Clinical trial NCT01468532
Conditions: Adenocarcinoma of the Prostate Hormone-resistant Prostate Cancer Recurrent Prostate Cancer Stage IV Prostate Cancer
Sponsor: Barbara Ann Karmanos Cancer Institute
Start date: 2011-10-01; Completion date: 2017-07-20
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I/II trial studies the side effects and best dose of pasireotide and to see how well it works when given together with docetaxel and prednisone in treating patients with metastatic hormone-resistant prostate cancer. Drugs used in chemotherapy, such as docetaxel and prednisone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pasireotide may inhibit the secretion of hormones. Giving pasireotide together with docetaxel and prednisone may kill more tumor cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose (MTD) level of SOM 230 (pasireotide) in combination with docetaxel and prednisone.

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability of the combination in metastatic castration-resistant prostate cancer (CRPC).

II. To evaluate preliminary efficacy of the combination of SOM 230 and docetaxel and prednisone as defined by response rates (measurable and prostate-specific antigen \[PSA\]), time to progression (TTP) and overall survival (OS).

III. To evaluate the pharmacokinetics (PK) of the combination. IV. To assess the pharmacodynamic (PD) effects of the combination as seen by baseline levels of and changes in insulin-like growth factor (IGF)-1, serum chromogranin A (SCA), and neuron specific enolase (NSE), and to associate them with TTP and OS.

V. To assess the pretherapy circulating tumor cell (CTC) counts and change in CTC after therapy, and to associate them with TTP and OS.

OUTLINE: This is a phase I dose-escalation study of pasireotide followed by a phase II study.

Patients receive pasireotide intramuscularly (IM) on day 1, docetaxel intravenously (IV) over 1 hour, and prednisone orally (PO) twice daily (BID) continuously. Courses with docetaxel repeat every 21 days and courses with pasireotide repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 28 days and then every 3 months thereafter.

Arms: arm 1: Patients receive pasireotide IM, 40 mg on day 1, docetaxel 75mg/m2 IV over 1 hour, and prednisone 5mg PO BID continuously. Courses with docetaxel repeat every 21 days and courses with pasireotide repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: docetaxel intervention 2: pasireotide intervention 3: prednisone
Intervention descriptions: intervention 1: Given IV intervention 2: Given IM intervention 3: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
1
Protocol # 2011-031 
Phase I/II trial to establish the safety and preliminary efficacy of the combination of 
docetaxel, prednisone, and SOM 230 (Pasireotide) in metastatic castrate resistant prostate 
cancer (CRPC) 
 Version date : July 27, 2011,  Sept 29, 2011, Nov 18 2011, Dec 27 2011, Dec 4, 2012 
IND#113004 
Principal Investigator:  
Ulka Vaishampayan M.D. 
4 Hudson Weber Research center 
4100 John R Road 
Detroit MI 48201. 
Tel #  313-576-8715 
Fax # 313-576-8487 
E mail vaishamu@karmanos.org 
Co-Investigators:           
Elisabeth Heath M.D.    
4HWCRC, 4100 John R  
Detroit MI 48201 
Tel# 313-576-8715 
Fax # 313-576-8767 
E mail heathe@karmanos.org 
Joseph Fontana M.D. 
VA Medical Center 
Oncology 11M-HO 
Room C3687 
4646 John R 
Detroit MI 48201. 
Tel# 313-576-3659 
E mail Joseph.Fontana@med.va.gov 
Lance Heilbrun Ph.D.  
Biostatistics  Unit 
716 Harper Professional Bldg 
4160 John R Road Detroit MI 48201. 
Tel# 313-576-8652 
E mail heilbrun@karmanos.org 
Study Coordinator 
Brenda Dickow, RN 
Clinical Trials Office 
NCT01468532


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
2
711, Harper Professional Bldg. 
 
 
4160 John R Road  
 
 
 
 
 
Detroit MI 48201 
Tel #  313-576-9372 
E mail: dickowb@karmanos.org 
 
 
 
 
 
 
  
 
Grants and Contracts: 
 
 
Mary Jo O’Loughlin 
 
 
 
 
 
Karmanos Cancer Institute 
 
110 E. Warren Ave., 5th Floor 
 
Detroit, MI 48201 
 
Tel # 313-578-4405 
 
Fax # 313-831-4039 
 
E mail: moloughl@med.wayne.edu 
 
 
 
 
 
 
 
 
 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
3
PHASE I/II TRIAL TO ESTABLISH THE SAFETY AND PRELIMINARY EFFICACY 
OF THE COMBINATION OF DOCETAXEL, PREDNISONE, AND 
PASIREOTIDE/SOM-230 IN METASTATIC CASTRATE RESISTANT PROSTATE 
CANCER (CRPC)  
 
 
 
 
 STUDY SCHEMA ……........................................................................................................... 4 
 
1.0 OBJECTIVES ......................................................................................................................  5 
 
2.0 BACKGROUND .................................................................................................................  5 
 
3.0 DRUG INFORMATION .....................................................................................................  7 
 
4.0 PATIENT ELIGIBILITY .................................................................................................... 17 
 
5.0 TREATMENT PLAN  ......................................................................................................... 19 
 
6.0 TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS ....................... 23 
 
7.0 STUDY CALENDAR ......................................................................................................... 29 
 
8.0 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION ................................. 30 
 
9.0 CRITERIA FOR REMOVAL FROM STUDY ................................................................... 33 
 
10.0 CORRELATIVE STUDIES .............................................................................................. 33 
 
11.0 STATISTICAL CONSIDERATIONS............................................................................... 36 
 
12.0 ADVERSE EVENTS REPORTING ................................................................................. 40 
 
13.0 REFERENCES .................................................................................................................. 45 
 
14.0 DATA AND SAFETY MONITORING PLAN ................................................................ 47 
 
15.0 PROTOCOL CONDUCT AND GUIDELINES…………………………………………..47 
 
16.0 APPENDICES ……………………………………………………………………………50 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
4
STUDY SCHEMA 
 
Castrate resistant metastatic prostate cancer 
 
 
PS - O - 2, adequate 
marrow, hepatic & renal function  
 
 
 
 
SOM-230  
 
 
 
 
Docetaxel  
Escalating doses,  
 
    + 
 
75mg/m2/week IV (1 hour 
infusion) 
  
 
Starting at 40 mg IM 
 
 
every 21 days  
every 28 days 
 
 
 
 
and 
prednisone 5 mg twice daily orally. 
 
 
 
 
 
Toxicity evaluation  
 
 
 
Determine max tolerated dose (MTD) or recommended phase II dose (RP2D) 
 
Study Dose Levels 
 
Dose levels 
SOM 230 LAR 
Docetaxel 
Prednisone 
1 
40mg IM every 28 
days 
75mg/m2 IV every 21 
days 
5 mg PO twice daily 
2 
60 mg IM every 28 
days 
75mg/m2 IV every 21 
days 
5 mg PO twice daily 
3 
80 mg IM every 28 
days 
75mg/m2 IV every 21 
days 
5 mg PO twice daily 
 
Doses of SOM-230 > 80 mg IM every 28 days, are being tested in an ongoing trial. If safety data 
of higher doses of SOM-230 (>80 mg every 28 days) is available, and the dose level 3 of the 
combination is well tolerated, then consideration will be done for adding higher dose levels of 
SOM-230 in this protocol. 
     
 
 
 
1.0 OBJECTIVES: 
 
Primary objective 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
5
1) To establish the maximum tolerated dose (MTD) level of SOM 230 in combination with 
docetaxel and prednisone. 
 
Secondary objectives: 
 
1) To evaluate the safety and tolerability of the combination in metastatic CRPC. 
2) To evaluate preliminary efficacy of the combination of SOM 230 and docetaxel and 
prednisone as defined by response rates (measurable and PSA), time to progression 
(TTP) and overall survival (OS).  
3) To evaluate the pharmacokinetics (PK) of the combination. 
4) To assess the pharmacodynamic (PD) effects of the combination as seen by baseline levels 
of and changes in IGF-1, serum chromogranin A (SCA), and neuron specific enolase 
(NSE), and to associate them with TTP and OS. 
5) To assess the pretherapy circulating tumor cell (CTC) counts and change in CTC after 
therapy, and to associate them with TTP and OS.  
 
2.0 BACKGROUND: 
 
Docetaxel based chemotherapy is FDA approved in metastatic CRPC due to the results of 2 
randomized trials [1,2] demonstrating improvement in progression free survival (PFS) and 
overall survival (OS) as compared to mitoxantrone and prednisone therapy. Despite the 
apparent success of docetaxel based therapy, the improvement in OS remains modest and 
usually does not achieve cure. The median progression free survival (PFS) with docetaxel 
and prednisone therapy is 6 months, hence better therapies are required to prolong the 
duration of remission in metastatic CRPC. After failure of docetaxel and prednisone, the 
management of metastatic CRPC is a significant problem. The patient morbidity is 
significant, since majority of the patients at this stage are symptomatic with bone pain, 
constitutional symptoms and anemia. Exploring novel therapeutic agents and combinations in 
metastatic CRPC, to improve the chance of remission and to prolong the remission with 
docetaxel based therapy is very important.  
      A number of agents such as capecitabine, calcitriol and GVAX have been evaluated in 
combination with docetaxel and prednisone to improve efficacy. To date none of the agents 
tested in combination with docetaxel have been proven to improve overall survival in a 
randomized trial setting. In addition, the chemotherapy based combinations have 
demonstrated increased risk of toxicity, and an increased rate of death as observed with the 
docetaxel and calcitriol  and docetaxel and GVAX combinations [3,4]  
Given the limited median progression free survival of 6 months noted in metastatic CRPC 
treated with docetaxel chemotherapy, it appears that resistance to docetaxel develops fairly 
quickly in majority of the prostate cancers. One of the mechanisms of resistance reported has 
been the multidrug resistance gene overexpression hence diminishing the exposure of the 
cancer cells to docetaxel. Currently a microtubule inhibitor agent called cabazitaxel [Sanofi- 
Aventis Inc] has demonstrated OS improvement in metastatic CRPC progressing after 
docetaxel therapy. This agent has efficacy possibly by overcoming the MDR pathway. One 
of the other mechanisms of resistance reported has been the neuroendocrine differentiation of 
prostate cancer cells leading to decreased efficacy of docetaxel. Overcoming these 
mechanisms of resistance with novel agents given in combination with docetaxel, is rational. 
In addition,there is a preponderance of elderly patients, with associated comorbidities in the 
metastatic CRPC population. Hence, the added novel agent has to be well tolerated and 
cannot significantly compromise docetaxel efficacy and dosing. Based on above, there 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
6
remains a need for effective and better tolerated therapies frontline in combination with 
docetaxel and prednisone therapy in metastatic CRPC.  
 
Pasireotide (SOM-230) is a multitargeted somatostatin receptor (sst) analogue that binds 
to 4 of the 5 receptors (sst1,2, 3 and 5) [5]. The binding occurs with extremely high affinity; 
30X higher for sst 1, comparable for sst 2, 5X higher for sst 3, and 40X higher for sst 5 as 
compared to the currently FDA approved  sst analog, octreotide. The binding results in 
dissociation of G proteins and subsequent downstream effects of apoptosis, and inhibition of 
trophic factor secretion, angiogenesis and proliferation. Cytokine release is also inhibited, 
hence inhibiting IL-6 and TNF-alpha secretion. Sst 1, 2 and 5 are expressed on prostate 
cancer cells and SOM-230 demonstrated 44% inhibition in xenograft models of human PC3 
tumors [6] The somatostatin analogs; octreotide and lanreotide increase the cytotoxic effect, 
and can overcome the resistance to docetaxel in PC3 cells, inhibit androgen-independent 
growth, and induce apoptosis (7, 8). Also the neuroendocrine component within metastatic 
prostate cancer is likely to be refractory to chemotherapy, but sensitive to somatostatin 
receptor analogues. Treatment of the human hormone and chemotherapy-refractory prostate 
cancer cell lines; PC3 and DU145, resulted in synergistic cytotoxic activity and apoptosis, 
and reduced secretion of stem cell factor and platelet-derived growth factor in PC-3 cells, and 
decrease in transforming growth factor-beta and basic fibroblast growth factor in DU-145 
cells [7,8]. One phase II study at UCSF investigated the effect of octreotide LAR on CRPC 
[ClinicalTrials.gov identifier NCT00510224]. Patients were treated with octreotide-LAR (30 
mg every 4 weeks) together with LHRH-analogs. No steroids were permitted as concomitant 
medication. The primary endpoint of PSA response was not met, but IGF-1 levels were 
reduced and IGFBP-1 levels were increased after 3 months of therapy, hence indicating the 
mechanism of IGF inhibition [9]. A phase II randomized trial of somatostatin analogue and 
dexamethasone ,versus combination of estramustine and etoposide revealed comparable 
response rates, palliative effects and comparable survival in metastatic CRPC. The toxicity 
profile however was much more favorable in the somatostatin analogue and steroid therapy 
arm [10].  Since pasireotide has increased affinity to the somatostatin receptors as compared 
to the other analogues, it is rational to hypothesize a higher level of activity in metastatic 
CRPC and a possibility of overcoming docetaxel resistance with the combination. The 
preclinical activity and clinical safety of pasireotide, and the efficacy of somatostatin 
analogues in metastatic CRPC, creates a strong rationale for exploring the safety and activity 
of the combination of SOM 230 and docetaxel in metastatic CRPC.    
 
 
 
 
 
 
 
 
3.0 DRUG INFORMATION: 
3.1 SOM230 
Study drug: Pasireotide/SOM-230 LAR (long-acting release) i.m. depot injection  
 
Chemical name 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
7
Pasireotide is an injectable somatostatin analogue. It is a novel cyclohexapeptide with the 
following chemical name:  
(2-Aminoethyl)carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-(4-aminobutyl)-5-benzyl-8-(4-
benzyloxybenzyl)-14-(1H-indol-3-ylmethyl)-4,7,10,13,16,19-hexaoxo-17-phenyloctadecahydro-
3a,6,9,12,15,18-hexaazacyclopentacyclooctadecen-2-yl ester, di[(S)-2-aminosuccinic acid] salt.    
CAS name (9CI): Cyclo[(2S)-2-phenylglycyl-D-tryptophyl-L-lysyl-O-(phenylmethyl)-Ltyrosyl- 
L-phenylalanyl-(4R)-4-[[[(2-aminoethyl)amino]carbonyl]oxy]-L-prolyl] 4,4'- 
methylenebis[3-hydroxy-2-naphthalenecarboxylate] 
Inactive 
ingredients 
of 
pasireotide 
LAR 
include: 
mannitol, 
carmellose 
sodium 
(carboxymethylcellulose sodium), poloxamer 188 and water for injection. Inactive ingredients 
of pasireotide s.c. include: mannitol, tartaric acid, sodium hydroxide and water for injection.  
For detailed information on pasireotide, please refer to the SOM-230 Investigator Brochure Ed 
9, version date Feb 2010.  
How supplied 
Study drug, Pasireotide LAR i.m. depot injections will be supplied in open-label packaging 
by Novartis as a powder in vials containing 20 mg and 40 mg  labeled as SOM230 LAR, with 
ampules containing 2 mL of vehicle (for reconstitution). No syringes or needles will be 
provided with the pasireotide study drug supplies.  
Preparation and storage 
Prior to reconstitution, vials should be brought to room temperature.  Pasireotide LAR should 
then be prepared as follows: 
Table 1 Handling and preparation of pasireotide LAR dose 
Dose  
Volume to be injected 
20 mg 
1 x 20 mg vial + 2 mL vehicle; whole volume to be injected 
40 mg 
1 x 40 mg vial + 2 mL vehicle: whole volume to be injected 
60 mg 
1 x 20 mg vial + 1 x 40 mg vial + 2 mL vehicle; whole volume to be 
injected 
80 mg 
2 x 40 mg vial + 2 mL vehicle: whole volume to be injected 
Doses should be prepared and administered immediately after preparation.  For additional 
details regarding preparation, refer to “Clinical instructions for administration of 
pasireotide/SOM-230”. This is attached as a Protocol Related Document. 
Novartis will supply pasireotide LAR as long as the patient remains on study, shows 
continuous benefit from treatment, and there are no safety concerns. Medication labels will 
comply with the legal requirements of the U.S. and will be printed in English. The storage 
conditions for pasireotide LAR will be described on the medication label. Bottles must be 
stored in a safe, secure location.  
All study medication will be supplied to each site directly by Novartis. Under the 
responsibility of each site’s lead investigator, drug supplies must be kept in an appropriate, 
secure area (e.g. locked cabinet) and stored in accordance with the conditions specified on the 
drug labels. The investigator must maintain an accurate record of the shipment and dispensing 
of the study drug in a drug accountability ledger. An accurate record of the date and amount of 
study drug dispensed to each subject must be available for inspection at any time. 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
8
All drug supplies are to be used only for this protocol and not for any other purpose. Unless 
specifically instructed by Novartis, the investigator must not destroy any drug labels, or any 
unused drug supply. 
 
The storage condition for the study drug will be described on the medication label. 
 
Administration 
Pasireotide LAR will be administered i.m., intragluteally, every 4 weeks. The starting dose 
will be 40 mg.  The reconstitution has to be performed just prior to administration of the 
suspension. A minimal standing time can be tolerated for the reconstituted suspension in the 
vial. Prior to administration, the reconstituted suspension in the vial should be shaken again 
before withdrawal in the syringe. The i.m. injection must be given immediately after 
withdrawal of the reconstituted suspension from the vial to the syringe. 
 
 
 Mechanism of Action 
Like natural somatostatin and other somatostatin analogues (SRIFa), pasireotide exerts its 
pharmacological activity via binding to somatostatin receptors (sst). There are five known 
somatostatin receptors: sst 1, 2, 3, 4 and 5. Somatostatin receptors are expressed in different 
tissues under normal physiological conditions. Somatostatin analogues activate these receptors 
with different potencies (Schmid and Schoeffter 2004) and this activation results in a reduced 
cellular activity and inhibition of hormone secretion. Somatostatin receptors are strongly 
expressed in many solid tumors, especially in neuroendocrine tumors where hormones are 
excessively secreted e.g. acromegaly (Freda 2002), GEP/NET tumors (Oberg, Kvols et al. 2004) 
and Cushing’s disease. 
The SRIFa currently approved for use in the clinic (octreotide and lanreotide) have a high 
affinity to the sst subtype 2 (sst2), with moderate or no affinity to the remaining subtypes. 
Pasireotide is a novel cyclohexapeptide somatostatin analogue that exhibits a unique binding 
profile, binding with high affinity to four of the five known human somatostatin receptors. 
(Table 1) Compared to Sandostatin® (octreotide acetate), pasireotide exhibits a binding affinity, 
which is 30-40 times higher for human sst1 and sst5, 5 times higher for human sst3, and 2.5 
times lower for human sst2. A detailed summary of available preclinical data is provided in the 
[Investigators' Brochure]. 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
9
Table 1 
Binding profile for octreotide and pasireotide at hsst1-5 (IC50, M) 
Compound 
sst 1 
sst2 
sst3 
sst4 
sst5 
octreotide 
acetate 
(SMS 201-
995) 
2.8x10-7 
3.8x10-10 
7.1x10-9 
>10-6 
6.3x10-9 
Pasireotide 
(SDZ 227-
230) 
9.3x10-9 
1.0x10-9 
1.5x10-9 
>10-6 
1.6x10-10 
Ratio of IC50: 
octreotide 
acetate/ 
pasireotide 
SMS/SOM23
0 
30 
0.4 
5 
-- 
40 
 
Additionally, preclinical studies suggest anti-tumor activity of SOM230.  SOM230 has been 
found to significantly reduce cell proliferation of the neuroendocrine tumor cell line NCI-H727, 
whereas the conventional analogue SMS 201-995 did not.(Ono, Suzuki et al. 2007) 
Clinical experience with pasireotide 
Pasireotide is available as a short-acting subcutaneous (s.c) formulation and a long acting release 
(LAR) intramuscular (IM) formulation.   
 
Pasireotide s.c. 
Pasireotide when given subcutaneously (s.c.) was well-tolerated at doses up to 600 µg b.i.d., 900 
μg b.i.d. and 1200 μg b.i.d by acromegalic, Cushing’s disease and carcinoid tumor patients, 
respectively. In addition, healthy volunteers have received pasireotide s.c. as a continuous 
infusion for seven days with total daily doses of up to 2025 µg being well tolerated. For all 
indications the most frequently reported adverse events were gastrointestinal, predominantly 
diarrhea, nausea and abdominal pain. Generally these events were mild, transient and only 
occasionally caused patients to discontinue treatment. 
Hyperglycemia was also observed for patients in all three indications. In general HbA1c was 
observed to increase by approximately 1%, corresponding to a blood glucose increase of 
approximately 30 mg/dL. Blood glucose increases tended to occur with increasing dose, and 
appeared to be more notable in patients who had a history of hyperglycemia or diabetes mellitus 
prior to receiving pasireotide. However hyperglycemia in these patients was responsive to 
appropriate diabetic management such as adjustments in oral antidiabetic treatment, or in some 
cases the addition of insulin. 
Occassionally laboratory abnormalities in liver function tests and pancreatic enzymes have been 
observed at higher doses of pasireotide. These events however have been transient. 
Further details on pasireotide s.c. can be found in the Investigator Brochure. 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
10 
 
Phase II studies of pasireotide s.c. in neuroendocrine tumors 
Preliminary safety data are available from a Phase II study [CSOM230B2202] in 45 patients with 
symptomatic metastatic carcinoid disease who received pasireotide s.c. doses from 300 µg s.c. 
b.i.d. up to 1200 µg b.i.d. for a mean of 20 weeks. Overall pasireotide s.c. has been found to be 
generally well-tolerated by these patients, with the most common adverse events being mild 
diarrhea, nausea and abdominal pain. Blood glucose increases tended to occur with increasing 
dose, but were moderate and generally managed easily by adjustment in oral hypoglycemic 
medications. Weight loss was also observed in 18 patients. Maximum weight loss occurred 
within 4 to 6 months on the study drug, with a stabilization of effect after approximately 6 
months. There was no apparent relationship between the weight loss and pasireotide dose. 
Preliminary efficacy data from this study also support that pasireotide is active in patients 
refractory/resistant to Sandostatin LAR, as partial or complete symptom control was observed in 
12 of 44 patients (27%). Complete response was achieved in two patients at the pasireotide 600 
µg s.c. b.i.d. dose and one at the 900 µg s.c. b.i.d. dose. Nine patients achieved partial response 
to treatment, three at each of the following doses: 600, 750, 900 µg s.c. b.i.d. 
 
Clinical Safety 
Pasireotide LAR has been evaluated as 5 different formulations (1, 2, 2b, 2c, and 3) at 
different dose levels varying between 10 and 60 mg in healthy volunteers [CSOM230C2101]. 
Formulation 2b at the tested doses of 40 and 60 mg demonstrated the most favorable PK 
profiles and was selected for further clinical development in acromegaly, carcinoid tumors, 
and Cushing’s disease. Therefore, only the data on formulation 2b are described here. 
Clinical PK 
Following a single i.m. injection of 40 mg or 60 mg in healthy volunteers [CSOM230C2101], 
the pasireotide LAR formulation demonstrated a controlled-release type of concentration-  
versus-time profile, with an initial spike phase on day 1 followed by a slow-release process 
for up to 42 days. The Cmax of the extended release phase was observed approximately on day 
20 for both dose levels. Pharmacokinetic exposure was dose-proportional for the doses tested. 
The relative bioavailability of pasireotide LAR to pasireotide s.c. was approximately 100%. 
Based on the single-dose data for 40 and 60 mg, PK simulation demonstrated that the LAR 
formulation would be suitable for monthly (every 28 days, q 28 d) dosing regimen and a 
steady state could be achieved after 3 injections in healthy volunteers. The accumulation 
(based on the ratio of Ctrough,ss/Ctrough,d28) was predicted to be approximately 20%. 
Following monthly (q 28 d) injections of 20 mg, 40 mg or 60 mg pasireotide LAR in patients 
with acromegaly or carcinoid tumors [CSOM230C2110], preliminary results showed an 
approximately linear dose-exposure proportionality and a steady state achieved following 
3 injections. The release patterns of pasireotide from the first injection of 40 and 60 mg LAR 
in acromegalic patients and patients with carcinoid tumors were similar to those from a single 
dose of 40 and 60 mg LAR in healthy volunteers. The PK exposure to pasireotide at steady 
state in acromegalic patients was comparable to the simulated PK exposure at steady state in 
healthy volunteers, whereas, the PK exposure in patients with carcinoid was roughly 2-fold 
that in acromegalic patients. The accumulation (based on the ratio of Ctrough,d84/Ctrough,d28) 
was 
observed as approximately 20-40% for acromegalic patients and 20-80% for patients with 
carcinoid, respectively. 
Clinical PK/PD of pasireotide LAR 
Following 3 monthly (q 28 d) i.m. injections of pasireotide LAR in acromegalic patients 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
11 
[CSOM230C2110], preliminary results from PD analysis has demonstrated dose-response 
relationship for both GH and IGF-1 following 3 monthly injections of 20, 40 or 60 mg 
pasireotide LAR. Emax, EC50, E0, and γ across dose groups for GH were estimated as 19.6 ± 
32.0 ng/mL, 5.9 ± 4.1 ng/mL, 4.4 ± 7.8 ng/mL, and 1, respectively. Emax, EC50, E0, and γ 
across dose groups for IGF-1 were estimated as 536 ± 174 ng/mL, 6.4 ± 4.4 ng/mL, 223 ± 143 
ng/mL, and 1, respectively. Pasireotide LAR demonstrated similar potency on both GH and 
IGF-1 suppression as the median values of EC50 were similar (4.6 and 4.8 ng/mL, 
respectively). The median value of EC50 for GH suppression was similar between pasireotide 
LAR (4.6 ng/mL) and s.c. (3.8 ng/mL for responders and 3.2 ng/mL for non-responders), 
suggesting a similar pharmacological activity between the s.c. and LAR formulations. 
 
Clinical safety 
Single doses of pasireotide s.c. up to 1500 μg q.d. and 750 μg b.i.d. multiple s.c. doses 
(7-14 days) up to 1500 μg q.d., 750 μg b.i.d, and 2100 μg b.i.d. (up to 5 days), and continuous 
(7-day) s.c. infusion by insulin pump, have been well-tolerated, with mostly mild, transient 
side effects reported. The most common adverse events (AEs) were gastrointestinal, 
predominantly mild diarrhea and nausea requiring no treatment or study discontinuation. 
These effects were seen at all doses, but occurred more frequently at higher doses in all 
studies. The frequency of the gastrointestinal events appeared to decrease with time in 
multiple-dose studies. A number of subjects also reported mild to moderate headaches; 
similarly these were also transient and required no treatment. 
Single and multiple doses of pasireotide s.c. have generally been well tolerated by patients 
with acromegaly, metastatic carcinoid tumor, or Cushing’s disease. Pasireotide has been 
tested in the Phase II studies at maximum doses of up to 600 μg b.i.d for acromegalic patients, 
900 μg b.i.d for patients with Cushing’s disease, and 1200 μg b.i.d for patients with carcinoid 
tumor, with maximum pasireotide treatment periods of 4 years, 4.8 years, and 1.6 years 
respectively. For all indications the most frequently reported AEs have been gastrointestinal, 
predominantly diarrhea, nausea and abdominal pain. Generally these events were mild, 
transient, and only occasionally caused patients to discontinue treatment. 
Hyperglycemia was also observed across all indications. The effect on blood glucose was 
more pronounced in patients with Cushing’s disease, a setting in which glucose metabolism is 
inherently dysregulated. Blood glucose increases tended to occur with increasing dose, and 
appeared to be more notable in patients who had a history of hyperglycemia or diabetes 
mellitus prior to receiving pasireotide. However, hyperglycemia in these patients was 
responsive to appropriate diabetic management such as adjustments in oral antidiabetic 
treatment, or in some cases the addition of insulin. In acromegalic patients, median changes in 
glycosylated hemoglobin (HbA1c) values over time in patients generally did not exceed 
0.60%, regardless of pasireotide dose level or duration of treatment. 
Although no pre-clinical or clinical studies have revealed any specific pasireotide-related 
cardiac toxicity issues, a thorough clinical QT/QTc evaluation was performed in healthy 
volunteers in [CSOM230B2113]. In Part I of the study, pasireotide doses from 900 μg to 
2100 μg were explored, after which the maximum tolerated dose (MTD) for pasireotide was 
defined as 1950 μg s.c. b.i.d. The MTD was then used as the pasireotide dose for Part II of the 
study (i.e. a three-way crossover design using moxifloxacin, placebo and pasireotide 1950 μg 
s.c. b.i.d). An effect of pasireotide (at MTD) on QTcF interval was demonstrated. This was 
based on the upper bound of the 95% one-sided CI for the difference from placebo in QTcF 
change from baseline being > 10 ms at one or more time intervals. Both pasireotide and 
moxifloxacin showed a peak effect at 2 hours postdose (of 17.5 ms and 8.5 ms QTcF change 
from baseline versus placebo, respectively). Pasireotide subjects also showed a reduction in 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
12 
HR at 0 to 4 hours postdose (maximum change versus baseline of 10.7 bpm). 
 
Pasireotide LAR in healthy volunteers 
Most of the experience with pasireotide comes from healthy volunteer and patient studies 
evaluating the subcutaneous formulation of pasireotide.  Pasireotide LAR is being evaluated in 
two studies, one healthy volunteer study and one study involving patients with acromegaly and 
carcinoid disease. 
Preliminary data from the healthy volunteer study found single IM doses of pasireotide LAR, at 
doses of up to 40 mg and 60 mg, respectively to be well-tolerated.  The most common adverse 
events were gastrointestinal.  Diarrhea was experienced by most of the subjects and was 
sometimes associated with abdominal pain, flatulence, and/or nausea.  The gastrointestinal 
events were mild or moderate in severity.  About 38% of subjects reported mild injection site 
pain and about 15% reported headaches. 
Transient elevations in liver function tests and/or pancreatic enzymes were observed in two 
subjects, both of which resolved and were not accompanied by any clinical symptoms.  Mild 
increases in fasting blood glucose were observed in some subjects during the pasireotide LAR 
treatment period.  All elevations were asymptomatic, considered not clinically significant and 
generally returned to normal within 3 to 4 weeks after the pasireotide LAR IM injection. 
 
Pasireotide LAR in acromegalic patients 
Preliminary safety data are available from 18 acromegalic patients treated with pasireotide LAR 
in an ongoing study [CSOM230C2110]. These patients had received pasireotide LAR  at doses 
of 20 (n=5), 40 (n=6) or 60 mg (n=7) for about six weeks at the time of the summary.  
Pasireotide LAR was well-tolerated by acromegalic patients in this study. The most common 
drug-related adverse events were gastrointestinal, predominantly diarrhea. Mild erythema 
reported as drug-related was experienced by three patients. Two patients on the 60 mg dose were 
reported to experience drug-related increases in blood glucose: mild diabetes mellitus was 
reported for one patient and mild hyperglycemia was reported for the other patient who also had 
a history of diabetes mellitus at baseline. A further patient who received the 20 mg dose 
experienced hyperglycemia, however this event was considered to be unrelated to study drug by 
the investigator. All three patients were given oral hypoglycemic agents and all continued in the 
trial.  
Following 2-3 injections of pasireotide LAR in acromegaly patients [CSOM230C2110], steady-
state concentrations of pasireotide were achieved.  The trough plasma concentrations of 
pasireotide at steady state (Cmin.ss) on day 84 were 3.8 ± 2.1, 5.6 ± 2.4, and 13.8 ± 10.2 ng/mL 
for 20 mg (N=9), 40 mg (N=9), and 60 mg (N=11) LAR, respectively, indicating an   
approximate dose proportionality. 
   
Pasireotide LAR in carcinoid patients 
An interim analysis of the results of [CSOM230B2202] showed that, at the time of response, 
pasireotide at total daily doses of >900 to ≤1200 μg, >1200 to ≤1500 μg, and >1500 to 
≤1800 μg s.c. successfully controlled (completely or partially) the symptoms of diarrhea and 
flushing, for at least 15 days for 12 (27%) of the patients with metastatic carcinoid tumors that 
were refractory or resistant to octreotide LAR. 
There was no evidence of tumor shrinkage. Patients who achieved complete or partial 
symptom control (treatment success) had stable disease. In responders, the median effective 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
13 
concentration of pasireotide was estimated as approximately 10 ng/mL. 
Clinical responses were observed at 600 μg s.c. b.i.d. and above doses. In view of the large 
inter-patient variability, doses above 600 μg s.c. b.i.d. will be considered for future clinical 
studies to maximize the clinical benefit of pasireotide in patients with metastatic carcinoid 
tumors. Preliminary safety data are available from nine carcinoid patients treated with 
pasireotide LAR in an ongoing study [CSOM230C2110]. These patients had received pasireotide 
LAR at doses of 20 (n=1), 40 (n=4) or 60 mg (n=4) for about six weeks at the time of the 
summary. Pasireotide LAR was well-tolerated by carcinoid patients. Six out of nine treated 
patients reported at least one AE and the most commonly reported AEs were gastrointestinal.  
However, most of these events were considered unrelated to study drug.  Two patients reported 
hyperglycemia judged as related to study drug, one was mild and one moderate.  The patient who 
experienced moderate hyperglycemia had a past history of diabetes mellitus at entry to the study 
and died due to carcinoid tumor progression. 
Although pasireotide exposures appear to be higher in patients in comparison with healthy 
volunteers, the data from studies assessing the subcutaneous formulatin of pasireotide support 
that pasireotide LAR at dose of 60 mg and below are expected to be well-tolerated by patients.  
A healthy volunteer study was conducted of pasireotide s.c. by continuous infusion tested doses 
of up to 2,025 mcg per day [SOM230B2108].  The dose of 2,025 mcg by s.c. infusion per day 
was well-tolerated and is equivalent to a dose of 56.7 mg from a single 28 day IM depot injection 
of pasireotide LAR.  Data resulting from studies [SOM230B2108] and [SOM230B2202] are 
described fully in the Pasireotide s.c Investigator’s Brochure. 
Possible indications and medical needs 
In all animal models investigated (rodent, dog, monkey) pasireotide is a more effective 
inhibitor of the GH/IGF-1 axis than octreotide. Thus, pasireotide should exhibit superior 
efficacy in acromegaly, and may be of use in patients either not responding or becoming 
resistant to octreotide therapy Lamberts, van der Lely, and Hofland 2002). Since pasireotide 
has a higher binding affinity and functional activity for receptors other than sst2 (Schmid and 
Schoeffter 2004), it may also have utility in carcinoid patients whose disease has either not 
responded or become resistant to therapy with other somatostatin analogues. In addition to the 
treatment of diseases for which other somatostatin analogues are currently approved, other 
possible indications are being explored, such as Cushing’s disease. In vitro experiments have 
shown that pasireotide inhibits ACTH secretion in cultured adenoma cells from patients with 
Cushing’s disease (Hofland, et al 2003). The hypothesis that pasireotide may be able to reduce 
cortisol levels by inhibiting ACTH and cortisol secretion has been confirmed in recent clinical 
studies. In 29 efficacy-evaluable patients with Cushing’s disease, there were reductions in the 
mean plasma ACTH and serum cortisol levels regardless of the extent of reduction in urinary 
free cortisol (UFC). 
The final development strategy for pasireotide will be based on early proof of concept (POC) 
studies in healthy volunteers and in disease settings where pasireotide may be effective, such 
as acromegaly, Cushing’s disease, or GEP-NET tumors. The pharmacodynamic and efficacy 
profile of pasireotide in humans elucidated in these studies will be used to refine the overall 
scope of possible clinical indications for pasireotide. 
 
 
3.2 
DOCETAXEL (TAXOTERE)  
 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
14 
3.21  Description:  Docetaxel is an antineoplastic agent belonging to the taxoid family. 
It is prepared by semisynthesis beginning with a precursor extracted from the renewable 
needle biomass of yew plants. The chemical name for docetaxel is (2R,3S)-N-carboxy-3-
phenylisoserine,N-tert-butyl ester, 13-ester with 5 -20-epoxy-1,2
,4,7 ,10 ,13
-
hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate.  Docetaxel is a white to 
almost-white powder with an empirical formula of C43H53NO14• 3H2O, and a molecular 
weight of 861.9. It is highly lipophilic and practically insoluble in water. TAXOTERE 
(docetaxel) for Injection Concentrate is a clear yellow to brownish-yellow viscous 
solution. Docetaxel is sterile, non-pyrogenic, and is available in single-dose vials 
containing 20 mg (0.5 mL) or 80 mg (2.0 mL) docetaxel (anhydrous). Each mL contains 
40 mg docetaxel (anhydrous) and 1040 mg polysorbate 80. 
 
Clinical Pharmacology:  Docetaxel is an antineoplastic agent that acts by disrupting the 
microtubular network in cells that is essential for mitotic and interphase cellular 
functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into 
stable microtubules while simultaneously inhibiting their disassembly. This leads to the 
production of microtubule bundles without normal function and to the stabilization of 
microtubules, which results in the inhibition of mitosis in cells. Docetaxel's binding to 
microtubules does not alter the number of protofilaments in the bound microtubules, a 
feature which differs from most spindle poisons currently in clinical use. 
 
A. Preparation of the Initial Diluted Solution 
 
1. Gather the appropriate number of vials of docetaxel for injection concentrate and 
diluent (13% Ethanol in Water for Injection).  If the vials were refrigerated, allow 
them to stand at room temperature for approximately 5 minutes. 
 
2. Aseptically withdraw the contents of the appropriate diluent vial into a syringe and 
transfer it to the appropriate vial of docetaxel for injection concentrate. If the 
procedure is followed as described, an initial diluted solution of 10mg 
docetaxel/ml will result.  
 
3.  Gently rotate the initial diluted solution for approximately 15 seconds to assure full 
mixture of the concentrate and diluent.  
 
4.  The initial diluted docetaxel solution (10 mg docetaxel/ml) should be clear; 
however, there may be some foam on top of the solution due to the polysorbate 80. 
Allow the solution to stand for a few minutes to allow any foam to dissipate. It is 
not required that all foam dissipate prior to continuing the preparation process.  
 
 The initial diluted solution may be used immediately or stored either in the  
 refrigerator or at room temperature for a maximum of eight hours.  
 
B. Preparation of the Final Dilution for Infusion 
 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
15 
    1.  Aseptically withdraw the required amount of initial diluted docetaxel solution  (10 
mg docetaxel/ml) with a calibrated syringe and inject into a NON- PVC infusion 
bag or bottle of either 0.9% sodium chloride solution or 5% dextrose solution to 
produce a final concentration of 0.3 to 0.74 mg/ml.  
 
2.  Thoroughly mix the infusion by manual rotation.  
 
3. As with all parenteral products, docetaxel should be inspected visually for 
particulate matter or discoloration prior to administration whenever the solution and 
container permit. If the docetaxel initial dilution (in vial) or final dilution for 
infusion is not clear or appears to have precipitation, it should be discarded.  
 
Contact of the docetaxel concentrate with plasticized PVC equipment or devices used to 
prepare solutions for infusion is not recommended. In order to minimize patient exposure 
to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC 
infusion bags or sets, the final docetaxel dilution for infusion should be stored in bottles 
(glass, polypropylene) or NON-PVC plastic bags (polypropylene, polyolefin) and 
administered through NON-PVC polyethylene-lined administration sets. 
 
Stability:  The initial diluted solution in the manufacturers vial may be used immediately 
or stored either in the refrigerator or at room temperature for a maximum of 8 hours. 
 
Fully prepared docetaxel infusion solution (in either NON -PVC 0.9% sodium chloride 
solution or NON-PVC 5% dextrose solution) stored between 2º and 25º C (36º and 77º F) 
is stable for 4 hours (which must include the IV administration time). 
 
3.22 
HOW SUPPLIED 
 
Docetaxel for Injection Concentrate is supplied in a single-dose vial as a sterile, pyrogen-
free, non-aqueous, viscous solution with an accompanying sterile, non-pyrogenic, diluent 
(13% ethanol in water for injection) vial. The following strengths are available: 
 
TAXOTERE 80 MG 
 
(NDC 0075-8001-80) 
TAXOTERE (docetaxel) 80 mg Concentrate for Infusion: 80 mg docetaxel in 2 ml 
polysorbate 80 and diluent for docetaxel 80 mg. 13% (w/w) ethanol in water for injection. 
Both items are in a blister pack in one carton. 
 
TAXOTERE 20 MG 
 
(NDC 0075-8001-20) 
TAXOTERE (docetaxel) 20 mg Concentrate for Infusion: 20 mg docetaxel in 0.5 ml 
polysorbate 80 and diluent for docetaxel 20 mg. 13% (w/w) ethanol in water for injection. 
Both items are in a blister pack in one carton. 
 
3.23 Storage: Refrigerate between 2º and 25° C (36º and 77º F).  Retain in the 
 original package to protect from bright light.  Freezing does not adversely affect the 
product.   


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
16 
 
3.24 Weekly Dosing: Infuse docetaxel at starting dose of 75 mg/m2over a minimum of 60 
minutes.   
 
3.25 
Human Toxicology 
 
Acute toxicities are uncommon, as is peripheral neuropathy.  Prolonged treatment with 
weekly docetaxel results in chronic toxicities, which include asthenia (fatigue), anemia, 
edema, excessive lacrimation (epiphora), and onycholysis.  Chronic toxicities are most 
prominent when docetaxel is administered on a continuous weekly basis, without a break, 
and are delayed in onset by providing breaks in treatment (for example, treating 6 of 8 
weeks or 3 of 4 weeks); these chronic toxicities occur at a lower cumulative dose when a 
continuous weekly schedule of docetaxel is utilized.  
 
The following covers current toxicity information for docetaxel at 100 mg/m2 infused on 
an every 3 to 4 week schedule, the highest dose, single-agent regimen: 
 
The dose limiting toxicity for docetaxel is neutropenia with 76% of patients with 
normal liver function (transaminases  1.5 times ULN or alkaline phosphatase  2.5 
times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times 
ULN) having grade IV neutropenia when docetaxel is used as a single agent at a dose of 
100 mg/m2.  Other toxicities include hypersensitivity reactions (with recommended 
premedication) in 15.7% of patients (severe, 0.9%), skin toxicity in 58.5% (severe, 
5.6%), and fluid retention (with recommended premedication) in 48.5% (severe, 5.2%).  
The latter symptoms can be ameliorated by pre-medication dexamethasone 8 mg PO bid 
starting the day prior to docetaxel, and then continuing the dexamethasone for 2-4 
additional days.  Fluid retention has been described in patients receiving docetaxel, and is 
manifested by peripheral edema and less frequently by pleural effusion, pericardial 
effusion, ascites, or weight gain.  When fluid retention occurs, peripheral edema usually 
begins in the lower extremities and may become generalized.  In clinical studies, the 
median weight gain in patients with fluid retention was 2 kg (Taxotere Prescribing 
Information, Jan. 2000).  Severe fluid retention has been characterized by poorly 
tolerated edema, generalized edema, effusion requiring urgent drainage, dyspnea at rest, 
tamponade, or pronounced abdominal distention (due to ascites) (Taxotere Prescribing 
Information).  It is important to note that fluid retention has not been accompanied by 
acute episodes of dehydration, oliguria, or hypotension (Taxotere Prescribing 
Information, Jan. 2000).  There are no common clinical features with acute capillary leak 
syndrome induced by exogenous cytokines such as IL-2 (Data on file, Aventis 
Pharmaceuticals).  A corticosteroid regimen (eg, oral dexamethasone 8 mg BID for 3-5 
days) was instituted during Phase II studies.  This regimen should be administered for 3-5 
days beginning 1 day prior to each docetaxel cycle to reduce the incidence and severity of 
fluid retention (Taxotere Prescribing Information). 
 
Fluid retention, when seen has been cumulative in incidence and severity, and usually did 
not occur until several courses of docetaxel treatment had been administered.  In Phase II 
clinical trials, this event was completely reversible following discontinuation of docetaxel 
(median: 29 weeks, range: 0 to 42+ weeks).  Among 229 patients who received the 
recommended corticosteroid regimen, moderate fluid retention was observed in 17.4%, 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
17 
severe fluid retention occurred in 6% and only 1.7% of patients required treatment 
discontinuation due to fluid retention (Taxotere Prescribing Information, Jan. 2000). 
 
The median cumulative dose to onset of moderate or severe fluid retention was 705 
mg/m2 in patients receiving the recommended corticosteroid regimen, compared with 490 
mg/m2 in patients who did not receive corticosteroids (Taxotere Prescribing 
Information, Jan. 2000).  In a recently reported study by Ravdin and colleagues, the 
incidence of fluid retention was assessed prior to and following the addition of the 
recommended corticosteroid regimen in 263 patients receiving docetaxel for treatment of 
advanced breast cancer.  The analysis confirmed that treatment with corticosteroids 
significantly (P<0.001) decreased the incidence, time to onset, severity and treatment 
discontinuation due to fluid retention. 
 
It is important to note that dexamethasone does not alter docetaxel clearance (Taxotere 
Prescribing Information, Jan. 2000).  Patients with preexisting effusions should be closely 
monitored from the first dose for possible exacerbation of the effusions.  Patients 
developing peripheral edema may be treated with standard measures (eg, salt restriction, 
oral diuretic[s]) (Taxotere Prescribing Information, Jan. 2000). Commercially available 
docetaxel and capecitabine is used in this study. 
 
 
4.0 ELIGIBILITY CRITERIA 
 
4.1  Inclusion Criteria 
 
1. Histologically confirmed prostate adenocarcinoma with metastasis, and objective progression 
or rising PSA despite androgen deprivation therapy and antiandrogen withdrawal when 
applicable. Patients with rising PSA must demonstrate a rising trend with 2 successive 
elevations at a minimum interval of 1 week. A minimum PSA of 5 ng/ml or new areas of 
bony metastases on bone scan are required for patients with no measurable disease. No 
minimum PSA requirement for patients with measurable disease.  
2. Patient must not have received any prior chemotherapy for metastatic disease. All patients 
must be documented to be castrate with a testosterone level < 0.5 ng/ml.  LHRH agonist 
therapy must be continued, if required to maintain castrate levels of testosterone. Patients 
must be off antiandrogens for a minimum of 4 weeks for flutamide and 6 weeks for 
bicalutamide or nilutamide.  
3. Age ≥ 18 years. 
4. Minimum of four weeks since any major surgery, completion of radiation, or completion of 
all prior systemic anticancer therapy (adequately recovered from the acute toxicities of any 
prior therapy). 
5. ECOG performance status  2. 
6. Life expectancy 12 weeks or more. 
7. Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, 
Hgb > 9 g/dL. 
8. Adequate liver function as shown by: serum bilirubin ≤ 1.5 x upper limit of normal (ULN), 
and serum transaminases (AST/ALT) activity ≤ 3 x ULN 
9. Adequate renal function as shown by serum creatinine ≤ 1.5 x ULN. 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
18 
10. Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x 
ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be 
included after initiation of appropriate lipid lowering medication and repeat fasting lipids 
should be within the inclusion range. 
11. Patients must be advised of the importance of using effective birth control measures during 
the course of the study. 
12. Signed informed consent to participate in the study must be obtained from patients after they 
have been fully informed of the nature and potential risks by the investigator (or his/her 
designee) with the aid of written information. 
 4.2  Exclusion criteria 
1. Prior treatment with any cytotoxic chemotherapy, radiation, immunotherapy, or any 
investigational drug within the preceding 4 weeks  
2. Patients who have undergone major surgery within 4 weeks prior to study enrollment 
3. Chronic treatment with immunosuppressive agents except steroids. 
4. Patients should not receive immunization with attenuated live vaccines during study period 
or within 1 week of study entry. 
5. Uncontrolled brain or leptomeningeal metastases, including patients who continue to require 
glucocorticoids for brain or leptomeningeal metastases. 
6. Patients with  prior or concurrent malignancy except for the following: adequately treated 
basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, or any 
other cancer from which the patient has been disease free for five years. 
7. Patients with uncontrolled diabetes mellitus, which is defined as a hemoglobin A1C >8% on 
therapy or >7% without therapy, or a fasting plasma glucose > 1.5 ULN. Note: At the 
principle investigator’s discretion, non-eligible patients can be re-screened after adequate 
medical therapy has been instituted. 
8. Patients with symptomatic cholelithiasis 
9. Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, 
sustained ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia, 
advanced heart block or a history of acute myocardial infarction within the six months 
preceding enrollment 
10. QT-related exclusion criteria: 
 Patients with baseline QTc  > 470 msec.  
 History of syncope or family history of idiopathic sudden death.  
 Sustained or clinically significant cardiac arrhythmias. 
 Patients with risk factors for Torsades de Pointes such as hypokalemia, 
hypomagnesemia, cardiac failure, clinically significant/symptomatic bradycardia, or 
high-grade AV block. 
 Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused 
by diabetes or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism or 
cardiac failure  
11. Concomitant medication(s) known to prolonge the QT interval  
12. Patients with the presence of active or suspected acute or chronic uncontrolled infection or 
with a history of immunocompromised disease. 
13. Patients who have any severe and/or uncontrolled medical conditions or other conditions that 
could affect their participation in the study such as: 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
19 
 
Severely impaired lung function 
 
Any active (acute or chronic) or uncontrolled infection/ disorders.   
 
Nonmalignant medical illnesses that are uncontrolled or whose control may be 
jeopardized by the treatment with the study therapy 
14. Known hypersensitivity to somatostatin analogues or any component of the pasireotide or 
octreotide LAR formulations  
15. History of noncompliance to medical regimens 
16. Patients unwilling to or unable to comply with the protocol. 
17. Men and any female partners of child-bearing potential must agree to use adequate 
contraception (hormonal or barrier method of birth control) prior to study entry and for the 
duration of study participation and for additional 2 months after finishing therapy.  Should a 
patient’s sexual partner become pregnant or suspect she is pregnant while patient is 
participating in this study, he should inform the treating physician immediately. 
18. History of liver disease, such as cirrhosis or chronic active hepatitis B and C.  
19. Presence of Hepatitis B surface antigen (HbsAg) 
20. Presence of Hepatitis C antibody test (anti-HCV)  
21. History of, or current alcohol misuse/abuse within the past 12 months 
22. Known gallbladder or bile duct disease, acute or chronic pancreatitis 
 
 
 
5.0 TREATMENT PLAN: 
 
 
5.1  Patient Registration and Data Collection:  
 
 
 All patients shall be registered with the Cancer Center Clinical Trials Office at (313) 
576-9372 (Brenda Dickow) or 313-576-9368 Cindy Silski or Stacy Freeman 313-576-8495 or 
Kimberlee Dobson 313-576-9837.   
 
At the time of registration, a pre-study form and all information required to verify eligibility 
shall be necessary on each patient prior to treatment. Data will be collected and maintained on 
study specific case report forms. 
 
 
5.2 Agent Administration 
Docetaxel and SOM-230 cycles should be designated by the number of cycles of each 
administered. For protocol purposes the day of administration should be specified, until the DLT 
period is completed. Then only cycle number of docetaxel and of SOM-230 can be designated. 
Starting doses of the agents are as follows: 
 
 
AGENT 
 
 
DOSE 
 
ROUTE 
 
 
 
DAYS 
 
 
FREQUENCY 
 
Docetaxel 
 
75mg/m2  
 
IV over at 
least 1 hour 
 
1 
 
Every 21 days 
 
SOM-230  
 
40mg 
 
IM 
 
1 
 
Every 28 days 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
20 
 
Prednisone 
 
5 mg 
 
Orally twice 
daily 
 
daily 
 
continuous 
Doses should be prepared and administered immediately after preparation.  For additional 
details regarding preparation, refer to “Clinical instructions for administration of 
pasireotide/SOM-230”. This is attached as a Protocol Related Document. 
 
Cohorts of 3 patients each will be treated for 56 days with escalating doses of SOM-230 
according to the dose levels defined until dose limiting toxicity DLT is observed. Dose 
escalation and expansion of cohorts to 3-6 patients will proceed according to the criteria 
listed in Section 6.0. DLT will be defined from the safety profile of cycles 1 and 2 for each 
dose level (Section 6.0). The MTD is the dose level at which 0/6 or 1/6 patients experiences 
DLT with at least 2 patients experiencing DLT at the next higher dose level.  
The escalating dose levels are given below and first cohort will be started with dose level 1.  If 3 
patients in each dose level do not demonstrate (DLT) then therapy will proceed to the next dose 
level. If 1 of 3 patients demonstrates DLT as defined below then 3 additional patients will be 
treated at the same dose cohort. If 2 or more patients have DLT at a dose level then this will be 
considered MAD and patients will then be treated at one dose level lower which will be 
considered the MTD (maximum tolerated dose). The patients are monitored for DLT in the first 
56 days of therapy. If no DLT observed at dose level 1 during the first 56 days of therapy, then 
escalation to dose level 2 will be performed in the next cohort. Toxicities requiring dose 
modification of prednisone will not be included in the dose limiting toxicity (DLT). 
 
 
 
Dose levels 
SOM 230 LAR 
Docetaxel 
Prednisone 
1 
40mg IM every 28 
days 
75mg/m2 IV every 21 
days 
5 mg PO twice daily 
2 
60 mg IM every 28 
days 
75mg/m2 IV every 21 
days 
5 mg PO twice daily 
3 
80 mg IM every 28 
days 
75mg/m2 IV every 21 
days 
5 mg PO twice daily 
Doses of SOM-230 > 80 mg IM every 28 days, are being tested in an ongoing trial. If safety data 
of higher doses of SOM-230 (>80 mg every 28 days) is available, and the dose level 3 of the 
combination is well tolerated, then consideration will be done for adding higher dose levels of 
SOM-230 in this protocol. 
 
 
 
5.2.1 Docetaxel administration 
On day 1 of each cycle docetaxel will be administered if ANC > 1500 and platelets > 
100K. If not, repeat CBC in 7 days and administer if above criteria met. If still no 
recovery, repeat CBC weekly, until recovery and then reduce docetaxel by one dose 
level (60 mg/m2).  If dose reduction is required for toxicity related to docetaxel after 
the first 56 days of therapy then protocol therapy can be continued with dose reduced 
to 60 mg/ m2 . If toxicity requiring dose modification of docetaxel recurs then patients 
should be taken off protocol therapy. Patients can continue on SOM-230 if ANC> 
500/mm3 and platelets > 50,000/ mm3 and no other grade 3 or 4 non hematologic 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
21 
toxicities related to SOM-230 are noted, except hyperglycemia. If grade 3 or 4, or any 
grade clinically relevant hyperglycemia occurs it should be treated appropriately. 
Premedications will be administered as appropriate per treating physician discretion. 
Docetaxel can be discontinued if toxicity recurs despite dose modification and SOM-
230 can be continued if patient continuing to demonstrate tolerance and clinical 
benefit.  
 
5.2.2  Prednisone Administration 
Starting day 1, prednisone at a dose of 5 mg orally twice daily will be administered after meals. 
If patients have grade 2 or greater toxicity, attributable to prednisone, decrease the dose to 5 mg 
once daily. If toxicity recurs, or any grade 3 or higher toxicity attributable to prednisone occurs, 
discontinue therapy or taper off prednisone. For grade 3 or 4 hyperglycemia, decrease or stop 
prednisone first and initiate medical management, then if recurs despite this then consider 
SOM230 dose reduction and call it a DLT. 
 
5.2.3 
SOM-230 administration 
Patients will receive SOM-230 at specified dose IM on day 1, after docetaxel therapy, 
and subsequently every 28 days. On the days of SOM-230 administration only, it can 
be administered if ANC>500/ mm3 and platelets > 50,000/ mm3 and no other grade 3 
or 4 non hematologic toxicities related to SOM-230 are noted , except hyperglycemia. 
If grade 3 or 4 hyperglycemia is noted then proceed with SOM-230 therapy and 
initiate appropriate therapy. If grade 3 or greater hyperglycemia recurs despite 
discontinuing prednisone and initiating optimal therapy then decrease SOM-230 by 1 
dose level. If this occurs at dose level 1 then discontinue SOM-230. If hyperglycemia 
persists or recurs despite above steps, then discontinue SOM-230 therapy.  
5.3   Retreatment 
 
Retreatment on day 1 of each docetaxel cycle 
CBC will be obtained on Day 1 of each cycle of docetaxel. During the first cycle 
CBC will be obtained weekly. On day 1 of each cycle of docetaxel therapy, patients 
will be retreated with docetaxel if the following criteria are met: 
• 
ANC > 1,500/mm3 
• 
Platelets > 100,000/mm3 
• 
Non-hematologic toxicity attributed to docetaxel should have resolved to 
baseline or < grade 1, with the exception of. alopecia and hyperglycemia. 
If patient cannot be treated on scheduled day 1 of docetaxel due to toxicity, then 
evaluate weekly until therapy can be resumed. If day 1 therapy has to be delayed >3 
weeks from the scheduled treatment date of docetaxel, due to toxicity then discontinue 
docetaxel therapy. SOM-230 can be continued if patient continuing to have clinical 
benefit, but this patient cannot be included for determination of MTD and will need to 
be replaced in that cohort. 
Laboratory tests may be performed up to 3 days prior to the scheduled study visit, and 
if the retreatment criteria are met, the patient may be retreated.  If the retreatment 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
22 
criteria are not met, the patient may not be retreated until they are met and the tests 
should be repeated weekly. 
 
 
5.4  Antiemetic Prophylaxis and Premedication for Docetaxel 
Anti-emetic prophylaxis and other premedication for docetaxel will be at the discretion of 
treating physician. However a prophylactic minimum steroid dose equivalent of 
dexamethasone 8 mg is highly recommended prior to docetaxel therapy. 5-HT3 
antagonists should be used with caution. 
5.5  Growth Factors 
Growth factors may be administered as per the judgment of the clinical investigator after the 
occurrence of cytopenias and in subsequent cycles. Prophylactic growth factor use is not 
permitted. 
 
5.6. 
Toxicity to be evaluated weekly for the first 8 weeks, and subsequently on the days of 
therapy, and radiologic response to be assessed every 12 weeks for the first 36 weeks 
and then every 16 weeks. PSA to be assessed on the days of therapy. 
  
5.7 
Retreatment with SOM-230 therapy 
On the days of SOM-230 administration, it can be administered if ANC>500 and platelets >50K 
and no other grade 3 or 4 non hematologic toxicities related to SOM-230 are noted. If SOM-230 
therapy has to be delayed > 4 weeks from the scheduled treatment date due to toxicity, then 
discontinue SOM-230 therapy. If any of the discontinuation criteria below are met, SOM-230 
should be discontinued immediately.   
 ALT or AST > 3 x ULN and Total Bilirubin ≥ 2 x ULN and ALP < 2 x ULN 
 ALT or AST > 5 x ULN and ≤ 8 x ULN persistent for more than 2 weeks   
 ALT or AST  > 8 x ULN 
In addition, proper safety follow-up management should be performed as outlined in 
section 6.7.   Re-challenge of study medication is prohibited once discontinuation 
criteria are met.  
5.8 
Reasons for Discontinuing Protocol therapy 
 
Patients will continue on treatment until they fulfill one of the following criteria for 
removal from treatment: 
 
i. 
Completion of two cycles of therapy, after documentation of a complete response. 
ii. 
Disease progression as defined in section  
iii. 
Unacceptable, severe grade 3 or 4 toxicity 
iv. 
>4 weeks delay in treatment due to toxicity. 
v. 
The patients may withdraw from the study at any time for any reason 
vi. 
Early study closure based on an unexpected high rate of toxicity or disease 
progression, major shift in disease management or loss of funding support 
 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
23 
5.9  
All patients will be followed every 3 months for progression and survival after study 
therapy is discontinued, unless consent is withdrawn by the patient. All reasons for 
termination of treatment should be clearly documented. 
 
 
 
 
6.0 TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATION: 
 
6.1 All toxicities will be graded as per NCI Common Toxicity version 4.0. 
 
Toxicity evaluation weekly for first 8 weeks and subsequently on days of administration of 
docetaxel or SOM-230 therapy. Radiologic evaluation every 12 weeks with scans, and PSA 
levels every 21 days.  
 
Three patients will be enrolled at each dose level (3 planned dose levels currently). The patients 
in a cohort will be monitored for toxicity for 56 days (time when Cmax of SOM-230 is 
achieved), before accrual begins for the next dose level cohort .  
Toxicities requiring dose modification of prednisone will not be included in the dose 
limiting toxicity (DLT).  
 
The DLT will be defined as any one of the following occurrences if they are at least possibly 
related per treating physician, to either docetaxel or SOM-230 in the first 56 days of therapy: 
1) Absolute neutrophil count nadir <500/mm3 for >7 days duration or occurrence of febrile 
neutropenia. 
2) Platelet count <50K for >7 days duration or Platelet count <50K of any duration with 
clinically significant bleeding. 
3) Persistent fasting hyperglycemia > grade 3, despite optimal therapy. 
4) Other grade 3 or higher non hematologic toxicities attributable to therapy, except alopecia, 
fatigue, nausea and emesis, except for grade 3 or higher fatigue (unrelieved by rest, and 
limiting self-care ADLs) lasting greater than 7 days or grade 3 or higher emesis that lasts 
>5 days despite optimal medical therapy. 
 
If 1 or more patients experience a DLT, then three additional patients will be enrolled at that 
dose level. The MAD will be determined if more than 2 of the 6 patients treated experience a 
DLT. Once MAD is determined, the recommended dose for phase II testing/MTD will be one 
dose level below the MAD dose level and a total of 12 patients will be treated at this dose level.   
Number of Patients with 
DLT at a Given Dose 
Level 
Escalation Decision Rule 
0 out of 3 
Proceed to the next dose level  
1 out of 3 
Enter three additional patients to a total of 6 at this dose level: 
If 0 of these patients experience DLT, proceed to the next dose 
level.  
If 1 additional patient or 2 of the 6 patients suffer DLT, then dose 
escalation is stopped, and this dose is declared the maximally 
administered dose . 
2 or more of 6 treated 
This dose level will be declared the maximum administered dose 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
24 
 
 
 
 
6.2 Docetaxel dose modifications: 
 
On day 1 of each cycle docetaxel will be administered if ANC > 1500 and platelets > 100K. If 
not, repeat CBC in 7 days and administer if above criteria met. If still no recovery, repeat CBC 
weekly, until recovery and then reduce docetaxel to one dose level lower (60 mg/m2). If dose 
reduction is required for toxicity related to docetaxel within the first 56 days of therapy then 
consider taking patient off protocol after discussion with the Principal Investigator. If dose 
reduction is required for toxicity related to docetaxel after the first 56 days of therapy then 
protocol therapy can be continued with docetaxel dose reduced to 60 mg/ m2 . 
 
If patient experiences a DLT and still wishes to resume therapy then one dose level decrease of 
the agent causing toxicity (docetaxel, or SOM-230, or both, depending on attribution of toxicity, 
as determined by the treating physician) is required, after resolution of the treatment related 
toxicities to grade 1 or less (except alopecia).  If toxicity occurs on starting dose level of SOM-
230 then discontinue the therapy. If toxicities recur at grade 2 or higher, or > 3 weeks delay from 
the scheduled date of therapy for docetaxel and >4 weeks from the scheduled date of therapy for 
SOM-230 is required, then discontinue protocol therapy. Docetaxel or SOM-230 only can be 
continued, at the discretion of the investigator, and if patient is continuing to benefit from 
therapy.  
 
 
6.3 Prednisone Dose Modifications: 
Toxicities requiring dose modification of prednisone will not be included in the dose limiting 
toxicity (DLT). If any toxicity grade 3 or higher attributable to prednisone, then decrease dose to 
5 mg once daily. If grade 3 or 4 toxicity recurs then consider tapering further, or discontinuing 
therapy, at the treating physician’s discretion. 
 
 
6.4 Criteria for dose-modification of SOM230  
 
Dose Level 
SOM-230 dose 
1 
40 mg IM every 28 days 
2 
60 mg IM every 28 days 
3 
80 mg IM every 28 days 
SOM-230 dose levels: Level 1 is the starting dose, if modification needed in the starting dose 
cohort for SOM-230 related toxicity then discontinue SOM-230. For liver toxicity attributable to 
patients 
 
(MAD).   
Dose escalation will be stopped.  No further patients will be entered 
at this dose level  


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
25 
SOM-230 LAR, please see guidelines for dose modifications/interruptions and monitoring as 
shown below and detailed in appendix VIII.  
If any of the criteria below are met, SOM-230 should be discontinued immediately.   
 ALT or AST > 3 x ULN and Total Bilirubin ≥ 2 x ULN and alkaline phosphatase 
(ALP) < 2 x ULN 
 ALT or AST > 5 x ULN and ≤ 8 x ULN persistent for more than 2 weeks   
 ALT or AST  > 8 x ULN 
In addition, proper safety follow-up management should be performed as outlined in section 6.7.   
Re-challenge of study medication is prohibited once discontinuation criteria are met. 
 
Adverse event 
Action 
*Grade ≤ 2  
No study drug adjustments 
*Grade ≥ 3 and 
judged as at 
least possibly 
drug related 
(except liver 
toxicity for 
which separate 
guidelines are 
included above 
and in 
appendix) 
 Further injections should be held for at least 7 days and until 
toxicity improves to ≤ Grade 1.  
 If toxicity improves to grade ≤ 1 within 7 days, no dose 
reduction is required. 
 If toxicity improves to grade ≤ 1 in 8-14 days, resume treatment 
with a single dose level reduction.  
 If toxicity improves to grade ≤ 1 in 15-28 days, resume 
treatment with two dose level reductions.  
 If toxicity fails to improve to grade ≤ 1 within 28 days, study 
treatment must be discontinued unless there is clear evidence of 
therapeutic benefit from the study regimen, in which case 
continued treatment is left to the discretion of the Overall 
Principal Investigator. 
 If any toxicity recurs at CTCAE grade ≥ 3, treatment must be 
discontinued. 
QTc CTC grade 
1 (≤ 480 msec)  
 No study drug adjustments 
QTc CTC grade 
2 (> 480 or ≤ 
500 msec) either 
drug related or 
drug unrelated 
Patient is to be referred to a cardiologist for evaluation and 
appropriate management, and the patient can remain in the study 
 Patient’s study drug dose will be reduced to 1 dose level down 
QTc CTC grade 
≥ 3 (> 500 
msec) 
Discontinue study drug 
Follow patient for safetyA 
*This guidance should be use for all possibly related AEs except for: 
 Changes in blood glucose which should be addressed as described in Section 
6.6 
 Dose adjustment criteria for QTc  interval are based on the QTc interval noted 
on the day of SOM-230 therapy. 
 
 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
26 
6.5 Follow-up for toxicities 
Patients who interrupt or permanently discontinue SOM230 due to an adverse event or abnormal 
laboratory value must be followed at least weekly for 28 days after the last dose of SOM230, and 
subsequently at monthly intervals until resolution or stabilization of the event, whichever comes 
first. If a patient requires a SOM230 dose delay of > 28 days from the intended day of the next 
scheduled dose, then the patient should be discontinued from the study. 
All patients will be followed for adverse events and serious adverse events for 28 days following 
the last dose of SOM230. 
 
6.6 Management Guidelines for Hyperglycemia 
 
During the study, all patients with HbA1c>7 % and or fasting plasma glucose (FPG) > 130 
mg/dL (7.2 mmol/L), or 2-hour post-prandial capillary glucose (PPG) > 180 mg/dL (10 mmol/L) 
on two consecutive measurements that are within 14 days, should be considered for the 
following: 
 
• 
Referral to a diabetes specialist for evaluation and appropriate management 
• 
Provided information and receive teaching on diabetes disease management 
• 
Monitoring of blood glucose by fingerstick twice daily (fasting morning blood glucose and 2-
hour post-meal) if not already done. Patients, who monitor blood glucose should keep a diary 
of their glucose values and present the collected data to their physician/ diabetes specialist for 
evaluation and appropriate management. 
 
6.7 Safety 
Safety assessments will consist of monitoring and recording all adverse events, including serious 
adverse events, the regular monitoring of hematology (including glycosylated hemoglobin and 
coagulation parameters), blood chemistry (including fasting glucose, thyroid function tests, GH, 
IGF-1, prolactin), urinalysis, regular monitoring of vital signs, gallbladder ultrasound, 
echocardiography, ECGs and body weight. Liver function tests: total bilirubin, AST, ALT and 
alkaline phosphatase should be evaluated and assessed prior to each dose of SOM-230 
administration. Concomitant medications and significant non-drug therapies will be recorded 
from study enrollment until study completion. 
Patients with diabetes are to be instructed to check blood glucose levels via a fingerstick several 
times daily, particularly for the first few days of treatment. 
Vital signs 
Body weight, body temperature, supine blood pressure, and supine pulse rate will be assessed. 
Height will be noted during the screening/baseline period. 
Performance status 
To be determined per ECOG score (Appendix I), and to be documented at baseline and the days 
of administration of therapy.  
 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
27 
Laboratory evaluations 
Patients are to fast overnight for 8 hours prior to all biochemistry samples being taken. Blood 
samples are to be taken in the morning. Water is allowed during this time. Laboratory samples 
will be analyzed locally at the clinical sites, unless indicated otherwise. 
Albumin, alkaline phosphatase, total bilirubin, calcium, chloride, creatinine, CPK, γ-GT, fasting 
blood glucose, LDH, inorganic phosphorus, lipase, α-amylase, potassium, total protein, SGOT, 
SGPT, sodium, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, urea/BUN and 
uric acid.  
Thyroid function tests 
Free T4 and TSH will be assessed at baseline and every 12 weeks for the first 36 weeks and then 
every 16 weeks thereafter.  
Urinalysis 
Specific gravity, pH, glucose, protein, bilirubin, ketones, leukocytes and blood will be assessed. 
Hormones 
IGF-1 will be assessed at baseline, day 22 and day 43.  
Chromogranin and neuron specific enolase will also be assessed at baseline, day 22 and day 43.  
Gallbladder ultrasound 
A gallbladder ultrasound will be performed at baseline and repeated if clinically indicated. 
Patients with a history of symptomatic cholelithiasis are excluded from participating in the study.  
Electrocardiogram (ECG) 
A 12-lead electrocardiogram (ECG) will be performed at baseline and pretherapy. Due to 
concern with prolonged QT interval, all patients treated with pasireotide/SOM-230 will have 
repeat EKGs performed on day 1 post SOM-230 therapy, 21 days after first and third dose of 
SOM-230 (Day 22 and day 78), every 14 days for 8 weeks, then every 28 days prior to SOM230 
administration for the remainder of the study period. If a clinically significant abnormality is 
detected, the electrocardiogram will be repeated at the discretion of the Investigator until the 
abnormality has been resolved.  
Echocardiogram 
To be done only if clinically indicated. 
Other concomitant medications 
Concomitant therapy 
Patients will be instructed not to take any additional medications (including over-the-counter 
products) during the course of the study without prior consultation with the investigator. At each 
visit, the investigator will ask the patient about any new medications he/she is or has taken after 
the start of the study drug. 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
28 
All Concomitant medications/Significant non-drug therapies taken ≤ 30 days prior to start and 
after start of study drug, including physical therapy and blood transfusions, should be recorded. 
Study drug discontinuation 
Patients experiencing unacceptable toxicity (AE grade 3 or higher) that the investigator considers 
directly attributable to the study drug should have their dose adjusted as per dose modification 
guidelines in the Table. If a patient has already decreased 2 dose levels of SOM-230 and 1 dose 
level of docetaxel, no further dose reductions are permitted, and the patient will be permanently 
discontinued from treatment. 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
29 
7.0 STUDY CALENDAR: 
Prestudy labs should be done within 28 days of day 1. Day 1 labs can be done within 3 days of 
day 1. A time period of +/- 3 days is permitted for each of the days listed in the calendar. 
 
Testing 
Pre D 1 D 8, 
15, 
36 
and 
50 
D 
22 
D 
29 
D 
43 
D 
57 
Day 
85 
Doce 
post  
day 57 
SOM-
230 post  
day 57 
Q 12 
wks 
for 
first 
36 
wks 
on 
study 
Q 16 
wks 
after 
first 
36wk 
on 
study 
H and P 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
VS, Wt 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
PS 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Tox 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
CBCdiff,pl
t 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Multiphasi
c1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Other 
Labs2 
X 
X 
 
 
X 
 
X 
X 
 
X 
 
 
PT, INR3 
X 
 
 
 
 
 
 
 
 
 
 
 
PSA 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Testostero
ne 
X 
 
 
 
 
 
 
 
 
 
 
 
TSH, free 
T4 
X 
 
 
 
 
 
 
 
 
 
X 
X 
UA 
X 
 
 
X 
X 
 
X 
 
 
 
 
 
EKG5 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Gall 
bladder US 
X 
 
 
 
 
X 
 
 
 
 
 
 
CXR4 
X 
 
 
 
 
 
 
 
 
 
X 
X 
CT5 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Bone scan5 
X 
 
 
 
 
 
 
 
 
 
X 
X 
PK6 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
Docetaxel 
 
X 
 
X 
 
X 
 
X 
X 
 
 
 
SOM-230 
 
X 
 
 
X 
 
X 
X 
 
X 
 
 
CTC7 
 
X 
 
X 
 
X 
 
 
 
 
 
 
PD8 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Follow up9 
 
X 
 
 
 
 
 
 
 
 
 
 
 
1. Multiphasic includes lytes, BUN and creatinine albumin, alkaline phosphatase, total bilirubin, 
calcium, total protein, AST, and ALT assessment. Fasting glucose should be measured. 2. Other 
labs include: Prestudy Hemoglobin A1C, Hepatitis B surface antigen (HbsAg) and anti-Hepatitis 
C virus antibody testing should be conducted. Magnesium, Total cholesterol, LDL cholesterol, 
HDL cholesterol, triglycerides, and uric acid.γ-GT, LDH, inorganic phosphorus, lipase, amylase 
and CPK to be done on days of SOM-230 adminstration only. Magnesium and potassium levels 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
30 
will be monitored and corrected prior to drug administration both at screening and prior to each 
dose of SOM-230. 
3. PT, INR to be done prestudy only; repeated weekly if patient is on warfarin > 2 mg daily. 
4. CXR is required pretherapy unless pulmonary metastases are noted. If pulmonary metasatses, 
then chest CT is needed at baseline and for subsequent tumor assessment If CT chest is done 
pretherapy then CXR is not needed.  
5. All tumor measurement scans, and prestudy labs and EKG must be within 28 days prior to 
treatment. CT abdomen /pelvis, and bone scan are required for pretreatment and subsequent 
tumor assessments.  A 12-lead electrocardiogram (ECG) will be performed at baseline and 
pretherapy. Due to concern with prolonged QT interval, all patients treated with 
pasireotide/SOM-230 will have repeat EKGs performed pre and post SOM-230 therapy on day 1 
only, and will be done once on days 15, 22, 29, 43, 57 and 78. On days 29 and 57, EKG should 
be done prior to SOM-230 therapy. After day 78, EKG will be done on the days of SOM230 
therapy (prior to administration)  for the remainder of the study period. 
6. Cycle 1 day 1:  Samples will be collected at predosing, end of infusion, 2, 3, 4 ,7, 24 and 48 h 
timepoints after the start of docetaxel infusion. Day 43: Blood samples will be collected at: pre-
dosing (for docetaxel and pasireotide/SOM-230), at the end of infusion, 2, 3, 4, 7, 24 h (day 44), 
and 48 h (day 45) after the start of infusion. Trough (pre-treatment) samples for pasireotide will 
be obtained on days 29, 57, and 85 prior to the administration of pasireotide. A time window of 
+/- 2 hours is permitted for the 24 and 48 hour PK draws. A maximum of 12 patients will have 
PK studies done.  
7. CTC samples will be drawn day 1, day 22 (pretherapy) and day 43 (pretherapy). Cell save tube 
minimum 7.5 ml collection and sent promptly for processing. 
8. PD samples for IGF-1, chromogranin and NSE will be drawn at prestudy, day 22 (pretherapy) 
and day 43 (pretherapy). IGF-1 – SST tube (min  1.0 mL) Chromogranin A – red top (min  1.0 
mL) –lab sendout test. NSE – red top (min  0.2 mL)- lab sendout test. 
9. Patients will be followed for progression/survival every 3 months, for a maximum of 24 months after 
discontinuing protocol therapy. 
 
   
 
8.0 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION: 
 
8.1 The RECIST 1.1 criteria with unidimensional measurement are to be used for 
measurable disease response evaluation [11].  
8.2 Methods of Assessment 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. CT is the best 
currently available and reproducible method to measure lesions selected for response 
assessment. MRI is also acceptable in certain situations (e.g., for body scans but not for 
lung).Lesions on a chest X-ray may be considered measurable lesions if they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
Clinical lesions will only be considered measurable when they are superficial and ≥10 
mm in diameter as assessed using calipers. For the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
Ultrasound (US) should not be used to measure tumor lesions. 
 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
31 
8.3 Baseline Disease Assessment 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
Measurable lesions must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm; when CT scans have 
slice thickness >5 mm, the minimum size should be twice the slice thickness). 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as nonmeasurable). 
• 20 mm by chest X-ray. 
• Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm in short axis when assessed by CT scan (CT 
scan slice thickness is recommended to be no greater than 5 mm). At baseline and in 
follow-up, only the short axis will be measured and followed. 
• Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered measurable if the soft tissue component meets the definition of measurability 
described above. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered measurable if 
they meet the definition of measurability described above. However, if non-cystic lesions 
are present in the same patient, these are preferred for selection as target lesions. 
 
Non-measurable lesions 
Non-measurable lesions are all other lesions, including small lesions (longest diameter 
<10 mm or pathological lymph nodes with 10 to <15 mm short axis), as well as truly 
non-measurable lesions.  
• Blastic bone lesions are non-measurable. 
• Lesions with prior local treatment, such as those situated in a previously irradiated area 
or in an area subjected to other loco-regional therapy, are usually not considered 
measurable unless there has been demonstrated progression in the lesion.  
Target Lesions 
• All measurable lesions up to a maximum of two lesions per organ and five 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 be representative of all involved organs, as well as their suitability for 
reproducible repeated measurements. 
• All measurements should be recorded in metric notation using calipers if clinically 
assessed. A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions 
Non-target Lesions 
All lesions (or sites of disease) not identified as target lesions, including pathological 
lymph nodes and all non-measurable lesions, should be identified as non-target lesions 
and be recorded at baseline. Measurements of these lesions are not required and they 
should be followed as ‘present’, ‘absent’ or in rare cases, ‘unequivocal progression’. 
 
8.4 Evaluation of target lesions 
Complete Response (CR): 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
32 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum of diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this may include the baseline sum). The sum must also 
demonstrate an absolute increase of at least 5 mm. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. 
 
8.5 Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of PR and 
CR is required to ensure responses identified are not the result of measurement error. 
This will also permit appropriate interpretation of results in the context of historical data 
where response has traditionally required confirmation in such trials. 
However, in all other circumstances, (i.e., in randomized phase II or III trials or studies 
where stable disease or progression are the primary endpoints), confirmation of response 
is not required since it will not add value to the interpretation of trial results. However, 
elimination of the requirement for response confirmation may increase the importance of 
central review to protect against bias, in particular in studies which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study 
entry at a minimum interval (in general not less than 6–8 weeks) that is defined in the 
study protocol. 
 
  
8.6 Prostate Cancer Specific Response criteria: [12] 
 
For measurable disease response, RECIST criteria 1.1 will be used [11]. The Prostate Cancer 
Clinical Trials Working Group (PCWG2) criteria will also be used to determine a response in 
non measurable disease [12]. PCWG2 recommends a two-objective paradigm in metastatic 
CRPC: (1) controlling, relieving, or eliminating disease manifestations that are present when 
treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. 
PSA decline and changes in imaging will also be reported. The progression for measurable 
disease will be per RECIST criteria, and for bone metastases will be defined as above. 
 
 8.7 Response Evaluable Patients 
 All patients registered on the protocol and completing a minimum of one cycle of therapy  
 followed by clinical, and radiologic or PSA assessment of disease status. 
 
 8.8 Toxicity- Evaluable patients 
 
All patients registered on the protocol and starting therapy with protocol medication, will be 
considered toxicity evaluable. 
 
 
8.9 Follow up /Overall survival 
Overall survival will be measured from date of registration to death or last follow up.  
After treatment is discontinued for any reason patients will be followed every 3 months for 
progression and survival for a maximum of 24 months after discontinuing protocol therapy. 
 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
33 
9.0 CRITERIA FOR REMOVAL FROM PROTOCOL TREATMENT: 
 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the 
investigator at any time. Patients may be withdrawn from the study if any of the following occur: 
a) Lack of efficacy 
b) Uncontrolled diabetes mellitus (DM) 
c) Unacceptable Adverse event(s) 
d) Abnormal laboratory value(s) 
e) Abnormal test procedure result(s) 
f) Protocol violation 
g) Subject withdrew consent 
h) Lost to follow-up 
i) Administrative problems 
j) Death 
j) New therapy for disease being investigated 
k) Disease progression 
 
 
 
10.0 
CORRELATIVE STUDIES 
Pharmacokinetic Studies: 
Treatment Schedule: 
 
On day 1, docetaxel will be given as 1-h intravenous infusion over 1 hour, followed by 
intramuscular administration of pasireotide.  The subsequent doses of docetaxel will be given 
every 21 days (i.e., on days 22, 43, 64…), and subsequent doses of pasireotide will be given every 
28 days (i.e., days 29, 57, and 85…). The PK evaluation is optional and will be done on a 
maximum of 12 patients. 
 
Pharmacokinetic (PK) Evaluation: 
 
In vitro liver microsome and in vivo animal studies have indicated that pasireotide is highly 
metabolically stable.  Therefore, docetaxel is not expected to influence the PK of pasireotide.  
However, pasireotide was found to be a weak inhibitor of CYP1A2, 2C8, 2C19, 2E1 and 
CYP3A4/5 with IC50 values ranging from ~10 to >100 μM, and a moderate inhibitor of 
CYP2C9 and CYP2D6 with IC50 values of ~5 μM.  Though no drug-drug interaction between 
pasireotide and CYP450 substrates such as docetaxel is expected at the intended therapeutic 
levels (<0.1 μM) of pasireotide, we will examine the PK of docetaxel in the presence of steady-
state concentration of pasireotide in all treated patients.   
 
Sampling time: 
      
Cycle 1 day 1 (to characterize baseline docetaxel PK):  Samples will be collected at predosing, 
end of infusion, 2, 3, 4 , 7, 24 and 48 h timepoints after the start of docetaxel infusion. A time 
window of +/- 2 hours is permitted for the 24 and 48 hour PK draws.   
Cycle 1 day 43: (to characterize the PK of docetaxel in the presence of steady-state concentration 
of pasireotide). A time window of +/- 2 hours is permitted for the 24 and 48 hour PK draws.   


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
34 
Previous studies have shown that pasireotide reaches the steady-state after at least 42 days of 
therapy, therefore the docetaxel PK will be obtained on day 43.   
Blood samples will be collected at: pre-dosing (for docetaxel and pasireotide), at the end of 
infusion, 2, 3, 4, 7, 24 h (day 44), and 48 h (day 45) after the start of infusion. A time window of 
+/- 2 hours is permitted for the 24 and 48 hour PK draws.   
 
Trough (pre-treatment) samples for pasireotide will be obtained on days 29, 57, and 85 prior to 
the administration of pasireotide. 
 
Sample processing: 
     At each time point specified above, 4 ml blood sample will be collected into a heparinized 
tube, and immediately placed on ice or in refrigerator (40C) until processed.  The actual day and 
time of sample collection will be recorded on the PK worksheet.  Within 1 h of the collection, the 
blood sample will be centrifuged at 40C, at 3000 rpm for 10 min, and plasma will be collected 
immediately after centrifugation and transferred to 2 screw-cap polypropylene cryogenic tubes (2 
aliquots, each with ~1 ml plasma).  The tube will be labeled with the patient’s initial, study 
number, sample collection day and time, and frozen at -700C or below until analysis. 
 
The PK samples for docetaxel will be shipped to the Karmanos Cancer Institute Pharmacology 
Core for analyses.  The shipping address is: 
 
Jing Li, PhD 
Assistant Professor of Pharmacology 
Director, Pharmacology Core 
Karmanos Cancer Institute 
Wayne State University 
4100 John R 
HWCRC, Room523 
Detroit, MI 48201 
Phone: 313-576-8258 
Email: lij@karmanos.org 
Bioanalysis assays: 
     The plasma concentrations of docetaxel will be determined using a validated high-
performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) methods in 
the Karmanos Cancer Institute Pharmacology Core Laboratory, Detroit, MI.  The plasma 
concentrations of pasireotide will be determined in a Norvatis laboratory. 
 
SOM-230 PK 
All blood samples will be taken by either direct venipuncture or indwelling cannula inserted in a 
forearm vein. 2.5 mL of blood will be collected into an EDTA tube to yield 1mL of plasma for 
analysis of pasireotide plasma concentration. Immediately after blood is drawn into EDTA tubes, 
they should be inverted gently several times to ensure the mixing of tube contents. Prolonged 
exposure to the rubber stopper should be avoided. The tube should be placed upright in tube rack 
surrounded by ice until centrifugation. Within 20 minutes, the sample should be centrifuged 
between 3 and 5ºC for 10 minutes at approximately 1000 x g. Immediately after centrifugation, 
1.0 mL plasma should be transferred to a polypropylene screw cap tube immersed in dry ice. The 
storage temperature for PK samples should be at or below -18°C. 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
35 
Bioanalytical method SOM-230 plasma concentrations will be measured using a validated radio-
immunoassay (RIA) with a lower limit of quantification (LLOQ) of at least 0.15 ng/mL (150 
pg/mL).  
 
PK samples will be batched and shipped to the following address: 
 
   
 
PK data analysis: 
     PK parameters for individual patients will be estimated using non-compartmental and 
compartmental analysis with the software WinNonlin 5.2 (Pharsight Corp., Mountain View, 
CA).   
 
Pharmacodynamic Studies 
 
Chromogranin A and NSE levels in serum will be tested at baseline and on days 22 and 43. 
These are markers of neuroendocrine differentiation and have demonstrated correlation with 
prognostic outcome in prostate cancer [13]. Also since neuroendocrine differentiation is a 
possible mechanism of resistance to chemotherapy, assessment of these markers will enable us to 
study the effect of combination of docetaxel and pasireotide on the neuroendocrine component of 
metastatic prostate cancer. The local CLIA certified laboratory would be performing these 
tests. 
 
The somatostatin analogues affect the dimerization of the IGF-1 pathway hence resulting in 
downregulation of secretion of IGF-1 protein in prostate cancer cell lines such as LNCaP. [14] 
Plasma IGF-1 levels will be evaluated by ELISA assay at baseline, and on days 22  and 43 
[15]. The local CLIA certified laboratory would be performing these tests. SOM-230 has 
demonstrated potent IGF-1 inhibition that is superior to octreotide and hence evaluating the 
change in IGF-1 levels from baseline to post therapy could be useful as an early predictor of 
outcome. Plasma IGF-1 levels will hence be evaluated by ELISA assay at baseline, and on days 
22 and 43 of the study. 
 
Circulating Tumor Cells (CTC) 
 
In metastatic CRPC, CTC are gaining importance as a method to assess response. In a disease 
where the sites of metastases are mainly in bone which is not measurable disease the CTC counts 
Jean Paul Freche 
Atlanbio SA 
Route de Saint-Andre des Eaux 
Z I de Brais 
BP 40309 
44605 Saint-Nazaire Cedex 
FRANCE 
Telephone: +33 2 51 10 10 88 
Fax: +33 2 51 10 01 09 
Email: jeanpaul.freche@atlanbio.com 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
36 
are a critically important less invasive method of predicting response and outcome. CTC counts 
will be measured at baseline (day 1), day 22 and day 43. The pre and post-therapy CTC 
counts ;<5/7.5 ml which is considered favorable, vs >5/7.5 ml which is considered unfavorable, 
have been shown to be prognostic in metastatic CRPC patients treated with cytotoxic 
chemotherapy [16].  In multivariable analysis, CTC count using Veridex technology was an 
independent risk factor, influencing overall survival (OS) in a multivariable analysis.  The 
differences in survival associated with CTC count status were clinically and statistically 
significant (e.g., ~1 year, depending on the comparison).  Investigators are now exploring the 
role of CTC counts as surrogate markers of survival in CRPC, especially when used in 
conjunction with cytotoxic chemotherapy. The CTC counts would be performed by the KCI 
pharmacokinetics core. 
Recently, phenotypic characterization of CTCs is gaining interest in several cancer types, 
especially with regard to prognosis [17].  In metastatic CRPC, ERG gene rearrangement and 
PTEN expression have been demonstrated in CTCs, establishing the feasibility of biomarker 
evaluation in CTCs in our population of interest [18].  Furthermore, we pioneered evaluation of 
CTC phenotype in prostate cancer, when we correlated disease recurrence to the proportion of 
micrometastatic cells actively proliferating [19].   
As new therapies enter the marketplace, development of prognostic biomarkers needs to 
occur simultaneously, but has tended to lag behind, and is currently an unmet need in 
appropriate selection of therapies in metastatic CRPC. Identification of biomarkers that correlate 
with clinical outcome will result in enrollment of an enriched patient population for targeted 
therapy trials, and aid in the identification of mechanisms of resistance.  Most importantly, it will 
assist clinicians in choosing between the therapies currently available in metastatic CRPC as 
well as assist in novel drug development.    
In metastatic CRPC, CTCs likely emanate from metastatic deposits in the skeleton and 
other metastatic sites (as opposed to the primary tumor), because the metastatic sites carry the 
heaviest tumor burden.  Therefore, the biology of CTCs is likely to reflect the biology of the 
metastatic deposits.  Based on our pre-clinical work, we hypothesize that pre-treatment CTC 
phenotype with regard to the PTEN-PDGF and PTEN-MT1-MMP axes will reflect the biology 
of the metastatic deposits and thus be prognostic with regard to TTP and survival.  In addition, 
assessment of post-treatment phenotype may allow insights into mechanisms of treatment 
resistance and disease progression.  The CTC phenotype will be performed only if funding is 
available. 
 
 
 
11.0 STATISTICAL CONSIDERATIONS: 
 
11.1 Study Design, Objectives, and Endpoints 
 
The Treatment Plan (see Section 5 above) predefines 3 dose levels of the SOM 230 and 
docetaxel (and prednisone) combination.   This trial will utilize a traditional Phase I study design 
with dose cohorts of 3-6 patients to determine the MTD (which will also be the RP2D).   The 
MTD will be one dose level below the MAD.   At whatever dose level is eventually determined 
to be the MTD, we plan to expand that dose cohort to 12 patients to further assess the PK/PD 
profiles of the drug regimen.   The prednisone dose is constant throughout the trial. 
 
The objectives and outcome measurements for the study are listed below: 
 
Primary objective:  To establish the MTD level of SOM 230 in combination with  


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
37 
   
 
docetaxel and prednisone. 
The outcome measures associated with this objective are the following: 
 Occurrence of DLTs and the associated NCI CTCAE grade 
 Occurrence of adverse events and the associated grade per NCI CTCAE 
version 4.0 
 Identification of the MTD of SOM 230 in combination with docetaxel and 
prednisone. 
 
Secondary objectives: 
 
1) To evaluate the safety and tolerability of the combination in metastatic CRPC. 
The outcome measures associated with this objective are the following: 
●  All specific types of toxicity will be assessed via NCI CTCAE Version 4.0, and 
 be tabulated separately by grade and by dose level. 
 
 
2)  To evaluate preliminary efficacy of the combination of SOM 230 and docetaxel and 
prednisone as defined by response rates (measurable and PSA per PSA working group II 
criteria, see section 8.9), time to progression (TTP) and overall survival (OS).  
 
The outcome measures associated with this objective are the following: 
 Measurements of tumor using RECIST criteria before and after treatment with 
the combination of SOM 230 in combination with docetaxel.   
 Percentage PSA decline noted. 
 TTP (defined in Section 8.6) 
 OS   (defined in Section 8.12) 
 
3) To evaluate the pharmacokinetics (PK) of the combination. 
The outcome measures associated with this objective are the following: 
 PK parameters, including, but not limited to, maximum observed plasma 
concentration (Cmax), time to maximum plasma concentration (tmax), plasma 
terminal half-life (t1/2), area under the plasma concentration–time curve 
(AUC), maximum observed plasma concentration at steady state (Css, max), 
and minimum observed plasma concentration at steady state (Css, min). 
 
4) To assess the pharmacodynamic (PD) effects of the combination as seen by baseline levels 
of and changes in IGF-1, serum chromogranin A (SCA), and neuron specific enolase 
(NSE), and to associate them with TTP and OS. 
The outcome measures associated with this objective are the following: 
●    Measurement of levels of IGF-1, SCA, and NSE, pre-therapy, post-therapy, 
and the change between timepoints. 
●    Duration of TTP and OS   


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
38 
 
5) To assess the pretherapy circulating tumor cell (CTC) counts and the change in CTC after 
therapy, and to associate them with TTP and OS.  
                    The outcome measures associated with this objective are the following: 
 Measurements of CTC counts  pre-therapy, post-therapy, and the change 
between timepoints. 
 Duration of TTP and OS   
 
 
11.2    Sample Size 
 
This is an open label Phase I trial of two agents used in combination, with 3 predefined dose 
levels.   We plan to use dose level cohorts consisting of 3 patients each. Three patients will be 
enrolled at each dose level and monitored for toxicity for 56 days before opening the next dose 
level cohort. If 1 or more patients have grade 3 or 4 toxicity attributable to therapy, then three 
additional patients will be enrolled at that dose level. If 2 or more patients have DLT at a dose 
level then this will be considered MAD and patients will then be treated at one dose level lower 
which will be considered the MTD (maximum tolerated dose). Once MTD is determined, a total 
of 12 patients will be treated at this dose level. 
 
The absolute minimum number of patients required for this Phase I trial would result from the 
unlikely (but possible) scenario in which there were ≥ 2 DLT’s among the first 3 patients treated 
at dose level 1, such that it became the MAD.   We would then treat 3-6 patients at a new dose 
level -1 (to be determined after conferring with the sponsor), and that dose level would likely 
then become the MTD.   We would then treat an additional 6-9 patients at dose level -1 to 
complete the goal of an MTD expansion cohort of 12 patients.   In this scenario, the absolute 
minimum number of patients required for this Phase I trial would then be 3 + 12 = 15. 
 
The maximum number of patients required for this Phase I trial would result from the 
following scenario:  first, needing a full cohort of 6 patients at each of dose levels 1-3; and then 
finding dose level 3 to be the MTD.   As per Section 6.1, that would make dose level 2 the MTD, 
and we would treat an additional 6 patients at that dose to complete the goal of an MTD  
expansion cohort of 12 patients.  Thus, the maximum number of patients required for this Phase I 
trial would then be (6*3)   + 6 = 24.  
   
 
11.3    Expected Accrual Rate and Accrual Duration 
 
   Our anticipated accrual rate is 12-15 metastatic CRPC patients/year.   Hence it would take 20-
24 months to accrue the maximum of 24 patients for this Phase I study.   Should fewer patients 
be required to determine the MTD, then the trial would be completed even faster. 
 
 
11.4    Statistical Analysis of Endpoints 
 
The Primary Objective of determining the MTD, as well as the specific DLT’s is just an 
identification process, hence no statistical analysis or estimation is required. 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
39 
 
For the Primary Objective of determining all adverse events, and for Secondary Objectives 1 and 
2, the occurrence rate of binary endpoints (eg, specific types of toxicity at a certain dose level 
and severity grade, response, etc.) will be described by point estimates and exact 90% confidence 
intervals (CIs) for proportions using Wilson’s method.    
 
For Secondary Objectives 3-4, the continuous endpoints (e.g., PK and PD parameters, and the 
pre/post therapy change in PD parameters) will be summarized with standard descriptive 
statistics (N, median, IQR, mean, standard deviation, minimum, maximum, and the 90% CI for 
the mean).   Statistical graphics (e.g., dot plots, box plots) will also be used to better visualize the 
PK and PD distributions and summary statistics.   For Secondary Objective 5, similar descriptive 
statistics will be computed for CTC counts:  pre-therapy, post-therapy, and the pre/post therapy 
change. 
 
For Secondary Objective 5, purely exploratory analysis of the association of each of the 3 PD 
endpoints (IGF-1, SCA, NSE) and CTC count with clinical outcome (e.g., TTP and OS) will be 
performed, using all the  patients.   For the pre-therapy levels of each of the 3 PD endpoints and 
CTC count, a univariable Cox regression model will be fit to the TTP data.   These models will 
be exploratory only. 
     The statistical goals would be to determine the direction, magnitude, and precision of the 
association, as indicated by the hazard ratio (HR) being > 1 or < 1, how far away from 1, and its 
90% CI width, respectively.   These HR estimates would provide a hint as to whether there might 
be any potential relationship between a given pre-therapy PD endpoint (or CTC count) and the 
duration of TTP. 
   A similar exploratory investigation of the association of each of the 3 PD endpoints and CTC 
count with OS will also be undertaken. 
 
   The association of post-therapy levels of the 3 PD endpoints and CTC count with TTP will 
also be explored.   These 4 associations (and those involving the pre/post therapy change in the 
same 4 predictors) will utilize the landmark method [20].   A suitable landmark timepoint (e.g., 
12 weeks, a point at which therapy should be completed in all patients in consideration of 
Section 5.8) will be chosen.   Post-therapy levels of the 4 candidate predictors will be determined 
at the landmark.   A univariable Cox regression model of each of these 4*2 = 8 predictors will be 
fit to the TTP as measured from the landmark (thus changing the definition of TTP time zero).   
Patients who are censored before the landmark or die without prior evidence of progression must 
be excluded from landmark analyses. 
     A similar exploratory investigation of the association (using the landmark method) of the 
post-therapy levels and the change in each of the 3 PD endpoints and CTC count with OS will 
also be undertaken. 
 
   
 
12.0    ADVERSE EVENTS REPORTING 
 
12.1  Regulatory and reporting requirements-  
These will be followed per IND requirements (if applicable) as well as Novartis Inc. 
requirements and WSU IRB requirements. 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
40 
 
12.2 REPORTING OF SERIOUS TREATMENT EMERGENT ADVERSE EVENTS 
 
An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-
existing) undesirable sign(s), symptom(s), or medical condition(s) occurring after signing the 
informed consent even if the event is not considered to be related to the study drug(s). Please 
refer to the adverse event section of the protocol for the protocol-specific definitions of study 
drug and study treatment. 
Adverse events will be assessed according to the Common Toxicity Criteria for Adverse Events 
[CTCAE] version 4.0. If CTCAE grading does not exist for an adverse event, the severity of 
mild, moderate, severe, and life-threatening, or grades 1 - 4, will be used. CTCAE grade 5 
(death) will not be used in this study; rather, this information will be collected in the End of 
Treatment or Survival Information CRF page. Adverse event monitoring should be continued for 
at least 4 weeks following the last dose of study treatment. 
Adverse events (but not serious adverse events) occurring before starting study treatment but 
after signing the informed consent form are recorded on the Medical History/Current Medical 
Conditions Electronic Case Report Form. Abnormal laboratory values or test results constitute 
adverse events only if they induce clinical signs or symptoms, are considered clinically 
significant or require therapy (e.g., any hematologic abnormality that requires transfusion or 
cytokine treatment); and should be recorded on the Adverse Events CRF under the signs, 
symptoms or diagnosis associated with them. In addition, isolated abnormal laboratory values 
that are considered clinically significant (e.g., cause study discontinuation or constitutes in and of 
itself a Serious Adverse Event) should be recorded on the Adverse Events CRF. SAEs occurring 
after signing the Informed Consent are recorded on the Adverse Event CRF. 
The occurrence of adverse events should be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
1. The severity grade (CTCAE grade 1-4) 
2. Its relationship to each study drug (suspected/not suspected) 
3. Its duration (start and end dates or if continuing at final exam) 
4. Action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study 
drug permanently discontinued due to this adverse event; concomitant medication taken; 
non-drug therapy given; hospitalization/prolonged hospitalization) 
5. Whether it is serious, where a serious adverse event (SAE) is defined as one which: 
 Is fatal or life-threatening 
 Results in persistent or significant disability/incapacity 
 Constitutes a congenital anomaly/birth defect 
 Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
41 
 Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
 Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
 Social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
 Is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see protocol section on Serious Adverse Event reporting. 
All adverse events should be treated appropriately. Such treatment may include changes in study 
drug treatment including possible interruption or discontinuation, starting or stopping 
concomitant treatments, changes in the frequency or nature of assessments, hospitalization, or 
any other medically required intervention. Once an adverse event is detected, it should be 
followed until its resolution, an assessment should be made at each visit (or more frequently, if 
necessary) of any changes in its severity, its suspected relationship to the study drug(s), any of 
the interventions required to treat it, and its outcome. 
Information about common side effects already known about the investigational drug can be 
found in the [Investigator’s Brochure] or will be communicated between IB updates in the form 
of Investigator Notifications. This information will be included in the patient informed consent 
and should be discussed with the patient during the study as needed. 
Information about all serious adverse events will be collected and recorded. To ensure patient 
safety each serious adverse event must also be reported to Novartis within 24 hours of learning 
of its occurrence. A serious adverse event is an undesirable sign, symptom or medical condition 
which: 
 is fatal or life-threatening 
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly/birth defect 
 requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
 treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
 social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
 is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
42 
Novartis instructions for rapid notification of serious adverse events [Appendix 
VII A and B] 
The principal investigator has the obligation to report all serious adverse events to the FDA, IRB, 
and Novartis Pharmaceuticals Drug Safety & Epidemiology (DS&E). All events reported to the 
FDA by the investigator are to be filed utilizing the Form FDA 3500A (MedWatch Form).  
All events must be reported, by FAX (877-778-9739), to Novartis Pharmaceuticals D S & E 
department within 24 hours of learning of it’s occurrence. This includes serious, related, labeled 
(expected) and serious, related, unlabeled (unexpected) adverse experiences. All deaths during 
treatment or within 30 days following completion of active protocol therapy must be reported 
within 1 working day. 
Any serious adverse event occurring after the patient has provided informed consent and until 4 
weeks after the patient has stopped study participation must be reported. This includes the period 
in which the study protocol interferes with the standard medical treatment given to a patient (e.g. 
treatment withdrawal during washout period, change in treatment to a fixed dose of concomitant 
medication). 
Serious adverse events occurring more than 4 weeks after study discontinuation need only be 
reported if a relationship to the Novartis study drug (or therapy) is suspected.  
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator. 
 
Pregnancies /Lactating mothers: 
 
Not applicable since this is a study in men only. 
 
 
 
12.3 Safety Reporting Requirements for IND Holders (if applicable) 
 
In accordance with 21 CFR 312.32, sponsor-investigators of studies conducted under an IND 
must comply with following safety reporting requirements:  
 
a. Expedited IND Safety Reports: 
 
7 Calendar-Day Telephone or Fax Report:   
The Sponsor-Investigator is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the use of  
SOM-230. An unexpected adverse event is one that is not already described in the Investigator 
Brochure.  Such reports are to be telephoned or faxed to the FDA within 7 calendar days of first 
learning of the event.  Each telephone call or fax transmission (see fax number below) should be 
directed to the FDA new drug review division in the Center for Drug Evaluation and Research or 
in the product review division for the Center for Biologics Evaluation and Research, whichever 
is responsible for the review of the IND. 
 
15 Calendar-Day Written Report:   
The Sponsor-Investigator is also required to notify the FDA and all participating investigators, in 
a written IND Safety Report, of any serious, unexpected AE that is considered possibly related to 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
43 
the use of SOM-230.  An unexpected adverse event is one that is not already described in the 
Investigator Brochure. 
 
Written IND Safety Reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32.  All safety reports previously filed with the IND concerning similar 
events should be analyzed.  The new report should contain comments on the significance of the 
new event in light of the previous, similar reports.   
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, 
Genentech Drug Safety, and all participating investigators within 15 calendar days of first 
learning of the event.  The FDA prefers these reports on a MedWatch 3500a Form but alternative 
formats are acceptable (e.g. summary letter). 
 
FDA fax number for IND Safety Reports: 
 
1 (800) FDA-0178. 
 
AND: 
 
Study Coordination Center/Principal Investigator:  
Ulka Vaishampayan M.D. 
Contact Information 4HWCRC, 4100 John R 
Detroit MI 48201.  
Tel# 313-576-8715 and fax # 313-576-8487 
 
 
 
b. IND Annual Reports  
In accordance with the regulation 21 CFR § 312.32, the Sponsor-Investigator shall within 60 
days of the anniversary date that the IND went into effect submit a brief report of the progress of 
the investigation.  Please refer to Code of Federal Regulations, 21 CFR § 312.32 for a list of the 
elements required for the annual report.  All IND annual reports submitted to the FDA by the 
Sponsor-Investigator should be copied to Novartis Inc.  Copies of such reports should be mailed 
to: 
 
12.4 WSU HIC Adverse Event reporting 
All adverse event reporting will be done in compliance with the Wayne State Human 
Investigation Committee as follows: 
A. Death or Life Threatening Adverse Reaction or Unexpected Event:  
If a death or immediately life-threatening Adverse Reaction/Unexpected Event occurs, it 
must be reported to the HIC office within three (3) business days of the PI becoming 
aware, even if the information in the report is incomplete. As more information is 
forthcoming, one or more additional reports should be filed with the HIC. The initial 
report of the Adverse Reaction or Unexpected Event and follow-up reports should be 
filed using the HIC Adverse Reaction and Unexpected Event Form.  
 
B. Serious Adverse Reaction or Unexpected Event:  


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
44 
If a Serious Adverse Reaction/Unexpected Event occurs (one that necessitates or 
prolongs hospitalization, results in a permanent or significant disability or congenital 
anomaly, or is judged to be serious by the principal investigator), and is unexpected, (not 
listed in the consent form) it must be reported to the HIC within five (5) business days of 
the PI becoming aware. If the Serious Adverse Event is listed in the consent form but a 
relationship to the study intervention/activity cannot be ruled out by the PI, it must be 
reported to the HIC within five (5) business days. If the information is incomplete on the 
initial filing, follow-up reporting is required. The HIC Adverse Reaction and Unexpected 
Event Form should be used in all reports pertaining to these reactions/events.  
 
C. Non-Serious (Moderate or Minor) Adverse Reaction or Unexpected Event:  
If a non-serious Adverse Reaction occurs that is unexpected (not listed in the informed 
consent), it must be reported to the HIC within ten (10) business days of awareness, 
unless the Principal Investigator can rule out the relationship to the study agent or 
intervention. If a non-serious Adverse Reaction occurs that is expected (listed in the 
informed consent), but is more frequent, more intense or longer lasting that expected, or 
requires medical treatment, it must be reported to the HIC within ten (10) business days. 
If the reaction that is listed in the consent form occurs as described in the informed 
consent, it does not need to be reported to the HIC.  
If an Unexpected Event occurs, it must be reported to the HIC within ten (10) business 
days of the awareness by the Principal Investigator. The Adverse Reaction/ Unexpected 
Event Form should be used for these submissions.  
 
D. Possibly-Related Adverse Reactions/ Unexpected Events 
In the rare case where a sponsor requires that a non-reportable (i.e., possibly related) 
Adverse Reaction/ Unexpected Event be reported to the HIC, an amendment should be 
submitted by the PI requesting that the non-reportable safety report be appended to the 
HIC file. It remains the primary responsibility of the WSU PI, the study sponsor, and any 
associated DSMB to identify trends that might require the event to be elevated to 
definitely or probably related status.  
If a trend is identified that elevates the Adverse Reaction to definitely or probably related 
status, an Adverse Reaction/ Unexpected Event Form should be completed, along with an 
amendment for consent form changes, if needed, and submitted to the HIC.  
 
 
 
 
 
 
13.0 References 
 
1) D.P. Petrylak, C.M. Tangen and M.H. Hussain et al., Docetaxel and estramustine compared 
with mitoxantrone and prednisone for advanced refractory prostate cancer, N Engl J Med 
351 (2004), pp. 1513–1520. 
 
2) Tannock IF, Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus 
prednisone for advanced prostate cancer. .N Engl J Med. 2004 Oct 7;351(15):1502-12. 
 
 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
45 
3) Scher H, Chi KN, De Wit R, et al. Docetaxel (D) plus high-dose calcitriol versus D plus 
prednisone (P) for patients (Pts) with progressive castration-resistant prostate cancer 
(CRPC): Results from the phase III ASCENT2 trial.  2010 Proc ASCO abstract# 4509. 
  
4) Small E, Demkow T, Gerritsen WR, et al. A phase III trial of GVAX immunotherapy for 
prostate cancer in combination with docetaxel versus docetaxel plus prednisone in 
symptomatic, castration-resistant prostate cancer (CRPC). GU Cancer Symposium 2009, 
abstract # 7. 
 
5) SOM-230 IB Ed 9.0 Feb 10, 2010. [Novartis Inc]. 
 
6) Tejeda M, Gaal D, Barna K, Csuka O, Kéri G.The antitumor activity of the somatostatin 
structural derivative (TT-232) on different human tumor xenografts.Anticancer Res. 2003 
Sep-Oct;23(5A):4061-6. 
 
7) Erten C, Karaca B, Kucukzeybek Y, et al. Regulation of growth factors in hormone- and 
drug-resistant prostate cancer cells by synergistic combination of docetaxel and octreotide. 
BJU Int. 2009 Jul;104(1):107-14. Epub 2009 Feb 3. 
 
8) Lo Nigro C, Maffi M, Fischel JL, Formento P, Milano G, Merlano M.The combination of 
docetaxel and the somatostatin analogue lanreotide on androgen-independent docetaxel-
resistant prostate cancer: experimental data. BJU Int. 2008 Aug 5;102(5):622-7. Epub 2008 
May 20. 
 
9)  Freidlander TW,. Weinberg VK, Sharib, A. L. et al., Effect of the somatostatin analog 
octreotide acetate on circulating IGF-1 and on PSA in patients with castration-resistant prostate 
cancer (CRPC): Results of a phase II study.2010 Abstract ASCO-GU abstract # 99 
 
10) Dimopoulos MA, Kiamouris C, Gika D,  et al. Combination of LHRH analog with 
somatostatin analog and dexamethasone versus chemotherapy in hormone-refractory prostate 
cancer: a randomized phase II study. Urology. 2004 Jan;63(1):120-5. 
 
11) Eisenhauer A, Therasse P, Bogaert J, et al. New response evaluation criteria in solid tumors. 
Eur J Cancer 2009, 45: 228-47.  
 
12) Scher H, Halabi S, Tannock I, et al. (2008) Design and End Points of Clinical Trials for 
Patients with Progressive Prostate Cancer and Castrate Levels of Testosterone: 
Recommendations of the Prostate Clinical Trials Working Group.   J Clin Oncol 26(7):1148-59, 
2008. 
 
13) Kamiya N, Akakura K, Suzuki H, et al. Pretreatment serum level of neuron specific enolase 
(NSE) as a prognostic factor in metastatic prostate cancer patients treated with endocrine 
therapy. Eur Urol. 2003 Sep;44(3):309-14; discussion 314. 
 
14) Schmid HA. Pasireotide (SOM230): development, mechanism of action and potential 
applications. Mol Cell Endocrinol. 2008 May 14;286(1-2):69-74.  
 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
46 
15) Ruscica M, Arvigo M, Gatto F, et al. Regulation of prostate cancer cell proliferation by 
somatostatin receptor activation. Mol Cell Endocrinol. 2010 Feb 5;315(1-2):254-62.  
 
16) De Bono, J.S., et al., Circulating tumor cells predict survival benefit from treatment in 
metastatic castration-resistant prostate cancer. Clin Cancer Res, 2008. 14(19): p. 6302-9. 
 
17) Gradilone, A., et al., Circulating tumor cells (CTCs) in metastatic breast cancer (MBC): 
prognosis, drug resistance and phenotypic characterization. Ann Oncol. 
 
18) Attard, G., et al., Characterization of ERG, AR and PTEN gene status in circulating tumor 
cells from patients with castration-resistant prostate cancer. Cancer Res, 2009. 69(7): p. 2912-8. 
19) Bianco, F.J., Jr., et al., Proliferation of prostate cancer cells in the bone marrow predicts 
recurrence in patients with localized prostate cancer. Prostate, 2001. 49(4): p. 235-42. 
 
  20) Anderson JR, Cain KC, Gelber RD:  Analysis of survival by tumor response.   J Clin Oncol, 
       1983.  1:710-719. 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
47 
14.0 Data and Safety Monitoring 
 
14.1 
Scheduled meetings will be held monthly or more frequently depending on the  
activity of the protocol.  These meetings will include the protocol investigators and data 
managers involved with the conduct of the protocol. 
 
14.2 
During these meetings the investigators will discuss matters related to: 
 
 
Safety of protocol participants (Adverse Event reporting) 
 
Validity and integrity of the data 
 
Enrollment rate relative to expectation of target accrual, characteristics of 
 
participants 
 
Retention of participants, adherence to the protocol (potential or real protocol 
violations) 
 
Data completeness on case report forms and complete source documentation 
 
14.3 
Completed Data and Safety Monitoring Reports of these regular investigator 
meetings will be kept on file in the office of the Clinical Trials Core (see form in 
appendix IV). The data manager assigned to the clinical trial will be responsible 
for completing the report form.  The completed reports will be reviewed and 
signed off by the Principle Investigator (PI) or by one of the Co-PI’s in the 
absence of the PI.  The signed off forms will then be forwarded to the Director, 
Clinical Trials Core for review of completeness and processing with the Data and 
Safety Monitoring Committee. 
 
14.4 
The Barbara Ann KARMANOS Cancer Institute, Data and Safety Monitoring Committee 
will meet on a monthly basis to review the prior month Serious Adverse Event forms and 
Data and Safety Monitoring study specific reports that have been filed. 
 
 
15.0 Protocol Conduct and Guidelines 
15.1 Protocol amendments, or changes in study conduct 
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be reviewed and approved. Amendments significantly affecting the safety 
of subjects, the scope of the investigation or the scientific quality of the study require additional 
approval by the IRB at each study center.  A copy of the written approval of the IRB must be 
provided to Novartis. Examples of amendments requiring such approval are: 
1. increases in drug dose or duration of exposure of subjects, 
2. significant changes in the study design (e.g. addition or deletion of a control group), 
3. increases in the number of invasive procedures, 
4. addition or deletions of a test procedure required for monitoring of safety. 
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator or by Novartis in the interests of preserving the safety of all patients 
included in the trial.  If an immediate change to the protocol is felt to be necessary by the 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
48 
investigator and is implemented for safety reasons Novartis must be notified and the IRB at the 
center must be informed immediately.   Amendments affecting only administrative aspects of the 
study do not require formal protocol amendments or IRB approval but the IRB must be kept 
informed of such administrative changes. Examples of administrative changes not requiring 
formal protocol amendments and IRB approval include: 
1. 
changes in the staff used to monitor trials  
2. 
minor changes in the packaging or labeling of study drug. 
 
15.2 Publication of results 
Any formal presentation or publication of data from this trial may be published after review and 
comment by Novartis and prior to any outside submission.  Novartis must receive copies of any 
intended communication in advance of publication (at least fifteen working days for 
presentational materials and abstracts and thirty working days for manuscripts).   These 
requirements acknowledge Novartis’ responsibility to provide peer input regarding the scientific 
content and conclusions of such publications or presentations.  Principal Investigation/Institution 
shall have the final authority to determine the scope and content of its publications, provided 
such authority shall be exercised with reasonable regard for the interests of Novartis and, in 
accord with the trial contract and shall not permit disclosure of Novartis confidential or 
proprietary information. 
 
15.3 Disclosure and confidentiality 
The investigators agree to keep all information provided by Novartis in strict confidence and to 
request similar confidentiality from their staff and the IRB/IEC/REB. Study documents provided 
by Novartis (investigators' brochures and other material) will be stored appropriately to ensure 
their confidentiality. The information provided by Novartis to the investigator may not be 
disclosed to others without direct written authorization from Novartis, except to the extent 
necessary to obtain informed consent from patients who wish to participate in the trial. 
 
15.4 Discontinuation of study 
The sponsor (Novartis Inc) reserves the right to discontinue the study under the conditions 
specified in the clinical trial agreement. 
 
12.9 Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and the principles of Good 
Clinical Practice, as described in Novartis standard operating procedures and: 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. Directive 91/507/EEC, 
The Rules Governing Medicinal Products in the European Community. 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations). 
Declaration of Helsinki and amendments, concerning medical research in humans 
(Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects). 
The investigator agrees to adhere to the instructions and procedures described in it and thereby to 
adhere to the principles of Good Clinical Practice that it conforms to. 
 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
49 
15.5 Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB). A signed and 
dated statement that the protocol and informed consent have been approved by the IRB/IEC/REB 
must be given to Novartis before study initiation. Any amendments to the protocol, other than 
administrative ones, must be reviewed by Novartis approved by this committee. 
 
15.6 Informed consent 
The investigator must explain to each subject (or legally authorized representative) the nature of 
the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any time 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating 
it, and should be given a copy of the signed document. If the subject cannot read or sign the 
documents, oral presentation may be made or signature given by the subject’s legally appointed 
representative, if witnessed by a person not involved in the study, mentioning that the patient 
could not read or sign the documents. No patient can enter the study before his/her informed 
consent has been obtained. 
The informed consent form is considered to be part of the protocol, and must be submitted by the 
investigator with it for IRB/IEC/REB approval. 
 
15.7 Declaration of Helsinki 
The investigator will conduct the trial in accordance with the principles of the Declaration of 
Helsinki. Copies of the Declaration of Helsinki and amendments will be provided upon request 
or can be accessed via the website of the World Medical Association at 
http://www.wma.net/e/policy/17-c_e.html. 
 
 
 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
50 
16.0 APPENDICES 
 
Appendix I 
 
Performance Status Criteria 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
51 
Appendix II 
MANAGEMENT OF ACUTE HYPERSENSITIVITY WITH DOCETAXEL 
 
Severity of Symptoms 
Treatment Guidelines 
Mild symptoms: localized cutaneous 
reactions such as mild pruritus, 
flushing, rash 
· 
consider decreasing the rate of infusion until 
recovery from symptoms, stay at bedside and 
monitor patient 
· 
then, complete  docetaxel (Taxotere) 
infusion at the initial planned rate 
Moderate symptoms: any symptom that 
is not listed above (mild symptoms) or 
below (severe symptoms) such as 
generalized pruritus, flushing, rash, 
dyspnea, hypotension with systolic  
BP > 80 mm Hg  
 
· 
interrupt docetaxel (Taxotere) infusion 
· 
give diphenhydramine 50 mg IV with or 
without dexamethasone 10 mg IV; monitor 
patient until resolution of symptoms  
· 
resume docetaxel (Taxotere) infusion after 
recovery of symptoms; depending on the 
physician’s assessment of the patient, 
docetaxel (Taxotere) infusion should be 
resumed at a slower rate, then increased 
incrementally to the initial planned rate, 
(e.g. infuse at an 8 hour rate for 5 minutes, 
then at a 4-h rate for 5 minutes, then at a 2-
h rate for 5 minutes, then finally, resume at 
the 1-h infusion rate) 
· 
depending on the intensity of the reaction 
observed, additional oral or IV premedication 
with an antihistamine should also be given 
for the next cycle of treatment, and the rate 
of infusion should be decreased initially and 
then increased back to the recommended 1-
hour infusion, (e.g. infuse at an 8 hour rate 
for 5 minutes, then at a 4-h rate for 5 
minutes, then at a 2-h rate for 5 minutes, and 
finally, administer at the 1-h infusion rate) 
Severe symptoms: any reaction such as 
bronchospasm, generalized urticaria, 
systolic BP  80mm Hg, angioedema 
· 
immediately discontinue docetaxel 
(Taxotere) infusion  
· 
give diphenhydramine 50 mg IV with or 
without dexamethasone 10 mg IV and/or 
epinephrine as needed; monitor patient until 
resolution of symptoms 
· 
the same treatment guidelines outlined under 
moderate symptoms (i.e. the third and fourth 
bullets) should be followed. 
Anaphylaxis (NCI grade 4 reaction) 
· 
NO FURTHER STUDY DRUG THERAPY 
 


 
Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
52 
APPENDIX III 
 
 
MANAGEMENT OF EDEMA / FLUID RETENTION WITH DOCETAXEL 
 
No dose reduction is required.  Patients developing new onset edema, progression of 
existing edema, or another sign of fluid retention (e.g. 2 pound weight gain) are to be 
treated with oral diuretics.  Regimens found to be effective in the management of fluid 
retention due to Taxotere are listed below. 
 
 HCTZ/triamterene (Dyazide, or generic equivalent) one capsule po daily, increase 
up to tid. 
 Furosemide 40 mg (Lasix or generic equivalent) po daily if edema progresses 
despite Dyazide (or equivalent) therapy.  Potassium supplementation should be 
given as needed. 
 If after a two week trial, furosemide 40 mg po daily is ineffective, the patient may be 
treated with furosemide 20 mg po daily plus metolazone 2.5 mg po daily with 
potassium supplementation as needed. 
 
Further therapy should be customized depending upon the clinical situation.  The clinical 
tolerance of the patient, the overall tumor response and the medical judgment of the 
investigator will determine if it is in the patient’s best interest to continue or discontinue 
treatment.  
 


 
Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
53 
Appendix IV  
Docetaxel is metabolized by the CYP3A4 isoenzyme, and its metabolism may be 
modified by the concomitant administration of compounds that induce, inhibit, or 
are metabolized by cytochrome P450 3A4.  Inhibitors of CYP3A4 and/or PgP 
Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, 
ritonavir) or P-glycoprotein (PgP) should be avoided. 
Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or 
PgP inhibitors should be used with caution.  If patient requires co-administration of 
moderate CYP3A4 inhibitors or PgP inhibitors, consider holding protocol therapy.  
Seville orange, star fruit, grapefruit and their juices affect P450 and PgP activity. 
Concomitant use should be avoided. 
Inducers of CYP3A4 and/or PgP 
Avoid the use of strong CYP3A4 inducers. If patient requires co-administration of 
strong CYP3A4 inducers (i.e., phenytoin, carbamazepine, rifampin, rifabutin, 
phenobarbital, St. John’s wort) considering discontinuing therapy temporarily or 
permanently. 
 
 Clinically relevant drug interactions: substrates, inducers, and inhibitors of 
isoenzyme CYP3A 
INDUCERS 
Barbiturates, carbamazepine, glucocorticoids, modafinil, oxcarbazepine, 
phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John’s wort, 
troglitazone, efavirenz, nevirapine, topiramate 
INHIBITORS 
Strong inhibitors:  
clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir,  mibefradil, 
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandamycin, 
voriconazole, 
Posaconazole (Krishna et al, 2009) 
 
Moderate inhibitors:  
aprepitant, atazanavir, cimetidine, ciprofloxacin, darunavir, diltiazem, erythromycin, 
fluconazole, grapefruit juice, imatinib,  tofisopam, verapamil,  
Table Clinically relevant drug interactions mediated by PgP 
PgP Substrates 
PgP Inhibitors in vivo 
PgP Inducers 
digoxin, fexofenadine,  
indinavir, vincristine, 
colchicine, topotecan, 
paclitaxel 
amiodarone, azithromycin, 
captopril, carvedilol, 
clarithromycin, conivaptan, 
cyclosporine, diltiazem, 
elacridar, erythromycin, 
felodipine, (GF120918), 
itraconazole, 
rifampin, St John’s wort 


 
Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
54 
PgP Substrates 
PgP Inhibitors in vivo 
PgP Inducers 
ketocoanzole, lopinavir, 
(LY335979), mibefradil, 
nifedipine, nitrendipine, 
(PSC833), quinidine, 
ranolazine, ritonavir, 
talinolol, valspodar, 
verapamil 
Reference: 
Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Dec. 2, 
2009, which summarizes DDI data from three sources including the FDA’s “Guidance 
for Industry, Drug Interaction Studies, the University of Washington’s Drug Interaction 
Database, and Indiana University School of Medicine's Drug Interaction Table.  
Appendix V 
Drugs that are generally accepted by the QTdrugs.org Advisory Board of the Arizona 
CERT to have a risk of causing torsades de pointes. Updated June 2011. 
 
Generic Name 
Brand 
Name 
Class/Clinical Use 
Comments 
Amiodarone  
Cordarone® Anti-arrhythmic / abnormal 
heart rhythm 
Females>Males,TdP risk 
regarded as low 
Amiodarone  
Pacerone® 
Anti-arrhythmic / abnormal 
heart rhythm 
Females>Males,TdP risk 
regarded as low 
Arsenic trioxide  Trisenox® 
Anti-cancer / Leukemia 
 
Astemizole  
Hismanal® 
Antihistamine / Allergic 
rhinitis 
No Longer available in 
U.S. 
Bepridil  
Vascor® 
Anti-anginal / heart pain 
Females>Males 
Chloroquine 
Aralen® 
Anti-malarial / malaria 
infection 
 
Chlorpromazine  Thorazine® Anti-psychotic/ Anti-emetic 
/ schizophrenia/ nausea 
 
Cisapride 
Propulsid® 
GI stimulant / heartburn 
Restricted availability; 
Females>Males. 
Clarithromycin 
Biaxin® 
Antibiotic / bacterial 
infection 
 
Disopyramide  
Norpace® 
Anti-arrhythmic / abnormal 
heart rhythm 
Females>Males 
Dofetilide  
Tikosyn® 
Anti-arrhythmic / abnormal 
 


 
Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
55 
heart rhythm 
Domperidone 
Motilium® 
Anti-nausea / nausea 
Not available in the U.S. 
Droperidol  
Inapsine® 
Sedative;Anti-nausea / 
anesthesia adjunct, nausea 
 
Erythromycin  
Erythrocin® 
Antibiotic;GI stimulant / 
bacterial infection; increase 
GI motility 
Females>Males 
Erythromycin  
E.E.S.®  
Antibiotic;GI stimulant / 
bacterial infection; increase 
GI motility 
Females>Males 
Halofantrine  
Halfan® 
Anti-malarial / malaria 
infection 
Females>Males 
Haloperidol  
Haldol® 
Anti-psychotic / 
schizophrenia, agitation 
When given intravenously 
or at higher-than- 
recommended doses, risk 
of sudden death, QT 
prolongation and torsades 
increases.  
Ibutilide 
Corvert® 
Anti-arrhythmic / abnormal 
heart rhythm 
Females>Males 
Levomethadyl 
Orlaam® 
Opiate agonist / pain control, 
narcotic dependence 
 
Mesoridazine 
Serentil® 
Anti-psychotic / 
schizophrenia 
 
Methadone 
Methadose® Opiate agonist / pain control, 
narcotic dependence 
Females>Males 
Methadone 
Dolophine® Opiate agonist / pain control, 
narcotic dependence 
Females>Males 
Moxifloxacin  
Avelox® 
Antibiotic / bacterial 
infection 
 
Pentamidine  
Pentam® 
Anti-infective / 
pneumocystis pneumonia 
Females>Males 
Pentamidine  
NebuPent® 
Anti-infective / 
pneumocystis pneumonia 
Females>Males 
Pimozide 
Orap®  
Anti-psychotic / Tourette's 
tics 
Females>Males 
Probucol 
Lorelco® 
Antilipemic / 
Hypercholesterolemia 
No longer available in 
U.S. 
Procainamide  
Pronestyl® 
Anti-arrhythmic / abnormal 
 


 
Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
56 
heart rhythm 
Procainamide  
Procan®  
Anti-arrhythmic / abnormal 
heart rhythm 
 
Quinidine 
Cardioquin® Anti-arrhythmic / abnormal 
heart rhythm 
Females>Males 
Quinidine 
Quinaglute® Anti-arrhythmic / abnormal 
heart rhythm 
Females>Males 
Sotalol  
Betapace®  Anti-arrhythmic / abnormal 
heart rhythm 
Females>Males 
Sparfloxacin  
Zagam®  
Antibiotic / bacterial 
infection 
 
Terfenadine 
Seldane® 
Antihistamine / Allergic 
rhinitis 
No longer available in 
U.S. 
Thioridazine 
Mellaril®  
Anti-psychotic / 
schizophrenia 
 
Vandetanib 
Zactima® 
Anti-cancer / Thyroid cancer 
"Zactima®" is the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
57 
 
APPENDIX VI   
Barbara Ann KARMANOS Cancer Institute: Protocol Specific Data and Safety 
Monitoring Report 
PROTOCOL #: 
 
 
REPORT DATE: 
     
                                                                                       
PROTOCOL TITLE 
  
 
ATTENDANCE 
  
  
 
  
  
 
  
 
 
  
 
 
PROTOCOL ACTIVITY SINCE LAST REPORT 
Accrual Goal: 
Eligible: 
 
Total number of AE’s to date:  
Accrual to Date: 
 Ineligible 
(provide reason):  
Accrual Since  
Last Monthly  
Report: 
 
Specifically for Phase I Trial &/or Dose Escalating Trials: 
Dose Level 
Accrual 
  1 
  
  2 
 
  3 
 
Record all Grade 3, 4, and 5 Adverse Events (AE).  Group by category of AE.  record the date
OF the occurrence, attribution and if reportable to the IRB.    Shade the rows of the AE’s that
have occurred for this Report.  attach the HIC UP report form for these reportable events that
occurred on this report. 
Pt. ID# 
Category and  type of adverse 
reaction 
 
Date of 
Occurrenc
e 
Grade1 
Attributio
n2 
Reportable to IRB 
(Y/N) 
Yes with date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Grade: 1-Mild, 2-Moderate, 3- Severe, 4-Life-threatening, or 5- Death. 
2. Attribution: 1-unrelated, 2 - unlikely, 3 - possibly, 4 - probably, or 5 - definitely   
 
OFF TREATMENT  Provide reason [progression, death, toxicity, completed therapy, etc]. 


 
Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
58 
  
 
PROTOCOL VIOLATIONS  Deviations from protocol treatment, monitoring, or study calendar. 
  
 
PROTOCOL AMENDMENTS  Include date submitted to regulatory bodies and date approved. 
  
 
OTHER COMMENTS 
 
 
 
Investigator Signature: 
 
Data Manager 
Signature: 
 
 


 
Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
59 
Appendix VII 
 
A) Interventional Clinical Trial SAE Fax Cover Sheet 
 
To: Local Novartis Drug Safety and Epidemiology Safety Desk  1 877 778 9739 
 
 
 
Investigator contact details: 
Name:  ___________________________________ 
Fax number : ______________________________ 
Phone number : ____________________________ 
 
Study Name 
 
Centre Number 
 
Patient Number 
 
 
 
 
 
Relationship between study treatment and event(s) is: 
 
Suspected/Unknown 
 
  
 


 
Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
60 
B) Interventional Clinical Trial SAE Fax Cover Sheet 
 
To: Local Novartis Drug Safety and Epidemiology Safety Desk  1 877 778 9739 
 
 
 
Investigator contact details: 
Name:  ___________________________________ 
Fax number : ______________________________ 
Phone number : ____________________________ 
 
Study Name 
 
Centre Number 
 
Patient Number 
 
 
 
 
 
Relationship between study treatment and event(s) is: 
 
Not Suspected 
 
  
 
 


 
Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
61 
Appendix VIII 
Revised SOM230 Abnormal liver function management  
 
Hepatic-related patient management for all ongoing studies  
Perform within 72 hours of awareness of abnormal LFTs:  
 
-directed medical history and physical examination (i.e. assess occupational 
hazards, concomitant medications including OTC meds, intercurrent illness, etc)  
 
ALT, AST, total bilirubin, (fractionate to direct/indirect bilirubin if total 
bilirubin is > 2.0x ULN), Alb, PT (INR), ALP, and GGT  
 
-HAV, IgM (to confirm acute hepatitis A), HbsAg, Anti-HBc, 
anti-HCV (if positive PCR viral load should be assessed), Anti-HEV, ANA antibodies, anti-
smooth muscle anti-bodies, CMV, EBV  
 
 
 
patient has taken prior to PK sampling.  
 
Liver chemistry tests should be monitored every 3-4 days for s.c. and LAR studies until 
resolution or return to baseline status.  
 
 
 
o Study medication should be temporarily interrupted and liver chemistry tests monitored 
every 3-4 days for s.c. and LAR studies until resolution or return to baseline  
 
o If resolution or return to baseline does not occur after 2 weeks, the patient should be 
discontinued.  
 
o If ALT or AST returns to less than 5x ULN, study drug can be resumed and patient can 
continue study per protocol  
 
o If ALT or AST rises above 5x ULN anytime after study drug is resumed, then study drug 
should be discontinued immediately.  
 
 
 
 
 
 


 
Protocol 2011-031 Version date July 27, 2011, Sept 29 2011, Nov 18 2011, Dec 27, 2011, Dec 4, 2012 
62 
 
 
 
SOM230 LFT Management Algorithm (s.c. and LAR studies) 
_