Clinical trial NCT01254864
Conditions: Prostate Cancer
Keywords: Castrate resistant prostate cancer Adenocarcinoma of the prostate Sunitinib Malate SUO11248 Sutent BMS-354825 Sprycel
Sponsor: M.D. Anderson Cancer Center
Start date: 2011-03-16; Completion date: 2023-12-07
Enrollment: 190 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
You are being asked to take part in this study because you have prostate cancer that has spread to other parts of the body.

This is an investigational study. Prednisone is FDA-approved and commercially available. Abiraterone acetate is FDA-approved and commercially available, but is still being researched. Sunitinib malate is FDA-approved for the treatment of gastrointestinal tumors and renal cell carcinoma, and dasatinib is FDA approved and commercially available for certain types of leukemia. The use of these drugs in prostate cancer and in combination with abiraterone acetate and prednisone is investigational.

Up to 180 patients will be enrolled in this study. All will be enrolled at MD Anderson.

Detailed description:
The Study Drugs:

Abiraterone acetate is designed to block male hormones in the body that may cause prostate cancer to grow.

Prednisone is commonly given in combination with other drugs to patients with prostate cancer. In this study, it is being used in combination with abiraterone acetate in order to help prevent side effects that abiraterone acetate may cause.

Sunitinib malate is designed to block pathways that control important events such as the growth of blood vessels that are essential for the growth of cancer.

Dasatinib is designed to change the function of genes. By changing the function of these genes, it may prevent cancer from growing and spreading.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will take 4 tablets of abiraterone acetate by mouth every day. The tablets should be taken all at once, at least 1 hour before a meal or 2 hours after a meal. You will also take 1 tablet of prednisone by mouth 2 times each day. You will take both of these drugs throughout the entire study.

If the disease gets worse while you are taking abiraterone acetate and prednisone, you will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups.

* If you are assigned to Group 1, you will start taking sunitinib malate. You will take 3 capsules by mouth 1 time each day, while continuing to take abiraterone acetate and prednisone.
* If you are assigned to Group 2, you will start taking dasatinib. You will take 2 tablets by mouth 1 time each day, while continuing to take abiraterone acetate and prednisone. Dasatinib tablets should be swallowed whole, with or without a meal. If you accidentally miss taking a dose of dasatinib, it may be taken within 12 hours later. If you vomit within 30 minutes of taking the tablets, that dose may be repeated. If you miss a dose due to side effects, the dose should not be replaced.

If the disease gets worse after you have been assigned to a group, and you are still eligible to continue taking the study drugs, you will "crossover" to the other group. If you were in Group 1, you would stop taking sunitinib malate and begin taking dasatinib. If you were in Group 2, you would stop taking dasatinib and begin taking sunitinib malate. No matter which group you crossover to, you will continue taking abiraterone acetate and prednisone.

Study Visits:

At each study visit, you will be asked about any other drugs you may be receiving and about any side effects you may be having.

Every 2 weeks during the first 12 weeks of taking abiraterone acetate and prednisone and during the first 3 cycles (9-12 weeks) of each new treatment combination, blood (about 1-2 tablespoons) will be collected to test your liver function.

Every 4 weeks, the following tests and procedures will be performed:

* You will have a physical exam, including measurement of your vital signs and weight.
* Blood (about 1-2 tablespoons) and urine will be collected for routine tests. Part of this blood will be used to measure your PSA and your levels of a specific marker of prostate cancer.
* You will be asked questions about how you are feeling and about any side effects you may have had since your last visit.
* You will be asked about any other drugs you may be taking.
* Your performance status will be recorded.

If the disease gets worse (or you change treatments) at any point in the study, the following tests and procedures will be performed:

* Blood (about 1-2 tablespoons) and urine will be collected for routine tests.
* You will have a bone marrow aspiration and biopsy or a tumor tissue biopsy to collect tumor tissue from places to which the tumor has spread to check the status of the disease.
* You will have an ECG and an echocardiogram or a MUGA scan.
* You will have a chest x-ray, CT scans of your abdomen and pelvis, and a bone scan to check the status of your disease.

If your doctor thinks it is necessary:

°You will have a chest x-ray, CT scans of your abdomen and pelvis, and a bone scan to check the status of your disease.

Length of Study:

You may continue taking the study drugs for as long as the doctor thinks it is in your best interest. You will be taken off study if the disease gets worse after crossover, if you experience intolerable side effects, or if the doctor thinks that it is in your best interest.

End of Treatment Visit:

After you stop receiving the study drugs for any reason, the following tests and procedures will be performed:

* You will have a physical exam, including measurement of your vital signs and weight.
* Blood (about 1-2 tablespoons) will be drawn for routine tests and to check your PSA level, your level of a specific marker of prostate cancer, and to check for a protein related to cancer.
* You will be asked questions about how you are feeling and about any side effects you may have had since your last visit.
* You will be asked about any other drugs you may be taking.
* Your performance status will be recorded.
* You will have a bone marrow aspiration and biopsy or a tumor tissue biopsy to collect tumor tissue from places to which the tumor has spread to check the status of the disease.

Post-Treatment (Safety) Follow-Up Visit:

About 30 days after your last dose of study drugs, the following tests and procedures will be performed:

* You will have a physical exam, including a measurement of your vital signs.
* Blood (about 1-2 teaspoons) will be drawn for routine tests.
* Your performance status will be recorded.
* You will be asked about any side effects you may have experienced since your last visit.
* You will be asked about any other drugs you may be taking.

Long-Term Follow-Up:

A member of the study staff will check up on you about every 6 months after your Post-Treatment (Safety) Follow-Up Visit. This will consist of a phone call, an e-mail, or a review of your medical and/or other records. If you are contacted by phone, the call will only last a few minutes.

After your End-of-Treatment visit, the study staff will contact you by phone, e-mail, or you will come in for a clinic visit. You will be asked about how you are feeling and any side effects you may have had. Each follow-up will take about 5 minutes. Follow-up will take place every 3 months for the first 2 years, every 6 months for the third year, and 1 time a year after that. The last follow-up will be about 5 years after the last patient is enrolled.

Arms: arm 1: Abiraterone Acetate at 1000 mg orally each day, given in combination with 5 mg of Prednisone orally twice daily. arm 2: AP (Abiraterone Acetate + Prednisone) Plus Sunitinib; Randomized from AP group to receive Sunitinib if disease worsens. Assignment to crossover group AP + Dasatinib with further disease progression. arm 3: AP (Abiraterone Acetate + Prednisone) Plus Dasatinib; Randomized from AP group to receive Dasatinib if disease worsens. Assignment to crossover group AP + Sunitinib with further disease progression.
Interventions: intervention 1: Abiraterone Acetate intervention 2: Prednisone intervention 3: Sunitinib intervention 4: Dasatinib
Intervention descriptions: intervention 1: 1000 mg by mouth each day of a 28 day cycle. intervention 2: 5 mg by mouth twice daily of a 28 day cycle. intervention 3: 37.5 mg by mouth daily for two weeks followed by a week of rest in a 28 day cycle. intervention 4: 100 mg by mouth each day of a 28 day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
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MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2010-0070 
Protocol Title 
Maximal Androgen Depletion with Abiraterone Acetate Followed 
by Randomization of Maximal Androgen Ablation with Molecular 
Targeted Therapies Dasatinib or Sunitinib Malate. (CA180-320, 
Pfizer IIR WS520211) 
Protocol Phase 
II 
Protocol Version 
1/8/2021 
Version Date 
1/8/2021 
Protocol PI 
Paul G Corn M.D., PhD 
Department 
Genitourinary Medical Oncology 
1515 Holcombe, Unit 1374 
Houston, TX 77030 
Phone: (713) 792-2830 
E-mail: pcorn@mdanderson.org 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
110822 
Supporters & 
Protocol Number 
Janssen Scientific Affairs LLC 212082PCR2002, Bristol Myers Squibb 
CA180-320, and Pfizer WS520211_IIR 
 
Statistician 
Peter F. Thall, PhD 
The University of Texas MD Anderson Cancer Center 
Biostatistics 


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LIST OF ABBREVIATIONS 
 
 
AE 
Adverse event 
ANC 
Absolute Neutrophil Count 
BID 
Twice a Day 
BMS 
Bristol-Myers Squibb Company 
CAT ( or CT scan) 
Computed Axial Tomography 
CBC 
Complete Blood Count 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EKG 
Electrocardiogram 
ESR 
Expedited Safety Report 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
GCP 
Good Clinical Practice 
HCG 
Human Chorionic Gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
HRT 
Hormone Replacement Therapy 
IB 
Investigators’ Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IST 
Investigator-Sponsored Trial 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
NSAE 
Non-Serious Adverse Event 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PO 
By Mouth 
PR 
Partial Response 


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QD 
Once Daily 
QoL 
Quality Of Life 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TNM Staging 
Tumor, Node and Metastasis Staging 
ULN 
Upper Limit of Normal 
WBC 
White Blood Count 
WOCBP 
Women of Child-Bearing Potential 


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1.0 
Objectives 
1.1 
Primary Objectives: 
• To compare two two-stage treatment strategies for patients with castrate resistant 
prostate cancer that has progressed after treatment with Abiraterone Acetate. 
 
 
1.2 
Secondary objectives: 
 
• Assess the time to treatment failure (TTF) prospectively in pretreated patients with 
abiraterone acetate and low-dose prednisone. 
 
o Assess the association between TTF with bone marrow testosterone 
concentrations. 
 
o Assess hypotheses generating associations between candidate pathway 
expression with response and progression free survival time. 
 
• Determine the toxicity of the Src inhibitor, dasatinib, in combination with 
abiraterone acetate and low-dose prednisone in patients following progression on 
abiraterone acetate/prednisone. 
 
o Assess the progression free survival time of dasatinib + abiraterone acetate in 
abiraterone pretreated patients. 
 
o Assess hypotheses generating associations between candidate pathway 
expression with response and progression free survival time. 
 
• Determine the toxicity of sunitinib in combination with abiraterone acetate and low- 
dose prednisone in patients following progression on abiraterone/prednisone. 
 
o Assess the progression free survival time of sunitinib + abiraterone acetate in 
abiraterone pretreated patients. 
 
o Assess hypotheses generating associations between candidate pathway 
expression with response and progression free survival time. 
 
• Assess response, toxicity and progression free survival of patients following 
crossover. 
 
• Identify associations with molecular markers implicated in prostate cancer with 
response and progression of each of the therapies investigated. 
 
• Create a deeply annotated tissue resource for hypothesis generating discovery. 


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2.0 
Introduction and Rationale 
Prostate cancer is the most common cancer in males. The cancer is a major health care 
problem in the US and worldwide. It is anticipated that the challenge of prostate cancer, an 
age dependent neoplasm, will only increase with progressive aging of the population 
worldwide. Unlike other cancer types only modest advances have been made in therapy. The 
mainstay of therapy for patients with advanced cancer remains androgen ablation, and 
chemotherapy achieves responses and clearly palliates patients with advanced disease. The 
effects are modest and the earlier use of therapy has yet to increase its effectiveness. These 
observations stress the need to develop new therapy strategies based on the improved 
understanding of the biology driving prostate cancer progression [1]. 
 
Clinically, prostate cancer is characterized by a predictable pattern of progression in the 
majority of patients. The disease progresses from the primary site to lymph nodes and then 
bone. Osseous metastases are the preferred area of castrate progression that inevitably follows 
the initial response to androgen ablation in patients with metastases. 
 
The mainstay of therapy for patients with prostate cancer metastases is androgen ablation. 
The vast majority of patients will initially benefit from a “response” and gratifying relief of 
symptoms. However, total disappearance of disease among patients presenting with 
metastases rarely occurs. Incurable castrate resistant progression occurs within three years in 
the vast majority of these patients. This stark reality prompted the study of chemotherapy 
upon castrate resistant progression. Prospective and properly powered randomized studies 
demonstrated meaningful palliation and subsequently a modest survival benefit. 
 
Thus, chemotherapy has been the only new approved treatment that prolongs the survival of 
patients with castrate resistant prostate cancer. 
 
2.1 
Role of microenvironment 
Bone is the dominant site of prostate cancer metastasis. Although the pattern of 
progression is predictable, the response to therapy has been unpredictable. This 
manifests clinically as variable results of therapy in otherwise similar patients. These 
observations suggest that prostate cancer bone metastasis is a biologic heterogeneous 
disease and understanding the various mechanisms that drive the progression in bone 
may improve the response to therapy. The inability to overcome the clinical 
heterogeneity of prostate cancer may account for the limited success of molecularly 
targeted therapies. In addition, the heterogeneity may account for our inability to apply 
our understanding of the biology of prostate cancer bone metastases to improving 
therapies for patients with prostate cancer. For example, two recent attempts to inhibit 
the osteoblast–epithelial interaction—blocking endothelin α receptor–mediated 
progression and blocking platelet-derived growth factor (PDGF)–mediated 
progression—resulted in modulation of bone-turnover markers without corresponding 
changes in the tumor. We interpret this experience as suggesting that the available 
experimental models of prostate cancer bone metastases do not reflect the complexity of 
the human disease and the multiple pathways that are implicated in its progression [1]. 


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An additional observation that may contribute to the failure to translate experimental 
observations into improvement in therapy may be emerging appreciation of the role of 
persistent androgen signaling in the progression of castrate resistant prostate cancer. The 
finding challenges the prevailing endocrine dogma of androgen signaling and suggests 
that androgen signaling is a stromal-epithelial interacting pathway implicated in prostate 
cancer progression. Thus it may be important to maximally deplete microenvironment 
androgens to avoid the potential resistance attributed to sustained androgen signaling as 
resulting from paracrine production or androgens. These observations led us to conclude 
that elucidating the clinical heterogeneity of prostate cancer bone metastases will lead to 
effective and personalized care for the patients with prostate cancer bone metastases [1]. 
 
2.2 
Paracrine androgen signaling 
There is increasing evidence that “intracrine” (autocrine /paracrine) androgen signaling 
is implicated in the castrate resistant progression of prostate cancer. Furthermore 
persistent androgen signaling may account for the limited effectiveness of blocking 
androgen independent stromal- epithelial interacting pathways despite the compelling 
experimental data generated principally in androgen independent model systems. This 
reasoning leads us to speculate that there is a hierarchy of stromal – epithelial / 
interacting pathways with androgen signaling as dominant. The line of reasoning leads 
to the hypothesis that efficient inhibition of “paracrine androgen signaling” will be a 
critical aspect of rational combinatorial strategies targeting the tumor 
microenvironment. 
 
2.3 
Rationale for lead-in Abiraterone acetate 
Abiraterone acetate has demonstrated antitumor activity in well-characterized patients 
with progressive castrate resistant prostate cancer. The response rates range from 40% 
to 60% by traditional criteria (Attard JCO 2008, JCO 2009, Danila ASCO 2008). These 
data provide confidence that further suppression of androgens can be achieved in 
patients with advanced castrate resistant prostate cancer. The expression of CYP 17 
androgen receptor and increased bone marrow concentration of androgens were 
preliminarily predictive of response to abiraterone (Efstathiou GU Cancers Symposium 
2009). These data support the hypotheses that resistance to castration results from 
increased expression of CYP 17, with “intracrine” production of androgens and 
increased androgen receptor expression. The initial suppression followed by continued 
suppression of the androgen signaling planned in this trial will test the hypotheses that 
the continued androgen signaling accounts for some of the resistance observed to 
targeted therapies in patients with castrate resistant prostate cancer. 
 
2.4 
Rationale for Sunitinib 
Sunitinib has been studied and found to be safe in patients with advanced prostate 
cancer. Sunitinib was initially given alone then combined with chemotherapy. The 
findings suggest that sunitinib has a favorable tolerance and efficacy profile. We have 
observed pathologic complete remissions which we have not observed in similar patients 
over the last seven years, which is very encouraging. Of particular relevance is the 


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observation that sunitinib in combination with LHRH agonist results in pathologic 
complete remission in patients with locally advanced prostate cancer. This was not 
achieved with preoperative imatinib or chemotherapy combined with LHRH agonist. [2, 
3] We interpret this finding to suggest that blocking of PDGF alone is inadequate where 
as inhibition of VEGF and PDGF signaling is efficacious by pathologic criteria in some 
patients with prostate cancer. Furthermore, the data suggest sunitinib may be superior to 
chemotherapy. The lack of a high rate of “response” by traditional cytoreduction 
analogous to that observed with vaccines. The addition of sunitinib to abiraterone will 
test the hypothesis that the combination of sunitinib and abiraterone acetate is safe and 
more effective than sunitinib alone in patients with castrate resistant prostate cancer. 
 
2.5 
Rationale for Dasatinib 
Src is experimentally and clinically by association implicated in the progression of 
prostate cancer. The role of Src in prostate carcinogenesis is complex, through its 
partitioned role in host cells (osteoclast, endothelial cell, and osteoblast) and the 
epithelial compartment of prostate tumors. The partitioned role of Src is central to the 
theoretical therapeutic advantage of Src inhibitors such as dasatinib when compared to 
agents that exclusively target the host compartment (bisphosphonates) or the epithelial 
component (chemotherapy). This rationale forms the basis for the use of dasatinib in 
patients with castrate resistant prostate cancer and demonstrates further modulation of 
bone turnover marker in the setting of maximal pretreatment with zoledronic acid. 
Dasatinib, a multi-kinase inhibitor that is a potent Src inhibitor, is safe and has 
promising antitumor effects when combined with docetaxel. Based on the experimental 
and clinical observation we conclude that Src is a “credentialed” target for advanced 
prostate cancer. These data lead us to the hypothesis that inhibition of Src signaling with 
dasatinib in patients with treated with maximal androgen ablation will be effective in 
prostate cancer [4-10]. 
 
2.6 
Rationale for Study 
The overall goal of this study is to efficiently establish a clinical foundation for the 
development of combinatorial microenvironment targeting therapies following maximal 
androgen depletion with abiraterone. The assumptions are that the pathways targeted in 
the context of this study are implicated in the paracrine and autocrine progression of the 
cancer and paracrine androgen signaling, which is the most important pathway 
implicated in CRPC. This study will efficiently validate candidate predictors of 
response to abiraterone acetate and assess the safety and efficacy of abiraterone acetate 
with the addition of two microenvironment targeting therapies with efficacy in prostate 
cancer. The result of the study will form the foundation for the development of a 
personalized treatment targeting the microenvironment for patient with advanced 
prostate cancer. 


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3.0 
Background Drug Information 
 
3.1 
Sunitinib 
 
Sunitinib is an orally administered small molecule that inhibits the tyrosine kinase 
enzymatic activities of VEGFR and PDGFR and also blocks signaling through KIT. 
Vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor 
receptor (PDGFR) have been implicated in prostate cancer progression to hormone- 
refractory state and metastatic involvement [11-13]. Bone metastasis can occur in more 
than 95% of mHRPC patients and contributes to morbidity and mortality in this disease. 
Overexpression of PDGFR occurs in bone metastases as well as in the primary prostate 
adenocarcinoma. 
 
Sunitinib has been approved multinationally for the treatment of gastrointestinal stromal 
tumor (GIST) after disease progression for intolerance to imatinib and for the treatment 
of advanced renal cell carcinoma (RCC). In clinical studies, sunitinib has been shown to 
have good oral bioavailability, linear pharmacokinetics, and a prolonged half-life for the 
parent compound, sunitinib (~40 hrs), and its active N-desethyl metabolite SU012662 
(~80 hrs). Steady state levels of sunitinib and its metabolite are reached 7 to 10 days 
after repeat daily dosing. Drug accumulation with repeated 3-, 4-, 6-week cycles, or 
continuous daily dosing has not been observed. The most common adverse events 
attributed to sunitinib have been constitutional symptoms (eg, fatigue/asthenia), 
gastrointestinal effects (eg, nausea, diarrhea, stomatitis, dyspepsia), myelosuppression 
(eg, neutropenia, thrombocytopenia), and dermatological effects (eg, dermatitis, skin 
discoloration, hair depigmentation). 
 
3.1.1 Mechanism of Action 
Sunitinib is a small molecule with antitumor properties that are pharmacologically 
mediated through inhibition of multiple receptor tyrosine kinases (RTKs) that are 
important in regulation of tumor cell growth, angiogenesis, and metastatic progression 
[14]. Specifically, sunitinib is a potent ATP-competitive inhibitor of the catalytic 
activity of a group of closely related RTKs consisting of PDGFR-α and -β, KIT, 
CSF-1R, FLT-3, VEGFR-1, -2, and -3, and RET. Due to its multi-targeted profile, the 
pharmacological activity of sunitinib is likely mediated by inhibition of multiple RTK 
targets and its antitumor mechanism is putatively mediated through inhibition of VEGF- 
and PDGF-dependent angiogenesis. 
 
In addition, sunitinib has demonstrated a higher response rate than that reported for anti- 
VEGF antibody treatment in patients with RCC [15]. Early evidence indicates that 
inhibition of multiple tumor targets may add to the efficacy of anticancer agents. This is 
consistent with results from preclinical experiments suggesting dual inhibition of 
VEGFRs and PDGFRs produces greater antiangiogenic and antitumor effects than 
inhibition of VEGF signaling alone [16]. 


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. 
 
 
 
3.1.2 Molecular Formula and Chemical Class 
Sunitinib has the molecular formula C22H27FN4O2. The free base has a molecular weight 
of 398.48 and the L-malate salt, the form used in clinical trials (Figure 1), has a 
molecular weight of 532.57. The chemical name of the L-malate salt is: (Z)-N-[2- 
(Diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4- 
dimethyl-1H-pyrrole-3-carboxamide (S)-2-hydroxysuccinate. 
 
 
Figure 1. The Structural Formula of SU011248 L-Malat Salt 
 
 
O 
 
N 
H 
 
N 
  
   H 
O 
OH 
N 
H 
HOOC 
H 
 
 
 
 
COOH 
 
 
 
Sunitinib has been shown to inhibit tumor growth of PC3 tumor cells in xenograft mouse 
models [17], as well as in subcutaneous, orthotopic and bone metastasis models by 75% 
to 88% compared to control animcals [Pfizer data on file]. It has also been shown to 
have direct growth inhibitory effect on LNCAP cells in vitro at concentrations as low as 
0.05 μM. Preliminary data from a Phase ½ study (Protocol A6181043) study in mHRPC 
suggest that sunitinib antitumor activity with acceptable safety profile. 
 
Protocol A6181043 is an ongoing open-label, dose finding study of sunitinib given once 
daily on a 2 weeks on, 1 week off treatment dosing regimen (Schedule 2/1) in 
combination with docetaxel and prednisone in patients with mHRPC in the first-line 
treatment setting. 
 
A 6-week sunitinib-only lead-in period (50mg/day administered on a 4 weeks on, 2 
weeks off treatment dosing regimen) was incorporated into the study design in order to 
provide data on PSA modulation by sunitinib alone. 
 
The Phase I portion of the study was recently completed:4 successive cohorts patients 
received escalating doses of sunitinib (12.5, 37.5, and 50 mg/day) given on Schedule 2/1 
in combination with 60 or 75 mg/m2 of docetaxel every 3 weeks and 5 mg BID of 
prednisone continuously. Dose-limiting toxicities (DLTs) were evaluated in the first 9 
 
 
 
F 


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weeks on study (lead-in and one combination cycle) and the recommended combination 
dose was defined as the dose level at which ≤ 2 out of 6 patients experienced a DLT, 
with the most acceptable pharmacokinetic profile. 
 
Two DLTs were observed among 25 patients which were manageable and reversible: 
one grade 3 hyponatremia in the 50mg sunitinib + 60 mg/m2 docetaxel cohort and one 
grade 4 neutropenia in the 37.5 mg sunitinib + 75 mg/m2 docetaxel cohort. Preliminary 
pharmacokinetic assessments in all patients indicated an increase in total sunitinib 
concentration when combined with docetaxel and prednisone, primarily related to an 
increase in the active metabolite SU012662 concentrations. There was also a small 
decrease in docetaxel concentrations, possibly related to prednisone induction. Based on 
these results, the combination dose was chosen as sunitinib 37.5 mg/day in combination 
with docetaxel 75 mg/m2 and prednisone 5 mg BID. 
 
As of the last data cutoff, a total of 14 patients had discontinued the study (6 due to 
disease progression and 8 due to adverse events, including 1 on-study death due to 
complications of the disease). Preliminary efficacy results showed a confirmed PSA 
response in 10 (40%) patients and an objective response rate of 20% (4 of 20 patients 
with measurable disease) [18]. The study has now proceeded to the Phase 2 portion to 
further assess the safety and efficacy of this regimen in the first-line treatment of 
mHRPC. 
 
During the lead-in period, elevations in PSA levels without correlation with clinical 
signs and symptoms of disease progression were commonly seen. PSA results showed 
three distinct patterns of sunitinib-induced PSA modulation during the lead-in period: 
 
1. PSA reduction: 7 patients (28%) exhibited a mean PSA decline of 40% (including 
3 patients with a confirmed PSA response [>50% decline confirmed by a second 
value]). 
 
2. Initial PSA increase: 12 patients had an initial PSA increase, followed by a drop 
during the sunitinib off-treatment period of 2 weeks (mean increase during the 
lead-in of 273%, followed by a decrease of 28%). 
 
3. PSA increase: 6 patients experience PSA progression (mean increase of 73%) and 
eventually discontinued the study due to disease progression. 
 
As seen with these results, further understanding of PSA kinetics during treatment with 
novel antiangiogenic agents is critical for the proper definition of efficacy, especially 
when the comparator arm is chemotherapy. Therefore, PSA alone is not likely to be a 
reliable marker for assessment of disease status in studies of sunitinib in patients with 
prostate cancer. Similar lack of correlation between PSA levels during treatment with 
clinical signs and symptoms of progressive disease has also been reported with sorafenib 
[19]. 


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Formulation and Packaging 
Sunitinib will be supplied to the clinical pharmacy by the sponsor as hard gelatin 
capsules containing 12.5-mg, 25-mg, 37.5-mg, or 50-mg equivalents of sunitinib free 
base, in light-resistant bottles containing 30 capsules each. 
 
Preparation and Dispensing 
Patients will receive one bottle containing 30 capsules of sunitinib every 4 weeks. Only 
one capsule strength will be dispensed to the patient at each dose level. In case of dose 
modifications, patients will be requested to return all of their previously dispensed 
medication to the clinic, and they will be dispensed new strength capsules. 
 
Drug Storage and Drug Accountability 
The investigator, or an approved representative, e.g., pharmacist, will ensure that all 
sunitinib is stored in a secure area, under recommended storage conditions (controlled 
room temperature 15-30°C) and in accordance with applicable regulatory requirements. 
All study drug supplies must be kept in a locked, limited access room. The study drug 
must not be used outside the context of this protocol. Under no circumstances should the 
investigator or other site personnel supply study drug to other investigators, patients, or 
clinics, or allow supplies to be used other than directed by this protocol without prior 
authorization from the sponsor. 
 
3.2 
Abiraterone Acetate 
 
Pharmacology 
 
Abiraterone acetate (CB7630) is the prodrug of abiraterone (CB7598). Once ingested, it 
is rapidly converted into abiraterone. Abiraterone is a selective steroidal inhibitor of 
17α-hydroxylase/C17, 20-lyase (cytochrome P450c17 [CYP17]). 
 
CYP17 is an important enzyme in the synthetic pathway for the production of androgens 
in the testes and adrenal glands. It catalyzes the conversion of pregnenolone or 
progesterone into dihydroepiandrosterone (DHEA) or androstenedione, respectively, 2 
precursors of testosterone. 
 
Thus, abiraterone inhibits the production of testosterone in adrenal glands and testes. 
Testosterone, a C19 androgen, is further converted to the more potent androgen, 
dihydrotestosterone (DHT), by testosterone 5α-reductase in the prostate; both 
testosterone and DHT are principal promoters of prostate cancer growth. 
 
Inhibitory effects of abiraterone on CYP17 activity have been demonstrated in vitro in 
rat and human testicular microsome preparations, and in vivo, in mouse, rat, and 
monkey animal models [20-21]. As expected, inhibition of CYP17 resulted in a 
reduction in circulating testosterone levels and, accordingly, the weight of androgen- 
sensitive organs. Reversible microscopic changes were observed in the tissues of 


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reproductive organs and in the adrenal gland. These effects were clearly demonstrated 
in established animal models after administration of abiraterone acetate. 
 
In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone 
(CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a 
single dose of 1,000 mg abiraterone acetate. Therefore, patients should be monitored 
closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic 
index if used concomitantly with ZYTIGA 
 
For the most current DDI information for abiraterone acetate, please refer to the full 
prescribing information. 
 
Toxicology 
 
Nonclinical safety studies (See Investigator’s Brochure) included the following: both in 
vitro and in vivo genotoxicity studies of abiraterone acetate and abiraterone; a single 
oral dose study of abiraterone acetate in mice; a single oral dose study in rats, two 28- 
day repeated oral dose toxicology studies of abiraterone acetate in rats (with 28-day 
recovery periods), a 13-week oral toxicity and toxicokinetic study in rats (with a 4-week 
recovery period), a 28-day repeated oral dose toxicity and toxicokinetic (TK) study 
(with a 28-day recovery period) in monkeys, and a 13-week oral toxicity and 
toxicokinetic study in monkeys (with a 4-week recovery period) in monkeys. 
 
In vitro and in vivo genotoxicity studies conducted with abiraterone acetate or 
abiraterone did not show any mutagenic or clastogenic activity. No carcinogenicity or 
developmental and reproductive toxicology studies have been conducted with 
abiraterone acetate at this stage of development. 
 
In both single oral dose and 28-day repeated oral dose studies, administration of 
abiraterone acetate to rats resulted in marked effects on the reproductive systems at all 
dose levels tested (40, 126, 400 mg/kg/d [240, 756, 2,400 mg/m2/d]). These effects were 
largely predictable from the pharmacological effects of the agent. The significance of 
changes seen in liver histology and liver function tests was further evaluated in 13-week 
toxicity studies in rats and monkeys. 
 
Higher doses administered for extended periods in both male and female rats (13 weeks 
treatment with dose levels up to 2000 mg/kg/d) resulted in severe morbidity in some 
animals, necessitating euthanasia. The study was continued at reduced doses: 50 
mg/kg/d (low dose), 250 mg/kg/d (mid) and 750 mg/kg/d (high). At the reduced low 
and mid dose levels, there were no test article-related clinical signs of toxicity during 
dosing or during the 4-week recovery period. 
 
At the new maximum dose of 750 mg/kg/d, the male rats lost weight in a manner 
consistent with inhibition of testosterone synthesis by abiraterone acetate, as reflected by 
very low plasma testosterone levels on Day 2 of treatment. At the high dose level (750 


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mg/kg/d), weight loss was also associated with reduced food consumption in male 
animals. Clinical chemistry findings, such as increased bilirubin and alkaline 
phosphatase, were suggestive of changes in liver function. Liver weights in both male 
and female rats were increased at the mid and high dose levels. Liver and gall bladder 
weights correlated with the minimal or slight bile duct hyperplasia observed 
microscopically in some animals. Bile duct hyperplasia correlated with increases in 
total bilirubin in female rats only. 
 
In male and female monkeys, 28-day repeated, once-daily, oral administration of 
abiraterone acetate induced effects in the adrenals, mammary gland, and reproductive 
organs at all doses tested (2, 10, 50, 250, and 1,000 mg/kg [24, 120, 600, 3,000, and 
12,000 mg/m2]). Treatment with abiraterone acetate was associated with hormonal, 
microscopic, and macroscopic changes that were considered to be consistent with the 
antiandrogenic activity of abiraterone acetate (ie, inhibition of CYP17). These changes 
were reversible during the 28-day recovery period following death of treatment. 
Clinical chemistry changes were fully reversible with the exception of plasma bilirubin 
levels in male monkeys in the 250 and 1000-mg/kg/d treatment groups, which remained 
elevated at the end of the recovery period. 
 
In a 13-week, repeated oral dose study in male and female monkeys with a 4 week 
recovery period, preliminary, unaudited results indicated no mortality or treatment- 
related adverse clinical signs other than white colored vomit and feces. The white color 
was presumed to be due to the presence of unabsorbed test article. There were no test- 
article effects on body weight or food consumption. Hormonal changes and organ 
weights, especially in reproductive organs and the adrenals, were again consistent with 
the antiandrogen properties of the agent. Abiraterone acetate administration was 
associated with higher triglyceride and total bilirubin concentrations suggesting some 
liver function changes. Dose-dependent increases in liver weights were observed in 
male and female animals. Clinical pathology changes showed reversibility following the 
4-week recovery phase. Minimal, slight or moderate bile duct hyperplasia was seen 
microscopically in some animals which correlated with increases in total bilirubin. The 
hyperplasia was partially reversed during the recovery period while the bilirubin levels 
returned to normal. 
 
Pharmacokinetics and metabolism 
 
The pharmacokinetic (PK) and toxicokinetic (TK) profiles of abiraterone, administered 
as abiraterone acetate has been characterized in mice (oral, intraperitoneal, and 
intravenous), rats (oral), and monkeys (oral). Abiraterone acetate administered orally 
was systemically absorbed by animals and rapidly converted to abiraterone. 
Bioavailability of abiraterone, administered as abiraterone acetate, was 37% in the 
mouse in one study. Toxicokinetic analyses revealed that animals were exposed mainly 
to the metabolite, abiraterone and TK values were not linear and did not increase 
proportionally to dose from 126 to 400 mg/kg/d in rats or from 2 to 1,000 mg/kg/d in 
monkeys. The exact mechanism(s) involved that would explain this observation 


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remain(s) to be determined. Lower Cmax and AUC at the end of the dosing period in 
the 28-day toxicology studies in rats and monkeys suggest a possible induction of 
hepatic catabolic metabolism of abiraterone. 
 
Preliminary data from in vitro studies with human hepatocytes indicate that human 
hepatocytes can convert abiraterone acetate to abiraterone and to other metabolites by 
hydroxylation and demethylation and conjugation reactions. 
 
3.2.1 Clinical Experience 
 
Three Phase 1 dose-escalation studies of abiraterone acetate were conducted in 
the United Kingdom by the Institute of Cancer Research (ICR) to investigate the 
safety and pharmacokinetics of oral abiraterone acetate in medically castrated or 
noncastrated men with prostate cancer [23]. In these 3 studies, 2 single-dose 
studies (Protocols PH1/054 and PH1/059) and one repeated daily dosing study 
(Protocol PH1/063) were carried out to determine the dose levels required to 
adequately suppress testosterone synthesis in these subjects. Other endocrine 
effects, particularly suppression of cortisol synthesis, were also examined. 
 
A total of 26 patients were treated at dose levels ranging from 10 to 800 mg/d in 
these Phase 1 studies. Overall, these studies showed that abiraterone acetate was 
safe and well tolerated. At doses of 500 and 800 mg/d, significant decreases in 
circulating testosterone were achieved in all 3 studies. 
 
In patients receiving 12-day repeated dosing at 500 and 800 mg/d (Protocol 
PHI/063), there were no apparent clinical signs of mineralocorticoid excess or 
glucocorticoid insufficiency. While basal levels of cortisol were within normal 
limits, use of the short Synacthen test (synthetic adrenocorticotropic hormone 
[ACTH1-24]) on Day 11 showed diminished cortisol response at 30 minutes 
when compared with pretreatment test responses. This observation suggests 
potential effects of abiraterone on the adrenal reserve which might be predicted 
from its known pharmacologic effects on steroid synthetic pathways. 
 
Subsequently, two Phase 1/2 studies (COU-AA-001 [124, 27, 28] and COU-AA- 
002 [15, 29]) have been sponsored by Cougar, to evaluate the safety and 
tolerability of abiraterone acetate administered continuously on a daily basis in 
patients who had castrate levels of testosterone, have been receiving ongoing 
GnRH agonists, and had not been treated with chemotherapy. These studies 
investigated the pharmacokinetics of abiraterone acetate, its effects on pituitary- 
adrenal axis, in addition to identifying the dose for additional antitumor activity 
assessment. At the conclusion of Phase 1 investigation, 1000 mg daily dose was 
selected for further evaluation of the antitumor activity of abiraterone acetate in a 
Phase 2 setting.  A plateau of biologic effect appears to have been reached at 
1000 mg daily dose in that the AUC values at a dose of 2000 mg are no higher 
than that for the 1000 mg dose. 


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Furthermore, a Phase 2 study (COU-AA-003 [26, 30]) was also initiated to 
assess the antitumor activity of abiraterone acetate in patients who have failed 
docetaxel-based chemotherapy. 
 
 
Study COU-AA-001 
 
Abiraterone acetate was well-tolerated at doses up to 2000 mg/day with no dose 
limiting toxicity being observed [27, 28]. Antitumor activity was observed with 
23 out of 38 patients having a greater than 50% decline in PSA lasting at least 
three months. 11 out of 20 patients with disease measurable by RESIST criteria 
had partial responses. There are 3 cases of regressing bone disease on imaging 
and reports of symptom improvement (stopping opiates). Furthermore, a 
reduction in levels of alkaline phosphatase and lactic dehydrogenase (LDH) and 
circulating tumour cells has been reported. Of particular interest, 4 patients have 
received abiraterone acetate treatment for more than 12 months as a result of 
sustained tumor response. 
 
For the Phase 2 study, the dose of 1000 mg has been selected as recommended 
dose as a plateau in endocrine effect was reached at that dose 
 
Study COU-AA-002 
 
In study COU-AA-002, a significant proportion of patients had prior treatment 
with ketoconazole for their prostate cancer [29]. Treatment with abiraterone 
acetate was found to be well-tolerated up to 1000 mg/day with no dose-limiting 
toxicity. All but one patient (24/25) had an initial decline in PSA and 12/25 
(48%) patients showed a greater than 50%. 
 
Study COU-AA-003 
 
Study COU-AA-003 is a Phase 2, open-label, multicenter study in patients who 
have androgen independent prostate cancer and failed docetaxel-based 
chemotherapy. Although patients had more advanced disease, abiraterone 
acetate was generally well tolerated [30]. Preliminary antitumor activity was 
also apparent. A >50% decline in PSA levels was seen in 7 (54%) of the first 13 
patients treated with abiraterone acetate. There were anecdotal reports of pain 
relief and decreased use of analgesics. 
 
In summary, continuous single daily dosing with abiraterone acetate was well- 
tolerated in patients with prostate cancer who have failed hormonal therapy with 
agents including GnRH agonists, antiandrogens, and ketoconazole, as well as 
chemotherapy. Dose-limiting toxicity was not observed in up to 2000 mg/day. 
Antitumor activities were apparent in these studies. 


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3.2.2 Packaging and Labeling 
Abiraterone acetate tablets will be provided to each site packaged in individual 
bottles for patient assignment at the time of randomization. Patients will be 
provided with a 30-day supply to allow for visits to occur every 28 days with a ± 
2 day window. 
 
Information presented on the labels for investigational product will comply with 
applicable local regulations. 
 
Site pharmacist or medically qualified staff will dispense the blinded study 
treatment to each patient in accordance with this protocol. 
 
3.2.3 Pharmacy Storage Requirements 
The study treatment must be stored in a secure area and administered only to 
patients entered into the clinical study in accordance with the conditions 
specified in this protocol. Bottles study treatment should be stored at room 
temperature [15º-30º C; 59º-86º F] in the original container/closure with the cap 
on tightly; it should never be refrigerated. Additional information is provided in 
the abiraterone acetate Investigator’s Brochure. 
 
3.2.4 Formulation of Study Drug 
Abiraterone acetate 250-mg tablets are oval, white to off-white and contain 
abiraterone acetate and compendial (USP/NF/EP) grade lactose monohydrate, 
microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl 
sulfate, magnesium stearate, colloidal silicon dioxide, and purified water, in 
descending order of concentration (the water is removed during tabletting). 
 
3.3 
Dasatinib 
 
Dasatinib [SPRYCEL®] is a potent, broad spectrum ATP-competitive inhibitor of 5 
critical oncogenic tyrosine kinase/kinase families: BCR-ABL, SRC, c-KIT, PDGF 
receptor β (PDGFRβ), and ephrin (EPH) receptor kinases, each of which has been linked 
to multiple forms of human malignancies.[31] 
 
Drug discovery and nonclinical pharmacology studies showed that dasatinib:[32] 
  
• 
Kills BCR-ABL dependent leukemic cell lines, including a number that are 
resistant to imatinib due to kinase domain mutations or overexpression of SRC 
family kinases and is effective against all imatinib-resistant kinase domain 
mutations tested to date, except T315I  
• 
Inhibited proliferation of cancer cell lines that express activated SRC or c-KIT  
• 
Potently inhibits VEGF-stimulated proliferation and migration in HUVECs  
• 
Has potent bone anti-resorptive activity 


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3.3.1 Preclinical Anti-tumor Activity 
 
3.3.1.1 
In Vitro Molecular Studies 
Dasatinib potently inhibits: SRC kinases, BCR-ABL, c-KIT, PDGFRβ and 
EPHA and was less potent against 16 other unrelated protein tyrosine kinases 
(PTKs) and serine/threonine kinases. Imatinib is less potent against several key 
enzymes: for example, Dasatinib was 260-, 8-, 60-, and >1000-fold more potent 
than imatinib versus BCR-ABL, c-KIT, PDGFRβ, and SRC kinases, 
respectively. [32] 
 
In vitro, dasatinib was active in leukemic cell lines representing variants of 
imatinib mesylate sensitive and resistant disease. Dasatinib inhibited the growth 
of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) 
cell lines overexpressing BCR-ABL. Under the conditions of the assays, 
dasatinib was able to overcome imatinib resistance resulting from BCR-ABL 
kinase domain mutations, activation of alternate signaling pathways involving 
the SRC family kinases (LYN, HCK), and multi-drug resistance gene 
overexpression. [31] 
 
Dasatinib inhibits the BCR-ABL kinase with an in vitro IC50 of 3 nM, a potency 
260-fold greater than that of imatinib mesylate (IC50 = 790 nM). In cellular 
assays, dasatinib killed or inhibited the proliferation of all BCR-ABL dependent 
leukemic cell lines tested to date. Dasatinib also demonstrated undiminished 
anti-tumor activity against several preclinically- and clinically-derived models of 
imatinib mesylate resistance. Evidence that SRC family kinase over expression 
may play a role in clinical resistance to imatinib mesylate was demonstrated in 
three CML cell lines established from patients who failed imatinib mesylate 
therapy. These cells remained highly sensitive to the cell-killing effects of 
dasatinib. [32] 
 
These results demonstrate that dasatinib is effective in reducing the proliferation 
or survival of both imatinib mesylate-sensitive and resistant cells, and its 
inhibitory activity is not solely dependent on BCR-ABL. 
 
3.3.1.2 
In Vivo Studies 
The activity of dasatinib against CML cells in vitro was reproduced in vivo 
against several human CML xenograft models grown subcutaneously in SCID 
mice. Against the K562/imatinib mesylate/R CML model, dasatinib was curative 
in 100% of the treated animals. In contrast, at its optimal dose and schedule, 
imatinib mesylate was inactive. 
 
3.3.2 Preclinical Toxicology 
Single or repeated oral administration of dasatinib principally affected the 
gastro-intestinal (GI) tract, including the liver, the hematopoietic and lymphoid 


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systems in rats and monkeys. Other prominent effects after single oral 
administration of dasatinib included renal and cardiac toxicity in rats at lethal 
doses, and cutaneous hemorrhage in monkeys. Dasatinib can also affect the 
immune system and bone turnover. 
 
Dasatinib in vitro activity in the HERG/IKr and Purkinje-fiber assays indicated a 
moderate liability for prolongation of cardiac ventricular repolarization (QT 
interval) in the clinic. However, there were no dasatinib -related changes 
observed in electrocardiograms, nervous system function, respirations and heart 
rate, blood pressure, or arterial oxygen saturation in single-dose, 10-day, or 1- 
month oral toxicity studies in monkeys. 
 
Dasatinib was found to exhibit a profile of broad-spectrum platelet inhibition 
best typified by anti-platelet agents such as the GPIIb/IIIa antagonists, integrelin 
and abciximab. 
 
Finally, modulation of SRC kinase activity could also affect osteoclast 
morphology and function and bone remodeling. This effect could potentially 
result in an increase in bone mineral density and a phenotype analogous to 
osteopetrosis. [32] 
 
3.3.3 Clinical Pharmacokinetics 
The pharmacokinetics of dasatinib have been evaluated in 229 healthy subjects 
and in 137 patients with leukemia (CML or Ph+ALL) from a Phase I clinical 
study (CA180002). 
 
3.3.3.1 
Absorption 
Maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 
and 6 hours (Tmax) following oral administration. Dasatinib exhibits dose 
proportional increases in AUC and linear elimination characteristics over the 
dose range of 15 mg to 240 mg/day. The overall mean terminal half-life of 
dasatinib is 3–5 hours. [31] 
 
Data from a study of 54 healthy subjects administered a single, 100-mg dose of 
dasatinib 30 minutes following consumption of a high-fat meal resulted in a 14% 
increase in the mean AUC of dasatinib. The observed food effects were not 
clinically relevant. 
 
3.3.3.2 
Distribution 
In patients, dasatinib has an apparent volume of distribution of 2505 L, 
suggesting that the drug is extensively distributed in the extravascular space. 
Binding of dasatinib and its active metabolite to human plasma proteins in vitro 
was approximately 96% and 93%, respectively, with no concentration 
dependence over the range of 100–500 ng/mL. [31] 


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3.3.3.3 
Metabolism 
Dasatinib is extensively metabolized in humans, primarily by the cytochrome 
P450 enzyme 3A4. CYP3A4 was the primary enzyme responsible for the 
formation of the active metabolite. Flavin-containing monooxygenase 3 (FMO- 
3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also 
involved in the formation of dasatinib metabolites. In human liver microsomes, 
dasatinib was a weak time-dependent inhibitor of CYP3A4. 
 
The exposure of the active metabolite, which is equipotent to dasatinib, 
represents approximately 5% of the dasatinib AUC. This indicates that the active 
metabolite of dasatinib is unlikely to play a major role in the observed 
pharmacology of the drug. Dasatinib also had several other inactive oxidative 
metabolites. 
 
Dasatinib is a time-dependent inhibitor of CYP3A3. At clinically relevant 
concentrations, dasatinib does not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 
or 2E1. Dasatinib is not an inducer of human CYP enzymes. [31] 
 
3.3.3.4 
Elimination 
Elimination is primarily via the feces. Following a single oral dose of [14C]- 
labeled dasatinib, approximately 4% and 85% of the administered radioactivity 
was recovered in the urine and feces, respectively, within 10 days. Unchanged 
dasatinib accounted for 0.1% and 19% of the administered dose in urine and feces, 
respectively, with the remainder of the dose being metabolites. [31] 
 
3.3.4 Anticipated Adverse Events 
 
Myelosuppression 
 
Treatment with dasatinib is associated with severe (NCI CTC Grade 3 or 4) 
thrombocytopenia, neutropenia, and anemia. Their occurrence is more frequent 
in patients with advanced CML or Ph+ ALL than in chronic phase CML. 
Complete blood counts should be performed weekly for the first 2 months and 
then monthly thereafter, or as clinically indicated. Myelosuppression was 
generally reversible and usually managed by withholding dasatinib temporarily 
or dose reduction. In a Phase 3 dose-optimization study in patients with chronic 
phase CML, Grade 3 or 4 myelosuppression was reported less frequently in 
patients treated with 100 mg once daily than in patients treated with 70 mg twice 
daily. [31] 


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Bleeding Related Events 
 
In addition to causing thrombocytopenia in human subjects, dasatinib caused 
platelet dysfunction in vitro. In all clinical studies, severe central nervous system 
(CNS) hemorrhages, including fatalities, occurred in <1% of patients receiving 
dasatinib. Severe gastrointestinal hemorrhage occurred in 4% of patients and 
generally required treatment interruptions and transfusions. Other cases of severe 
hemorrhage occurred in 2% of patients. Most bleeding events were associated 
with severe thrombocytopenia. 
 
Patients were excluded from participation in dasatinib clinical studies if they 
took medications that inhibit platelet function or anticoagulants. In some trials, 
the use of anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs 
(NSAIDs) was allowed concurrently with dasatinib if the platelet count was 
>50,000. Caution should be exercised if patients are required to take medications 
that inhibit platelet function or anticoagulants. [31] 
 
Fluid Retention 
 
Dasatinib is associated with fluid retention. In all clinical studies, severe fluid 
retention was reported in 8% of patients, including pleural and pericardial 
effusion reported in 5% and 1% of patients, respectively. Severe ascites and 
generalized edema were each reported in <1% of patients. Severe pulmonary 
edema was reported in 1% of patients. Patients who develop symptoms 
suggestive of pleural effusion such as dyspnea or dry cough should be evaluated 
by chest X-ray. Severe pleural effusion may require thoracentesis and oxygen 
therapy. Fluid retention events were typically managed by supportive care 
measures that include diuretics or short courses of steroids. 
 
In the Phase 3 dose-optimization study in patients with chronic phase CML, fluid 
retention events were reported less frequently in patients treated with 100 mg 
once daily than in patients treated with 70 mg twice daily. [31] 
 
QT Prolongation 
 
In vitro data suggest that dasatinib has the potential to prolong cardiac 
ventricular repolarization (QT interval). In single-arm clinical studies in patients 
with leukemia treated with dasatinib, the mean QTc interval changes from 
baseline using Fridericia’s method (QTcF) were 3–6 msec; the upper 95% 
confidence intervals for all mean changes from baseline were <8 msec. Nine 
patients had QTc prolongation reported as an adverse event. Three patients 
(<1%) experienced a QTcF >500 msec. 
 
Dasatinib should be administered with caution to patients who have or may 
develop prolongation of QTc. These include patients with hypokalemia or 


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hypomagnesemia, patients with congenital long QT syndrome, patients taking 
anti-arrhythmic medicines or other medicinal products that lead to QT 
prolongation, and cumulative high-dose anthracycline therapy. Hypokalemia or 
hypomagnesemia should be corrected prior to dasatinib administration. [31] 
 
3.3.5 Phase I experience in Solid Tumors 
 
In a Phase I study (CA180003) conducted by Bristol Myers Squibb (BMS), 
dasatinib was administered on a BID schedule to 42 subjects with refractory 
solid tumor. As of 10-Feb-2006, 33 subjects were treated for a full 4 weeks for 
evaluation of dose-limiting toxicities (DLTs). This study explored 8 dose levels 
with 2 different dosing schedules. The first schedule assessed 5 days of dasatinib 
followed by 2 days off-drug each week, and the second schedule assessed 
continuous daily dosing that was added in Amendment #3 (7-Mar-2005). In the 5 
days on/2 days off schedule, the following dose levels were explored: 35 mg 
BID, 50 mg BID, 70 mg BID, 90 mg BID, 120 mg BID and 160 mg BID. Of the 
six subjects enrolled and evaluable for DLT determination at the dose level of 90 
mg BID given on a continuous daily schedule, two episodes were considered 
possibly to represent DLT reported by 2 subjects. These were recurrent Grade 2 
rash in 1 subject and removal from study for Grade 2 nausea and vomiting and 
lightheadedness in the other subject. Given the otherwise acceptable tolerability 
of this dose level with toxicities that are medically manageable with a maximum 
severity of Grade 2, further escalation to the next dose level of 120 mg BID 
continuous daily schedule is currently under investigation. No further escalation 
above 160 mg BID was explored on this schedule because, as per protocol, this 
represents the maximum tolerated dose (MTD). [32] 
 
The preliminary safety results from CA180003 demonstrate that no severe 
clinical toxicity has been encountered. Dasatinib did not induce significant 
myelosuppression in this patient population Gastrointestinal symptoms including 
nausea and vomiting were reported in most subjects, fatigue was reported in 17 
subjects (40%) and rash in 9 subjects (21%). Edema, lethargy and headache were 
uncommon, and appear to be dose-related. Additionally, the incidence and 
severity of fluid retention and of pleural effusion, in particular, appear to be less 
in subjects with solid tumors than in those with leukemia receiving comparable 
doses of dasatinib. There were 4 subjects with drug-related AEs leading to 
discontinuation of treatment; none of these events were related to 
myelosuppression or fluid retention. [32] 
 
In another Phase I study (CA180021), dasatinib was administered on a QD 
schedule to 24 subjects with solid tumors in a drug-drug interaction and multi- 
ascending dose (MAD) study at doses up to 180 mg. This ongoing study 
investigated the effect of ketoconazole, a potent inhibitor of CYP3A4, on the PK 
of dasatinib (Segment 1) and the effect of dasatinib on pharmacodynamic 


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markers in subjects with advanced solid tumors that are refractory to standard 
therapies or for which no standard therapy exists (Segment 2). 
 
Segment 1 includes 18 subjects, of which 16 subjects were treated with dasatinib 
as of 2-Jan-2006. Segment 2 includes approximately 30 additional subjects, of 
which 14 subjects were treated with dasatinib as of 2-Jan-2006. A total of 4 
deaths, all related to disease progression, were reported. There were 4 subjects 
with drug-related AEs leading to discontinuation: 1 subject with Grade 1 
amnesia, 1 with Grade 2 pleural effusion, 1 with Grade 3 dehydration, and 1 
subject with Grade 3 dysphagia and Grade 3 dehydration. Hypocalcemia, GI 
symptoms and skin rash have been mild and infrequent. [32] 
 
To date, the safety profile in solid tumor subjects has been similar to that in CP 
CML subjects with the exception of severe myelosuppression, which has not 
been observed in solid tumor subjects and is considered related to efficacy 
against the leukemia as noted above, and severe bleeding which is secondary to 
thrombocytopenia in most instances.[32] 
 
3.3.6 Dasatinib Experience in Prostate Cancer 
In a Phase I study (CA180085) conducted by Bristol Myers Squibb (BMS), 
dasatinib was administered to 95 subjects with metastatic prostate cancer and 
rising PSA who progressed during first-line androgen ablation or progressed 
despite multiple-androgen suppression after discontinuation of androgen 
ablation. Treatment was given in two study groups, one with a BID dosing 
schedule and one with QD dosing. Twenty-five of 95 treated subjects were 
responders. Confirmed prostate-specific antigen (PSA) response was observed in 
2 subjects, 1 in each of the QD and BID groups. Stabilization of visceral/nodal 
disease as measured by RECIST was observed in 10 subjects in the QD group 
and 12 subjects in the BID group, and a partial response was observed in 1 
(1.1%) subject (QD group). Stabilization of bone disease was also noted. The 
QD dosing schedule led to fewer and less severe side-effects [47]. 
 
In a Phase I/II study (CA180086) being conducted by Bristol Myers Squibb 
(BMS), dasatinib (QD schedule; dose escalation) is being administered in 
combination with docetaxel. Preliminary results indicate: Of the 46 treated 
subjects, confirmed partial response was observed in 16 subjects and 
stabilization of disease was observed in 9 subjects. Confirmed PSA response was 
observed in 28 subjects and confirmed bone scan improvement was observed in 
10 subjects. Reduction of bone turnover markers (uNTX and BAP) was also 
observed. No drug-drug interactions (between dasatinib and docetaxel) were 
observed as demonstrated by extensive PK profiling, and neither compound 
interfered with the metabolism of the other [47]. 


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3.3.7 Identification 
Dasatinib is provided in 3 different strengths: 
 
Table 5.1.1: 
Description of Dasatinib Dosage Forms 
Strength 
Description 
5 mg 
white, round, film coated tablet 
20 mg 
white to off-white, biconvex, round, film coated tablet with 
either “20” or “BMS” debossed on one side and “527” on 
the other side 
50 mg 
white to off-white, biconvex, oval, film coated tablet with 
either “50” or “BMS” debossed on one side and “528” on 
the other side 
 
 
 
3.3.8 Packaging and Labeling 
 
Dasatinib is supplied as 5 mg, 20 mg, and 50 mg film-coated tablets containing 
dasatinib with lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating 
contains hydroxypropyl methylcellulose, titanium dioxide, and polyethylene 
glycol (triacetin in the 5 mg film-coated tablet). Tablets for clinical studies are 
supplied in high-density polyethylene bottles containing a desiccant and cotton. 
The bottles are heat-induction sealed with child resistant caps. 
 
Each bottle is labeled in an open label manner. Labels contain, at a minimum, the 
following information: product name, tablet strength, batch number, directions 
for use, storage conditions, and appropriate caution statements. 
3.3.9 
Storage, Handling, and Dispensing 
 
3.3.9.1 Storage 
 
Bottles containing dasatinib tablets should be stored at 15° - 25°C. 
All investigational product should be stored in a secure area according to local 
regulations. The investigator is responsible for ensuring that it is dispensed 
only to study subjects and only from official study sites by authorized 
personnel, as dictated by local regulations. 


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The investigator is responsible for ensuring that the investigational product is 
stored under the appropriate environmental conditions (temperature, light, and 
humidity. 
 
If concerns regarding the quality or appearance of the investigational product 
arise, do not dispense the investigational product, and contact BMS 
immediately. 
 
3.3.9.2 Handling and Dispensing 
Procedures for proper handling and disposal of anticancer drugs should be 
considered. 
 
Dasatinib tablets consist of a core tablet (containing the active drug substance), 
surrounded by a film coating to prevent exposure of pharmacy and clinical 
personnel to the active drug substance. If tablets are crushed or broken, 
pharmacy and clinical personnel should wear disposable chemotherapy gloves. 
Personnel who are pregnant should avoid exposure to crushed and/or broken 
tablets. 
 
The Investigator (or assigned designee, i.e., study pharmacist) will dispense the 
proper number of each strength tablet to the subject to satisfy dosing 
requirements for the study. The containers provided to the subject should be 
labeled with proper instructions for use. The lot numbers, dosing start dates 
and the number of tablets for each dosage strength must be recorded on the 
drug accountability pages of record for the site. The subject must be instructed 
to return all unused dasatinib in the provided packaging at each subsequent 
visit. 
 
4.0 
Patient Eligibility 
 
4.1 
Inclusion 
Each patient must meet the following criteria to be enrolled in this study. 
1. Willing and able to provide written informed consent 
2. Male aged 18 years and above 
3. Histologically or cytologically confirmed adenocarcinoma of the prostate 
4. Metastatic disease documented by positive bone scan or metastatic lesions other than 
liver or visceral metastasis on CT or MRI. 
5. Prostate cancer progression documented by PSA according to PCWG2 or 
radiographic progression according to modified RECIST criteria 
6. Surgically or medically castrated, with testosterone levels of ≤ 50 ng/dL (≤ 2.0 nM). 
If the patient is being treated with LHRH agonists (patients who have not undergone 
orchiectomy), this therapy must have been initiated at least 4 weeks prior to Cycle 1 
Day 1 and must be continued throughout the study. 


25 
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7. If the patient received previous anti-androgen therapy, then they have shown 
progression after withdrawal. Patients who received combined androgen blockade 
with an anti-androgen must have shown PSA progression after discontinuing the 
anti-androgen prior to enrollment (≥ 4 weeks since last flutamide, ≥ 6 weeks since 
last bicalutamide or nilutamide). If progression is documented prior to this time 
interval, patients are eligible. 8. 
Previous treatment with docetaxel is allowed. 
Patients must have recovered from any acute toxicity related to the treatment to be 
eligible. 
9. Eastern Cooperative Oncology Group (ECOG) Performance Status of < 1. 
10. Hemoglobin ≥ 9.0 g/dL 
11. Platelet count ≥100,000/μL 
12. Serum albumin ≥ 3.5 g/dL 
13. Serum creatinine ≤ 1.5 x ULN or a calculated creatinine clearance ≥ 60 mL/min 
14. Serum potassium ≥ 3.5 mmol/L 
15. Serum sodium, magnesium, potassium, phosphate, and calcium ≥ LLN (lower limit 
of normal) 
16. ANC value ≥ 1,000/mm3 
17. Liver function: 
i. Serum bilirubin ≤ 1.5 x ULN (except for patients with documented Gilbert’s 
disease) 
ii. AST or ALT ≤ 2.5 x ULN 
18. Able to swallow the study drug whole as a tablet/capsule. 
19. Patients who have partners of childbearing potential (e.g. female that has not been 
surgically sterilized or who are not amenorrheic for ≥ 12 months) must be willing to 
use a method of birth control with adequate barrier protection as determined to be 
acceptable by the principal investigator during the study and for 13 weeks after last 
study drug administration. 
20. Concomitant Medications 
(i) Patient agrees to discontinue St. Johns Wort while receiving dasatinib therapy (at 
least 5 days prior). 
(ii) Patient agrees that IV bisphosphonates will be withheld for the first 8 weeks of 
dasatinib therapy due to risk of hypocalcemia. 
(iii) Patient agrees to discontinue use of drugs primarily metabolized by CYP3A4 
enzyme (see Section 5.6.1.1 for a list of these drugs). 
(iv) Patient agrees to discontinue use of H2 Inhibitors or proton inhibitors prior to 
dasatinib administration. 
 
4.2 
Exclusion 
Patients who meet any of the following criteria will be excluded from the study: 
1. Active infection (requiring oral or IV antibiotics) or other medical condition that 
would make prednisone/prednisolone (corticosteroid) use contraindicated 
2. Any chronic medical condition requiring a higher dose of corticosteroid than 5mg 
prednisone/prednisolone BID. 
3. Pathological finding consistent with small cell carcinoma of the prostate 


26 
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4. Radiation therapy for treatment of the primary tumor within 6 weeks of Cycle 1, 
Day 1. Patients who have received palliative radiation to a single site and recovered 
are eligible. 
5. No malignancy [other than the one treated in this study] which required 
radiotherapy or systemic treatment within the past 5 years. 
6. Previously treated with ketoconazole (for prostate cancer) for greater than 7 
consecutive days OR previously treated with any other -azole drug (e.g. 
fluconazole, itraconazole) within 4 weeks of Cycle 1, Day 1. 
7. Prior flutamide (Eulexin) treatment within 4 weeks of Cycle 1, Day 1 (patients 
whose PSA did not decline for three or more months in response to antiandrogen 
given as a second line or later intervention will require only a two week washout 
prior to Cycle 1, Day 1) 
8. Bicalutamide (Casodex), nilutamide (Nilandron) within 6 weeks of Cycle 1 Day 
1(patients whose PSA did not decline for three or more months in response to 
antiandrogen given as a second line or later intervention will require only a two 
week washout prior to Cycle 1, Day 1). 
9. Uncontrolled hypertension (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg). 
Patients with a history of hypertension are allowed provided blood pressure is 
controlled by anti-hypertensive treatment 
10. Prolonged QTc interval on pre-entry electrocardiogram (≥ 450 msec) 
11. Active or symptomatic viral hepatitis or chronic liver disease 
12. History of pituitary or adrenal dysfunction 
13. Known brain metastasis 
14. Clinically significant heart disease as evidenced by myocardial infarction, or 
arterial thrombotic events in the past 6 months, severe or unstable angina, history of 
clinically significant ventricular arrhythmias (such as ventricular tachycardia, 
ventricular fibrillation, or Torsades de pointes), Subjects with hypokalemia or 
hypomagnesemia if it cannot be corrected prior to dasatinib administration or New 
York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection 
fraction measurement of < 50% at baseline 
15. History of significant bleeding disorder unrelated to cancer, including: 
i) 
Diagnosed congenital bleeding disorders (e.g., von Willebrand’s disease) 
ii) Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor 
VIII antibodies) 
iii) Ongoing or recent (≤ 3 months) significant gastrointestinal bleeding 
16. Atrial fibrillation or other cardiac arrhythmia requiring digitalis 
17. Other malignancy, except non-melanoma skin cancer, with a ≥ 30% probability of 
recurrence within 24 months 
18. Clinically significant pleural effusion as determined by the Principal Investigator. 
19. Administration of an investigational therapy for prostate cancer within 30 days of 
Cycle 1, Day 1 
20. Any condition which, in the opinion of the investigator, would preclude participation 
in this trial. 


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21. Patients taking category I drugs that are generally accepted to have a risk of causing 
Torsades de Pointes including: (Patients must discontinue drug 7 days prior to 
starting dasatinib) 
i) 
quinidine, procainamide, disopyramide 
ii) amiodarone, sotalol, ibutilide, dofetilide 
iii) erythromycin, clarithromycin 
iv) chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide 
v) cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, 
halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine. 
22. Prisoners or subjects who are involuntarily incarcerated. 
23. Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical (eg, infectious disease) illness. 
 
5.0 
Treatment Plan 
 
Patients found to be eligible based on the criteria above, will provide informed consent and 
begin treatment with abiraterone acetate at 1000 mg orally each day, given in combination 
with 5mg of prednisone orally twice daily. 
 
If a patient demonstrates “progression” (as defined in Section 10.0) after treatment with 
abiraterone acetate in combination with prednisone, he will then be evaluated and 
randomized to receive either sunitinib at a dose of 37.5 mg orally daily for two weeks 
followed by a week of rest or dasatinib at a dose of 100 mg orally each day, both while 
continuing treatment with abiraterone acetate and prednisone. All patients will remain on 
treatment until “composite progression” is established or toxicity (see Section 10.1). After 
composite progression, patients will crossover to the alternate agent (a patient treated with 
sunitinib will cross over to treatment with dasatinib in combination with abiraterone and 
prednisone, while those randomized to dasatinib will crossover to treatment with sunitinib in 
combination with abiraterone and prednisone). A 4 week washout period is planned between 
targeted agents; and patients must have fully recovered from treatment related adverse events 
prior to starting the second targeted agent. Patients will be taken off study following the 
crossover based on the accepted criteria in the initial portion of study. 
 
Abiraterone, dasatinib, and sunitinib will be provided free of charge by the manufacturer 
during trial participation. 


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Study Schema 
 
 
 
 
     
   
 
 
 
   
 
 
 
 
 
At first PD 
Crossover at second PD 
At third PD 
 
5.1 
Registration 
 
All patients will be registered in the University of Texas M. D. Anderson Cancer 
Center Office of Research Administration database. Registration should occur 
following informed consent process and prior to initiation of investigational therapy. 
All eligibility criteria must be satisfied. 
 
5.2 
Study Drug Administration: 
 
Abiraterone Acetate: Patients will be instructed to take 4 tablets (250 mg each) orally 
(PO) at least 1 hour before a meal or 2 hours after a meal. Treatment with abiraterone 
will continue throughout the duration of participation. 
 
Prednisone: Patients will be instructed to take 5-mg oral prednisone, twice daily. 
Treatment with prednisone will continue throughout the duration of participation. 
 
Patients will be randomized to receive either dasatinib or sunitinib after progression on 
single-agent abiraterone. 
 
Dasatinib Starting Dose: Patients will be instructed to take 100 mg (2 tablets @ 50 mg 
each) of dasatinib orally once daily. Dasatinib is formulated in 20, 50 mg and 100mg 
tablets. Tablets should not be crushed or cut; they should be swallowed whole. 
Dasatinib can be taken with or without a meal. The dosing time may be adjusted as 
required. If doses are missed for toxicity, they should not be replaced. If a dose is not 
Abira terone 
Acetate/ 
Prednisone 
Dasatinib in 
combination 
w/ abiraterone 
acetate/ 
prednisone 
Dasatinib in 
combination 
w/ abiraterone 
acetate/ 
prednisone 
O 
F 
F 
S 
T 
U 
D 
Y 
Sunitinib in 
combination 
w/a biraterone 
acetate/ 
prednisone 
Sunitinib in 
combination 
w/a biraterone 
acetate/ 
prednisone 
R 
A 
N 
D 
O 
M
I 
Z 
A 
T 
I 
O 
N 


29 
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taken due to an error, it may be taken up to 12 hours later. If vomiting occurs within 30 
minutes of intake, that dose may be repeated. 
 
Sunitinib Starting Dose: Patients will be instructed to take 37.5 mg (3 capsules at @ 
12.5 mg each) of sunitinib orally once daily. 
 
A total of 4 weeks (± 3 days) will constitute a course of therapy. A pill diary will be 
provided to each patient to document study drug compliance. 
 
5.3 
Laboratory Assessments and Imaging Studies: 
Patients may have standard lab studies drawn by a local physician and results faxed 
to MDACC prior to their scheduled clinic visit. If a patient is unable to return for 
restaging scans due to symptoms of progressive disease, a patient may have scans 
done at a local physician. These scans should be sent to the PI for review. 
 
5.4 
Duration of therapy: 
Patients will continue on each treatment arm until progression by PCWG2 criteria or 
persistent grade 3 toxicity after dose modification or patient withdraws consent. 
 
5.5 
Response to Therapy: 
 
Clinical patient assessments will occur at four week intervals. Response to therapy 
will be determined by PCWG2 criteria with tumor evaluations taken as clinically 
indicated. Detailed information regarding response criteria is located in section 9.0. 
 
5.6 
Concomitant therapy: 
 
5.6.1 
Prohibited and/or Restricted Treatments 
At each visit, all concomitant treatments, including blood and blood products, must be 
reported on the source documentation and on the Concomitant Medications page of the 
case report form. Concomitant medications must also be documented at the time of 
discontinuation and at the 30 day follow-up visit. 
 
No other systemic therapy for treatment of prostate cancer is permitted while subject is 
on study. Concomitant palliative radiotherapy is not permitted for disease progression 
on treatment, but is allowed for pre-existing non-target lesions with approval from the 
Principal Investigator. Bisphosphonate treatment may not be initiated during study; if 
already begun, it may be continued at Investigator discretion. 
 
Subjects requiring any prohibited therapy should not be enrolled. If enrolled, the 
prohibited agent(s) will be withdrawn prior to first dose of study drug. 
 
5.6.1.1 Potent CYP3A4 Inhibitors 


30 
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Dasatinib is primarily metabolized by the CYP3A4 enzyme. In drug-drug interaction 
studies, concomitant use of ketoconazole (a potent CYP3A4 inhibitor) produced an 
increase of > 5-fold in dasatinib exposure. Therefore, potent inhibitors of CYP3A4 are 
prohibited during study; for such medications, a wash-out period of ≥ 7 days is 
required prior to starting dasatinib. Subjects should be advised not to consume 
substantial quantities of grapefruit or pomegranate juice. (Less-potent inhibitors, 
inducers and substrates of CYP3A4 are restricted, see Section 5.6.2.1.) Most 
commonly-used potent CYP3A4 inhibitors are: 
o itraconazole, ketoconazole, miconazole, voriconazole; 
o amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir; 
o ciprofloxacin, clarithromycin, diclofenac, doxycycline, enoxacin, imatinib, 
isoniazid, ketamine, nefazodone, nicardipine, propofol, quinidine, 
telithromycin. 
 
5.6.1.2 Medications that prolong QT Interval 
Subjects enrolled in this study may not take concomitant medications known to 
prolong the QT interval (Class I; see http://www.qtdrugs.org/medical-pros/drug- 
lists/drug-lists.htm). For such medications, a wash-out period of ≥ 7 days is required 
prior to starting dasatinib. Agents which possibly prolong the QT interval are 
restricted; see Section 5.6.2.3. Medications known to prolong the QT interval are: 
o quinidine, procainamide, disopyramide, amiodarone, sotalol, ibutilide, 
dofetilide; 
o erythromycins, clarithromycin; 
o chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide; 
o cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, 
halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine. 
 
5.6.2 
Other Restrictions and Precautions 
The following restricted therapies are not recommended, but are permitted with 
caution when clearly medically indicated. 
 
5.6.2.1 CYP3A4 Inducers, Inhibitors, Substrates 
Drugs that induce CYP3A4 activity may decrease both dasatinib and exemestane 
plasma concentrations. In subjects in whom enzyme-inducing anticonvulsants (eg, 
phenytoin, carbamazepine, phenobarbital) are used, alternative agents with lesser 
enzyme-induction potential should be considered. 
 
Dasatinib is predominantly metabolized by the CYP3A4 isoenzyme. Potent inhibitors 
are prohibited, but less-potent inhibitors may also increase exposure to dasatinib. If 
administration of a CYP3A4 inhibitor cannot be avoided in subjects receiving 
dasatinib, close monitoring for toxicity and dasatinib dose reduction should be 
considered. Subjects should be advised not to consume substantial quantities of 
grapefruit or pomegranate juice. 


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Other CYP3A4 substrates known to have a narrow therapeutic index such as 
alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) 
should be administered with caution in subjects receiving dasatinib. Note: subjects 
treated with a fentanyl patch are eligible for this trial. 
 
As warfarin is metabolized through the CYP450 system, therapeutic anticoagulation 
with warfarin (eg, Coumadin or Cournadine) is not recommended. As an 
alternative, therapeutic anticoagulation may be accomplished using low-molecular 
weight heparin (eg, Lovenox) or heparin. Mini Dose Coumadin (eg, 1 mg QD) is 
permitted for prophylaxis of central venous catheter thrombosis. 
 
Please see a comprehensive list of CYP drugs at the following web address. 
http://www.medicine.iupui.edu/Flockhart/table.htm) 
 
5.6.2.2 CYP2D6 and CYP1A2 inhibitor Inducers, Inhibitors, Substrates 
Drugs metabolized through the CYP2D6 and CYP1A2 pathways should be used with 
caution while participating in this study. A list of these drugs can be found at the link 
provide above. 
 
5.6.2.3 Medications that may Prolong QT Interval 
Concomitant medications known to prolong the QT interval are prohibited 
(Section 5.6.1.2); medications which may possibly prolong the QT interval 
(non-Class I; see http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm) are 
restricted. Should the Investigator believe that beginning therapy with a potentially 
QT-prolonging medication (other than those prohibited) is vital to an individual 
subject’s care, the Investigator must check that the prior on-therapy ECG does not 
show QTcF ≥ 450 msec or an increase in QTc ≥ 60 msec over the baseline value. 
 
5.6.2.4 Antacids 
Nonclinical data demonstrate that the solubility of dasatinib is pH dependent and a 
clinical study has shown that dasatinib exposure is substantially and durably reduced 
after treatment with famotidine. Administration of dasatinib with H2 inhibitors or 
proton pump inhibitors should therefore be avoided. If antacid therapy is needed, a 
locally-acting antacid may be used, and should be administered at least 2 hours before 
or after the dose of dasatinib. 
 
 
5.6.2.5 St. John's Wort (Hypericum perforatum) 
Data suggests that St. John’s Wort may decrease dasatinib and exemestane plasma 
concentrations unpredictably. Subjects receiving dasatinib should not take St. John's 
Wort. Subjects should discontinue St. John’s Wort at least 5 days before starting 
dasatinib. 


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5.6.2.6 Medications that Inhibit Platelet Function and Anticoagulants 
Src-family kinase inhibition potentially reduces platelet aggregation. Caution should 
thus be exercised if subjects are required to take medications that inhibit platelet 
function or anticoagulants. Such medications include:aspirin or aspirin-containing 
combinations, clopidogrel, dipyridamole, tirofiban, dipyridamole, epoprostenol, 
eptifibatide, cilostazol, abciximab, ticlopidine, cilostazol warfarin, heparin/low 
molecular weight heparin [eg, danaparoid, dalteparin, tinzaparin, enoxaparin] 
exceptions are low-dose warfarin for prophylaxis to prevent catheter thrombosis and 
heparin for flushes of intravenous lines. 
 
5.6.2.7 Bisphosphonates 
Subjects who had been receiving bisphosphonates prior to study entry may continue 
on therapy with caution. Although concomitant use of bisphosphonates is not 
recommended, clinically-significant hypocalcemia has been uncommon. Oral serum 
calcium (Ca+2) supplementation, including Vitamin D if appropriate, is warranted. 
 
5.6.3 
Supportive Care Guidance 
Supportive care, especially pain control, will be optimized in all subjects. Guidance is 
provided for management of common side effects of dasatinib in order to maximize 
opportunity for benefit. Investigators are strongly urged to discuss with Medical 
Monitor prior to discontinuing study treatment for reasons other than radiographic PD. 
 
Non-hematologic side effects are typically CTCAE v4.0 Grade 1 - 2. Interruption 
and/or dose reduction may be necessary, especially if Grade ≥ 2. Usual supportive care 
measures should be used for nausea/emesis, diarrhea, pain, fever or headache. Neither 
clinically significant myelosuppression nor use of hematopoietic growth factors is 
expected. 
 
Osteoclast inhibition is expected; therefore, calcium supplementation (eg, calcium 
carbonate 500 mg PO TID) is warranted to maintain serum Ca+2 above LLN during 
dasatinib treatment. Vitamin D supplementation (eg, ergocalciferol 400 IU PO QD) 
may be appropriate for persistent hypocalcemia. Bisphosphonate therapy should be 
deferred in the presence of hypocalcemia. 
 
Fluid retention, including clinically-significant pleural effusion, has been observed 
during dasatinib treatment. Refer to Section 3.3.4 for treatment recommendations. 
 
5.7 
Treatment and evaluation outside M.D. Anderson Cancer Center (MDACC): 
 
Patients enrolled at MDACC may have their interim evaluations performed with their 
local oncologist according to the protocol after 2 cycles of initial treatment or 
treatment change. The patient will return to MDACC at 8 week intervals. A two 
month drug supply will be dispensed to patients ensuring adequate supply before their 
return visit to MDACC. The patient will be given a follow-up phone call by the 
research team approximately at 4 weeks between MD Anderson visits for safety 


33 
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assessment. The M. D. Anderson Study Chair will provide the local oncologist with 
the protocol treatment plan, evaluation schedule and data collection requirements. 
 
5.7.1 
MDACC Physician communication with the outside physician is required 
prior to the patient returning to the local physician. This will be documented 
in the patient record 
 
5.7.2 
A letter to the local physician outlining the patient's participation in a clinical 
trial will request local physician agreement to supervise the patient's care 
(Appendix M) 
 
5.7.3 
Protocol required evaluations performed outside MDACC will be provided by 
the local physician to the MDACC investigator and will include drug 
administration records, progress notes, laboratory reports, diagnostic 
studies, and documentation of any hospitalizations. The outside evaluations 
will be reviewed by the investigator and the review will be documented in the 
patient record. 
 
5.7.4 
Changes in drug dose and/or schedule must be discussed with and approved 
by the MDACC physician investigator, or their representative prior to 
initiation, and will be documented in the patient record. 
 
5.7.5 
A copy of the informed consent, protocol abstract, treatment schema and 
evaluation during treatment will be provided to the local physician. 
 
5.7.6 
The home physician will be requested to report to the MDACC physician 
investigator all life threatening events within 24 hours of documented 
occurrence. 
 
5.7.7 
Patients will return to MDACC every 8 weeks for evaluation. 
 
6.0 
Pre-treatment evaluation 
 
6.1 
Within 21 days of study entry: History and physical to include ECOG performance 
status, weight, height, and documentation of concurrent non-malignant disease and 
medical therapy. Any residual toxicity from prior therapies that is unresolved by date 
of study registration must be recorded, using the grading schema in NCI Common 
Toxicity Criteria v4.0. 
 
Laboratory studies shall include a CBC w/differential, platelet count, PT, PTT, 
urinalysis, serum chemistries including albumin, alkaline phosphatase, ALT, AST, 
calcium, LDH, total bilirubin, BUN, creatinine, magnesium, phosphate, electrolytes 
(sodium, potassium, chloride, CO2), PSA, Testosterone, and Prostatic Acid 
Phosphatase. 


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6.2 
Within six weeks of study entry: Tumor assessment shall include a chest X-ray, ECG, 
ECHO or MUGA scan, bone scan, bone marrow biopsy and aspirate, and CT scans of 
the abdomen and pelvis. Appropriate additional studies should be obtained to fully 
define the extent and severity of existing or suspected malignant disease. Location, 
type, and size of representative measurable lesions must be recorded prior to 
treatment. At least one lesion representative of all involved organ sites must be 
recorded prior to treatment. 
 
6.3 
Use of archival pathology material may be requested of the patient, e.g. paraffin 
embedded block, unstained slides, etc. (Appendix 1). 
 
7.0 
Evaluation During Study 
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. If necessary, imaging scans and/or laboratory testing 
may be completed at a local physician’s office. The results must be received via fax or other 
medium prior to the scheduled clinic visit. 
Screening 
Every 2 
Weeks 
Every 4 
weeksh 
PD/Treatment 
Change 
End of 
Treatmente 
Safety 
FUf 
Long- 
Term 
FU 
Medical History 
xa 
Physical Exam 
xa 
x 
x 
x 
Vital Signs 
xa 
x 
x 
x 
Weight 
xa 
x 
x 
Height 
xa 
ECOG PS 
xa 
x 
x 
x 
CBC/ diff. and plt. 
xa 
x 
x 
x 
Serum Chemistryc 
xa 
xg 
x 
xg 
x 
x 
PT/PTT 
xa 
x 
PSA 
xa 
x 
x 
Testosterone 
xa 
Prostatic Acid 
Phosphatase 
xa 
x 
x 
Urinalysis 
xa 
Bone Marrow Asp/Bx 
or Bx of metastatic 
site 
xb 
x 
x 
CT Scan Abd/Pelvis 
xb 
xd 
Chest X-ray 
xb 
xd 
MUGA or ECHO 
xb 
x 
ECG 
xb 
x 
Bone Scan 
xb 
xd 
Monitor Adverse 
Events 
<  
> 
Concomitant 
Medications 
<  
> 
Blood for Correlative 
Studies 
x 
x 
x 
x 


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Archived Tissue for 
Correlative Studies 
x 
Survival Follow Up 
xi 
a. Within 21 days of registration 
b. Within 6 weeks of registration 
c. Serum chemistries including albumin, alkaline phosphatase, ALT, AST, calcium, LDH, total bilirubin, BUN, 
creatinine, magnesium, phosphate, electrolytes (sodium, potassium, chloride, CO2). 
d. May be at other timepoints as clincally indicated. Will not have to be repeated if done within 8 weeks of 
treatment change 
e. Off study visit will occur after final PD or early removal from the study. 
f . To be completed 30 days after the last dose of study drug 
g. Patients will have liver function tests (including alkaline phosphatase, AST, ALT, total bilirubin, and LDH 
every 2 weeks f or the first 3 cycles of abiraterone, and every 2 weeks for the first 3 cycles of each 
combination arm. 
h. Follow up visits may be rescheduled for every 8 weeks at the discretion of the treating physician. 
i. Every 6 months after Safety Follow Up (+/- 1 month) 
 
 
8.0 
Criteria for Toxicity and Dose Modification: 
 
8.1 
Intrapatient dose reduction will be permitted once a patient has experienced 
unexpected toxicity provided the criteria for patient withdrawal from study treatment have not 
been met. All intrapatient dose reductions are relative to the lowest dose of the current cycle. 
Dose modifications may involve sunitinib in a single decrement of 12.5 mg to a minimum of 
25 mg. Table 1 describes the recommended dose modifications for study treatment-related 
toxicities. 
 
Table 1. Dose Modifications for sunitinib associated toxicity 
Toxicity 
Gra de 1 
Gra de 2 
Gra de 3 
Gra de 4 
Non-hematologic Continue at the 
same dose level. 
Continue at the 
same dose level. 
Withhold dose 
until toxicity is 
grade ≤1 or has 
returned to 
baseline, then 
resume treatment 
at the same dose 
level, or reduce the 
dose by 1 level at 
the discretion of 
the investiga tor.* 
discontinue 
thera py 
Hematologic 
Continue at the 
same dose level. 
Continue at the 
same dose level. 
Withhold dose 
until toxicity is 
grade ≤2 or has 
returned to 
baseline, then 
resume treatment 
at the same dose 
level.** 
Withhold dose 
until toxicity is 
grade ≤2, then 
reduce the dose by 
1 level and resume 
treatment.** 


36 
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* Patients who develop grade 3 hyperlipasemia or hyperamylasemia without clinical or other evidence of 
pancreatitis, grade 3 hypophosphatemia without clinical symptoms may continue study treatment without 
interruption at the discretion of the investigator. Nausea, vomiting, or diarrhea must persist at grade 3 despite 
maximal medical therapy. 
** Patients with recurrent gra de 3 neutropenia or thrombocytopenia for >7 days will dose reduce in the next 
cycle. Patients who develop grade 3 or grade 4 lymphopenia may continue study treatment without interruption. 
 
Dose Re-Escalation 
 
Doses reduced from the 37.5-mg/d level for drug-related toxicity should generally not be re- 
escalated. However, intrapatient re-escalation back to the previous dose level may be 
permitted provided the toxicity responsible for dose reduction has not recurred at a grade 2 for 
at least 30 days, and with the agreement of the principal investigator of the study. 
 
Overdose Instructions 
 
In the event of an overdose, the supporting drug company should be contacted to discuss the 
details of the overdose and formulate a clinical management plan. However, this contact will 
not delay patient care under any circumstance. 
 
8.2 
Dasatinib 
 
8.2.1 
If patients taking dasatinib present with recurring dyspnea and fatigue after an 
initial dose interruption, with no explanation or evident underlying cause, the 
diagnosis of pulmonary arterial hypertension (PAH) should be considered. If 
PAH is confirmed, dasatinib should be permanently discontinued and patients 
will be followed per standard practice guidelines. 
 
Dose Levels: 
Dose level 0 (100mg daily) 
Dose level -1 (70mg daily) 
Dose level -2 (50mg daily) 
 
Dose Modification Schema for Hematological Toxicity 
Grade 1 
ANC < LLN - 1500/mm3 
None 
Platelets < LLN - 75,000/mm3 
Grade 2 
ANC < 1500 - 1000/mm3 
None 
Platelets < 75,000 - 50,000/mm3 
Grade 3 
ANC < 1000 - 500/mm3 
Hold therapy, resume at 100mg after 
recovery to ≤ Gr 1. If recurrence at 


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Platelets < 50,000 - 25,000/mm3 
100 mg, hold therapy and resume at 
70mg after recovery to ≤ Gr 1.If 
recurrence at 70mg reduce dasatinib 
dose to 50mg. If recurrence at 50mg 
discontinue treatment due to 
intolerance. 
Grade 4 
ANC < 500/mm3 
Withhold dasatinib until recovery to 
≤ G1. Reduce dose to 70mg. If 
recurrence at 70mg , reduce dose to 
50mg. If recurrence at 50mg, 
discontinue treatment due to 
intolerance. 
Platelets < 25,000/mm3 
o Subjects who develop Grade 4 hematologic toxicity and are receiving 
dasatinib at 70 mg QD should have therapy withheld until recovery to 
Grade 0 – 1. Decrease dasatinib to 50mg Daily. 
 
o Treatment should be withheld and counts rechecked in one week. If 
hematological toxicity persists for > 14 days, patient is to be removed 
from study. 


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Non-hematological Toxicity 
 
Toxicity 
Drug Modification 
Grade 2 
Withhold dasatinib until recovery to Grade ≤ 1 or baseline, with the exception 
of toxicities which are non life-threatening and for which resolution to Grade 
1 may not occur and/or may require > 21 days, such as alopecia, nail changes, 
weight changes, and peripheral neuropathy (unless it is persistent and/or 
repeating) 
Resume dosing without dose reduction 
Grade 3 
Withhold dasatinib until recovery to Grade ≤ 1 or baseline 
If the identical toxicity recurs at Grade 3, withhold dasatinib until recovery to 
Grade ≤ 1 or baseline 
Decrease dasatinib to 70 mg QD starting with the next dose 
Grade 4 
Discontinue treatment with dasatinib 
 
Discontinue Treatment with Dasatinib for any delay in scheduled therapy of 2 weeks or 
more secondary to any form of toxicity 
 
8.3 
Abiraterone Acetate 
 
Dose‐Reduction Procedure for Adverse Event Management 
In the event where dose‐reduction is used for AE management, 2 dose reductions are allowed. 
At each dose reduction, one tablet of abiraterone will be removed, e.g., 4→3 tablets, and 3→2 
tablets. Any return to protocol dose level after dose reduction must follow documentation of 
AE resolution and a discussion with the Principal Investigator. 
 
Patients experiencing any Grade 4 non-hematological toxicity will be withdrawn from the 
study. 
 
8.4 
Clinical Vigilance During Combination Treatment 
 
No formal phase I trial has been conducted for the proposed two-drug combinations to be 
used in this study. Although we do not expect severe toxicity with the proposed 
combinations, we will assure patient safety through clinical vigilance during the combination 
phase. The assigned research nurse and the Principal Investigator will review all study 
patients at weekly intervals during the combination treatment portion of the trial. Any 


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unusual clinical observations will be discussed immediately with the Principal Investigator 
or a sub-investigator if the PI is absent or not available. All patients will be treated at M.D. 
Anderson Cancer Center and will be provided with their treating physicians and research 
nurse contact information. 
 
Any Grade 4 toxicity will be communicated directly with the sponsors (in the combination phase or 
in a single arm phase) by the study team. 
 
Toxicities attributed to the treatment will be reported as described in Section 13. 
 
 
9.0 
Criteria For Response and Progression (RECIST v1.1) 
 
9.1 
Tumor Measurements: 
 
9.1.1 
A measurable lesion can be accurately measured in at least one dimension 
(longest diameter to be recorded). The minimum measurable lesion size on CT 
should be 1.5 cm (15 mm). All superficial disease (e.g. palpable lymph nodes) is 
considered measurable. All measurable lesions up to a maximum of 5 lesions per 
organ and 10 lesions in total representative of all involved organs should be 
identified as target lesions and recorded and measured at baseline. Target lesions 
should be selected on the basis of their size (lesions with the longest diameter) 
and their suitability for accurate repetitive measurements (either by imaging 
techniques or clinically). A sum of the longest diameter for all target lesions will 
be calculated and reported as the baseline sum LONGEST DIAMETER (LD). 
The baseline sum of the LD will be used as reference to further characterize the 
objective tumor response of the measurable dimension of the disease. 
 
9.1.2 
Sites of disease detected by bone scan will be recorded. Note will be made of 
changes in number of lesions seen on subsequent studies. 
 
9.1.3 
Serum PSA will be also used as a basis for assessing response and will be 
reported along with measurable disease outcomes. 
 
9.1.4 
Measurable disease will be evaluated and recorded by the attending physician 
and the radiologist. The Principal Investigator will be the final arbiter for any 
discrepancies. The oncology research nurse may assist with the documentation 
under the supervision of the Principal Investigator. 
 
9.1.5 
An estimate of disease status will be made and recorded on clinic notes at each 
visit as complete response (CR), partial response (PR), stable disease (SD) or 
progressive disease (PD). 
 
9.2 
Response Definitions (per PCWG2 guidelines [40]): 


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9.2.1 
Complete Response (CR): Disappearance of target lesions. 
 
9.2.2 
Partial Response (PR): PSA: Decline of PSA by > 50% without normalization 
maintained for 6 weeks will be reported as a PSA-response. Patients with 
measurable disease must demonstrate 30% decrease in the sum of the longest 
diameter (LD) of target lesions on the restaging study, taking as reference the 
baseline sum LD.  No evaluable lesion may increase in size and no new lesion 
may appear. 
 
9.2.3 
Stable Disease (SD): Neither PR or CR and in the absence of progression as 
defined below. 
 
9.2.4 
Progressive Disease (PD): Any increase of 20% in the sum LD of target lesions 
taking as reference the smallest sum LD recorded since treatment began; or the 
appearance of an unequivocally new lesion on pre-operative restaging studies or 
on post-operative surveillance studies. Worsening symptoms clearly 
attributable to disease progression qualifies as progression e.g. worsening 
malignant bony pain. There are no biochemical definitions of progressive 
disease for this study. 
 
9.2.5 
PSA criteria for failure to further respond: A failure to further decline or a rise 
in serum PSA concentration measured at four week intervals: A change in 
either will be considered a 5 ng/ml or 25% change nadir measurement. 
 
9.2.6 
Progression-free survival (PFS) and overall survival (OS): The time from 
randomization to disease progression or death (if earlier than progression) will be 
referred to as progression-free survival. The time from randomization to death 
from any cause will be annotated as well. Patients will be followed for PFS and 
OS, and will consist of phone call, an e-mail, or a review of medical and/or other 
records every 6 months (+/- 1 month). 
 
10.0 
Criteria for Initial Randomization/Crossover/Discontinuation/Removal 
 
10.1 Criteria for Initial Randomization: Patients will be randomized after treatment on 
abiraterone acetate in combination with prednisone until composite progression is 
established as defined by one of the following criteria: 
 
1) PCWG2 criteria for progression(see Appendix L) 
OR 
2) Failure to achieve PCWG2 response by 8 weeks 
 
OR 


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Plateau of PSA as only manifestation of "progression"(Failure to further suppress PSA 
measured at 4 week intervals) - For PSA, less than 25% decrease from previous PSA for 
2 consecutive measurements. For PSA less than 5ng/ml, a single measurement above 
1ng/ml following nadir is sufficient. 
 
If patients require dose reduction on two consecutive times or suffer from grade 3 or 
greater toxicity despite maximal dose reduction, the patient will be taken off the study 
and will be counted as exhibiting progression. 
 
10.2 Criteria for Crossover: The criteria for crossover are progression by PCWG2 criteria or 
excess toxicity as defined in criteria for initial randomization 
 
10.3 Criteria for Discontinuation of Therapy: Discontinuation of therapy will either occur for 
progression or excessive toxicity. Progression criteria will include composite criteria 
which includes PSA working group to criteria, patients withdrawal from the study due to 
failure. 
 
10.4 Criteria for removal from study: (a) Patient withdrawal of consent, progressive disease, 
or investigator/PI discretion for safety concerns; (b) Non-compliance by patient with 
protocol requirements; (c) The development of unacceptable toxicity as defined in 
Section 8.0 or serious inter-current events. 
 
11.0 
Statistical Considerations 
 
11.1 Preliminaries and Background: This is a randomized clinical trial to evaluate and 
compare two two-stage treatment strategies for patients with castrate resistant prostate 
cancer that has progressed despite treatment with Abiraterone. The design is motivated 
by the presence of multiple pathways that facilitate survival of the tumor cells. The 
factors motivating the design include (1) the redundancy of these pathways for paracrine 
tumor survival, (2) the substantial variability between patients with regard to the 
likelihood and duration of response to any particular agent (3) the desire to obtain 
unbiased comparisons of clinical effects among three qualitatively different agents, (4) 
the desire to account for the common and appropriate clinical practice, when treating an 
individual patient, of switching away from an agent at the time of its clinical treatment 
failure and replacing it with a different agent and (5) the desire to account for effects of 
baseline patient covariates characterizing pathway activity levels. 
 
11.2 Treatment Regimes: Each patient’s treatment regime will consist of up to three stages, 
indexed by s = 1, 2, 3. In stage s=1, all patients will receive the CYP17 blocker 
Abiraterone acetate (A) alone. At the time of disease progression (defined below, in 
11.3) with A alone, the patient will be randomized between A + Dasatinib (D) or A + 
Sunitinib (S) for their stage s=2 treatment. The randomization will be dynamically 
balanced on three binary patient covariates using the method of Pocock and Simon [41]. 
The covariates are (i) quality if response to Abiraterone, defined as time to progression 


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being either > 3 months or < 3 months, (ii) alkaline phosphatase either > 120 or < 120, 
and (iii) performance status either 0, 1 or > 1. At the time of disease progression with the 
assigned treatment in stage s=2, the patient will be crossed over to the other stage 2 
treatment combination for treatment in stage s=3.  Consequently, two three-stage 
treatment regimes are possible, either (A, A+D, A+S) or (A, A+S, A+D). For brevity, 
since A is given in all three stages, below these two two-stage regimes will be denoted 
by (D, S) and (S, D). 
 
This randomization will be carried out using the Pocock-Simon software on the 
MDACC Biostatistics website https://biostatistics.mdanderson.org/ClinicalTrialConduct. 
 
11.3 Outcomes: For the purpose of treatment evaluation, in each of the three stages of 
treatment, the following events are defined: Composite disease progression is defined in 
Section 10.1. In any stage, treatment failure is defined as disease progression or death, 
whichever occurs first. The time to treatment failure in each stage is denoted by TTF. 
From the start of therapy, overall survival (OS) time is defined as the time to death 
. 
11.4 Primary Outcome: Comparison of the two strategies (D, S) and (S, D) will be done in 
terms of the subgroup of patients for whom the first failure with A is disease 
progression. For this purpose, the time to the final treatment failure will be recorded 
from the time of randomization, which is carried out at the start of stage 2. The primary 
outcome will be U = the time to final treatment failure starting from the time that 
treatment is initiated in stage 2 (randomization) after the patient’s disease has progressed 
on Abiraterone alone in stage 1. Consequently, aside from censoring, since only patients 
who progress but do not die in stage 2 proceed to stage 3, U equals either (i) the time to 
death in stage 2, or (ii) the time to progression in stage 2 plus the time to death or 
progression in stage 3. 
 
11.5 Group Sequential Design: Based on historical experience, the null values of the mean 
time to failure in each of stages 2 and 3 are both 4 months and the probability that the 
failure in stage 2 is a progression and not a death is .90. These give null value 7.6 
months for the mean of U = time to final failure, as defined. The primary goal will be 
to test the null hypothesis that there is no difference between the two strategies in terms 
of these two means. A two-sided group-sequential log rank testing procedure will be 
used [41], with one interim test and possibly a second, final test, having overall size .05 
and power .90 to detect a 75% increase in the mean from 7.6 to 13.3 months. O’Brien- 
Fleming boundaries will be used, with the null hypothesis of no treatment difference 
rejected if the absolute value of the observed Z-score computed from the log rank 
statistic, |Zobs|, is larger than the Z-score test cut-off in the following table. 


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Number of Failure 
Events when the tests 
are conducted 
Z-score cut-offs for 
concluding there is 
a difference 
Test 1 
68 
+/- 2.9626 
Test 2 
136 
+/- 1.9686 
 
Based on an assumed accrual rate of 7 patients per month, and assuming that 
approximately 90% of all patients progress with A and thus 6 patients per month are 
randomized between A+D and A+S in stage 2, the expected trial duration will be 35 
months with total expected accrual (1.1)x153 = 168 patients under the alternative and 
(1.1)x 164 = 180 patients under the null. All computations were carried out using East 
version 5 (Cytel Corporation), [42]. 
 
11.6 Safety Monitoring: For the purpose of safety monitoring, toxicity will be defined as 
grade 2 or higher cardiac toxicity or grade 3 or higher hepatotoxicity, that is possibly 
attributed to the agents, occurring at any time within the first 3 months from the start of 
treatment. Denote the probability of this event by pTOX. Based on clinical experience 
and judgment, a toxicity rate of 0.05 will be considered acceptably low while a toxicity 
rate of 0.16 or higher will be considered unacceptably high. Assuming that pTOX follows 
a non-informative beta(.05, .95) prior, the trial will be terminated early if the following 
Bayesian criterion for excessive toxicity is met, with the criterion applied starting when 
20 patients have been accrued and their toxicity evaluated at 3 months, and at every 20th 
patient thereafter, up to a maximum of 180 patients. The trial will be stopped early if 
Prob(pTOX > 0.05 | data) > 0.98. This translates to stopping the trial if [number of 
patients with toxicity]/ [number of patients evaluated for toxicity] is greater than or 
equal to 4/20, 6/40, 8/60, 10/80, 11/100, 13/120, 14/140, or 15/160. If the true value of 
pTOX is 0.16 then the probability that this rule will stop the trial early is > .99 and the 
sample size quartiles are all 180. If the true value of pTOX is 0.05 then the probability 
that this rule stops the trial early is .04 and the sample size quartiles are 20, 40, 60. 
Consequently, if the true value of pTOX is .05 the nominal power figure .90 of the group 
sequential test will be reduced to .90 x (1- .04) = .86 due to the possibility of a false 
negative stop by the toxicity monitoring rule. 
 
As an additional precaution, in the first three patients of the combination study (post 
initial randomization), if grade III or higher toxicity is observed, that is possibly 
attributed to the agents, the combination will be held. If two or more grade III toxicities 
possibly attributed to the drugs are observed in the first six patients, the arm will be held 
until further assessment. The overall trial will continue with patients on the alternative 
arm. 
 
 
11.7 Detailed Notation for Patient Outcomes: 


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2 
2 
2 
2 
2 
2 
1 
1 
1 
1 
1 
1 
3 
3 
3 
3 
3 
3 
 
11.7.1 Death 
A patient’s treatment is continued from stage 1 to stage 2, or from stage 2 to stage 3, if 
progression occurs. Denote the TTF in stage 1 by T1, the time from progression at T1 to 
second treatment failure by T2, and the time from progression at T2 to third treatment 
failure by T3. Thus, the total time to first, second and third treatment failure are T1, T1 
+T2, and T1 +T2+T3, respectively. Since a patient’s therapy may end at any time due to 
Death, denote the indicator that Ts is the time of disease progression rather than a death 
time by Ys, for s=1, 2, 3. In particular, (Y2 , T2 , Y3, T3) are defined only if Y1 = 1 and 
(Y3, T3) are defined only if Y2= Y1 = 1. Denote the time in stage s=1 to treatment 
failure or death by T o, so that T o = T if Y = 1 or T o is the time of death if Y = 0 at 
stage s=1. Similarly, the time from T1 to second treatment failure is T o, with T o = T if 
Y2 = 1 or T o the time of death if Y = 0 at stage s=2. Finally, the time from T to 
treatment failure is T o, with T o = T if Y = 1 or T o the time of death if Y = 0 at stage 
s=3. 
 
11.7.2 Overall final failure time: The time to final failure from the start of therapy with 
A is T = T1 + Y1(T2 + Y2T3 ) = T1 + Y1T2 + Y1Y2T3 . Thus, the overall final 
failure time from the start of therapy equals: 
• T1 if Y1=0, which is death on A in stage 1 before randomization 
between A+S and A+D in stage s=2, 
• T1 + T2 if Y1=1 and Y2 = 0, which is progression with A followed by 
randomization between A+S and A+D followed by death before 
crossover or 
• T1 + T2 + T3 if Y1= Y2=1, which is progression with A followed by 
randomization between A+S and A+D followed by progression with the 
stage 2 treatment combination followed by crossover followed by a 
failure of any type in stage 3. The 4 weeks washout period between 
stage 2 and 3 (see section 5.0) will be included in TTF. 
 
11.7.3 Response: For evaluating the effects of A in stage 1, response will be defined as 
non-increasing PSA as measured at 8 weeks compared to baseline. 
 
11. 8 Failure times following randomization between A+S and A+D: For comparing the 
two strategies (D, S) and (S, D), we will consider the subgroup of patients for whom the 
first failure with A is disease progression (Y1=1) and start at the time of randomization, 
which is the start of stage 2. In this subgroup, we will use as primary outcome variable 
the time from randomization to final failure defined as U = T2 + Y2T3. Thus, U = T2 if 
Y2 = 0, which is Death before crossover, and U = T2 + T3 if Y2=1, which is progression 
with the stage 2 treatment combination followed by crossover followed by a failure (P or 
Death) in stage 3. An essential point regarding evaluation of U is that U may be 
censored by the non-failure events C in either stage 2 or stage 3 


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11.81 Parameters. Denote µs = E(Ts) for s=1,2,3 and πs = Pr(Ys=1) for s = 1,2. The 
mean overall final failure time is µT = E{T} = E{T1 + Y1(T2 +Y2 T3)} = E{T1 } 
+ Pr(Y1= 1)E{T2 +Pr(Y2=1) E(T3)} = µ1 + π1 µ2 + π1 π2 µ3. The mean final 
failure time from randomization is E(U) = µU = E(T2 +Y2 T3) = µ2 + π2 µ3. 
 
11.8.2 Parameter of Primary Interest. The parameter of primary interest for 
evaluation and comparison of the two strategies (D,S) and (S,D) is E(U) = µU = 
µ2 +  π2 µ3., the mean time from randomization to final failure in either stage 2 or 
stage 3. 
 
11.8.3 Parameter of Secondary Interest. The parameter of secondary interest for 
evaluation and comparison of the two strategies (D,S) and (S,D) is E(T2) = µ2, 
the mean time from randomization to first failure in stage 2. 
 
11.9 Data Analyses: The distributions of Y1, Y2 and Y3 will be estimated using logistic 
regression. The unadjusted distributions of T1, T2 and T3 and of the composite times T = 
T1 + Y1(T2 +Y2 T3) and U = T2 + Y2T3 will be estimated using Kaplan-Meier (KM) 
plots [43]. For each time, an appropriate time-to-event regression model determined 
by goodness-of-fit analyses will be fit to account for treatment strategies and patient 
covariates [44]. Denote the stage 2 and stage 3 treatments by τ2 and τ3, each equal to 
either D = Dasatinib or S = Sunitinib. Thus, (τ2,τ3) = (D,S) or (S,D). To account for 
the effects of the stage 2 treatment, τ2, on Y2 and T2, the linear terms of the logistic 
model for Pr(Y2 = 1) and of the event-time regression model for T2 will be of the general 
form β2Z2 + γ2 I(τ2 = D), where β2Z2 denotes a linear combination of patient 
covariates and γ2 is the D-versus-S effect on the stage 2 outcome. Similarly, to account 
for the effects of the treatment pair (τ2, τ3) given at stages 2 and 3 on the stage 3 
outcome, the linear terms of the logistic model for Pr(Y3 = 1) and of the event-time 
regression model for T3 will be of the general form β3Z3 + γ3 I(τ2 = D, τ3 = 
S),where β3Z3 is a linear combination of patient covariates and γ3 is the (D,S)- 
versus-(S,D) effect on the stage 3 outcome. The covariate vectors Z2 and Z3 are indexed 
by stage to allow updated values, and this includes the possibility that T2 or possibly 
log(T2) will be used as a covariate in Z3. Thus, there are two treatment effects, the D- 
versus-S between-treatment effect γ2 on the stage 2 outcomes and the (D,S)-versus-(S,D) 
between-strategy effect γ3 on the stage 3 outcomes. These estimates will be used, in turn, 
to estimate the mean of the primary outcome, the time to overall failure, 
specifically the mean of U = T2 + Y2T3 , for each of the two strategies (D,S) and (S,D). 
 
12.0 
Data and Protocol Management 
 
12.1 Protocol Compliance: All required interim and pretreatment data should be available and 
the physician must have made a designation as to toxicity grade and performance status 
as defined by structured clinical notes. If dose modifications or treatment interruptions 
are necessary, the reasons including grade and type of toxicity must be documented. 
When relevant, the reasons for removal from study must be documented. If treatment 


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related toxicity accompanies progression events then these must be documented (type 
and grade) by the specified criteria. 
 
The Investigator will follow the MDACC policy for protocol deviations and violations. 
Documentation or a report of these events will be available for all monitoring visits. 
The Principal Investigator will be the final arbiter of these events and the continuation of 
a patient on study. 
 
12.2 Data Entry: All data will be entered to the Department of Genitourinary Medical 
Oncology Oracle database (GURU). GURU is a password protected database with an 
audit trail. Data can be collated with a unique GURU identification in order to de-link 
information. The minimum required fields will be entered to the MDACC required data 
collection systems (CORe/PDMS). Data will be derived from the patient chart and the 
Principal Investigator will be the final arbiter of any conflicting entries. The Principal 
Investigator will be the final arbiter of response, toxicity, or progression should a 
difference of opinion exist. 
 
Patient Confidentiality: In order to maintain patient privacy, all database generated case 
report forms, study drug accountability records, study reports and communications will 
identify the patient by initials and the assigned patient number. The patient’s 
confidentiality will be maintained and will not be made publicly available to the extent 
permitted by the applicable laws and regulations (21CFR312.63, 21CFR312.68). 
 
12.3 Study Drug Management 
 
Returned or expired study drug will be destroyed on site per MDACC Investigational 
Pharmacy policies. 
 
12.4 Data Safety Monitoring 
 
An independent data safety monitoring committee, comprised of Richard Theriault, DO 
(medical oncologist) and Xuemei Wang, MS (biostatistician) will be utilized to monitor 
safety. Toxicity will be monitored after 20 patients have been enrolled and every 20 
patients thereafter in order to apply the above listed stopping rules. Enrollment will 
continue during these safety analyses. 
 
13.0 
Reporting Requirements 
 
13.1 Adverse Drug Reaction Reporting 
Toxicity will be scored using CTC Version 4.0 for toxicity and adverse event reporting. 
A copy of the CTC Version 4.0 can be downloaded from the CTEP homepage 
(http://ctep.info.nih.gov). All appropriate treatment areas have access to a copy of the 
CTC Version 4.0. 


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Adverse events will for this protocol will be documented and entered into the case report 
form according the Recommended Adverse event Recording Guidelines for Phase II 
protocol. 
 
Recommended Adverse Event Recording Guidelines 
Attribution 
Gra de 1 
Gra de 2 
Gra de 3 
Gra de 4 
Gra de 5 
Unrelated 
Pha se I 
Pha se I 
Pha se I 
Phase II 
Pha se I 
Phase II 
Phase III 
Pha se I 
Phase II 
Phase III 
Unlikely 
Pha se I 
Pha se I 
Pha se I 
Phase II 
Pha se I 
Phase II 
Phase III 
Pha se I 
Phase II 
Phase III 
Possible 
Pha se I 
Pha se II 
Pha se I 
Phase II 
Phase III 
Pha se I 
Phase II 
Phase III 
Pha se I 
Phase II 
Phase III 
Pha se I 
Phase II 
Phase III 
Probable 
Pha se I 
Pha se II 
Pha se I 
Phase II 
Phase III 
Pha se I 
Phase II 
Phase III 
Pha se I 
Phase II 
Phase III 
Pha se I 
Phase II 
Phase III 
Definitive 
Pha se I 
Pha se II 
Pha se I 
Phase II 
Phase III 
Pha se I 
Phase II 
Phase III 
Pha se I 
Phase II 
Phase III 
Pha se I 
Phase II 
Phase III 
 
The Investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for each event for all 
subjects enrolled on the trial. 
 
13.2 Serious Adverse Event Reporting (SAE) 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it 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 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• A congenital anomaly/birth defect. 


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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, 
IND Office. 
 
• All events occurring during the conduct of a protocol and meeting the definition 
of a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “The University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy for Investigators on Reporting Unanticipated 
Adverse Events for Drugs and Devices”. Unless stated otherwise in the protocol, 
all SAEs, expected or unexpected, must be reported to the IND Office, regardless 
of attribution (within 5 working days of knowledge of the event). 
 
• All life-threatening or fatal events, that are unexpected, and related 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 the IND Office. 
 
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized 
for safety reporting to the IND Office and MDACC IRB. 
 
• Serious adverse events will be captured from the time of the first protocol- 
specific intervention, until 30 days after the last dose of drug, unless the 
participant withdraws consent. Serious adverse events must be followed until 
clinical recovery is complete and laboratory tests have returned to baseline, 
progression of the event has stabilized, or there has been acceptable resolution of 
the event. 


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• Additionally, any serious adverse events that occur after the 30 day time period 
that are related to the study treatment must be reported to the IND Office. This 
may include the development of a secondary malignancy. 
 
Reporting to FDA: 
 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) 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. 
 
 
13.3 Investigator Communication with Supporting Companies: 
 
Toxicities are to be assessed according to the National Cancer Institute Common 
Toxicity Criteria for Adverse Events (CTCAE), Version 4.0. 
 
Following the subject’s written consent to participate in the study, all SAEs must be 
collected, including those thought to be associated with protocol-specified procedures. 
Collection of all SAEs must continue for 30 days after the last administration of the 
investigational product. If applicable, SAEs must be collected that relate to any later 
protocol-specified procedure (eg, a follow-up skin biopsy). The investigator should 
notify the supporting companies of any SAE occurring after this time period that is 
believed to be related to the investigational product or protocol-specified procedure. 
 
All SAEs, whether considered related or unrelated to dasatinib, must be reported to 
BMS (by the investigator or designee) within 24 hours of study personnel becoming 
aware of the event. If only limited information is initially available, follow-up reports 
are required. The original SAE form must be kept on file at the study site. 
 
All non-serious adverse events must be reported to Janssen Scientific Affairs, LLC on a 
quarterly basis.  The summary of non-serious AEs should include a listing of: Patient ID, 
AE term (uncoded), severity, relationship to abiraterone acetate, and action taken with 
abiraterone acetate. 
 
Additionally, all SAEs, whether considered related or unrelated to abiraterone acetate, 
must be reported to Janssen Scientific Affairs, LLC (by the investigator or designee) 
within 24 hours of study personnel becoming aware of the event. If only limited 
information is initially available, follow-up reports are required. The original SAE form 
must be kept on file at the study site. 


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All SAEs should be faxed or emailed to the following supporting companies: 
 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
Janssen Scientific Affairs, LLC 
Fax #: 1-866-451-0371 
  
Pfizer, Inc 
Fax #: 1-866-997-8322 
 
If the investigator believes that an SAE is not related to the investigational product but 
is potentially related to the conditions of the study (such as withdrawal of previous 
therapy, or a complication of a study procedure), the potential relationship should be 
specified in the narrative section of the SAE report. 
 
If an ongoing SAE changes in its intensity or relationship to the investigational 
product, a follow-up SAE report should be sent within 24 hours to the supporting 
companies. As follow-up information becomes available it should be sent within 
24 hours using the same procedure used for transmitting the initial SAE report. All 
SAEs should be followed to resolution or stabilization. 
 
13.4 
Abnormal Laboratory Results 
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 
(merely repeating an abnormal test, in the absence of any of the above conditions, 
does not meet criteria for reporting and an AE), and/or 
3. Test result leads to a change in study dosing or death 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 serious 
adverse event, and/or 
5. Test result is considered to be an adverse event by the investigator or sponsor 
 
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. Clinically significant laboratory results must be recorded in the patient’s CRF 


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Fizazi K. The role of Src in prostate cancer. Ann Oncol 2007;18:1765-1773. 
 
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Appendix 1 – Tissue Collection for Correlative Studies 
 
Assay / Matrix 
Medium 
Frequency 
Required Storage 
Serum Biomarkers 
(Bone markers, 
Cytokines and Caveolin- 
1) 
Serum (~20ml) 
Total required volume 
2 X 10ml SST 
Vacutainers 
Screening/baseline, every 
4 weeks on study, 
randomization, crossover 
and end of treatment 
Samples are aliquoted into 
500 ul fractions, frozen and 
stored at -80 oC until 
analysis. 
Whole Blood 
Whole blood (1 X 10ml) 
Heparin Vacutainer 
Screening/baseline, every 
4 weeks on study 
randomization, crossover 
and end of treatment 
Samples are frozen and 
stored at 
-80 oC until analysis 
Tumor Tissue 
Bone marrow biopsy 
collected in formalin and 
sodium heparin. 
Aspirate 
(1 x4 ml) Sodium 
Heparin Vacutainer 
Biopsy Tissue 
Pretreatment, Prior to 
randomization, Prior to 
crossover and at 
progression of disease (4 
total) 
Fresh frozen or Paraffin 
embedded (biopsy) 
Samples are aliquoted into 
500 ul fractions, frozen and 
stored at -80 oC until 
analysis. (Aspiration) 
Fresh frozen or Paraffin 
Archived Diagnostic 
Tissue 
Bone marrow or tissue 
At the time of any routine 
test or procedure (not 
related to this study) 
Fresh frozen or Paraffin 
Plasma and circulating 
cells 
Sodium Citrate CPT (2 
X 8 mL)Vacutainers 
Screening/baseline, every 
4 weeks on study 
randomization, crossover 
and end of treatment 
Samples are aliquoted into 
500 ul fractions, frozen and 
stored at -80 oC until 
analysis. 
PBMCs are stored at LN2 
until analysis. 


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Circulating Tumor Cells 
(see Appendix K) 
Streck Cell-Free DNA 
BCT (1 x 10mL) 
CTC at baseline, at 8 
weeks, at time of first 
randomization, and at 
cross-over 
Specimens to be shipped 
ambient, on the same day as 
collection to Kuhn 
Laboratory USC. 
(see Appendix K) 
 
*Specimens will be sent to Kuhn Laboratory USC for analysis 
 
All left over samples will be stored and banked for future use, including genetic testing, in the GU 
Biorepository (blood and bone marrow) and the Prostate Tissue Bank (tissue).