growth inhibition (TGI) was 
calculated as % (mean tumor volume of treated group /mean tumor volume of control 
group)-1.  
 
1.5.2.1 IN VIVO ACTIVITY OF TKI258 IN PROSTATE TUMOR MODELS 
The antitumor activity of TKI258 was evaluated in the human prostate tumor 
xenograft models PC3, DU145 and 22RV1. In single agent tumor growth inhibition 
studies, TKI258 was administered at daily oral doses ranging from 10 to 100 mg/kg, 
with tumor growth inhibition seen at doses above 20 mg/kg. In general TKI258 was 
well tolerated at the lower doses. Daily dosing at 100 mg/kg incurred significant body 
weight loss requiring cessation of dosing in most studies. 
 
Tumor growth inhibition (%TGI) determined from several studies in DU145, PC3 or 
22RV1 is summarized in Figure 1-8. In these studies, subcutaneous DU145, PC3 or 
22RV1 human prostate tumors in male nude mice (300-500 mm3) were treated with 
vehicle (p.o. daily x 15- 21 days) or TKI258 (p.o., daily x 21 days) at the indicated 
doses. Data represent mean tumor growth inhibition compiled from multiple 
independent studies, with n = 10 mice/group/study. 
 
 
 


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Figure 1-8 - Mean tumor growth inhibition 
                         
 
 
The effect of TKI258 in combination with Taxotere (docetaxel) was evaluated in the 
DU145 and 22RV1 tumor models. Suboptimal doses of single agents were used in 
these studies in order to reveal potential combination effects. 
 
In the DU145 model, mice treated with a combination of TKI258 and Taxotere 
showed substantially greater tumor inhibition (> 86% TGI) compared to single agent 
TKI258 (60% TGI) or Taxotere (47 or 69% TGI) treatment at the end of 3 weeks 
(Figure 1-9). Tumor shrinkage occurred by day 18 in response to combined treatment 
with a response greater than either agent alone. The durability of response of was also 
evident from the analyses of tumor growth delay (to 1500mm3), where, combination 
of TKI258 and Taxotere not only significantly suppressed tumor growth but also 
increased growth delay of the tumors (TKI258 + Taxotere >37days vs. TKI258 = 8 
days or Taxotere = 15 days. Maximum average body weight loss in the groups treated 
with TKI258 ranged from 7-10%, while in the Taxotere monotherapy groups the 
maximum body weight loss was 10% at the lower dose and 20% at the higher dose. 
The combinations of Taxotere and TKI258 were relatively well-tolerated with no 
more than 10% maximum average body weight loss. 
 
 
 
 
 
 
 
 
 


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Figure 1-9 - Response of subcutaneous DU145 prostate tumor to TKI258 and 
Taxotere in nude mice 
                          
 
 
TKI258 was also evaluated in combination with Taxotere in the androgen-receptor 
positive 22RV1 prostate xenograft model. Combination therapy of TKI258 (40 
mg/kg) and Taxotere (20 or 30 mg/kg) produced pronounced tumor inhibition and 
delayed time to tumor regrowth compared to monotherapies (> 98% inhibition; 
p<0.001 vs. vehicle; see Figure 1-10). In this study TKI258 was well tolerated as 
monotherapy, with average body weight loss of 0 and 2 % respectively for the 30 and 
40 mg/kg groups. In the Taxotere monotherapy group’s maximal body weight loss 
was 2 and 5%, respectively for the 20 mg/kg and 30 mg/kg groups. In the 
combination group’s maximal average body weight loss ranged from 5 to 7 %. 
 
 
 
Figure 1-10 - Combination therapy of TKI258 and Taxotere in the subcutaneous 
22RV1 prostate tumor model in nude mice 
                             
 
 


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22RV1 tumor xenografts in vivo secrete PSA, permitting analysis of the effect of 
TKI258 and Taxotere on total serum PSA levels in tumor-bearing nude mice (Figure 
1-11). Basal levels of total serum PSA were undetectable in naïve, non-tumored male 
mice. The mean total PSA level was 0.67 ng/ml in serum of vehicle-treated mice 
bearing 22RV1 tumors of approximately 2cm3. Treatment with TKI258 at 20 or 40 
mg/kg produced a dose-dependent decrease of total serum PSA levels, with 
statistically significant inhibition in total PSA observed with 40 mg/kg (0.07 ng/ml 
vs. vehicle or Taxotere; p<0.001). Taxotere therapy (30 mg/kg) did not change total 
serum PSA levels compared to vehicle treatment (p>0.05). Substantial reduction in 
total PSA levels was observed with combined TKI258 and Taxotere therapy (p<0.001 
vs vehicle or single agents). The decrease in total serum PSA levels with combination 
therapy correlated well with tumor growth inhibition (see Figure 1-11). 
 
Figure 1-11 - PSA levels in serum following combination therapy of TKI258 and 
Taxotere in the subcutaneous 22RV1 prostate tumor model in nude mice 
 
 
1.5.3  Safety Pharmacology 
An in vitro HERG assay and in vivo monkey safety pharmacology studies were 
performed and described below. Additional cardiovascular safety measurements were 
part of the GLP dog study [Study No. N103753]. There was no effect on 
cardiovascular parameters during 28 days of dosing in the dog. A GLP oral safety 
pharmacology study in rats was also performed to evaluate effects on CNS and 
respiratory function [Study No. 0770153]. TKI258 at 100 mg/kg did not have any 
effects on CNS functional observation battery (FOB) and respiratory function. 
 
Effects on HERG were evaluated in GLP [Study No. SPH03-029] “Effects of CHIR-
258LC on HERG Tail Current Recorded from Stably Transfected HEK293 Cells” 
(Table 1-12). The purpose of this study was to assess the effect of TKI258 on the 
human ether-a go-go-related gene (HERG)-encoded channel tail current recorded 
from human embryonic kidney 293 (HEK293) cells stably transfected with HERG 


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complementary DNA. TKI258 was tested at 0.1, 0.3, 1, 3, and 10 μM along with a 
positive control (E-4031) previously validated in the assay. Single cells were 
continuously exposed in the bath solutions to TKI258, the positive control or vehicle, 
for the duration of the measurements. The concentration-response curve was fit with a 
sigmoidal function. The IC25 and IC50 values were estimated from the best-fit 
results. No statistically significant inhibition in HERG tail current was observed at 
concentrations below 1 μm. The IC25 and IC50 values were 2.5 and 6.6 μM, 
respectively. The positive control used produced an 84% decrease in tail current at 
100 nM. 
 
Table 1-12 - In vitro safety pharmacology studies 
 
 
In GLP [Study No. UBAW-0200] “A Cardiovascular Safety Study of CHIR154258 
Administered to Naïve Telemetered Cynomolgus Monkeys”, a group of telemetered 
cynomolgus monkeys, 3 per sex, received single escalating oral gavage doses of 
vehicle and 30, 100, and 300 mg/kg (370, 1222, and 3700 mg/m2) TKI258 (Table 1-
13). Doses were escalated weekly. The dose levels chosen for this study were at or 
above dose levels that produced lethality in the multiple daily dose GLP monkey 
study. Monkeys were monitored for changes in heart rate, blood pressures (systolic, 
diastolic, and mean), body temperature, and electrocardiogram parameters 1.5 hours 
prior to dosing and for 24 hours post dosing. 
 
Emesis occurred with a dose dependent increase in frequency and duration starting at 
≥ 100 mg/kg. Heart rates were decreased in all animals (10 to 30 bpm) following 
treatment with TKI258 at all dose levels compared with vehicle administration 
beginning 8 to 10 hours post dose administration. This response was not dose 
dependent and was similar at all 3 dose levels. Several animals demonstrated an 
increase in mean arterial blood pressure during the period of decreased heart rate. One 
of the six treated animals had a potentially biologically significant prolongation of 
QTc interval (22 to 39 msec) at each dose of CHIR-258LC. This finding occurred 
within a very narrow time period at night. This particular animal had wide variations 
in heart rate making QTc interval determination difficult to interpret. The relevance 
of these findings at such high single dose levels compared to tolerated multiple doses 
at 5 mg/kg (60 mg/m2) in the monkey is not known. Although decreased heart rates 
were observed, this observation did not appear to be dose related. Cardiac 
arrhythmias, conduction disturbances, or quantitative ECG abnormalities (including 
QTc prolongation) were not consistently observed following the oral administration 
of TKI258 at any of the dose levels tested. 
 
 
 
 


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Table 1-13 - in vivo safety pharmacology studies 
 
 
1.5.4 Development of pharmacodynamic monitoring of TKI258 activity for use in 
clinical trials 
 
The rationale for utilizing biomarker or pharmacodynamic marker evaluation in phase 
1 clinical trials of TKI258 is to evaluate target modulation in patients as an indicator 
of the biological effect of the compound. An objective of these studies is to identify 
dose and plasma exposures necessary for inhibiting targets of TKI258. These results 
will support selection of optimal dose and schedule for clinical use of TKI258. 
 
Potential pharmacodynamic markers that may be utilized to assess target modulation 
by TKI258 in clinical specimens were explored nonclinically, as described earlier. In 
addition to inhibition of target receptor phosphorylation, inhibition of downstream-
signaling components of the target RTKs were demonstrated in tumor xenografts. In 
both cell lines and xenografts, TKI258 inhibited phosphorylation of FLT3 in AML 
models and FGFR3 in multiple myeloma models. ERK and STAT5 phosphorylation 
were also shown to be reduced in several models. 
 


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1.5.5  Distribution 
Following a single oral dose of radiolabeled compound to rats, TKI258 was widely 
distributed with highest concentrations of the radiolabel observed in the harderian 
gland, liver, renal medulla, spleen, adrenal gland, and kidneys (30 to 100 fold higher 
than plasma). The radioactivity in both tissues and plasma peaked within 4 hours after 
dosing and was significantly lower at 24 hours after dosing. 
 
In murine xenograft models, oral dosing with TKI258 demonstrated extensive 
distribution to tumors relative to plasma or normal tissue (up to 200 fold higher at 48 
hours after cessation of dosing). Plasma or normal tissue concentrations declined 
rapidly relative to those in tumors, suggesting that TKI258 may be preferentially 
retained in tumors. TKI258 was highly bound to plasma proteins (90.8% to 98.2%), 
mainly to albumin, and its binding was independent of concentration (0.5 to 10 
μg/mL) and gender in mouse, rat, dog, monkey, and human plasma. 
 
The blood cell to plasma partitioning ratios of TKI258 ranged from 1.45 to 2.64 and 
were, in general, independent of concentration and gender in mouse, rat, dog, 
monkey, and human blood. These results indicate that the majority of TKI258 in 
blood was associated with blood cells. 
 
1. 5.6 Metabolism 
TKI258 is metabolized mainly by CYP1A1/2 and FMO. FMO is not readily induced 
or inhibited by any other agents, therefore the drug-drug interactions between TKI258 
and FMO inducers/inhibitors are of lesser concern. To a lesser extent, TKI258 could 
be metabolized by CYP3A4, CYP2C8, and CYP2D6 enzymes. 
 
Though no drug interactions have been studied clinically, drugs that inhibit 
(ciprofloxacin, clinafloxacin, enoxacin, fluvoxamine, oltipraz, propranolol, rofecoxib, 
thiabendazole, and zafirlukast) or induce CYP1A1/2 (omeprazole and tobacco) may 
interact with TKI258 and should be used with caution. 
 
1.5.6.1 IN VITRO STUDIES 
The induction potential of TKI258 was evaluated in primary cultures of rat, dog, 
monkey and human hepatocytes. TKI258 treatment was not associated with the 
induction of CYP2B or CYP3A protein or enzyme activity in these species. However, 
TKI258 treatment was associated with the induction of CYP1A1 and CYP1A2 
protein and activity, as well as with the induction of UGT protein in dog, monkey and 
human hepatocytes. 
 
In vitro, TKI258 has a potential to induce CYP1A2 activity 2- to 14-fold, as well as 
CYP2C9 and CYP2C19 activity to a lesser extent (< 3- to 4-fold). Therefore, 
CYP1A2, CYP2C9, and CYP2C19 substrates as listed below should also be used 
with caution: 


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• CYP1A2 substrates: clozapine, cyclobenzaprine, imipramine, mexiletine, naproxen, 
riluzole, tacrine, and theophylline. 
• CYP2C9 substrates: losartan, irbesartan, diclofenac, ibuprofen, piroxicam, 
tolbutamide, glipizide, celecoxib, fluvastatin, naproxen, phenytoin, rosiglitazone, 
sulfamethoxazole, tamoxifen, tolbutamide, torsemide, and warfarin. 
• CYP2C19 substrates: diazepam, phenytoin, phenobarbital, lansoprazole, 
omeprazole, pantoprazole, rabeprazole, amitriptyline, clomipramine, clopidogrel, 
cyclophosphamide and progesterone. 
 
 
1.5.6.2 IN VIVO STUDIES 
After a single intravenous or oral dose of radiolabeled (14C ) TKI258 to rats and 
monkeys ([Studies No. 6549 177] and [-178], respectively), unchanged TKI258 and 
its N des methyl metabolite accounted for most of the radioactivity in plasma. In 
other studies, N desmethyl TKI258 and TKI258 N oxide were the two major 
metabolites detected in plasma from mice, rats, dogs, and monkeys following single 
or multiple oral doses of TKI258. The ratios of plasma concentrations of each of 
these two metabolites to unchanged TKI258 were comparable after single and 
multiple dose administration in each species examined, suggesting that the time 
dependent kinetics (observed in rats, dogs, and monkeys) is likely independent of the 
formation of these two metabolites. An additional mono-hydroxy metabolite was 
found in plasma and urine samples from dogs after a single oral dose. The proportion 
of this metabolite relative to unchanged TKI258 increased after multiple dosing 
suggesting possible induction of metabolic enzymes responsible for the formation of 
the hydroxylated metabolite. Such a hydroxy metabolite was not identified in plasma, 
urine, and feces from rats, or in plasma and urine from monkeys. 
 
Livers collected from rats treated with once daily oral doses of 30, 50, or 80 
mg/kg/day TKI258 for 14 days exhibited only a modest (3.7 to 4.7 fold) increase in 
CYP1A1/2 and CYP2A1 activities compared to those from control animals. 
However, about a 9 to 17 fold increase in uridyl glucuronosyl transferase (UGT) 
activity was observed in the treated animals compared to those in the control group. 
In a similar study in monkeys, livers collected after multiple oral dosing with TKI258 
(5, 30, or 80 mg/kg/day; [Study No. 02 3008]) demonstrated up to a 15 fold increase 
in CYP450 1A1/2 and a modest 3.2 fold increase in thyroxine glucuronidation 
compared to those from control animals. 
 
In another study, significant differences were observed in the metabolic profiles of rat 
bile after single oral dose of TKI258 compared to that after multiple oral doses. After 
a single oral dose (20 mg/kg), unchanged parent, the N desmethyl (minor), and the N 
oxide (major) metabolites were detected in the rat bile. After multiple dosing (20 
mg/kg/day for 7 days), several conjugated metabolites, including conjugated products 
of hydroxylated TKI258, were observed. It is noteworthy that the mono hydroxylated 
metabolite or the conjugated metabolites were not identified in plasma, urine, and 
feces from rats. 
 


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Therefore, taken together, these results suggest that after a single oral dose, TKI258 
appears to be primarily metabolized by N demethylation and N oxidation, with a 
minor contribution of the hydroxylation pathway. However, after multiple oral 
dosing, the metabolism of TKI258 increases, possibly due to induction of metabolic 
enzymes responsible for the formation of the hydroxylated and conjugated 
metabolites. Such an increase in the metabolic rate may explain the time dependent 
reduction in TKI258 exposure following repeated oral dosing. 
 
 
1.6 
Human studies 
 
All data presented in this section are preliminary. All clinical studies described in this 
TKI258 (dovitinib) Investigator’s Brochure (edition 8) have been designed and 
implemented  in accordance with the ICH Harmonized Tripartite Guidelines for Good 
Clinical Practice, with applicable local regulations, and with the ethical principles 
described in the Declaration of Helsinki. 
 
Description and status of clinical studies with TKI258 
TKI258 is being studied as a single agent in ten Phase I and three Phase II clinical 
trials designed to characterize safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD), and anti-tumor activity. 
 
Table 1-14 provides detailed description and status of clinical trials with TKI258. As 
of 10 September 2010, a total of 420 patients have received single agent TKI258. 
Among them, 35 patients (advanced solid tumors) were treated in study 2101 (dose 
range: 25 - 175 mg continuous once daily), 32 patients (acute myeloid leukemia) were 
treated in study 2102 (dose range: 50 - 600 mg continuous once daily), 21 patients 
(multiple myeloma) were treated in study 2103 (dose range: 50 - 500 mg continuous 
once daily), 7 patients (multiple myeloma) were treated in study 2104 (dose range: 
100 - 325 mg continuous once daily), 47 patients (locally advanced or metastatic 
melanoma) were treated in study 2105 (dose range: 200 – 500 mg continuous once 
daily), 13 patients (advanced solid malignancies) were treated in study 2106 (4 
enrolled into the ADME [absorption, distribution, metabolism and excretion] part 
using TKI258 at 500 mg single radiolabelled dose on day 1 followed by 400 mg 
continuous once daily starting from day 15, and 9 enrolled into the extension part 
using TKI258 at 400 mg continuous once daily), 78 patients (locally 
advanced/metastatic renal cell cancer) were treated in study 2107 (dose range: 500 - 
600 mg for 5 days on/2 days off), 23 patients  
 
 
 
 
 
 
 
 


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Table 1-14 - Summary of clinical trials conducted with TKI258 as of 10 September 2010 
 
 
 


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1.7  
Adverse Events 
1.7.1  Common adverse events (AEs; greater than or equal to 10%) 
Table 1-15 to Table 1-17 summarize the most commonly reported adverse 
events (AEs) regardless of relationship to TKI258 treatment, which are 
defined as events that occurred in ≥ 10% of the patients who received TKI258 
based on AE data in the clinical database as of the 10 September 2010 cutoff 
date. 
 
The five most commonly reported non-laboratory AEs were nausea,  
fatigue/asthenia, diarrhea, vomiting and anorexia/decreased appetite for all 3 
data groups (continuous daily dosing, global 5 days on/2 days off, and 
Japanese 5 days on/2 days off (study 1101)). Commonly reported AEs were 
reversible and manageable; most were mild or moderate in severity 
(CTCAE grade 1 or 2). 
 
 
 
 
 
 
 


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Table 1-15 Commonly reported adverse events (occurring in greater than or 
equal to 10% patients) regardless of study drug relationship, by 
preferred term and treatment group (continuous daily dosing: studies 
2101, 2102, 2103, 2104, 2105 and 2106) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1-16 Commonly reported adverse events (occurring in greater than or 
equal to 10% patients) regardless of study drug relationship, by 
preferred term and treatment group (5 days on/2 days off dosing: 
study 2107, 2112*, 2201*, 2202, 2204*) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1-17 Commonly reported adverse events (occurring in greater than or 
equal to 10% patients) regardless of study drug relationship, by 
preferred term and treatment group (5 days on/2 days off dosing: 
study 1101) 
 
 


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1.7.2  CTCAE grade 3 and grade 4 adverse events regardless of study drug 
relationship (greater than or equal to 2%) 
 
The majority of these events were grade 3 across all dosing regimens. 
In the continuous dosing regimen studies, grade 4 events included 5 cases of 
fatigue, 2 cases of pyrexia, 1 case of deep vein thrombosis, 5 cases of 
pulmonary embolism, 2 cases of neutropenic sepsis, and 1 case of pain in 
extremity. In the global 5 days on/2 days off dosing regimen studies, grade 4 
events included 3 cases of pumonary embolism and 1 case of stomatitis. In the 
Japanese 5 days on/2 days off dosing regimen study (1101), there were no 
grade 4 events for these AEs. 
 
 
1.7.3 Laboratory Data 
The majority of the hematology laboratory abnormalities were grade 1 or 2 
events across all dosing regimens. In continuous dosing regimen studies, five 
patients (3.5%) had grade 4 hemoglobin values, 7 patients (7.4%) had grade 4 
ANC values, 19 patients (14.6%) had grade 4 platelet counts, and 9 patients 
(6.9%) had grade 4 WBC values during study participation. 
 
The relatively higher incidence rate of grade 3/4 hematology abnormalities in 
the continuous daily dosing regimen was mainly due to acute myeloid 
leukemia (study 2102) and multiple myeloma (studies 2103 and 2104) 
patients. In global 5 days on/2 days off dosing regimen studies, 2 patients 
(1.3%) had grade 4 ANC values, 1 patient (0.5%) had grade 4 platelet counts, 
and no patients had grade 4 hemoglobin or white blood counts during study 
participation. Also, one patient (4.5%) had grade 4 hemoglobin in the 
Japanese 5 days on/2 days off dosing regimen study and no patients had grade 
4 ANC, platelet or white blood cell counts during study participation. 
 
The majority of the chemistry laboratory abnormalities were also grade 1 or 2 
events across all dosing regimens. In continuous dosing regimen studies, only 
1 patient (0.7%) had grade 4 creatinine value and 2 patients (1.6%) had grade 
4 triglyceride values. There were no grade 4 abnormalites observed in 
cholesterol or amylase laboratory values in the continuous dosing regimen. In 
global 5 days on/2 days off dosing regimen studies, 2 patients (1.2%) had 
grade 4 triglycerides and 2 patients (1.1%) had grade 4 cholesterol values. 
There were no grade 4 abnormalites observed in amylase or creatinine 
laboratory values in this dosing regimen. Also, there were no grade 4 
chemistry laboratory abnormalities observed in Japanese patients. 
The majority of the liver function test laboratory abnormalities were also 
grade 1 or 2 events across all dosing regimens. In the continuous dosing 
regimen studies, there were no grade 4 laboratory values observed in AST, 
ALT, total bilirubin or alkaline phosphatase. In global 5 days on/2 days off 
dosing regimen studies, there were no grade 4 AST laboratory values; 


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however, 1 patient (0.5%) had a grade 4 ALT value, 1 patient (1.1%) had a 
grade 4 total bilirubin value, and 3 patients (1.6%) had a grade 4 alkaline 
phosphatase values. In the Japanese 5 days on/2 days off dosing regimen 
study, only 1 patient (4.5%) had grade 4 total bilirubin values and no grade 4 
values were observed in the AST, ALT or alkaline phosphatase values during 
study participation. 
 
1.7.4  Hepatic dysfunction as defined by laboratory criteria 
As of the 10 September 2010 data cut-off, there were 12 cases with hepatic 
dysfunction, defined as total bilirubin >2X ULN and AST or ALT > 3X ULN. 
From the Novartis perspective, in 6 of these cases, data available do not 
provide any evidence supporting a causal relationship of hepatic dysfunction 
and dovitinib treatment. The cause of liver injury in these patients was 
progression of underlying metastatic liver disease, with signs suggestive of 
pre-existing cholestatic liver injury in 5 out of 6 patients. 
 
For 6 out of 12 patients, a contribution of dovitinib treatment to liver injury 
cannot be excluded, based on time relationship of onset or worsening of 
elevated enzyme activities to study treatment and improvement of enzyme 
activities after stop/interruption of treatment. 
 
None of the above cases qualifies as a “Hy’s law” case (Rueben 2004). All of 
the cases demonstrate a clear cholestatic component, only 2 of 12 cases would 
qualify as mixed type cholestatic/hepatocellular injury, the remaining 10 cases 
are of cholestatic injury type. Moreover, factors confounding any qualification 
as “Hy’s law” were present in all 12 patients in terms of underlying disease 
(malignancy, 10 of 11 solid tumor cases with liver metastases at baseline), and 
in 10 of 12 patients in terms of concomitant medication. One heavily pre-
treated, advanced breast cancer patient with liver, bone and lymph nodes 
metastases was assessed by the investigator as having drug-related cholestatic 
hepatic injury leading to death. Confounding factors were present in this fatal 
case including liver metastases and concomitant medications. Of the 
remaining 11 patients: 1 patient remains on study, for 1 patient there is no 
available survival data, and in 9 patients, the deaths were due to disease 
progression. 
 
2.0 STUDY OBJECTIVES 
2.1 
Primary Objective  
The primary objective of this study is: 
• To estimate overall survival and early response as characterized by a drop in 
PSA 
• To identify the PSA modulation in 40 selected patients with advanced prostate 
cancer, and to correlate PSA Modulation with changes in bone remodeling 
markers. 
 


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Secondary Objectives  
The secondary objectives of this study are: 
 
• To estimate the objective tumor response rate for subjects with measurable 
disease at baseline. 
• To explore the potential association between serum PSA and bone turnover 
markers  with bone marrow FGF R 1 and FGF9 while on TKI 258 
• To explore the predictive values of baseline FGF R 1, FGF9, and FGF 
signaling  in serum and those in the bone marrow before and during treatment 
with TKI258 
• To identify candidate mRNA gene expression changes in bone marrow biopsy 
aspirate following treatment with TKI258 
• To collect and archive bone marrow biopsies and aspirates, serum and plasma 
in study patients for later hypothesis generating associations 
• To explore FGF R expression following eight weeks of TKI 258. 
 
3.0 INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is an observational study to explore the effect of TKI258 therapy on bone 
turnover markers (serum bone specific alkaline phosphatase and urinary N-
telopeptides), and expression of FGF R 1, on both tumor and host cell compartments 
in bone marrow. 
 
3.2 
Study Duration and Dates 
In this oncology study, patients will receive study treatment until clinical disease 
progression.   
 
4.0 STUDY POPULATION SELECTION 
 
 
Approximately 40 medically or surgically castrated male patients with metastatic castration-
resistant prostate cancer (CRPC) will be enrolled from one study site. 
 
4.1 
Inclusion Criteria 
Each patient must meet the following criteria to be enrolled in this study. 
1) Histologically proven adenocarcinoma of the prostate with evidence for skeletal 
metastases on bone scan and/or CT scan.  
2) Eastern Cooperative Oncology Group (ECOG) performance status < 2. 
(Karnofsky Performance Status ≥ 50%) (Appendix F) 
3) Serum testosterone levels < 50ng/ml 


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4) Ongoing gonadal androgen deprivation therapy with LHRH analogues or 
orchiectomy.  Patients, who have not had an orchiectomy, must be maintained on 
standard dosing of LHRH analogue therapy at appropriate frequency for the 
duration of the study 
5) Progression of disease despite androgen ablation (either documented osseous or 
soft tissue metastatic disease progression or by PSA criteria progression).   
a) Definition of Progressive disease by PSA evidence: a PSA level of at least 5 
ng/ml which has risen on at least 2 successive occasions, at least 2 weeks 
apart.  The participant will need a baseline test and a test to show that the PSA 
has increased. 
6) Discontinue diethylstilbestrol (DES) for ≥ 4 weeks and  antiandrogens > 6 weeks 
prior to study drug. 
7) Discontinue any steroids prescribed to specifically treat prostate cancer (for e.g as 
a secondary hormonal manipulation or for cord compression) > 4 weeks prior to 
study drug. Steroids chronically prescribed for a non-cancer-related illness (e.g. 
asthma or COPD) that is well controlled with medical management are 
permissible to an equivalent of <10 mg Prednisone daily. 
8) Antiandrogen Withdrawal: Patients who are receiving an antiandrogen as part of 
primary androgen ablation must demonstrate disease progression following 
discontinuation of antiandrogen. Disease progression after antiandrogen 
withdrawal is defined as 2 consecutive rising PSA values, obtained at least 2 
weeks apart, or documented osseous or soft tissue progression. 
9) For patients receiving flutamide, at least one of the PSA values must be obtained 
4 weeks or more after flutamide discontinuation. 
10) For patients receiving bicalutamide or nilutamide, at least one of the PSA values 
must be obtained 6 weeks or more after antiandrogen discontinuation 
11) Laboratory Requirements: 
 Adequate adrenal function (absence of symptoms or electrolyte imbalances 
that indicate adrenal insufficiency). 
 WBC count > 3,000/µl 
 Absolute Neutrophil Count (ANC) > 1,500/µl 
 Hemoglobin ≥ 8.0 g/dL independent of transfusion 
 Platelet count ≥ 75,000/µL 
 Serum albumin ≥ 3.0 g/dL 
 Serum creatinine < 1.5 x ULN or a calculated creatinine clearance > 60 
mL/min 
 Serum potassium ≥ 3.5 mmol/L 
12) No evidence of chronic or acute DIC (Disseminated Intravascular Coagulation) or 
bleeding tendency and no angina at rest. 
13) Patient must be willing and able to comply with protocol requirements.  All 
patients must sign an informed consent indicating that they are aware of the 
investigational nature of this study.  Patients must also have signed an 
authorization for the release of their protected health information.   
 


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4.2 Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study. 
1. Histologic variants other than adenocarcinoma in the primary tumor  
2. Abnormal liver functions consisting of any of the following: 
a) Serum bilirubin ≥ 1.5 x ULN 
 
b)  AST and ALT > 2.5 x ULN 
3. Therapy with other hormonal therapy, including any dose of  Ketoconazole,  
finasteride (Proscar), dutasteride (Avodart) any herbal product known to decrease 
PSA levels (eg, Saw Palmetto and PC-SPES) within 4 weeks of study drug. 
4. Requirement for corticosteroids greater than the equivalent of 7.5 mg of 
prednisone daily. 
5. Therapy with samarium or strontium within 8 weeks prior to first dose of study 
drug. 
6. Active infection or concomitant illness that is not controlled with medical 
management. 
7. Prior radiation therapy completed < 4 weeks or single fraction of palliative 
radiotherapy within 14 days prior to first dose of study drug. 
8. Any “currently active” second malignancy, other than non-melanoma skin cancer. 
Patients are not considered to have a "currently active” malignancy, if they have 
completed therapy and are considered by their physician to be at least less than 
30% risk of relapse over next 3 months. 
9. Active psychiatric illnesses/social situations that would limit compliance with 
protocol requirements. 
10. Active or uncontrolled autoimmune disease that may require corticosteroid 
therapy during study 
11. Severely compromised immunological state, including being positive for the 
human immunodeficiency virus (HIV) 
12. Acute or chronic hepatitis B or C 
13. Chemotherapy and other investigational therapies (targeted or immunotherapy) 
will require a 4-week washout period before treatment initiation 
14. Initiation of bisphosphonate therapy within 4 weeks prior to first dose of study 
drug. Patients on stable doses of bisphosphonates that show subsequent tumor 
progression may continue on this medication; however, patients are not allowed to 
initiate bisphosphonate therapy during the study. 
15. 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 (whichever is higher) or multiple gated acquisition scan (MUGA) < 
45% or lower limit of normal (whichever is higher) 


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d. Any of the following within 6 months prior to study entry: myocardial 
infartction (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. 
f. Previous pericarditis; clinically significant pleural effusion in the previous 12 
months or current ascites requiring 2 or more interventions per month. 
16. History of pituitary or adrenal dysfunction 
17. History of gastrointestinal disorders (medical disorders or extensive surgery) 
which may interfere with the absorption of the study drug. 
18. Prior therapy with TKI258  
19. Any acute toxicities due to prior chemotherapy and/or radiotherapy that have not 
resolved to a NCI CTCAE (version 3.0 ) grade of ≤ 1. Chemotherapy induced 
alopecia and grade 2 neuropathy is allowed. 
20. Condition or situation which, in the investigator’s opinion, may put the patient at 
significant risk, may confound the study results, or may interfere significantly 
with the patient’s participation in the study.  
21. Men whose partner is a woman of child-bearing potential, (i.e. biologically able to 
conceive), and who is not employing two forms of highly effective contraception. 
Highly effective contraception (e.g. male condom with spermicide, diaphragm 
with spermicide, intra-uterine device) 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. Women of 
child-bearing potential is defined as sexually mature women who have not 
undergone a hysterectomy or who have not been naturally postmenopausal for at 
least 12 consecutive months (e.g., who has had menses any time in the preceding 
12 consecutive months). 
 
 
5.0 STUDY TREATMENT(S) 
 
5.1   
TKI258 dose and schedule 
Patients will receive a single daily oral dose of  of TKI258 for 5 consecutive days, 
followed by a 2-days rest period. Following an initial 4-week cycle at a starting dose 
of 400 mg 5 days- on and 2 days off, TKI258 may be escalated to 500 mg/day 5 days-
on/2 days off if no significant Grade3/4 AEs or laboratory abnormalities are 
observed.  The dose of TKI258 is NOT individually adjusted by weight or body 
surface area. TKI258 should be ingested with sufficient amount of water at least 1 
hour prior to a meal (breakfast) or at least 2 hours following a meal (breakfast). 
Alternatively, TKI258 may be taken with a. low-fat meal of ≤ 500 calories with ≤ 20 
grams fat. 
 


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Treatment cycle  
A cycle is arbitrary defined as 28 days (4 weeks) for the purposes of scheduling 
procedures and evaluations.  
A complete treatment cycle is defined as 28 days or 4 weeks. 
• TKI258 if given on days 1-5, 8-12, 15-19, 22-26 (5 days on/2 days off) of each 
cycle.  
• The first administration of TKI258 defines Day 1 of the cycle. The last day of a 
complete cycle is Day 28. 
 
 
5.2  
Permitted study drug adjustments 
5.2.1. Dosing schedule. 
The decision whether to continue with study drug should be based on individual 
circumstances and the physician’s judgment that continuation is in the patient’s best 
interest. If the study treatment is interrupted, because of its toxicity or a lack a 
compliance to the treatment schedule by the patient, the following guidelines should 
apply. 
• If TKI258 is taken on a “rest days”, then the patient will resume the original 5 
days on/2 days off schedule starting with the next day of dosing as follows:  if the 
patient takes an additional dose on Day 6, then the patient will rest on Day 7 and 
start the 5 days on/2 days off dosing on Day 1; if patient takes a dose on Day 7, 
then the patient will skip Day 1 of the 5 days on/2 days off and start dosing the 
following day (Day 2). If patient takes a dose on Day 6 and 7, then the patient will 
skip Day 1 and 2 of the 5 days on/2 days off and start dosing the following day 
(Day 3). 
• If the patient missed TKI258 dose on Day 1, 2, 3 or 4, he should restart TKI258 
the next  dosing day and rest on Days 6 and 7 
• If the patient missed TKI258 dose on Day 5, 6, 7, he should rest on Days 6 and 7 
and restart TKI258 on Day 1 of the next week. 
Regardless of the reason for the delay in study treatment, patient must discontinue 
study treatment when the interval between 2 administrations of treatment exceeds 21 
days.  
These changes must be recorded on the Dosage Administration Record of the 
electronic Case Report Form (eCRF).  
 
5.2.2 Dosing modifications.  
For patients who are unable to tolerate the protocol-specified dosing schedule of 
TKI258, dose reduction is permitted to a minimum of 300 mg Table 5-1: 


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Table 5-1 Dose reduction steps for TKI258 
 
Tables 5-1 and 5-2 provide guidelines for reducing the dose of TKI258 or delaying 
the treatment when toxicity related to TKI258 occurs. Dose reduction should be based 
on the worst toxicity demonstrated at the last TKI258 administration. Dose 
modifications or delays may occur in the setting of lower grade toxicity than defined 
below if the investigator believes that it is in the interest of the subject’s safety. 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 dose reductions to a minimum of 300 mg. 
Dose reduction* 
 
Dose level - 0 
Dose level - 1 
Dose level - 2 
TKI258 
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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Table 5-2 TKI258 related toxicity management guidelines 
Toxicity intensity a 
Dose modification 
Hematologic 
Neutropenia 
 
Grade 1 (ANC < LLN - 
1500/mm3) 
Grade 2 (ANC < 1500 - 
1000/mm3) 
Maintain dose level 
Grade 3 (ANC < 1000 - 
500/mm3) 
Grade 4 (ANC < 500/mm3) 
Delay study treatment until resolved to ≤ grade 2, then: 
If resolved by ≤ 7 days after suspending TKI258, 
maintain dose level 
If resolved by > 7 days after suspending TKI258, ↓ 1 
dose level 
Thrombocytopenia (Platelets)  
 
Grade 1 (PLT < LLN - 
75,000/mm3) 
Grade 2 (PLT < 75,000 - 
50,000/mm3) 
Maintain dose level 
 
Grade 3 (PLT < 50,000 - 
25,000/mm3) 
Delay study treatment until resolved to ≤ grade 1, then: 
If resolved by ≤ 7 days after suspending TKI258, 
maintain dose level 
If resolved by > 7 days after suspending TKI258, ↓ 1 
dose level 
Grade 4 (PLT < 25,000/mm3) 
Delay study treatment until resolved to ≤ grade 1, then ↓ 
1 dose level 
Febrile neutropenia  
fever of unknown origin without 
clinically or microbiologically 
documented infection (ANC 
<1.0 x 109/L, fever ≥ 38.5°C)  
Delay study treatment until resolved, then ↓ 1 dose level 
Renal 
Serum creatinine 
 
Serum creatinine < 1.5 x ULN 
Maintain dose level 
Serum creatinine 1.5 - 3 x ULN 
Delay study treatment until resolved to ≤ grade 1, 
then ↓ 1 dose level 
Grade 3 (> 3.0 - 6.0 x ULN) 
Grade 4 (> 6.0 x ULN) 
Discontinue study treatment. 


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Toxcity Intensity                                  Dose Modification 
 
Hepatic 
Bilirubin 
 
Total bilirubin < 1.5 x ULN 
Maintain dose level 
Total bilirubin 1.5 - 3 x ULN 
Delay study treatment until resolved to ≤ grade 1, then ↓ 
1 dose level 
Grade 3 (> 3.0 - 10.0 x ULN) 
Grade 4 (> 10.0 x ULN) 
Discontinue study treatment  
Note: If Grade 3 or Grade 4 hyperbilirubinemia is due to 
the indirect component only, and hemolysis as the 
etiology has been ruled out as per institutional guidelines 
(e.g. review of peripheral blood smear and haptoglobin 
determination), then ↓ 1 dose level and continue 
treatment at the discretion of the investigator. 
Discontinuation of study treatment is required if 
concurrent elevations of total bilirubin > 2.0 X upper 
limit of normal (ULN) and ALT or AST > 3.0 X ULN 
are observed. 
In order to characterize hepatic toxicity more precisely, 
fractionation of bilirubin and alkaline phosphatases will 
be required for elevated values > 2.0 X ULN and ≥ 
CTCAE grade 2, respectively. 
AST or ALT 
 
Grade 1 (> ULN - 2.5 x ULN) 
Grade 2 (> 2.5 - 5.0 x ULN) 
Maintain dose level 
 
Grade 3 (> 5.0 - 20.0 x ULN) 
Delay study treatment until resolved to ≤ grade 1 (or ≤ 
grade 2 if liver infiltration with tumor present), then  
If resolved by ≤ 7 days after suspending TKI258, 
maintain dose level 
If resolved by > 7 days after suspending TKI258, ↓ 1 
dose level 
Discontinuation of study treatment is required if 
concurrent elevations of total bilirubin > 2.0 X upper 
limit of normal (ULN) and ALT or AST > 3.0 X ULN 
are observed. 
In order to characterize hepatic toxicity more precisely, 
fractionation of bilirubin and alkaline phosphatases will 
be required for elevated values > 2.0 X ULN and ≥ 
CTCAE grade 2, respectively. 
Grade 4 (> 20.0 x ULN) 
Delay study treatment until resolved to ≤ grade 1, then ↓ 
1 dose level 


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Cardiac – Other 
 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Delay study treatment until resolved to ≤ grade 1, then ↓ 1 
dose level 
Grade 4 
Discontinue study treatment 
Gastrointestinal 
Diarrhea 
At the first sign of abdominal cramping, loose stools, or 
onset of diarrhea, it is recommended that the patient be 
treated according to institutional standard of care 
Grade 1 (despite maximal anti-
diarrheal medication) 
Maintain dose level 
Grade 2 (despite maximal anti-
diarrheal medication) 
 
Delay study treatment, until resolved to ≤ grade 1, then re-
start at the current dose level.  
If diarrhea returns as ≥ grade 2, then suspend dose until 
resolved to ≤ grade 1, then ↓ 1 dose level 
Grade 3/4  (despite maximal 
anti-diarrheal medication) 
Delay study treatment until resolved to ≤ grade 1, then ↓ 1 
dose level 
Neurotoxicity 
Cardiac 
Hypertension 
Treatment-emergent hypertension should be treated as 
per standard cardiology practice. Recommended agents 
for the management of blood pressure elevations on 
TKI258 include angiotensin-converting enzyme 
inhibitors and calcium channel blockers. 
Grade 1 
Maintain dose level 
 
 
Grade 2 / 3 
Delay the study treatment and initiate/intensify 
antihypertensive therapy. 
TKI258 may be restarted in conjunction with standard 
anti-hypertensive medication if BP is controlled (i.e BP ≤ 
150/100 mmHg). 
If BP is controlled ≤ 7 days after suspending TKI258, 
maintain dose level 
If BP is controlled > 7 days after suspending TKI258, ↓ 1 
dose level 
Grade 4 
Delay the study treatment and initiate/intensify 
antihypertensive therapy. ↓ 1 dose level 
TKI258 may be restarted in conjunction with anti-
hypertensive medication if BP is controlled (i.e BP ≤ 
150/100 mmHg).  


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≥ 1 CTCAE grade level 
increase 
 
Grade 0 → Grade 1: maintain dose level 
Grade 0 or 1 → Grade 2 : delay study treatment until 
resolved to ≤ grade 1, then ↓ 1 dose level 
≥ CTCAE grade 3 
Discontinue study treatment 
Hypertriglyceridemia and/or hypercholesterolemia 
Grades 1, 2 or asymptomatic 
grade 3 
 
Maintain dose level. Initiation or adjustment of an 
existing triglyceride-and/or cholesterol-lowering agent 
will be at the discretion of the investigator. 
Grade 3 with symptoms or 
grade 4 
Delay study treatment and initiate/ optimize triglyceride-
and/or cholesterol-lowering therapy. 
If the toxicity returns to ≤ grade 3 without symptoms by ≤ 
14 days, treatment with TKI258 may resume at the same 
dose level.  
At the re-occurrence of grade 3 with symptoms or grade 
4 toxicity. If within 14 days the patient returns to ≤ grade 
3 without symptoms, dosing with TKI258 may resume at 
the next lower dose level  
If toxicity does not returns to ≤ grade 3 without symptoms 
within 14 days, discontinue study treatment. 
Amylase and/or lipase elevations 
Grade 1 or 2 
Maintain dose level 
Asymptomatic grade 3 or 4 
Delay TKI258 and evaluate at least twice weekly until ≤ 
grade 2 then restart at current dose level. If levels have not 
returned to ≤ grade 2 within 3 weeks then no further 
TKI258 may be given and the patient should discontinue 
permanently from the study. A CT scan or other imaging 
study to assess the pancreas, liver and gallbladder must be 
performed within 1 week of the first occurrence of any 
grade 3 elevation of amylase and/or lipase. 
Symptomatic grade 3 or 4 
TKI258 must be stopped immediately and proper medical 
intervention taken. Evaluate at least twice weekly until 
resolution to ≤ grade 1. Clinical manifestations should be 
monitored as needed until resolution or stabilization of the 
disease condition. No further TKI258 may be 
administered. 
Pancreatitis 
 
Grade 1 
Maintain dose level 
Grade 2, 3 or 4 
Discontinue study treatment. 
Other adverse events 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Delay dose until resolved to ≤ grade 1, then ↓ 1 dose level 


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Grade 4 
Discontinue TKI258 
Suspend dose for ≥ CTCAE grade 3 vomiting or nausea 
only if it could not be controlled despite the use of 
standard anti-emetics. 
All dose modifications should be based on the worst preceding toxicity. 
Isolated values of ≥ grade 3 alkaline phosphatase values will NOT require dose interruption. 
≥ Grade 3 anemia judged to be a hemolytic process secondary to study drug will require 
discontinuation of study treatment. 
≥ Grade 3 lymphopenia considered clinically significant will require dose interruption until 
resolved to ≤ grade 1, then ↓ dose level. 
Patients are allowed two dose reductions. If a patient requires a dose interruption of > 21 
days, then the patient must be discontinued from the study. Patients who discontinue the 
study for a study related adverse event or abnormal laboratory value must be followed at 
least once a week for 28 days and subsequently at 28 day intervals until resolution or 
stabilization of the event, whichever comes first. 
a. Common Terminology Criteria for Adverse Events (CTCAE Version 3.0 ) otherwise 
specified values. 
 
5.3 
Restrictions 
5.3.1  Patients must be instructed not to take additional medications including over-
the-counter products and herbal/alternative medications during the study without 
prior consultation with the investigator. It is important to avoid concomitant 
medications that are known to cause hepatotoxicity. 
 
Oral contraceptives are generally metabolized by CYP3A4/2C9, and act also as a 
moderate inhibitor of CYP1A2, therefore should not be used. Thus, patients who are 
sexually active and are using oral contraceptives as a method of contraception, should 
change to two highly effective contraceptive methods during the study participation. 
 
Permitted treatments during the study include, but are not limited to the following: 
 
•  Pain medication to allow the patient to be as comfortable as possible 
•  Localized radiotherapy and treatment with bisphosphonates for pre-existing, 
painful bone metastases is permitted only if evidence of radiological progression 
is not present. Treatment with bisphosphonates must begin before the study 
treatment is initiated. 
• 
Nutritional support or appetite stimulants (e.g. megestrol) 
•  Oxygen therapy and blood products or transfusions 
•  Prophylactic anti-emetics are allowed for patients who, at the discretion of the 
investigator, have experienced ≥ grade 1 nausea or vomiting. 
•  Hematopoietic growth factors should be used according to the guidelines 
established by the American Society of Clinical Oncology (ASCO) or as dictated 


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by local practice. The ASCO guidelines are available 
[http://jco.ascopubs.org/cgi/content/full/24/19/3187] 
•  The administration of anticoagulation and antiaggregation agents (e.g. 
eptifibatide, epoprosterol, prasugrel, dipyridamole, fondaparinix) should be 
allowed except prasugrel, due to its potential drug-drug interaction with either 
sorafenib or TKI258. Prasugrel is primarily metabolized by the CYP3A4 and 
CYP2B6 and to a lesser extent by the CYP2C9 and CYP2C19. Co-administration 
of prasugrel with sorafenib could increase the systemic exposure of parsugrel, 
since sorafenib could inhibit CYP2B6. In addition, in vitro study demonstrated 
that TKI258 is an inducer of CYP2C9 and CYP2C19, co-administration of 
TKI258 with parsugrel is likely to reduce the exposure of parsugrel. For oral 
anticoagulants, the upper limit of INR is < 1.5. 
 
The following concomitant treatments are not allowed during the study: 
 
•  Concurrent use of isoniazid, labetolol, trovafloxacin, tolcapone, and felbamate are 
not permitted, since alternative less hepatotoxic drugs are available to use. 
•  Concurrent use of other investigational drugs is not permitted. 
•  The administration of other antineoplastic therapy (e.g. chemotherapy, hormone 
therapy, immunotherapy, targeted therapy, monoclonal antibodies and radiation 
therapy) is not permitted. Patients requiring radiation therapy after the start of the 
study are considered as having progression of disease and must discontinue study 
treatment. 
 
 
5.3.2 Concomitant therapy with the following is prohibited: 
 Chemotherapy 
 Multifraction radiation therapy  
 Immunotherapy 
 Radiopharmaceuticals such as strontium (89Sr) or samarium (153Sm) 
 
Patients who require the use of any of these therapies will be discontinued from 
study-treatment, entered into long-term follow-up for overall survival 
assessments.  Patients who discontinue from the study will be followed for 
safety outcomes for 30 days following the patient’s last dose or until the patient 
receives another anticancer therapy, whichever occurs first. 
 
5.3.3 Concomitant therapy with the following is restricted: 
 5 α-reductase inhibitor 
 Ketoconazole, diethylstilbestrol, PC-SPES, and other preparations such as 
saw palmetto thought to have endocrine effects on prostate cancer 
 Potent inhibitors/inducers of the following CYP450 enzymes including 
quinidine (a CYP2D6 inhibitor), fluvoxamine (CYP1A inhibitor), 
omeprazole (a CYP1A inducer), ketoconazole, itraconazole, erythromycin 
and glibenclamide (CYP3A4 inhibitors), as well as phenobarbital, 
phenytoin, carbamazepine and rifampicin (all CYP3A4 inducers), should be 


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used with caution. A comprehensive list of medications that inhibit, induce, 
and/or are metabolized by the various CYP 450 enzyme isoforms can be 
found at http://medicine.iupui.edu/flockhart. See also, Appendix H. 
 
The decision to administer a restricted therapy should be made based on the 
consideration of the safety of study participant.  Such therapies will be used 
with careful monitoring. 
 
5.4 
Treatment Compliance 
The investigator must keep an accurate accounting of the number of investigational 
capsules received from Novartis, dispensed to the patients, the number of units 
returned to the investigator by the patient, and the number of units returned to 
Novartis during and at the completion of the study.  The study drug must be 
dispensed only by an appropriately qualified person to patients in the study.  The drug 
is to be used in accordance with the protocol by patients who are under the direct 
supervision of an investigator. 
  
 
5.5 
Packaging and Labeling 
 
TKI258 100 mg is supplied as a hard gelatin capsule/tablet. The capsules will be 
provided in either blisters or bottles. TKI258 medication labels will comply with the 
legal requirements of each country and be printed in the local language.  The inactive 
ingredients for the dovitinib capsules are pregelatanized starch, colloidal silicon 
dioxide, microcrystalline cellulose, and magnesium stearate. 
   
 
5.6 
Storage and Accountability 
The study drug must be stored in a secure area, limited access area. The storage 
conditions are described on the medication label. It will be administered only to 
patients entered into the clinical study, at no cost to the patient, in accordance with 
the conditions specified in this protocol.  The capsules/tablets should be stored 
according to the label in a secured, limited access area until required.  
 
5.7 
Investigational Product Retention at Study Site 
 
The study site must maintain accurate records demonstrating dates and amount of 
study treatment received, to whom dispensed (patient by patient accounting), and 
accounts of any study treatment accidentally or deliberately destroyed.  At the end of 
the study, reconciliation must be made between the amount of study treatment 
supplied, dispensed, and subsequently destroyed or returned to Novartis or its 
representative. 
 


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6.0 STUDY PROCEDURES 
6.1 
Informed Consent 
The study will be discussed with the patient, and any patient wishing to participate 
must give informed consent and Authorization for Use and Release of Health and 
Research Study Information prior to any study-related procedures or change in 
treatment. 
 
A signed, Institutional Review Board (IRB) approved, informed consent must be 
obtained from patients before any study specific procedures or registration for study 
treatment can occur.  
 
 6.2 
Medical History 
Medical history, such as previous treatments, procedures, and conditions will be 
collected during the screening period. 
 
6.3 
Physical Examination 
Physical examination includes weight, HEENT (head, eyes, ears, nose, and throat), 
chest, cardiac, abdominal, extremities, neurologic, and lymph node examinations. 
 
6.4 
Vital Signs 
Vital signs include blood pressure, heart rate, respiratory rate, and oral body 
temperature. 
 
6.5 
Adverse Events Assessments 
6.5.1 Performing Adverse Events Assessments 
All study patients who have received any dose of TKI258 will be evaluable for safety.   
Adverse events including laboratory adverse events deemed clinically significant by 
the investigator will be graded and summarized according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 
3.0.  
 
6.5.2 
Definition of an Adverse Event 
An adverse event (AE) is any reaction, side effect, or other untoward medical 
occurrence, regardless of relationship to study drug that occurs any time from the 
beginning of the first study dose administration until the final study visit or early 
termination visit.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product.   


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6.5.3 Timing 
Any AE or SAE experienced by the patient from Day 1 to 30 days post last dose 
should be followed-up to determine if any new or ongoing drug-related AE or any 
SAE regardless of relationship to study drug exists.  Follow-up could be conducted by 
site via telephone attempts. 
 
6.5.4 Severity 
Adverse-event severity is a clinical determination of the intensity of an AE.  The 
severity assessment for a clinical AE should be completed using the NCI CTCAE 
(version 3.0). 
 
6.5.5 Relationship 
A determination should be made by the investigator regarding the relationship (if any) 
between an AE and the study drug.  A causal relationship is present if a determination 
is made that there is a reasonable possibility that the AE may have been caused by the 
study drug. 
 
6.5.6 Expectedness 
 
Management of Symptoms Related to Castration 
Treatment with androgens, estrogens, and progestin to control hot flushes is not 
allowed.  Antidepressants are permitted for the management of hot flashes.  Selective 
serotinin reuptake inhibitors (SSRIs) are also permitted. 
 
Management of Persistent and Refractory Toxicity 
Utilizing the NCI CTCAE (version 3.0), events which are moderate and interfere with 
function that are not consistent with a patient’s medical history, and are refractory to 
medical treatment, should be investigated carefully to ensure that no other etiology is 
present.  Study drug will be held for any toxicity events deemed definitely, probably, 
or possibly drug-related (such as diarrhea, hypertension, vomiting, diarrhea, and 
dizziness) and that are greater than grade 2.  Drug will be held until severity is 
reduced to Grade 1 or less and then resumed daily dosing with a dose reduction of 1 
capsule as outlined in section 5.2.  Up to 2 dose reductions, ie, 5→4 capsules, 4→3 
capsules, are allowed as outlined in section 5.2. Patients with toxicities that fail to 
resolve to <Grade 1 within 21 days will be taken off study.  
 
Management of All Other Toxicities 
Other toxicities may occur.  Supportive care should be prescribed as needed.  They 
may also be prescribed prophylactically to prevent toxicity from developing or 
recurring.  The examples include anti-emetics for nausea/vomiting, analgesics for 
pain, antipyretics for fever and antidiarrheals for diarrhea.  Because long-term 


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androgen deprivation may lead to metabolic diseases, such as glucose intolerance, 
hypercholesterolemia, osteoporosis, and anemia, appropriate medication may be 
prescribed. 
 
Abnormal laboratory values will be only be captured as adverse events if deemed 
“clinically significant” by the investigator. 
 
 
6.5.7 Clinical Laboratory Adverse Events 
The results of all laboratory tests required by the protocol will be recorded in the 
patient’s medical record.  All clinically important abnormal laboratory tests occurring 
during the study will be repeated at appropriate intervals until they return either to 
baseline or to a level deemed acceptable by the investigator or until a diagnosis that 
explains them is made.   
 
The criteria for determining whether an abnormal laboratory test result should be 
reported as an adverse event are as follows: 
 
1. Test result is associated with accompanying symptoms, and/or 
2. Test result requires additional diagnostic testing or medical/surgical 
intervention, and/or 
3. Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment or other therapy, and/or 
4. Test result leads to any of the outcomes included in the definition of a SAE, 
and/or 
5. Test result is considered to be an adverse event by the investigator or sponsor. 
 
 
*Merely repeating an abnormal test, in the absence of any of the above 
conditions, does not meet Condition 2 above for reporting as an adverse event. 
 
Any abnormal test result that is determined to be an error does not require reporting 
as an adverse event, even if it did meet one of the above conditions except for 
Condition 4. 
 
6.7 
Serious Adverse Event (SAE) Reporting 
A serious adverse event is – any adverse drug experience occurring at any dose that 
results in any of the following outcomes:  
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places 
the patient, in the view of the initial reporter, at immediate risk of death from the 
adverse experience as it occurred. It does not include an adverse experience that, 
had it occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 


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• A persistent or significant disability/incapacity – a substantial disruption of a 
person’s ability to conduct normal life functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse (21 CFR 312.32). 
 
• Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as an 
SAE if deemed appropriate by the Principal Investigator or the IND Sponsor, 
Office of Research Education and Regulatory Management (ORERM). 
 
• All events occurring during the conduct of a protocol and meeting the definition 
of a SAE must by reported to the IRB in accordance with the timeframes and 
procedures outlined in  “University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy on Reporting Serious Adverse Events”.  Unless 
stated otherwise in the protocol, all SAEs, expected or unexpected, must be 
reported to ORERM, regardless of attribution.  
 
• All life-threatening or fatal events, expected or unexpected, and regardless of 
attribution to the study drug, must have a written report submitted within 24 hours 
(next working day) of knowledge of the event to the Safety Project Manager in 
ORERM.   
 
• The MDACC “Internal SAE Report Form for Prompt Reporting” will be used for 
reporting to ORERM.  
 
• Serious adverse events will be captured from the time the patient signs consent 
until 30 days after the last dose of drug. Serious adverse events must be followed 
until clinical recovery is complete and laboratory test have returned to baseline, 
progression of the event has stabilized, or there has been acceptable resolution of 
the event. 
 
• Additionally, any serious adverse events that occur after the 30 day time period 
that are related to the study treatment must be reported to ORERM. This may 
include the development of a secondary malignancy. 
 
 


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Reporting to FDA: 
 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager ORERM) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, 
the protocol guidelines, the sponsor’s guidelines, and Institutional Review Board 
policy. 
 
Investigator Communication with Supporting Companies: 
 
The principal investigator has the obligation to report all serious adverse events to the 
FDA,  IRB, and Novartis Pharmaceuticals Integrated Medical Safety. 
All events reported to the FDA by the investigator are to be filed utilizing the 
MDACC Serious Adverse Events form.  
 
All events must be reported, by FAX (877-778- 9739) along with Novartis SAE 
Report FAX Cover sheet, to Novartis Pharmaceuticals Integrated Medical Safety 
Department within 24 hours of learning of it’s occurrence.  This includes serious, 
related, labeled (expected) and serious, related, unlabeled (unexpected) adverse 
experiences. All deaths during treatment or within 30 days following completion of 
active protocol therapy must be reported within 5 working days. 
 
Any serious adverse event occurring after the patient has provided informed consent 
and until 4 weeks after the patient has stopped study participation must be reported. 
This includes the period in which the study protocol interferes with the standard 
medical treatment given to a patient (e.g. treatment withdrawal during washout 
period, change in treatment to a fixed dose of concomitant medication). 
 
Serious adverse events occurring more than 4 weeks after study discontinuation need 
only be reported if a relationship to the Novartis study drug (or therapy) is suspected.  
 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious 
adverse experiences will be forwarded to the product manufacturer by the 
investigator. 
 
 
6.8 
Concomitant Medication Assessments 
Supportive care medications are permitted with their use following institutional 
guidelines. For patients who did not undergo orchiectomy, concurrent treatment with 
LHRH analogue is mandatory and must be recorded. 
 
The concurrent administration of other anticancer therapy, including cytotoxic, 
hormonal (except LHRH agonists), or immunotherapy is prohibited during study 


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treatment phase.  Use of other investigational drug therapy for any reason is 
prohibited. 
 
6.9 
Removal of Patients from the Study or Study Drug 
6.9.1 The investigator must withdraw a patient from study treatment or the study for 
any of the following reasons: 
 
• Progressive disease. As clinical benefit may be independent of PSA-
modulation, progressive disease will not be defined by PSA criteria alone. 
Rather progressive disease will be defined as any skeletal related event (6.9.2) 
or tumor progression as defined by RECIST criteria (Appendix I) 
accompanied by PSA progression or investigator defined clinical progression: 
• A serious or intolerable AE occurs as described in 6.7. 
• The sponsor or investigator terminates the study. 
• The patient requests to be discontinued from the study. 
6.9.2 Definition of skeletal-related events (SREs) consisting of the following discrete 
clinical events or unequivocal radiological changes related to underlying disease 
progression: 
 
• Progression by radionuclide bone scan with 2 or more new lesions. If 
progression is noted at the first assessment (ie, Week 12), then a confirmation 
by a second scan is required 6 or more weeks later that shows a minimum of 2 
or more additional new lesions. 
• Pathologic bone fracture in the region of cancer involvement that occur 
spontaneously or as the result of trivial trauma. Each pathologic fracture 
(vertebral and non-vertebral is to be documented by appropriate diagnostic 
imaging. 
• Radiation therapy to bone - radiation administered to bone to palliate painful 
lesions or prevent or treat pathologic fractures or spinal cord compression. 
• Administration of a radioisotope, such as strontium 89, will be included as 
radiation to bone. 
• Cancer-related surgery to bone - procedures that are performed to set or 
stabilize pathologic fractures or areas of spinal cord compression, and surgical 
procedures that are performed to prevent a pathologic fracture or spinal cord 
compression. 
• Spinal cord or nerve root compression - these will be confirmed by MRI. If 
spinal cord compression occurs in conjunction with vertebral compression, 
each will be counted seapartely. 
 
6.9.3. Tumor progression as defined by RECIST criteria (see Appendix I).  
 
Bone lesions will not be considered measurable for purposes of RECIST evaluation 
of disease. 


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6.10 
Other Study Procedures 
Supportive care medications are permitted with their use following institutional 
guidelines.  As mentioned in the eligibility criteria, patients must have ongoing 
gonadal androgen deprivation therapy with LHRH analogues or orchiectomy.  
Patients, who have not had an orchiectomy, must be maintained on effective LHRH 
analogue therapy for the duration of the trial. 
 
The concurrent administration of other anticancer therapy, including cytotoxic, 
hormonal (except LHRH agonists), or immunotherapy is prohibited during study 
treatment phase.  Use of other investigational drug therapy for any reason is 
prohibited. 
 
7.0 STUDY ACTIVITIES (Appendix J) 
 
On-study tests/visits that must occur within a defined time frame shall have a standing 
window of allowance that is equal to +/- 2 days for any laboratory testing.  
 
7.1 
Screening Period (Days –30 to Day 1) 
The following activities/procedures will be conducted during the screening period 
which may occur within 30 days prior to registration the following baseline 
evaluations shall be performed:  
 
• Complete medical history must be available in the patient’s medical record 
• Chest X-ray 
• CT or MRI scans of the pelvis and abdomen.  
• Bone Scan 
• Baseline (pre-treatment) bone marrow biopsy and aspiration within 30 days prior 
to registration.  The specimens will be evaluated by pathology.  A portion of bone 
marrow will be banked for bone marker testing. Patients who have undergone a 
bone marrow aspirate and biopsy outside the context of this clinical trial are 
eligible for the trial and may elect not to repeat these baseline studies if the 
samples were collected within 12 weeks prior to initiation of TKI258 therapy. If a 
portion of the tissue collected from a previous bone marrow aspirate and biopsy 
was banked for future use under Lab02-152, Lab03-0320, or another GU clinical 
trial, the tissue will be requested for this timepoint. 
• Electrocardiogram (ECG) 
• Echocardiogram or MUGA scan 
7.2 
Screening Period (Days –14 to Day 1) 
The following activities/procedures will be conducted during the screening period 
which may occur within 14 days prior to registration the following baseline 
evaluations shall be performed:  
 


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• Interim medical history including demographics 
• Oncology history 
• Physical examination  
• Vital signs including blood pressure, heart rate, respiratory rate, oral body 
temperature, weight and height. 
• List of concurrent medications and baseline adverse events  
• Assessment of ECOG Performance Status 
• Laboratory testing: 
o CBC with differential/platelets 
o Serum chemistry must include:  BUN , creatinine, total bilirubin, albumin, 
SGOT [AST],  SGPT [ALT], GGT, LDH, amylase, lipase, alkaline 
phosphatase, fasting glucose, calcium, sodium, magnesium, phosphorus, 
and potassium 
o PSA assessment.  
o Serum testosterone and DHT levels.  
o Bone Specific Alkaline Phosphatase 
o Blood for Biomarker Studies 
o N-telopeptides in urine 
 
Correlative Studies:  Assessment of serum and bone marrow aspirate androgen levels, 
plus additional serum/plasma banking. 
 
 
7.3 
Treatment Period (Day 1 to Termination of Treatment) 
 
7.3.1 Day 1 
Patients who are eligible after screening will be registered and start study treatment 
after the Screening visit. For all patients, a minimum of 3 sequential ECGs, separated 
by at least 5-10 minutes, must be performed on cycle 1 day 1 prior to the first 
administration of TKI258. This is necessary to get an accurate baseline QTc 
calculation.  ECGs will also be performed during the course of treatment (see section 
7.4 below) 
 
7.3.2 Day 1 Treatment 
At initiation (Day 1) and for the duration of the study, patients will be instructed to 
take five 100mg capsules by mouth once daily (total of 500 mg of TKI 258 per day).  
TKI258 should be ingested with sufficient amount of water at least 1 hour prior to a 
meal (breakfast) or at least 2 hours following a meal (breakfast). 
 
7.4 
Evaluation during Treatment 
On-study tests/visits that must occur within a defined time frame will have a standing 
window of allowance that is equal to +/- 3 days for any laboratory testing.  If 


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screening lab tests take place less than 7 days prior to C1D1, laboratory testing will 
not be repeated. 
 
7.4.1 Beginning on Cycle 1 Day 1 and continuing every 4 weeks thereafter, patients 
will undergo the following additional testing: 
 
• History and physical exam 
• Vital Signs (BP, pulse) 
• Weight 
• PS (ECOG) 
• Assessment of concurrent medications 
• Assessment of AEs 
• PSA test 
• Blood for Biomarker studies (Day 1 of Cycles 2 and 3 only) 
• Serum chemistry must include:  BUN , creatinine, total bilirubin, albumin, SGOT 
[AST],  SGPT [ALT], GGT, LDH, amylase, lipase, alkaline phosphatase, fasting 
glucose, calcium, sodium, magnesium, phosphorus, and potassium   
 
7.4.2 On Cycle 1, Days 12 and 26 and Cycle 2 Day 12 patients will undergo the 
following tests: 
 
• CBC with differential/platelets 
• Serum chemistry must include:  BUN , creatinine, total bilirubin, albumin, SGOT 
[AST],  SGPT [ALT], GGT, LDH, amylase, lipase, alkaline phosphatase, fasting 
glucose, calcium, sodium, magnesium, phosphorus, and potassium 
• There will be a blood draw for a TKI258 trough concentration (Cycle 2 Day 12  
Only) to evaluate the potential relationship of safety and efficacy in regards to 
steady state drug concentrations. 
 
 
Note that the Day 26 of Cycle 1 visit could end up being scheduled on the same day 
as the Day 1 of Cycle 2 visit described above. 
 
7.4.3 Beginning on Cycle 1 Day 1 and every 4 weeks for the first 8 weeks, and every 
8 weeks thereafter, patients will undergo the following additional testing: 
• Urine N-telopeptide 
• Bone Alkaline Phosphatase 
 
 
7.4.4 ECGs, cardiac enzymes, and MUGA/ECHO during therapy will be assessed as 
shown below in Table 7.1: 
 
 
 
 


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Table 7.1 
 
Assessment 
Cycle and Day 
Time Point 
12-lead ECG 
Screening 
Anytime 
 
Cycle 1, Day 1 
3 sequential ECGs, separated 
by at least 5 to 10 minute 
intervals pre-dose 
 
Cycle 1, Day 1 
1 ECG six hours post-dose 
 
Cycle 1, Day 26  
1 ECG pre-dose 
 
Cycle 2, Day 26 
1 ECG pre-dose 
 
Cycle 3, Day 26 
1 ECG pre-dose 
 
Cycle 4+, Day 1 
Anytime at the end of the 
previous cycle 
 
EOT 
Anytime 
Cardiac enzymes (troponin I 
or B, CPK, and CPK-MB) 
Screening 
Anytime to coincide with 
ECHO/MUGA  
 
Every 12 weeks while 
receiving therapy 
To coincide with 
ECHO/MUGA  
 
EOT 
Anytime to coincide with 
ECHO/MUGA  
ECHO/MUGA 
 
Screening 
Anytime to coincide with 
cardiac enzymes 
 
Every 12 weeks while 
receiving therapy 
To coincide with cardiac 
enzymes 
 
EOT 
Anytime to coincide with 
cardiac enzymes. 
 
 
7.4.5 A bone marrow biopsy and aspirate will be performed between 7 and 10 weeks 
(preferably at week 8) after beginning treatment. The specimens will be evaluated by 
pathology.  A small portion of the bone marrow aspirate will be used for bone marker 
testing (to include bone marrow androgen levels). 
 
7.4.6 Routine restaging scans and/or other disease assessment diagnostics will be 
performed every 8 weeks for the first 6 months and every three months thereafter. 
Such studies can be also be performed at the time of clinical disease progression (at 
the discretion of the study investigator).  
 
7.5 
Final Study Visit: 
At the end of the study and within 4 weeks of study drug termination the following 
will be performed 
• History and physical exam 
• Vital Signs (BP, pulse) 
• Weight 


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• Eastern Cooperative Oncology Group (ECOG) Performance Status 
• Assessment of concurrent medications 
• Adverse event evaluation 
• Laboratory testing: 
• CBC with differential/platelets 
• Serum chemistry must include: BUN , creatinine, total bilirubin, albumin, SGOT 
[AST],  SGPT [ALT], GGT, LDH, amylase, lipase, alkaline phosphatase, fasting 
glucose, calcium, sodium, magnesium, phosphorus, and potassium  
• PSA test 
• N-telopeptides in urine 
• Correlative Studies (serum and bone marrow androgen testing, plus additional 
serum/plasma banking) 
• Disease Status Assessment 
• Chest X-ray 
• Electrocardiogram (if not done in the past 6 weeks) 
• CT or MRI scans of the pelvis and abdomen (if indicated) 
• Bone scan (if indicated) 
• Bone marrow biopsy and aspirate: The specimens will be evaluated by pathology.  
A small portion of the bone marrow aspirate will be used for bone marker testing. 
 
7.6 
Long-Term Follow Up 
Patients will be followed a minimum of every 3 months by clinic visit (at M.D. 
Anderson or a local physician), telephone or e-mail correspondence to assess delayed 
toxicity and survival time.  
 
8.0 
WITHDRAWAL FROM STUDY TREATMENT 
The investigator may withdraw a patient from study treatment phase for any of the following 
reasons: 
 Dosing noncompliance:  Study drug administration and dosing compliance will be 
assessed on Week 4 visit.  A count of study drug will be conducted during this visit 
and patient dosing compliance will be assessed.  If dosing compliance is not 100% in 
the absence of toxicity, patient should be re-instructed regarding proper dosing 
procedures and continue in the study.  Subsequent dosing compliance procedure will 
be conducted at each study visit.  If a patient misses 14 or more doses within a single 
28-day cycle, the patient should be discontinued from the study treatment phase.  All 
End-of-Study treatment procedures should be followed.  The patient will be followed 
for survival. 
 Sustained Side Effects:  Patients who have sustained toxicities, such as described in 
6.5.6, which does not return to NCI CTCAE (version 3.0) Grade 1 or less with 
appropriate medical management, should be discontinued from the study treatment 
phase.  All End-of-Study treatment procedures should be conducted.  The patient will 
be followed for survival. 
 Initiation of new anticancer treatment:  Patients will be discontinued from the study 
treatment when investigator, in his or her judgment, determines new treatment for 


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prostate cancer is warranted.  All End-of-Study treatment procedures should be 
conducted and the patient will be followed for survival. 
 Administration of prohibited medications:  The patient will be discontinued from the 
protocol treatment when prohibited drug is administered.  All End of Study treatment 
procedures should be conducted.  The patient will be followed for survival.  
Supportive care medications are permitted with their use following institutional 
guidelines.  For patients who did not undergo orchiectomy, concurrent treatment with 
LHRH analogue is mandatory and must be recorded.  The concurrent administration 
of other anti-cancer therapy, including cytotoxic, hormonal (except LHRH agonists), 
or immunotherapy is prohibited during study treatment phase.  Use of other 
investigational drug therapy for any reason is prohibited 
 Patient’s withdraws consent.  In this event, the reason(s) for withdrawal must be 
documented A patient’s decision to take part in the study is voluntary and he may 
choose not to take part in the study or to stop taking part at anytime.  If he chooses 
not to take part or to stop at anytime, it will not affect his future medical care or 
medical benefits. 
 
 
9.0 QUALITY CONTROL AND ASSURANCE 
 
During and/or after completion of the study, quality assurance officers named by Novartis or 
the regulatory authorities may wish to perform on-site audits.  The investigators will be 
expected to cooperate with any audit and to provide assistance and documentation (including 
source data) as requested. 
 
Novartis representatives are responsible for contacting and visiting the investigator for the 
purpose of inspecting the facilities and, upon request, inspecting the various records of the 
clinical study (eg, CRFs and other pertinent data) provided that patient confidentiality is 
respected. 
 
10.0 PLANNED STATISTICAL METHODS 
 
This is a phase IIA activity trial of TKI258 for treatment of castrate resistant prostate cancer 
with skeletal metastases. The two primary outcomes are survival time and early response as 
characterized by a drop in PSA as defined by working group criteria. Based on historical 
mean survival time 8 months, a mean survival time on average > 10 months with TKI258 
would be considered promising evidence of anti-disease activity.  The planned sample size is 
40 patients, with an anticipated accrual rate of 3 patients per month. Based on historical 
experience using carefully selected candidates with evidence for iliac involvement on bone 
scan, we anticipate that ~60% of patients will have positive biopsies. No early stopping rule 
in terms of the probability of PSA response will be employed because it is not known 
whether blocking the stromal-epithelial interactive pathway (SE-pathway) will be related to 
clinical benefit.  Consequently, it may be the case that PSA does not drop but survival time is 
prolonged due to inhibition of disease progression by TKI258. Given the short survival time 
of these patients and anticipated accrual rate of 3 patients per month, it also will not be 


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feasible to implement an early stopping rule in terms of observed survival times.  Based on 
an historical rate of 20% grade 3 or 4 toxicity with standard therapies the method of Thall 
and Sung (1998) will be used to monitor toxicity. Unadjusted survival time will be estimated 
using the method of Kaplan and Meier (1958) and  the effects of the following four potential 
prognostic covariates: Inhibition of FGF signaling by bone marrow biopsy at 4 weeks, 
modulation of the bone markers (a) urinary NTX and (b) bone specific alkaline phosphatase, 
and baseline signature of FGF signaling in terms of FGF R-1, FGF R-3 and FGF 9 on 
Prob(PSA response) will be estimated using logistic regression, and on survival time will be 
estimated using the Cox model or an appropriate time-to-event regression model. 
 
Preliminaries: This is a phase IIA activity trial of TKI258 for treatment of castrate resistant 
prostate cancer with skeletal metastases. The two primary outcomes are survival time and 
early response as characterized by a drop in PSA as defined by working group criteria (25).   
 
Historical Experience and Goals: Based on the historical experience in which the mean 
survival time was 8 months, under a Bayesian model we assume that the unadjusted mean 
survival time with TKI258 follows an uninformative inverse gamma with mean 8 and 
variance 1000, equivalently with scale parameter 2.064 and shape parameter 8.512, denoted 
mE ~ IG(2.064, 8.512).  A mean survival time on average > 10 months would be considered 
promising evidence of anti-disease activity.  Formally, assuming that the historical mean 
survival mH ~ IG(52, 400),  TKI258 will be considered promising if, based on the data from 
the trial,  Pr(mE >  mH | data ) > .95. The planned sample size is 40 patients, with an 
anticipated accrual rate of 3 patients per month.  In addition, the relationships between 
several potential prognostic covariates and the above clinical outcomes will be explored, as 
described below. 
 
Monitoring Rules: No early stopping rule in terms of the probability of PSA response will be 
employed because it is not known whether blocking the stromal-epithelial interactive 
pathway (SE-pathway) will be related to clinical benefit.  Consequently, it may be the case 
that PSA does not drop but survival time is prolonged due to inhibition of disease 
progression by TKI258. Given the short survival time of these patients and anticipated 
accrual rate of 3 patients per month, it will not be feasible to implement an early stopping 
rule in terms of observed survival times.  However, based on an historical rate of 20% grade 
3 or 4 toxicity with standard therapies, it will be assumed that p = Prob(grade 3 or 4 with 
TKI258) follows a beta prior with parameters (.20, .80).  Using the method of Thall and 
Suung (26), based on the observed toxicity data, accrual to the trial will be stopped early if 
Pr(p > .20 | data)  > .95, with this rule applied after successive cohorts f size 5.  This rule says 
to stop the trial if [# patients with a grade 3 or 4 toxicity]/[# patients evaluated] is greater 
than or equal to 3/5, 5/10, 7/15, 8/20, 9/25, 11/30, 12/35. The operating characteristics of this 
rule are summarized in the following table. 
 
 
True Prob(toxicity) 
Prob(Stop Early) 
Achieved Sample Size 
25th, 50th, 75th percentiles 


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.10 
.01 
40  40  40 
.20 
.11 
40  40  40 
.30 
.47 
20  40  40 
.40 
.86 
5  15  25 
 
Data Analysis. If the data on the 40 patients yield a sample mean of 10 months (the targeted 
25% improvement) based on total follow-up time 400 months (all 40 deaths observed) then 
the posterior of m would be IG(42.064, 408.512), which has mean 9.95 months and posterior 
95% credible interval 7.33 – 13.4 months.  Similarly, if 35 deaths are observed with 5 death 
times administratively censored and total follow-up 460 months at the final analysis then the 
posterior of m would be IG(37.064, 468.512), ), which has mean 13 months and posterior 
95% credible interval 9.39 – 17.95 months.  Unadjusted survival time will be estimated using 
the method of Kaplan and Meier (27).  The effects of the following four potential prognostic 
covariates on Prob(PSA response) will be estimated using logistic regression (28), and on 
survival time will be estimated using the Cox model or, if the proportional hazards 
assumption is not satisfied, using an appropriate time-to-event regression model chosen 
based on preliminary goodness-of-fit analyses of the data (29).  Each of the following 
covariates is a binary indicator. 
 
1. Inhibition of FGF signaling by bone marrow biopsy at 4 weeks. 
 
2. Modulation of the bone markers (a) urinary NTX and (b) bone specific alkaline 
phosphatase  
 
3. Baseline signature of FGF signaling in temrs of FGF R-1, FGF R-3 and FGF 9. 
 
Time of disease progression if defined by PSA alone is defined as follows:  Three 
consecutive PSA elevations above nadir or baseline are required.  Each increment in PSA 
should be a minimum of 1 ng/ml and at least 2 weeks apart or will not count.  The time of 
PSA progression will be taken as the time of the first of these PSA elevations that represents 
an increment by at least 25% above the nadir or baseline.  Given that increments in PSA do 
not always represent treatment failure, particularly when novel agents with uncertain effects 
on PSA levels are being evaluated, clinical and radiological correlation is recommended at 
the discretion of the treating physician.  In patients with PSA progression alone without 
clinical or radiological evidence of disease progression, continued therapy on study is at the 
discretion of the treating physician in consultation with the principal investigator. 
 
 
 
 
 
 


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5. Casanovas O, Hicklin D, Bergers G, et al (2005) Drug resistance by evasion of 
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6. Cohen P (2002) Protein kinases: the major drug targets of the twenty-first century. Nat 
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10. DeMatteo RP (2002) The GIST of targeted cancer therapy: a tumor (gastrointestinal 
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27. Kaplan EL, Meier P:  Nonparametric estimation from incomplete observations.  J Am 
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