Clinical trial NCT02215070
Conditions: Hematological Malignancies
Keywords: Allogeneic Stem Cell Transplantation Acute Myeloid Leukemia Acute Lymphoid Leukemia Acute Non-Lymphocytic Leukemia Myelodysplastic Syndrome Chronic Myeloid Leukemia Lymphoma
Sponsor: Anthony Sung, MD
Start date: 2015-01-21; Completion date: 2019-10-15
Enrollment: 37 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate if the drug, Pasireotide, is safe and effective in reducing the gastrointestinal side effects of the drugs received to prepare for allogeneic stem cell transplant. The study will also evaluate if Pasireotide is effective in reducing acute and chronic Graft-versus-Host-Disease (GvHD) after transplant.

Detailed description:
The study design will be a non-randomized phase II. Forty patients receiving an ablative preparatory regimen will receive pasireotide subcutaneous (0.9 mg, b.i.d.) one day prior to initiation of the preparatory regimen and continuing for eight days following the completion of the preparatory regimen not to exceed 14 days total dosing. We select matched controls from existing patients who did not take the drug to minimize the time it takes to complete the trial.

Myeloablative preparatory regimens are defined as those including either TBI ≥ 1200 cGy or busulfan ≥ 12.8 mg/kg. The most common regimens combine TBI with cyclophosphamide (TBI/Cy) or busulfan with cyclophosphamide (Bu/Cy) (Appendix E). However, any regimen meeting the above definition of myeloablative preparatory regimen may be used.

The study will collect data at screening, at baseline prior to initiation of the drug (day of study drug start), transplant day 0, day +7, day +14 and weekly thereafter until day +100, and on days +180, +270, and +365. The total days on pasireotide therapy will be recorded as well as any SAE that is outside the expected for stem cell transplantation. We will also follow the incidence and severity of acute and chronic GVHD.

At Duke only, a video capsule endoscopy will be performed in a subset of ten study patients between transplant days +4 through +6. This substudy is descriptive in nature and only used to collect a source of preliminary data that may suggest further study.

Patients must agree to participate in this portion of the study and will be asked to sign a clinical consent for performance use of the video capsule endoscopy. Patients will be given detailed instructions to prepare for the procedure. An investigator who is blinded to the group allocation of the patients/volunteers separately will review the images obtained from each of the capsule examinations. Images will be examined for evidence of the four following types of abnormalities: reddened/edema/villous blunting, erosion, ulcer and stenosis. Each of these categories will be scored from 0-3 and summed to obtain an overall index that will range from 0 (normal study) to 12 (severely abnormal in all categories).

Citrulline assay Measurement of citrulline concentration has been used as a marker for cytotoxic treatment-induced intestinal damage and it is highly reproducible. The citrulline concentration appears to be a quantitative parameter that is independent of the underlying cause for epithelial cell loss and functions well in the post-SCT setting. Six mls of blood will be collected in heparinized tubes on days 0, 7, and 14. Tubes will be centrifuged according to manufacturer's instructions and the plasma will be collected and stored at -80C until shipment to the laboratory performing the assay.

Calprotectin assay Calprotectin has been described as another biomarker of GI injury. During radiation-induced inflammation, leucocytes infiltrate the mucosa and increase the level of fecal calprotectin. At least 50 mg of stool specimen will be collected from patients on days 0, 7, and 14. Samples will be stored at -80C until shipment to the laboratory performing the assay. Calprotectin will be measured with an ELISA kit (CALPRO, Oslo, Norway) in accordance with the manufacturer's instructions.

Arms: arm 1: Eligible subjects will receive pasireotide daily for 5 days before stem cell transplant, the day of the stem cell transplant, and daily for 8 days following the stem cell transplant. Preparatory regimen will be given 4 days before stem cell transplant.
Interventions: intervention 1: Pasireotide
Intervention descriptions: intervention 1: Eligible subjects will receive pasireotide daily for 5 days before stem cell transplant, the day of the stem cell transplant, and daily for 8 days following the stem cell transplant. Preparatory regimen will be given 4 days before stem cell transplant.

Protocol documents:
Prot_SAP_000.pdf: 
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A Phase II Trial for the Prevention of Gastrointestinal Toxicity from Total Body 
Irradiation or High Dose Chemotherapy with Pasireotide 
 
 
 
Principal Investigator: 
 
Anthony Sung, MD 
Duke University Medical Center  
DUMC Box 3961 
Durham, NC  27710 
Phone: 919-668-5710 
Fax: 919-668-1091 
 
 
Co-Investigators: 
 
Nelson Chao, MD, MBA 
Cristina Gasparetto, MD 
Mitchell Horwitz, MD 
Gwynn Long, MD 
Ashley Morris Engemann, PharmD 
David Rizzieri, MD 
Stefanie Sarantopoulus, MD, PhD 
Keith Sullivan, MD 
Richard Lopez, MD 
Daniel Wild, MD 
 
 
Study Statistician:  
Zhiguo Li, Ph.D.  
 
 
Duke IRB Protocol: 00051736 
 
 
ClinicalTrials.gov Identifier: NCT02215070 
 
 


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TABLE OF CONTENTS 
 
1 
ABBREVIATIONS .................................................................................................... 5 
2 
OBJECTIVES ........................................................................................................... 5 
2.1 Primary Objective: ............................................................................................................................................. 5 
2.2 Secondary Objectives: ...................................................................................................................................... 5 
2.3 Exploratory Objectives: ..................................................................................................................................... 5 
3 
ENDPOINTS ............................................................................................................. 6 
3.1 Primary Endpoint ............................................................................................................................................... 6 
3.2 Secondary Endpoints ........................................................................................................................................ 6 
3.3 Exploratory Endpoints ....................................................................................................................................... 6 
4 
BACKGROUND AND RATIONALE FOR USE OF PASIREOTIDE ......................... 6 
5 
DESCRIPTION OF PASIREOTIDE .......................................................................... 8 
5.1 Mechanism of Action ......................................................................................................................................... 9 
5.2 Pharmacodynamics ......................................................................................................................................... 10 
5.3 Pharmacokinetics ............................................................................................................................................ 10 
5.4 Absorption and Distribution ............................................................................................................................ 10 
5.5 Metabolism and Excretion .............................................................................................................................. 11 
5.6 Steady-state pharmacokinetics ..................................................................................................................... 11 
5.7 Special Populations ......................................................................................................................................... 11 
5.8 Hepatic impairment ......................................................................................................................................... 11 
5.9 Renal impairment ............................................................................................................................................ 12 
5.10 Pediatric Patients............................................................................................................................................. 12 
5.11 Geriatric patients ............................................................................................................................................. 12 
5.12 Drug Interaction Studies: ................................................................................................................................ 12 
6 
NONCLINICAL TOXICOLOGY .............................................................................. 12 
6.1 Carcinogenesis ................................................................................................................................................ 12 
6.2 Mutagenesis ..................................................................................................................................................... 12 
6.3 Impairment of Fertility ..................................................................................................................................... 12 
7 
CLINICAL STUDIES .............................................................................................. 13 
7.1 Clinical Studies in Children ............................................................................................................................ 15 
7.2 Geriatric Use .................................................................................................................................................... 15 
8 
STUDY DRUG INFORMATION .............................................................................. 15 
8.1 Dosage .............................................................................................................................................................. 15 
8.2 Renal or hepatic insufficiency: ....................................................................................................................... 15 
8.3 Storage and Handling ..................................................................................................................................... 16 
8.4 Adverse Events ................................................................................................................................................ 16 
8.5 Drug Interactions ............................................................................................................................................. 19 
8.5.1 
Effects of Other Drugs on Pasireotide ................................................................................................. 19 


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8.5.2 
Effects of Pasireotide on Other Drugs ................................................................................................. 19 
8.6 Contraindications ............................................................................................................................................. 19 
8.7 Warnings ........................................................................................................................................................... 20 
8.7.1 
Hypocortisolism ....................................................................................................................................... 20 
8.7.2 
Hyperglycemia and Diabetes ................................................................................................................ 20 
8.7.3 
Bradycardia and QT Prolongation ........................................................................................................ 21 
8.7.4 
Liver Test Elevations .............................................................................................................................. 21 
8.7.5 
Cholelithiasis ............................................................................................................................................ 22 
8.7.6 
Monitoring for Deficiency of Pituitary Hormones ................................................................................ 22 
9 
PATIENT ELIGIBILITY .......................................................................................... 22 
9.1 Inclusion Criteria .............................................................................................................................................. 22 
9.2 Exclusion Criteria ............................................................................................................................................. 22 
9.3 Patient Numbering ........................................................................................................................................... 24 
10 MATERIAL AND DATA ......................................................................................... 24 
11 TREATMENT PLAN AND MODIFICATIONS ........................................................ 25 
11.1  Study Design: ................................................................................................................................................... 26 
11.2  Video Capsule Endoscopy ............................................................................................................................. 26 
11.3 Biomarker Assays ........................................................................................................................................... 27 
11.3.1 Citrulline assay ......................................................................................................................................... 27 
11.3.2 Calprotectin assay ................................................................................................................................... 27 
11.4  Dose Modifications and Treatment Interruptions/Discontinuation............................................................ 28 
11.5 Study Withdrawal ............................................................................................................................................. 29 
12 ANTICIPATED TOXICITIES................................................................................... 29 
12.1 Myelosuppression: ........................................................................................................................................... 30 
12.2 Gastrointestinal: ............................................................................................................................................... 30 
12.3 Hyperglycemia .................................................................................................................................................. 30 
12.4 Cardiac: ............................................................................................................................................................. 30 
12.5 Pulmonary: ........................................................................................................................................................ 30 
12.6 Hepatic: .............................................................................................................................................................. 31 
12.7 Renal: ................................................................................................................................................................. 31 
12.8 GVHD: ................................................................................................................................................................ 31 
12.9 Neurologic: ........................................................................................................................................................ 31 
12.10 Miscellaneous: ................................................................................................................................................ 31 
13 DATA MANAGEMENT AND DATA SAFETY MONITORING ................................ 32 
13.1 Data Management ........................................................................................................................................... 32 
13.1.1 Electronic Case Report Forms (eCRFs) .............................................................................................. 32 
13.1.2 Data Management Procedures and Data Verification ........................................................................ 32 
13.1.3 Study Closure ........................................................................................................................................... 33 
13.2 Data Safety Monitoring ................................................................................................................................... 33 
14 SAFETY AND STUDY DATA MONITORING .......................................................... 33 
14.1  Safety ................................................................................................................................................................ 33 
14.1.1 Adverse Event Reporting. ....................................................................................................................... 33 
14.1.2 SAE Reporting .......................................................................................................................................... 35 


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14.1.3 Pregnancy ................................................................................................................................................. 36 
14.2 Data Monitoring: .............................................................................................................................................. 37 
15 STATISTICAL CONSIDERATIONS ......................................................................... 37 
15.1  Objectives ......................................................................................................................................................... 38 
15.1.1 Primary Objective: .................................................................................................................................... 38 
15.1.2 Secondary Objectives: ............................................................................................................................ 38 
15.2  Exploratory Objectives: ................................................................................................................................... 38 
15.3  Endpoints: ......................................................................................................................................................... 38 
15.3.1 Primary Endpoint ...................................................................................................................................... 38 
15.3.2 Secondary Endpoints .............................................................................................................................. 39 
15.3.3 Exploratory Endpoints ............................................................................................................................. 39 
15.4  Stopping Rules................................................................................................................................................. 39 
16  REFERENCES ....................................................................................................... 41 
APPENDIX A: STUDY CALENDAR FOR SPECIAL STUDIES ................................... 43 
APPENDIX B: CAPSULE ENDOSCOPY PREPARATION INSTRUCTIONS .............. 45 
APPENDIX C: GUIDANCE FOR HYPERGLYCEMIA MANAGEMENT ....................... 47 
APPENDIX D: QT PROLONGING MEDICATIONS (INEXHAUSTIVE) ........................ 48 
APPENDIX E: STUDY DRUGS AND EXAMPLE PREPARATORY REGIMENS ......... 50 
E1.  Total Body Irradiation ...................................................................................................................................... 50 
E2. Busulfan (Myerlan) NSC #750 ....................................................................................................................... 50 
E3. Cyclophosphamide (Cytoxan, CTX) NSC #26271 ..................................................................................... 50 
E4. Cyclosporine (Sandimmune) ......................................................................................................................... 51 
E5. Methotrexate (MTX) ........................................................................................................................................ 52 
E6. Example Schedule ............................................................................................................................................. 54 
APPENDIX F: ACUTE GVHD SCORING ..................................................................... 55 
APPENDIX G: CHRONIC GVHD SCORING ................................................................ 56 
 
APPENDIX H: SAE COVERSHEETS……………………………...……………………….60 
  


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1 ABBREVIATIONS 
 
 
CTX 
Cytoxan 
G-CSF 
Granulocyte colony stimulating factor 
GI 
Gastrointestinal 
GVHD 
Graft vs Host Disease 
KGF 
keratinocyte growth factor 
MTX 
methotrexate 
sc 
subcutaneous 
SCT 
Stem Cell Transplantation 
TBI 
Total Body Irradiation 
VCE 
Video Capsule Endoscopy 
 
 
2 OBJECTIVES 
 
 
2.1 
Primary Objective:  
To evaluate the efficacy and safety of pasireotide in mitigating GI toxicity from the 
preparatory regimens for allogeneic stem cell transplantation.   
 
2.2 
Secondary Objectives:   
To evaluate the efficacy of pasireotide in reducing the incidence and severity of acute 
GVHD at 100 days post-transplant compared to historical controls.   
 
To evaluate the efficacy of pasireotide in reducing the incidence and severity of chronic 
GVHD at 1 year post-transplant. 
 
To compare the rate of overall survival in patients treated with pasireotide at 1 year 
post-transplant to historical controls.  
 
To compare the rate of disease free survival in patients treated with pasireotide at 1 
year post-transplant to historical controls.  
 
Historical controls will be drawn from a group of patients matched for age, disease, graft 
source, preparatory regimen, GVHD prophylaxis, and number of prior therapies but who 
will not receive pasireotide.   
 
2.3 
Exploratory Objectives:  
To evaluate plasma citrulline and fecal calprotectin levels as biomarkers of GI tract 
health and function in SCT patients. 
 
To evaluate GI toxicity assessments by video capsule endoscopy. 
 
 


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3 ENDPOINTS   
 
 
3.1 
Primary Endpoint 
The incidence of Grades 3-4 Gastrointestinal toxicity in SCT patients who are treated 
with pasireotide, based on CTCAE 4.0 criteria, through transplant day 30. 
 
3.2 
 Secondary Endpoints 
The secondary endpoints will be: 
• Incidence and maximum severity of Acute GVHD at 100 days post-transplant. 
• Incidence and maximum severity of Chronic GVHD at 1 year post-transplant. 
• Rate of overall survival at 1 year post-transplant. 
• Rate of Disease free survival at 1 year post-transplant. 
 
3.3 
Exploratory Endpoints 
As exploratory endpoints, citrulline levels as well as fecal calprotectin will be measured 
at baseline, transplant Day 0 and at weekly intervals for the first two weeks post-
transplant. These results will be correlated with other signs and symptoms of GI toxicity 
for the first two weeks post-transplant.   
 
GI toxicity will also be assessed by use of video capsule endoscopy in a subset of 10 
patients and five controls. Images will be scored by an experienced endoscopist 
(Dr.Wild). 
 
 
4 BACKGROUND AND RATIONALE FOR USE OF PASIREOTIDE 
 
 
Total body irradiation (TBI) or high dose busulfan is a standard preparatory regimen for 
the treatment of hematological disease prior to stem cell transplantation. Unfortunately, 
these approaches are associated with significant acute and chronic toxicities, and 
injuries to the bone marrow and gastrointestinal (GI) tract are the main determinants of 
lethality after total-body irradiation (TBI) [1, 2]. Specifically, the use of this modality 
results in acute gastrointestinal toxicity such as nausea, vomiting and diarrhea. The 
inflammatory response is also likely important in setting up the appropriate milieu for the 
induction of graft versus host disease (GVHD). Some progress has been made in the 
management of radiation injury of the hematopoietic/immune system. However, 
effective and safe countermeasures against structural injury and dysfunction in the GI 
tract remain an unmet need [2]. 
 
In the intestine, radiation damages crypt stem cells and proliferating transit cells, 
thereby leading to disruption of the epithelial barrier that normally protects the 
subepithelial matrix from the influence of the digestive enzymes that are normally 
present in the intestinal lumen [3]. Among the various intraluminal factors, pancreatic 
enzymes exert a particularly prominent influence on development of intestinal radiation 
toxicity [4]. Hence controlling pancreatic enzyme secretion has been explored as a 


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method to attenuate acute mucosal injury and increases survival after abdominal 
irradiation [5, 6]. 
 
Efforts to counter the GI toxicity have included drugs such as keratinocyte growth factor 
(KGF) that has been shown to decrease mucositis associated with TBI. Unfortunately, 
the data with KGF is relatively marginal and this drug has not been universally accepted 
into routine clinical use.  Somatostatin analogs are known as inhibitors of growth 
hormone (GH) and other hormones (including gastro-intestinal hormones) and, among 
many different activities that influence the GI tract, inhibit the secretion of pancreatic 
enzymes into the bowel lumen [7, 8]. Earlier studies showed that the “prototype” 
somatostatin analog, octreotide, markedly ameliorated mucosal injury in the small bowel 
after localized irradiation [9]. Subsequent randomized clinical trials have translated this 
to patients with severe radiation-induced GI toxicity, thus confirming therapeutic efficacy 
in humans [10]. 
 
While octreotide can be used in the clinical situation to reduce side effects of radiation 
therapy, its short half-life is a serious limitation in situations where intravenous or 
multiple subcutaneous (s.c.) administrations are not logistically feasible. A more recently 
developed synthetic somatostatin analog, SOM230 (pasireotide, Pasireotide), however, 
has much greater metabolic stability and thus circumvents this obstacle [11]. It was also 
reported in 2009 that SOM230 administered prior to or 4 h after TBI in a mouse model 
conferred a highly statistically significant survival benefit, even though we also 
demonstrated that SOM230 did not appear to have direct cytoprotective effects on the 
bone marrow or the intestine [12]. Hence, while post-TBI intestinal crypt survival and 
hematopoietic injury were similar, the intestinal barrier was structurally and functionally 
preserved. Moreover, protection was reversed by co-administration of pancreatic 
enzymes, thus strongly suggesting that reduced secretion of proteolytic enzymes into 
the bowel lumen was the mechanism of action [12].   
 


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Figure 1.  Effect of SOM230 administration on mucosal surface area. Panel A: TBI (8 
Gy) induced a reduction in mucosal surface area. SOM230 administration significantly 
diminished the radiation-induced decrease in mucosal surface area (P < 10−6) (n = 6). 
Panel B: Representative image of intestine from a vehicle-treated animal on day 3.5 
after 8 Gy TBI. Panel C: Representative image of intestine from an SOM230-treated 
animal on day 3.5 after 8 Gy TBI. SOM230: 0.5 mg/kg b.i.d. 
 
The beneficial effects of SOM230 were seen even when administered as late as 24 hrs. 
after total body irradiation. 
 
 
Figure 2.  Dose-dependent radiation-mitigating effects of SOM230. Kaplan-Meier 
survival curves from mice exposed to 8.5, 9 and 9.5 Gy radiation (SOM230 
administration beginning 24 h after TBI). SOM230 significantly reduced lethality in a 
dose-dependent manner across radiation doses (P < 0.0001). n = 8. 
 
Pasireotide has recently been approved for the treatment of adult patients with 
Cushing’s disease for whom pituitary surgery is not an option or has not been curative.  
Pasireotide, with its ability to perform a near complete chemical pancreatectomy, is an 
excellent candidate for mitigation of the toxicities associated with TBI or high dose 
chemotherapy. The impact on the GI tract is likely related to pasireotide’s ability to block 
the somatostatin receptor sst 2 leading to the cessation of export of pancreatic 
enzymes. Moreover, its advanced development as an agent for mitigation of GI 
toxicities after unplanned radiation exposure further adds excitement for its use in a 
clinical trial.   
 
 
5 DESCRIPTION OF PASIREOTIDE 
 
 
Pasireotide (pasireotide) injection is prepared as a sterile solution of pasireotide 
diaspartate in a tartaric acid buffer for administration by subcutaneous injection. 
Pasireotide is a somatostatin analog. Pasireotide diaspartate, chemically known as (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, is a cyclohexapeptide with pharmacologic properties 
mimicking those of the natural hormone somatostatin. 
 


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The molecular formula of pasireotide diaspartate is C58H66N10O9 • 2 C4H7NO4 and the 
molecular weight is 1313.41.  
 
The structural formula is: 
 
 
 
 
Pasireotide is supplied as a sterile solution in a single-dose, 1 mL colorless glass 
ampule containing pasireotide in 0.3 mg/mL, 0.6 mg/mL, or 0.9 mg/mL strengths for 
subcutaneous injection. 
 
Each glass ampule contains:  
 
 
0.3 mg 
0.6 mg 
0.9 mg 
Pasireotide 
0.3762* 
0.7524* 
1.1286* 
Mannitol 
49.50 
49.50 
49.50 
Tartaric acid 
1.501 
1.501 
1.501 
Sodium hydroxide 
ad pH 4.2 
ad pH 4.2 
ad pH 4.2 
Water for injection 
ad 1ml 
ad 1ml 
ad 1ml 
* corresponds to 0.3/0.6/0.9 mg pasireotide base 
 
Note: Each ampule contains an overfill of 0.1ml to allow accurate administration of 1 ml 
from the ampule. 
 
5.1 
Mechanism of Action 
Pasireotide is an injectable cyclohexapeptide somatostatin analogue. Pasireotide 
exerts its pharmacological activity via binding to somatostatin receptors. Five human 
somatostatin receptor subtypes are known: sst 1, 2, 3, 4, and 5. 
 


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These receptor subtypes are expressed in different tissues under normal physiological 
conditions. Pituitary corticotroph tumor cells from Cushing’s disease patients frequently 
over-express sst5 whereas the other receptor subtypes are often not expressed or are 
expressed at lower levels. Pasireotide binds and activates the sst receptors resulting in 
inhibition of ACTH secretion, which leads to decreased cortisol secretion. 
 
The binding affinities of endogenous somatostatin and pasireotide are shown in Table 2. 
 
Table 2- Binding affinities of somatostatin (SRIF-14) and pasireotide to the five 
human sst receptor subtypes (hsst1-5) 
 
Compound 
hsst1 
hsst2 
hsst3 
hsst4 
hsst5 
Somatostatin (SRIF-14) 
0.93±0.12 
0.15±0.02 
0.56±0.17 
1.5±0.4 
0.29±0.04 
Pasireotide 
9.3±0.1 
1.0±0.1 
1.5±0.3 
> 1000 
0.16±0.01 
Results are the mean±SEM of IC50 values expressed as nmol/l 
 
5.2 
Pharmacodynamics 
Cardiac Electrophysiology 
QTcF interval was evaluated in a randomized, blinded, crossover study in healthy 
subjects investigating pasireotide doses of 0.6 mg b.i.d. and 1.95 mg b.i.d. The 
maximum mean (95% upper confidence bound) placebo-subtracted QTcF change from 
baseline was 12.7 (14.7) ms and 16.6 (18.6) ms, respectively. Both pasireotide doses 
decreased heart rate, with a maximum mean (95% lower confidence bound) placebo-
subtracted change from baseline of -10.9 (-11.9) beats per minute (bpm) observed at 
1.5 hours for pasireotide 0.6 mg bid, and -15.2 (-16.5) bpm at 0.5 hours for pasireotide 
1.95 mg b.i.d. The supra-therapeutic dose (1.95 mg b.i.d.) produced mean steady-state 
Cmax values 3.3-fold the mean Cmax for the 0.6 mg b.i.d. dose in the study. 
 
5.3 
Pharmacokinetics 
In healthy volunteers, pasireotide demonstrates approximately linear pharmacokinetics 
(PK) for a dose range from 0.0025 to 1.5 mg. In Cushing’s disease patients, pasireotide 
demonstrates linear dose-exposure relationship in a dose range from 0.3 to 1.2 mg. 
 
5.4 
Absorption and Distribution  
In healthy volunteers, pasireotide peak plasma concentration is reached within Tmax 
0.25-0.5 hour. Cmax and AUC are dose-proportional following administration of single 
and multiple doses. 
 
No studies have been conducted to evaluate the absolute bioavailability of pasireotide 
in humans. Food effect is unlikely to occur since pasireotide is administered via a 
parenteral route. 
 
In healthy volunteers, pasireotide is widely distributed with large apparent volume of 
distribution (Vz/F >100 L). Distribution between blood and plasma is concentration 
independent and shows that pasireotide is primarily located in the plasma (91%). 
Plasma protein binding is moderate (88%) and independent of concentration. 
 


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Pasireotide has low passive permeability and is likely to be a substrate of P-gp (P-
glycoprotein), but the impact of P-gp on ADME (absorption, distribution, metabolism, 
excretion) of pasireotide is expected to be low. Pasireotide is not a substrate of efflux 
transporter BCRP (breast cancer resistance protein), influx transporter OCT1 (organic 
cation transporter 1), or influx transporters OATP (organic anion-transporting 
polypeptide) 1B1, 1B3, or 2B1. 
 
5.5 
Metabolism and Excretion 
Pasireotide was shown to be metabolically stable in human liver and kidney 
microsomes systems. In healthy volunteers, pasireotide in its unchanged form is the 
predominant form found in plasma, urine and feces. Somatropin (growth hormone) may 
increase CYP450 enzymes and, therefore, suppression of growth hormone secretion by 
somatostatin analogs including pasireotide may decrease the metabolic clearance of 
compounds metabolized by CYP450 enzymes. 
 
Pasireotide is eliminated mainly via hepatic clearance (biliary excretion) with a small 
contribution of the renal route. In a human ADME study 55.9 ± 6.63% of the radioactivity 
dose was recovered over the first 10 days post dosing, including 
48.3 ± 8.16% of the radioactivity in feces and 7.63 ± 2.03% in urine. 
 
The clearance (CL/F) of pasireotide in healthy volunteers and Cushing’s disease 
patients is ~7.6 liters/h and ~3.8 liters/h, respectively. 
 
5.6 
Steady-state pharmacokinetics 
Following 
multiple 
subcutaneous 
doses, 
pasireotide 
demonstrates 
linear 
pharmacokinetics in the dose range of 0.05 to 0.6 mg once a day in healthy volunteers, 
and 0.3 mg to 1.2 mg twice a day in Cushing’s disease patients. Based on the 
accumulation ratios of AUC, the calculated effective half-life (t1/2,eff) in healthy 
volunteers was approximately 12 hours (on average between 10 and 13 hours for 0.05, 
0.2 and 0.6 mg once a day doses). 
 
5.7 
Special Populations  
Population PK analyses of pasireotide indicates that body weight, age, and gender do 
not affect pasireotide pharmacokinetics and there is no meaningful difference in 
pharmacokinetics between Caucasian and non-Caucasian PK parameters. 
 
5.8 
Hepatic impairment 
In a clinical study in subjects with impaired hepatic function (Child-Pugh A, B and C), 
subjects with moderate and severe hepatic impairment (Child-Pugh B and C) showed 
significantly higher exposures than subjects with normal hepatic function. Upon 
comparison with the control group, AUCinf was increased by 12%, 56% and 42% and 
Cmax increased by 3%, 46% and 33%, respectively, in the mild, moderate and severe 
hepatic impairment groups. 
 


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5.9 
Renal impairment 
Clinical pharmacology studies have not been performed in patients with impaired renal 
function. However, renal clearance has a minor contribution to the elimination of 
pasireotide in humans. Renal function is not expected to significantly impact the 
circulating levels of pasireotide [see Use in Specific Populations (8.7)]. 
 
5.10 Pediatric Patients  
No studies have been performed in pediatric patients. 
 
5.11 Geriatric patients 
No clinical pharmacology studies have been performed in geriatric patients. 
 
5.12 Drug Interaction Studies: 
There was no significant drug interaction between pasireotide and metformin, 
nateglinide or liraglutide. 
 
5.13 Rationale for dose in this study: 
In a phase III study of Cushing's Disease ([SOM230B2216] and [SOM230B2124] 
patients randomized to 0.6 mg bid and 0.9 mg bid, adverse events were similar between 
doses (Table 1, page 18). Therefore, in order to maximize the potential for clinical 
efficacy, and because we do not think there would be a significant difference in toxicity, 
we chose to use 0.9 mg bid as the starting dose. If significant toxicities occur, we could 
consider reducing to 0.6 mg bid, but we believe there is sufficient safety data to justify 
0.9 mg bid as the starting dose. 
 
 
6 NONCLINICAL TOXICOLOGY 
 
 
6.1 
Carcinogenesis 
A life-time carcinogenicity study was conducted in rats and transgenic mice. Rats were 
given daily subcutaneous doses of pasireotide at 0.01, 0.05, 0.3 mg/kg/day for 104 
weeks. There were no drug-related tumors in rats at exposures up to 7- fold higher than 
the maximum recommended clinical exposure at the 1.8 mg/day dose. Mice were given 
subcutaneous doses of pasireotide at 0.5, 1.0, 2.5 mg/kg/day for 26 weeks and did not 
identify any carcinogenic potential. 
 
6.2 
Mutagenesis 
Pasireotide was not genotoxic in a battery of in vitro assays (Ames mutation test in 
Salmonella and E coli. and mutation test in human peripheral lymphocytes). Pasireotide 
was not genotoxic in an in vivo rat bone marrow nucleus test. 
6.3 
Impairment of Fertility 
 
Subcutaneous dosing at 0.1 mg/kg/day before mating and continuing into gestation in 
rats at exposures less than the human clinical exposure based on body surface area 
comparisons across species resulted in statistically significant increased implantation 


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loss and decreased viable fetuses, corpora lutea, and implantation sites. Abnormal 
cycles or acyclicity were observed at 1 mg/kg/day (5-fold higher than the maximum 
therapeutic exposure based on surface area, comparisons across species). 
 
 
7 CLINICAL STUDIES 
 
 
A Phase III, multicenter, randomized study was conducted to evaluate the safety and 
efficacy of two dose levels of pasireotide over a 6-month treatment period in Cushing’s 
disease patients with persistent or recurrent disease despite pituitary surgery or de novo 
patients for whom surgery was not indicated or who had refused surgery. 
 
Patients with a baseline 24-hour urine free cortisol (UFC) >1.5 x upper limit of normal 
(ULN) were randomized to receive a pasireotide dosage of either 0.6 mg subcutaneous 
b.i.d. or 0.9 mg subcutaneous b.i.d. After three months of treatment, patients with a 
mean 24-hour UFC ≤ 2.0 x ULN and below or equal to their baseline values continued 
blinded treatment at the randomized dose until Month 6. Patients who did not meet these 
criteria were unblinded and the dose was increased by 0.3 mg b.i.d. After the initial six 
months in the study, patients entered an additional 6-month open-label treatment period. 
The dosage could be reduced by 0.3 mg b.i.d. at any time during the study for 
intolerability. 
 
A total of 162 patients were enrolled in this study. The majority of patients were female 
(78%) and had persistent or recurrent Cushing’s disease despite pituitary surgery (83%) 
with a mean age of 40 years. A few patients (4%) in either treatment group received 
previous pituitary irradiation. The median value of the baseline 24-hour UFC for all 
patients was 565 nmol/24 hours (normal range 30 to 145 nmol/24 hours). About two-
thirds of all randomized patients completed six months of treatment. 
 
The primary efficacy endpoint was the proportion of patients who achieved normalization 
of mean 24-hour UFC levels after six months of treatment and did not dose increase 
during this period. 
 
24-Hour Urinary Free Cortisol Results 
 
At Month 6, the percentages of responders for the primary endpoint were 15% and 26% 
in the 0.6 mg b.i.d. and 0.9 mg b.i.d. groups, respectively (Table 3). The percentages of 
patients with mUFC ≤ ULN or ≥ 50% reduction from baseline, a less stringent endpoint 
than the primary endpoint, were 34% in the 0.6 mg bid and 41% in the 0.9 mg bid 
groups. Dose increases appeared to have minimal effect on 24-hour UFC response. 
Mean and median percentage changes in UFC from baseline are presented in Table 3. 
 
 
 
 
 


09/20/2017 
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Table 3- 24-Hour Urinary Free Cortisol (UFC) Study Results at
Month 6 in Patients with Cushing’s Disease 
 
Pasireotide 
0.6 mg b.i.d. 
N=82 
Pasireotide 
0.9 mg b.i.d. 
N=80 
UFC Responders n/N 
% (95% CI) 
12/82 
15% (7%, 22%) 
21/80 
26% (17%, 36%) 
 
 
 
UFC 
Levels 
(nmol/24hr) 
Baseline 
N=78 
N=72 
Mean (SD) 
868 (764) 
750 (930) 
Median 
704 
470 
 
 
 
% Change from 
baseline Mean 
(95% 
CI) 
Median 
-22% (-44%, +1%) 
-47% 
-42% (-50%, -33%) 
-46% 
 
Pasireotide resulted in a decrease in the mean 24-hour UFC after 1 month of treatment 
(Figure 1). For patients (n=78) who stayed in the trial, similar UFC lowering was 
observed at Month 12. 
 
 
Figure 1 - Mean 
(±SE) Urinary Free 
Cortisol 
(nmol/24h) 
at time points up to 
Month 
6 
by 
randomized 
dose 
group 
 
 
 
 
 
 
 
 
Note: Only patients 
who 
completed 
6 
months of treatment are included in this analysis (n=110). The reference line is the 
upper limit of normal for UFC, which is 145 nmol/24hour; +/-Standard errors are 
displayed. 
 
Other endpoints 
 
Decreases from baseline for blood pressure were observed at Month 6, including 
patients who did not receive any antihypertensive medication. However, due to the fact 


09/20/2017 
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that the study allowed initiation of antihypertensive medication and dose increases in 
patients already receiving such medications, the individual contribution of pasireotide or 
of antihypertensive medication adjustments cannot be clearly established. 
 
The mean decreases from baseline at Month 6 for weight, body mass index and waist 
circumference were 4.4 kg, 1.6 kg/m2 and 2.6 cm, respectively. Individual patients 
showed varying degrees of improvement in Cushing's disease manifestations but 
because of the variability in response and the absence of a control group in this trial, it 
is uncertain whether these changes could be ascribed to the effects of pasireotide. 
 
7.1 
Clinical Studies in Children 
Safety and effectiveness of pasireotide have not been established in pediatric patients. 
 
7.2 
Geriatric Use 
Clinical studies of pasireotide did not include sufficient numbers of patients aged 65 and 
over to determine whether they respond differently from younger patients. Other 
reported clinical experience has not identified differences in responses between the 
elderly and younger patients. In general, dose selection for an elderly patient should be 
cautious, usually starting at the low end of the dosing range, reflecting the greater 
frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or 
other drug therapy. 
 
 
8 STUDY DRUG INFORMATION 
 
 
8.1 
Dosage  
The dose of pasireotide to be used in this study is 0.9 mg by subcutaneous injection 
every 12 hours.  It will be supplied in 0.9 mg/mL in a single-dose, 1 mL colorless glass 
ampules. 
 
It is expected that patients will receive their pasireotide injections in the hospital and that 
these will be administered by medical staff. However, for patients who are not admitted 
and receive their pasireotide at home (e.g. the night before admission for conditioning), 
they will be taught by medical staff how to self-administer pasireotide. As a 
subcutaneous injection, this process is similar to giving self-injections of insulin and is 
done routinely by patients with Cushing’s who are receiving pasireotide. Note that this 
does not apply to the first dose: as per protocol, all first doses of pasireotide will be 
given by medical personnel in the hospital or clinic with EKG monitoring. 
 
8.2 
Renal or hepatic insufficiency:  
No dosage adjustment of pasireotide in patients with impaired renal function is required. 
 
Dose adjustment is not required in patients with mild impaired hepatic function (Child-
Pugh A).   Patients with moderately impaired hepatic function (Child-Pugh B). and 
severe hepatic impairment (Child-Pugh C) will be excluded from the study. 


09/20/2017 
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8.3 
Storage and Handling 
Store at 25° C (77°F); excursions permitted to 15°-30°C (59°-86°F), protect from light. 
 
8.4 
Adverse Events 
Because clinical trials are conducted under widely varying conditions, adverse reaction 
rates observed in clinical trials of a drug cannot be directly compared to rates in clinical 
trials of another drug and may not reflect the rates observed in practice. Of note, 
pasireotide has not been studied in children and the below data are from trials in adults. 
 
A total of 162 Cushing’s disease patients were exposed to pasireotide in the Phase III 
study. At study entry, patients were randomized to receive twice a day (b.i.d.) doses of 
either 0.6 mg or 0.9 mg of pasireotide given subcutaneously. The mean age of patients 
was approximately 40 years old with a predominance of female patients (78%). The 
majority of the patients had persistent or recurrent Cushing’s disease (83%) and few 
patients (≤ 5%) in either treatment group had received previous pituitary irradiation. The 
median exposure to the treatment was 10.4 months (0.03-37.8) with 68% of patients 
having at least six months exposure. 
 
In the Phase III trial, adverse reactions were reported in 98% of patients. The most 
common adverse reactions (frequency ≥20% in either group) were diarrhea, nausea, 
hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes mellitus. 
There were no deaths during the study. Serious adverse events were reported in 25% of 
patients. Adverse events leading to study discontinuation were reported in 17% of 
patients. 
 
Adverse reactions with an overall frequency higher than 5% are presented in Table 
1 by randomized dose group and overall. Adverse reactions are ranked by 
frequency, with the most frequent reactions listed first. 
 
Table 1 - Adverse reactions [n (%)] with an overall frequency of more than 5% in 
the combined dose group in the Phase III study in Cushing’s disease patients 
 
Pasireotide 
0.6 mg bid 
N=82 
Pasireotide 
0.9 mg bid 
N=80 
Overall 
N=162 
Diarrhea 
48 (59) 
46 (58) 
94 (58) 
Nausea 
38 (46) 
46 (58) 
84 (52) 
Hyperglycemia 
31 (38) 
34 (43) 
65 (40) 
Cholelithiasis 
25 (30) 
24 (30) 
49 (30) 
Headache 
23 (28) 
23 (29) 
46 (28) 
Abdominal pain 
19 (23) 
20 (25) 
39 (24) 
Fatigue 
12 (15) 
19(24) 
31 (19) 
Diabetes mellitus 
13 (16) 
16 (20) 
29 (18) 
Injection site reactions 
14 (17) 
14 (18) 
28 (17) 
Nasopharyngitis 
10 (12) 
11 (14) 
21 (13) 


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Alopecia 
10 (12) 
10 (13) 
20 (12) 
Asthenia 
13 (16) 
5 (6) 
18 (11) 
Glycosylated hemoglobin increased10 (12) 
8 (10) 
18 (11) 
Alanine 
aminotransferase
i
d
11 (13) 
6 (8) 
17 (10) 
Gamma-glutamyl 
transferase increased 
10 (12) 
7 (9) 
17 (10) 
Edema peripheral 
9 (11) 
8 (10) 
17 (10) 
Abdominal pain upper 
10 (12) 
6 (8) 
16 (10) 
Decreased appetite 
7 (9) 
9 (11) 
16 (10) 
Hypercholesterolemia 
7 (9) 
9 (11) 
16 (10) 
Hypertension 
8 (10) 
8 (10) 
16 (10) 
Dizziness 
8 (10) 
7 (9) 
15 (9) 
Hypoglycemia 
12 (15) 
3 (4) 
15 (9) 
Type 2 diabetes mellitus 
10 (12) 
5 (6) 
15 (9) 
Anxiety 
5 (6) 
9 (11) 
14 (9) 
Influenza 
9 (11) 
5 (6) 
14 (9) 
Insomnia 
3 (4) 
11 (14) 
14 (9) 
Myalgia 
10 (12) 
4 (5) 
14 (9) 
Arthralgia 
5 (6) 
8 (10) 
13 (8) 
Pruritus 
6 (7) 
7 (9) 
13 (8) 
Lipase increased 
7 (9) 
5 (6) 
12 (7) 
Constipation 
7 (9) 
4 (5) 
11 (7) 
Hypotension 
5 (6) 
6 (8) 
11 (7) 
Vomiting 
3 (4) 
8 (10) 
11 (7) 
Back pain 
4 (5) 
6 (8) 
10 (6) 
Dry skin 
5 (6) 
5 (6) 
10 (6) 
Electrocardiogram QT prolonged 
5 (6) 
5 (6) 
10 (6) 
Hypokalemia 
6 (7) 
4 (5) 
10 (6) 
Pain in extremity 
6 (7) 
4 (5) 
10 (6) 
Sinus bradycardia 
8 (10) 
2 (3) 
10 (6) 
Vertigo 
4 (5) 
6 (8) 
10 (6) 
Abdominal distension 
4 (5) 
5 (6) 
9 (6) 
Adrenal insufficiency 
4 (5) 
5 (6) 
9 (6) 
Aspartate 
aminotransferase
increased 
6 (7) 
3 (4) 
9 (6) 
Blood glucose increased 
6 (7) 
3 (4) 
9 (6) 
Other notable adverse reactions which occurred with a frequency less than 5% 
were: anemia (4%); blood amylase increased (2%) and prothrombin time 
prolonged (2%). 
 
Gastrointestinal Disorders 
Gastrointestinal disorders, predominantly diarrhea, nausea, abdominal pain and 
vomiting were reported frequently in the Phase III trial (see Table 1). These events 


09/20/2017 
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began to develop primarily during the first month of treatment with pasireotide and 
required no intervention. 
 
Hyperglycemia and Diabetes 
Hyperglycemia-related terms were reported frequently in the Phase III trial. For all 
patients, these terms included: hyperglycemia (40%), diabetes mellitus (18%), 
increased HbA1c (11%), and type 2 diabetes mellitus (9%). In general, increases in 
fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) were seen soon after 
initiation of pasireotide and were sustained during the treatment period. In the 
pasireotide 0.6 mg group, mean fasting plasma glucose (FPG) levels increased from 
98.6 mg/dL at baseline to 125.1 mg/dL at Month 6. In the pasireotide 0.9 mg group, 
mean fasting plasma glucose (FPG) levels increased from 97.0 mg/dL at baseline to 
128.0 mg/dL at Month 6. In the pasireotide 0.6 mg group, HbA1c increased from 5.8% 
at baseline to 7.2% at Month 6. In the pasireotide 0.9 mg group, HbA1c increased 
from 5.8% at baseline to 7.3% at Month 6. 
 
At one month follow-up visits following discontinuation of pasireotide, mean FPG 
and HbA1c levels decreased but remained above baseline values. Long-term 
follow-up data are not available. 
 
Elevated Liver Tests 
In the Phase III trial, there were transient mean elevations in aminotransferase values 
in patients treated with pasireotide. Mean values returned to baseline levels by Month 
4 of treatment. The elevations were not associated with clinical symptoms of hepatic 
disease. 
 
In the clinical development program of pasireotide, there were 4 patients with concurrent 
elevations in ALT greater than 3 x ULN and bilirubin greater than 2 x ULN: one patient 
with Cushing’s disease and three healthy volunteers. In all four cases, the elevations 
were noted within the first 10 days of treatment. In all of these cases, total bilirubin 
elevations were seen either concomitantly or preceding the transaminase elevation. The 
patient with Cushing’s disease developed jaundice. All four cases had resolution of the 
laboratory abnormalities with discontinuation of pasireotide. 
 
Hypocortisolism 
Cases of hypocortisolism were reported in the Phase III study in Cushing’s disease 
patients. The majority of cases were manageable by reducing the dose of 
pasireotide and/or adding low-dose, short-term glucocorticoid therapy. 
 
Injection Site Reactions 
Injection site reactions were reported in 17% of patients enrolled in the Phase III trial 
in Cushing’s disease. The events were most frequently reported as local pain, 
erythema, hematoma, hemorrhage, and 
pruritus. These events resolved 
spontaneously and required no intervention. 
 
Thyroid function 


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Hypothyroidism with the use of pasireotide was reported for seven patients 
participating in the Phase III study in Cushing’s disease. All seven patients 
presented with a TSH close to or below the lower limit at study entry which 
precludes establishing a conclusive relationship between the adverse event and 
the use of pasireotide. 
 
Other Abnormal Laboratory Findings 
Asymptomatic and reversible elevations in lipase and amylase were observed in 
patients receiving pasireotide in clinical studies. Pancreatitis is a potential adverse 
reaction associated with the use of somatostatin analogs due to the association 
between cholelithiasis and acute pancreatitis. 
 
For hemoglobin levels, mean decreases that remained within normal range were 
observed. Also, post-baseline elevations in PT and PTT were noted in 33% and 47% of 
patients, respectively. The PT and PTT elevations were minimal. 
 
These laboratory findings are of unclear clinical significance. 
 
8.5 
Drug Interactions  
 
8.5.1 Effects of Other Drugs on Pasireotide 
Anti-Arrhythmic Medicines and Drugs that Prolong QT 
Co-administration of drugs that prolong the QT interval with pasireotide may have 
additive effects on the prolongation of the QT interval. Caution is required when co-
administering pasireotide with anti-arrhythmic medicines and other drugs that may 
prolong the QT interval [see Warnings and Precautions (5.3)]. 
 
8.5.2 Effects of Pasireotide on Other Drugs 
Cyclosporine 
Concomitant administration of cyclosporine with pasireotide may decrease the relative 
bioavailability of cyclosporine and, therefore, dose adjustment of cyclosporine to 
maintain therapeutic levels may be necessary 
 
Bromocriptine 
Co-administration of somatostatin analogues with bromocriptine may increase the blood 
levels of bromocriptine. Dose reduction of bromocriptine may be necessary. 
The use of anticoagulant medication should be avoided. Patients currently receiving 
supplemental pancreatic enzymes may be enrolled, but they should not start such 
treatment or increase the dose while on study. 
 
8.6 
Contraindications 
None 
 
 
 


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8.7 
Warnings 
 
8.7.1 Hypocortisolism 
Treatment with pasireotide leads to suppression of adrenocorticotropic hormone 
(ACTH) secretion in Cushing’s disease. Suppression of ACTH may lead to a decrease 
in circulating levels of cortisol and potentially hypocortisolism. 
 
Monitor and instruct patients on the signs and symptoms associated with 
hypocortisolism (e.g. weakness, fatigue, anorexia, nausea, vomiting, hypotension, 
hyponatremia or hypoglycemia). If hypocortisolism occurs, consider temporary dose 
reduction or interruption of treatment with pasireotide, as well as temporary, exogenous 
glucocorticoid replacement therapy.   
 
In a phase III study of patients with Cushing’s Disease, adrenal insufficiency was noted 
in 6% of patients that received a median of 10.4 months of pasireotide therapy (0.9mg 
BID).  Hypocortisolism is not expected to occur in this trial due to the relatively short 
duration of treatment. Therefore, cortisol assessment will not be required on this 
protocol, however, it may be performed at the investigator’s discretion. 
 
8.7.2 Hyperglycemia and Diabetes 
Elevations in blood glucose levels have been seen in healthy volunteers and patients 
treated with pasireotide. In the Phase III trial, the development of pre-diabetes and 
diabetes was observed [see Clinical Studies (14)]. In this trial, nearly all patients—
including those with normal glucose status at baseline, pre-diabetes, and diabetes—
developed worsening glycemia in the first two weeks of treatment. Cushing’s disease 
patients with poor glycemic control (as defined by HbA1c values >8% while receiving 
anti-diabetic therapy) may be at a higher risk of developing severe hyperglycemia and 
associated complications, e.g. ketoacidosis. 
 
Because of this predictable adverse reaction, the glycemic status [fasting plasma 
glucose (FPG) or hemoglobin A1c (HbA1c)] should be assessed prior to starting 
treatment with pasireotide. In patients with uncontrolled diabetes, intensive anti-diabetic 
therapy should be initiated prior to treatment with pasireotide. Monitoring of blood 
glucose and/or FPG assessments should be done at baseline, and transplant day 14. 
During pasireotide administrations, patients will typically be hospitalized as part of their 
preparative regimen and will follow standard of care hyperglycemia testing and 
management practices for inpatients.  
 
If hyperglycemia develops in a patient treated with pasireotide, the initiation or 
adjustment of anti-diabetic treatment is recommended. The optimal treatment for the 
management of pasireotide-induced hyperglycemia is not known. If uncontrolled 
hyperglycemia persists, despite appropriate medical management, the dose of 
pasireotide should be reduced or discontinued. 
 
After treatment discontinuation, glycemic monitoring (e.g. FPG or HbA1c should be 
done according to clinical practice. Patients who were initiated on anti-diabetic therapy 


09/20/2017 
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as a result of pasireotide may require closer monitoring after discontinuation of 
pasireotide, especially if the anti-diabetic therapy has a risk of causing hypoglycemia. 
 
8.7.3 Bradycardia and QT Prolongation 
Bradycardia 
Bradycardia has been reported with the use of pasireotide [see Adverse Reactions (6)]. 
Patients with cardiac disease and/or risk factors for bradycardia, such as history of 
clinically significant bradycardia, high-grade heart block, or concomitant use of drugs 
associated with bradycardia, should be carefully monitored. Dose adjustments of beta-
blockers, calcium channel blockers, or correction of electrolyte disturbances may be 
necessary. 
 
QT Prolongation 
Pasireotide is associated with QT prolongation. In two thorough QT studies with 
pasireotide, QT prolongation occurred at therapeutic and supra-therapeutic doses. 
Pasireotide should be used with caution in patients who are at significant risk of 
developing prolongation of QTc, such as those [see Clinical Pharmacology (12.2)]: 
•  
with congenital long QT prolongation. 
•  
with uncontrolled or significant cardiac disease including recent myocardial 
infarction, congestive heart failure, unstable angina or clinically significant 
bradycardia. 
•  
on anti-arrhythmic therapy or other substances that are known to lead to QT 
prolongation. 
•  
with hypokalemia and/or hypomagnesemia. 
  
A baseline ECG will be done at screening and at hours 1, 1.5, and 2 after the first dose 
of pasireotide.. Hypokalemia and hypomagnesemia must be corrected prior to the first 
dose of pasireotide administration and should be monitored and corrected per 
institutional practice during therapy. Prolonged QTc should be managed as per section 
11.4  
 
8.7.4 Liver Test Elevations 
In the Phase III trial, 5% of patients had an ALT or AST level greater than 3 times the 
upper limit of normal (ULN). In the entire clinical development program of pasireotide, 
there were 4 cases of concurrent elevations in ALT (alanine aminotransferase) greater 
than 3 x ULN and bilirubin greater than 2 x ULN: one patient with Cushing’s disease and 
three healthy volunteers [see Adverse Reactions (6)]. In these cases, total bilirubin 
elevations were seen either concomitantly or preceding the transaminase elevation. 
 
Monitoring of liver tests should be done at baseline and weekly starting day 0 through 
transplant day +100. If ALT is normal at baseline and elevations of ALT of 3-5 times the 
ULN are observed on treatment, repeat the test within a week or within 48 hours if 
exceeding 5 times ULN. If ALT is abnormal at baseline and elevations of ALT of 3-5 
times the baseline values are observed on treatment, repeat the test within a week or 
sooner if exceeding 5 times ULN. Tests should be done in a laboratory that can provide 
same-day results. If the values are confirmed or rising, interrupt pasireotide treatment 


09/20/2017 
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and investigate for probable cause of the findings, which may or may not be pasireotide-
related. Serial measures of ALT, aspartate aminotransferase, alkaline phosphatase, and 
total bilirubin, should be done weekly, or more frequently, if any value exceeds 5 times 
the baseline value in case of abnormal baselines or 5 times the ULN in case of normal 
baselines. If resolution of abnormalities to normal or near normal occurs, resuming 
treatment with pasireotide may be done cautiously, with close observation, and only if 
some other likely cause has been found.   See section 11.4 for dosing modification 
guidelines. 
 
8.7.5 Cholelithiasis 
Cholelithiasis has been frequently reported in clinical studies with pasireotide [see 
Adverse Reactions (6)]. For this reason, a gallbladder ultrasound will be performed at 
baseline (within 30 days prior to starting pasireotide) and between transplant days +4 
through +6 after the last day of pasireotide dosing. 
 
8.7.6 Monitoring for Deficiency of Pituitary Hormones 
As the pharmacological activity of pasireotide mimics that of somatostatin, inhibition of 
pituitary hormones, other than ACTH, may occur. Monitoring of pituitary function (e.g., 
TSH/free T4, GH/IGF-1) should occur at screening and at transplant day +14. . Patients 
who have undergone transsphenoidal surgery and pituitary irradiation are particularly at 
increased risk for deficiency of pituitary hormones. 
9 PATIENT ELIGIBILITY 
 
9.1 
Inclusion Criteria 
• 18 years of age or older at the time of study enrollment. 
• Histologically confirmed diagnosis for which an allogeneic transplant is utilized. 
• Plan to receive an allogeneic transplant from a 4-6/6 single or dual umbilical cord 
blood graft, or a 7-8/8 HLA-matched sibling or unrelated donor (High resolution 
HLA-A, B, C, DRB1). 
• Meet standard criteria as defined by the institution for a myeloablative allogeneic 
stem cell transplantation, with myeloablative defined as using conditioning 
regimens containing: 
o TBI ≥ 1200 cGy, or 
o Busulfan ≥ 12.8mg/kg 
• Patient must have given written informed consent according to FDA guidelines. 
• Willingness and ability to comply with scheduled visits, treatment plans, 
laboratory tests and other study procedures. 
 
 
9.2 
Exclusion Criteria 
• Female patients who are pregnant or lactating, or are of childbearing potential 
(FCBP, defined as all women physiologically capable of becoming pregnant) and 
not practicing an effective method of contraception/birth control 
• 
 FCBP must have a current negative serum pregnancy test prior to 
transplant per institutional practice. 
• Use of an investigational drug within 1 month prior to dosing.  


09/20/2017 
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• Concurrent enrollment on other clinical research studies that contain an 
interventional therapy is not permitted while subjects are receiving pasireotide or 
within 5 half-lives of finishing pasireotide. However, subjects may concurrently 
enroll in non-interventional studies (e.g. biobanking, mobile health tracking). 
• Active CNS disease (related to primary malignancy) at the time of enrollment. 
• Patients with existing grade 2 toxicities, except as approved by the investigator. 
• Any of the following diseases or conditions: 
• 
Cardiac: 
 History of unexplained syncope or family history of idiopathic 
sudden death. 
 Sustained or clinically significant cardiac arrhythmias. 
 Risk factors for Torsades de Pointes such as: 
• Uncontrolled hypokalemia 
• Uncontrolled hypomagnesemia or hypermagnesemia 
• Cardiac failure (New York Heart Association Class II or 
higher) 
• Clinically significant/symptomatic bradycardia (HR<50), or 
high-grade AV block. 
• Known diagnosis of QT prolongation (QTc ≥470) or family 
history of long QT syndrome 
• 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. 
• Concomitant medications known to prolong the QT interval 
during the same time as pasireotide is to be administered 
(unless approved by PI and QTc <470; standard transplant 
medications that are known to prolong the QT (e.g. azoles, 
ondansetron, etc.) are permitted but caution is advised and 
patients should be closely monitored). 
• 
Endocrine: 
 Uncontrolled diabetes at the time of cytoreduction. All patients with 
diabetes must be optimized on their diabetes regimen prior to 
initiating pasireotide. 
• If a patient is diabetic: uncontrolled diabetes as defined by 
HbA1c > 8%* despite adequate therapy  
 Patients who are not biochemically euthyroid. Patients with known 
history of hypothyroidism are eligible if they are on adequate and 
stable replacement thyroid hormone therapy for at least 3 months. 
 Known diagnosis of hypocortisolism 
 Known diagnosis of pituitary hormone deficiency. 
 Known hypersensitivity to somatostatin analogs or any component 
of the pasireotide LAR or s.c. formulations.  
• 
Infectious: 
 Uncontrolled (not being treated) infections at the time of 
cytoreduction. 


09/20/2017 
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 A positive HIV test result (ELISA and Western blot) or history of 
known HIV. An HIV test will not be required; however, previous 
medical history will be reviewed. 
• 
Gastrointestinal: 
 Moderately impaired hepatic function (Child-Pugh B) or severe 
hepatic impairment (Child-Pugh C)  
 Known gallbladder or bile duct disease, symptomatic cholelithiasis, 
acute or chronic pancreatitis. 
 Known malabsorption syndrome, short bowel or chologenic 
diarrhea not controlled by specific therapeutic means. 
• 
Hematologic: 
 Abnormal coagulation (PT or aPTT >30% above normal limits). 
 Continuous anticoagulation therapy. Patients who were on 
anticoagulant therapy must complete a washout period of at least 
10 days and have confirmed normal coagulation parameters before 
study inclusion. 
• 
Miscellaneous: 
 Major surgery/surgical therapy for any cause within 1 month prior to 
pasireotide administration. Patients should have recovered and 
have a good clinical condition before entering the study. 
 Any co-morbid condition which, in the view of the Principal 
Investigator, renders the patient at high risk from treatment 
complications. 
• Patients with a history of non-compliance to medical regimens or who are 
considered potentially unreliable or will not be able to complete the entire study. 
 
9.3 
Patient Numbering 
Each subject consented to this study will be assigned a unique study ID consisting of 
the abbreviation of the site name followed by consecutive three-digit numbering. 
 
In the case of screen failures, study IDs will not be reassigned and patient numbering 
will continue with the next consecutive number at that site. For example: 
 
Duke 
Massachusetts General 
DUK-001 
MGH-001 
DUK-002 
MGH-002 
DUK-003 
MGH-003 
 
 
10 MATERIAL AND DATA  
 
 
This protocol will require collection of basic demographic data, data on GVHD, and all 
toxicity data (related and unrelated to pasireotide).   
 
Study-specific data to be collected following initiation of study pasireotide:  


09/20/2017 
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• Basic demographic information to be collected at screening. 
• Data will be recorded regarding the subject’s conditioning regimen, GVHD 
prophylaxis, and any GVHD treatment received. 
• Routine labs and LFTs will be collected at screening, baseline, and transplant 
Days 0, +7, +14, continuing weekly through Day +100. 
• Serum hCG pregnancy test will be performed at screening. 
• Fasting plasma glucose or HbA1c, TSH, Free T4, Growth Hormone, and IGF-1 to 
be assessed at screening and on transplant Day +14. 
• Plasma citrulline samples will be collected at baseline and on transplant days  0, 
+7, and +14. 
• Fecal calprotectin samples will be collected at baseline and on transplant days 0, 
+7, and +14.  A +/- 1 day window is allowed for the collection of fecal samples. 
• 12-Lead ECGs will be completed at screening, and at 1 hour, 1.5 hours, and 2 
hours after the first dose of pasireotide.. 
• A gallbladder ultrasound will be completed at baseline (acceptable to perform 
within 30 days prior to pasireotide initiation) and transplant days +4 through +6. 
• Toxicity assessments will be completed at baseline, daily while on pasireotide 
and recorded at transplant days +7, +14, +21, +28 and +35.  The maximum 
grade of each toxicity occurring in the preceding period will be recorded at each 
assessment point.   
• Starting at Transplant Day 0, acute graft-versus-host disease is to be graded 
weekly through day +100, and on Day +180, and +365 using the BMT CTN 
Manual of Procedures, Version 3 (BMT CTN, 2013)17.  The maximum grade of 
GVHD that occurred during each assessment period should be reported. 
• Chronic graft-versus-host disease is to be graded at Transplant Day +100, +180, 
+270, and +365 using the 2014 NIH Consensus Criteria (Jagasia et. Al., 2014)18.  
The maximum grade of GVHD that occurred during each assessment period 
should be reported. 
•  Overall and disease-free survival, along with cause of death (if applicable) is to 
be assessed at transplant day +100, +180, and +365.  
 
Duke Only: 
• A subset of 10 patients will complete a video capsule endoscopy between 
Transplant Days +4 through +6. 
 
 
11 TREATMENT PLAN AND MODIFICATIONS 
 
 
The plan would be an initial phase II study to measure efficacy, as well as toxicity, of 
pasireotide in decreasing grade 3-4 GI toxicities through Transplant Day +30. 
 
 
 
Study Phase:  
 


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The proposed study will be a phase II, non-randomized study. If the phase II study 
demonstrates improved efficacy, we would propose to move this to a phase III. Data 
collected from these patients would be significant to help inform the design and potential 
efficacy of this drug.  
 
11.1  Study Design:   
The study design will be a non-randomized phase II. Forty patients receiving an ablative 
preparatory regimen will receive pasireotide subcutaneous (0.9 mg Q12H.) one day 
prior to initiation of the preparatory regimen (at least 15 hours prior to initiation of 
conditioning) and continuing for four days following stem cell transplant not to exceed 
14 days total dosing of pasireotide (i.e. stop on Day +4 after transplant or Day 14 of 
pasireotide, whichever is sooner - maximum of 28 doses). Myeloablative preparatory 
regimens are defined as those including either TBI ≥ 1200 cGy or busulfan ≥ 12.8 
mg/kg. We will select matched controls from existing patients who did not enroll on the 
pasireotide study to minimize the time it takes to complete the trial.  
 
The most common regimens combine TBI with cyclophosphamide (TBI/Cy) or busulfan 
with cyclophosphamide (Bu/Cy) (Appendix E).  However, any regimen meeting the 
above definition of myeloablative preparatory regimen may be used. 
 
The study will collect data at screening, at baseline prior to initiation of the drug (day of 
study drug start), transplant day 0, day +7, day +14  and weekly thereafter until day 
+100, and on days +180, +270, and +365.. The total days on pasireotide therapy will be 
recorded as well as any SAE that is outside the expected for stem cell transplantation. 
We will also follow the incidence and severity of acute and chronic GVHD. 
 
11.2  Video Capsule Endoscopy 
At Duke only, a video capsule endoscopy will be performed in a subset of ten study 
patients between transplant days +4 through +6. This substudy is descriptive in nature 
and only used to collect a source of preliminary data that may suggest further study.   
 
Patients must agree to participate in this portion of the study and will be asked to sign a 
clinical consent for performance use of the video capsule endoscopy. Patients will be 
given detailed instructions to prepare for the procedure (Appendix B). 
  
An investigator who is blinded to the group allocation of the patients/volunteers 
separately will review the images obtained from each of the capsule examinations. 
Images will be examined for evidence of the four following types of abnormalities: 
reddened/edema/villous blunting, erosion, ulcer and stenosis.  Each of these categories 
will be scored from 0-3 and summed to obtain an overall index that will range from 0 
(normal study) to 12 (severely abnormal in all categories). 
 
A baseline video capsule endoscopy will not be performed, as at baseline  patients will 
not yet have begun myeloablative conditioning (e.g., pasireotide starts Day -5, 
myeloablative conditioning starts Day -4). Therefore, endoscopies should be normal in 
all patients (all scores = 0). As a result, we do not think it is ethical to subject patients to 


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a video capsule endoscopy at baseline as we do not think there is any scientific 
benefit. Furthermore, we do not propose to compare video capsule endoscopy at end of 
trial to baseline; rather, we propose to compare video capsule endoscopy at transplant 
Day 4-6 in 10 treated patients to Day 4-6 in 5 untreated control patients.  
 
Of note, because citrulline and calprotectin may vary at baseline, and because we do 
plan to evaluate changes in these studies over time, we will collect these studies at 
baseline, Day 0, Day +7, and Day +14. 
 
11.3 Biomarker Assays 
 
11.3.1 Citrulline assay 
Measurement of citrulline concentration has been used as a marker for cytotoxic 
treatment-induced intestinal damage and it is highly reproducible.  The citrulline 
concentration appears to be a quantitative parameter that is independent of the 
underlying cause for epithelial cell loss and functions well in the post-SCT setting [13].   
 
• Citrulline Assay: Collect one 6.0ml Sodium Heparin (NaH – green top) tube at 
each timepoint. Sample should be labeled with patient’s study ID, sample type, 
and date and time of sample collection.  Process sample within 2 hours. 
o Thoroughly mix the blood by inverting the tube 8 to 10 times.  
o Centrifuge at approximately 2500 rpm for 10 minutes until serum is well 
separated.  
o Use pipette to aliquot the plasma evenly into 3 sterile 2ml cryovials. 
o Ensure that each cryovial is labeled with patient’s study ID, sample type, 
and date and time of sample collection; no PHI should be included.  
o Freeze at -80°C until shipment.  
o Ship frozen on dry ice. 
 
11.3.2 Calprotectin assay 
Calprotectin has been described as another biomarker of GI injury.  During radiation-
induced inflammation, leucocytes infiltrate the mucosa and increase the level of fecal 
calprotectin [15, 16].  Calprotectin will be measured with an ELISA kit (CALPRO, Oslo, 
Norway) in accordance with the manufacturer’s instructions. 
 
• Calprotectin Assay: Collect at least a 50 mg (walnut-sized) stool sample into a 
sterile specimen container (with no additive) at each timepoint (+/- 24 hours). 
Sample should be labeled with patient’s study ID, sample type, and date and 
time of sample collection. Refrigerate until processed. Process sample within 24 
hours as follows: 
o Stool should be mixed using a disposable sterile spatula (if solid) or 
dropper (if liquid) and transferred into cryovials using that same spatula or 
dropper. 
o Aliquot stool sample evenly into 9 sterile 2-ml cryovials.  
o Ensure that each cryovial is labeled with patient’s study ID, sample type, 
and date and time of sample collection; no PHI should be included.  


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o Freeze at -80°C until shipment.  
o Ship frozen on dry ice. 
 
Please ship all samples to the attention of: 
 
Chao Lab c/o Megan Baker 
 
 
905 S. LaSalle St 
Genome Sciences Research Building I, Rm 4022 
Durham, NC  27710 
 
11.4  Dose Modifications and Treatment Interruptions/Discontinuation 
 
If the patient experiences toxicities requiring dose reduction of pasireotide, the reduced 
dose will be maintained for all subsequent doses unless further toxicities occur. No dose 
re-escalation is permitted. 
 
If pasireotide dosing is held, the study calendar is not affected and all study visits will 
remain due at the originally scheduled time.  Pasireotide therapy should end by 
Transplant Day +4 or 14 days of treatment (28 total doses), whichever is sooner. 
 
Pasireotide Dose Adjustment Schedule 
 
Dose Level 0 (Starting Dose) 
0.9mg Q12H 
Dose Level -1 
0.6mg Q12H 
Dose Level -2 
0.3mg Q12H 
Dose Level -3 
Discontinue Pasireotide 
 
If the patient experiences a toxicity ≥ Grade 3 (CTCAE v.4) suspected to be related to 
pasireotide, hold pasireotide until the toxicity resolves to ≤ Grade 3 and restart 
pasireotide  with a one level dose reduction according to the table above. 
 
If the patient experiences a toxicity ≥ Grade 4 that is judged to be unrelated to 
pasireotide, hold pasireotide until the toxicity resolves to < Grade 4 then 
restart pasireotide at the same dose. No dose reduction is required. 
 
Toxicities of Special Interest 
 
Hyperglycemia – should be managed per institutional practice [guidance for glucose 
management suggested in Appendix C] 
• For Glucose > 250 but < 500 mg/dL, treat according to institutional practice. 
Pasireotide dosing may continue at same dose. 
• For Glucose >500 mg/dL, hold pasireotide and treat according to institutional 
practice. Pasireotide may be restarted with a one level dose reduction when 
glucose has been reduced to < 500mg/dL. 
 
Elevated LFTs 


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• If ALT, AST, or Alkaline Phosphatase is ≥ Grade 3, regardless of attribution, 
hold pasireotide. Pasireotide may be restarted with a one level dose reduction 
when toxicity has resolved to < Grade 3. 
  
In addition, if any of the following criteria are met, study drug may be discontinued at the 
discretion of the investigator: 
• Unacceptable toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the 
subject’s best interest  
• Subject request to discontinue for any reason 
• Proven non-compliance with treatment or scheduled evaluation 
• Discontinuation of the study at the request a regulatory agency, or the governing 
institutional review board (IRB) 
11.5 Study Withdrawal 
The subject is to be withdrawn from study in the event of: 
• Disease relapse,  
• Subject never receives pasireotide,  
• Graft failure (withdrawal to occur at the time when new antineoplastic therapy or 
conditioning chemotherapy for a 2nd transplant is initiated), 
• Transfer to Hospice, 
• or other such events approved by study PI. 
 
 
12 ANTICIPATED TOXICITIES.   
 
 
Safety will be assessed based on CTCAE v. 4.0 criteria. Patients receiving stem cell 
transplantation have an expected rate of events. While we realize 21CFR312.32 
(http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32) does 
not draw a distinction between suspected events related to the study drug and 
suspected events related to normal medical care (i.e. HSCT), because HSCT is 
associated with such a high rate of expected adverse events, we believe the distinction 
between "suspected-related to HSCT" and "suspected-related to study drug" is relevant, 
and prefer this terminology to "expected", "labeled", and "non-labeled" (though we retain 
the category of "unexpected" as suggested and per 21CFR312.32). We will specifically 
assess for unexpected adverse events as these patients are closely monitored on a 
daily basis. 
 
Clinically significant adverse reactions associated with the administration of pasireotide 
that appear in “Warnings” sections of this protocol include: 
 
• Hyperglycemia and Diabetes 
• Bradycardia and QT prolongation 
• Liver test elevations 
• Cholelithiasis  
• Pituitary hormone deficiency 


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• Hypocortisolism  
 
The following toxicities are anticipated following allogeneic stem cell transplantation and 
will therefore not be reportable to the IRB unless they occur at a frequency that 
suggests association with the study drug. 
 
12.1 Myelosuppression:   
Following donor stem cell engraftment, persistent pancytopenia is common following 
allogeneic stem cell transplantation.  Marrow aplasia may be incited by an adverse drug 
reaction or by infection such as cytomegalovirus. 
 
12.2 Gastrointestinal:   
Nausea and vomiting can be expected during the post-transplant period.  The most 
common cause for GI disturbance is drug-related or residual mucosal damage from the 
bone marrow preparative regimen. Mucositis and diarrhea may also occur and will be 
supported with standard measures. 
 
12.3 Hyperglycemia 
 
Hyperglycemia has been observed in patients using pasireotide therapy. Based on this 
finding, we suggest that optimal glucose control should be achieved before starting a 
patient on pasireotide. 
 
12.4 Cardiac:   
High-dose chemotherapy can cause acute cardiotoxicity in doses used in this protocol 
(congestive heart failure, pericardial effusion, arrhythmias, EKG changes).  Rarely, 
these may prove to be lethal.  Pericardial effusions can also occur as an unusual 
manifestation of graft versus host disease. 
 
A small number of cases of QT prolongation have been reported in some           
participants in pasireotide clinical trials.  QT is one of the measurements taken during 
an ECG (heart tracing) and increase (prolongation) in QT may lead to an irregular 
heartbeat which in rare instances can develop into a sudden, life-threatening condition. 
The majority of cases that were reported in the pasireotide clinical trials resolved or 
improved spontaneously without discontinuation of the study drug. Though the risk is 
small, these findings may indicate a potential risk for an irregular heart rate associated 
with the treatment with pasireotide. 
 
12.5 Pulmonary:   
Pulmonary toxicity from the preparative regimen has been described, and often 
presents as diffuse alveolar hemorrhage. Hemorrhage may also occur within the first 
100 days following transplantation, although the inciting event is likely not the bone 
marrow preparative regimen.  Diffuse interstitial pneumonitis of unknown etiology 
(infectious, toxic, or multifactorial) is a well-described toxicity of intensive chemotherapy 
and TBI regimens and may prove lethal. TBI may also cause late pulmonary 
dysfunction. 


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12.6 Hepatic:   
Tacrolimus or other hepatoxic drugs may result in elevated levels of hepatic enzymes 
and may also cause elevations in bilirubin. 
 
12.7 Renal:   
Mild elevations of BUN and creatinine may be seen in patients treated with high dose 
chemotherapy and/or Tacrolimus.  These are generally reversible.  Renal dysfunction, 
which is usually mild and reversible, may rarely be seen after TBI at the doses used in 
this protocol.  A syndrome of moderate renal insufficiency and hemolysis (Thrombotic-
thrombocytopenic purpura/hemolytic uremic syndrome) has been seen 5-18 months 
post-bone marrow transplantation after intensive multi-agent conditioning +/- TBI.  This 
also is usually reversible, but the long-term sequelae are not yet clear.  
 
12.8 GVHD:   
Grade II-IV acute GVHD occurs in 20-40% of patients receiving matched-sibling or 
partially matched allogeneic stem cell transplantation.  GVHD typically causes skin rash, 
liver function test abnormalities and colitis. The severity of the acute GVHD is quite 
variable, however the severe cases can be fatal.  Chronic GVHD occurs greater than 
100 days following stem cell transplantation and affects approximately 50% of 
recipients.  Chronic GVHD is manifested in the skin, liver, mucous membranes and less 
commonly in the lung and intestinal tract.  10 to 20% of those patients who develop 
chronic GVHD will ultimately die of complications stemming from this disease. 
 
12.9 Neurologic:   
Posterior reversible encephalopathy syndrome (PRES) may occur as a consequence of 
the total body irradiation.     
 
12.10 Miscellaneous: 
• 
Transfusion reactions 
• 
Glucose intolerance due to multiple medications ( e.g. calcineurin inhibitors and 
glucocorticoids 
• 
Late effects of transplant regimens including: cataracts, infertility, growth 
impairment, hypothyroidism, and dental caries. 
• 
Headache, insomnia, psychosis, mood changes, disorientation, seizures from 
metabolic imbalance. 
• 
Well-characterized drug reactions - allergic manifestations, "red man" syndrome. 
well-characterized drug side effects from drugs used routinely in transplant 
recipients (e.g.; preparative regimen chemotherapy, immunosuppressive drugs, 
antimicrobials) 
• 
Common side effects of antiemetics, analgesics, anti-inflammatory agent and 
known complications of steroid therapy. 
• 
Complications from intravenous catheters, thrombotic occlusion, infection, local 
reactions, cardiac arrhythmia.Post-transplant microangiopathy. 
 
 


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13 DATA MANAGEMENT AND DATA SAFETY MONITORING 
 
 
13.1 Data Management 
 
13.1.1 Electronic Case Report Forms (eCRFs) 
This study will utilize eCRFs in a REDCap database for data reporting. REDCap is a 
software tool that does not require client local software and can be accessed from 
anywhere on the Internet and is secured on a Duke Health Technology Services 
(DHTS) server. This database will be developed and maintenance performed with 
support of the School of Medicine (SOM) Duke Office of Clinical Research (DOCR). 
SOM’s DOCR has partnered with the School of Medicine (SOM) to implement REDCap 
(developed by Vanderbilt’s CTSA and currently used and supported by more than 1600 
consortium partners. REDCap provides: 1) a stream-lined process for rapidly building a 
database; 2) an intuitive interface for collecting data (with data validation and audit trail); 
3) automated export procedures for seamless data downloads to common statistical 
packages (SAS, SPSS, etc.); 4) branching logic, file uploading, and calculated fields; 
and 5) a quick and easy protocol set-up.  
 
REDCap accounts are stored within the DTMI LDAP server hosted by the Duke Office 
of Information Technology (OIT). Authentication occurs via the OIT implementation of 
Kerberos. All connections to the system, both external and internal, occur over 
encrypted channels. Access to components of the system is role-based and can only be 
granted by administrators of the system. All collected information is stored on a 
database server hosted by Duke Health Technology Services (DHTS). The database 
server resides behind the DHTS internal firewall and access to the server is controlled 
via firewall rules. All collected data are backed up daily, both on the local server and by 
the DHTS enterprise backup system. The Office of Research Informatics-App 
Engineering-DHTS (ORI) via ServiceNow (919 668-7286) is responsible for managing 
the server for REDCap. Duke Office of Clinical Research (Ceci Chamorro 919-668-
9262) is responsible for managing the database platform for REDCap. At the time of this 
submission, REDCap is on version 6.5.15.19 
 
The eCRFs will be the primary data collection documents for this study.  Sites will 
update the eCRFs in a timely manner following acquisition of new source data.   
 
13.1.2 Data Management Procedures and Data Verification 
Data collected for the study and entered into the RedCap database will be verified 
against original source documents.  Source documentation for study data points may be 
redacted, labeled with the subjects’ study ID, and sent to the coordinating site via email 
or fax.  This source documentation will be filed in individual subject study binders for 
verification at monitoring visits and study audits.   
  
Alternatively, source documentation may be verified remotely through direct access to 
the electronic medical record via secure methods approved by Duke and the PI of the 
study. 


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13.1.3 Study Closure 
Following completion of the studies, the PI will be responsible for ensuring the following 
activities: 
 
• 
Data clarification and/or resolution 
• 
Accounting, reconciliation, and destruction/return of used and unused study 
drugs 
• 
Review of site study records for completeness 
• 
Shipment of all remaining laboratory samples to the designated laboratories 
 
13.2 Data Safety Monitoring 
The DCI Monitoring Team will conduct monitoring visits to ensure subject safety and to 
ensure that the protocol is conducted, recorded, and reported in accordance with the 
protocol, standard operating procedures, good clinical practice, and applicable 
regulatory requirements.  As specified in the DCI Data and Safety Monitoring Plan, the 
DCI Monitoring Team will conduct routine monitoring after the third subject is enrolled, 
followed by annual monitoring of 1- 3 subjects until the study is closed to enrollment and 
subjects are no longer receiving study interventions that are more than minimal risk. 
 
The Safety Oversight Committee (SOC) will perform annual reviews on findings from 
the DCI Monitoring Team visit and additional safety and toxicity data submitted by the 
Principal Investigator. 
 
Additional monitoring may be prompted by findings from monitoring visits, unexpected 
frequency of serious and/or unexpected toxicities, or other concerns and may be 
initiated upon request of DUHS and DCI leadership, the CPC, the Safety Oversight 
Committee (SOC), the sponsor, the Principal Investigator, the Duke Clinical Trials 
Quality Assurance (CTQA) office or the IRB.  All study documents must be made 
available upon request to the DCI Monitoring Team and other authorized regulatory 
authorities, which may include but is not limited to the FDA.  Every reasonable effort will 
be made to maintain confidentiality during study monitoring. 
 
 
 
14 SAFETY AND STUDY DATA MONITORING  
 
 
14.1  Safety 
 
14.1.1 Adverse Event Reporting.   
The investigator is required by Federal Regulations to report adverse events (AEs) that 
occur through the duration of the study according to the appropriate procedures listed 
below.  The investigator is required to notify the FDA, and Duke University Health 
System (DUHS) Institutional Review Board (IRB) Office if an event is serious, 
unexpected, and related or possibly related to the drug. 


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We will record all grades 2-4 adverse events (excluding lab values) from the time of 
consent through 30 days after the last dose of pasireotide. It will be noted if the event 
arose from a preexisting or grade 1 toxicity. 
•         Each event needs to be categorized as one of the following: 
o   Expected – Related to transplant (sections 12.1-12.10) 
o   Expected – Related to Pasireotide (section 12.0) 
o   Unexpected – Related to Transplant  
o   Unexpected – Related to Pasireotide 
 
 
All "life-threatening" and "serious adverse events" will be reported regardless of 
suspicion of etiology. In addition, we plan to report "suspected-related to study drug" 
and "unexpected" events. We do not propose to report adverse events that 
are "suspected-related to HSCT" that are not "life-threatening" or "serious adverse 
events" as nearly 100% of patients undergoing HSCT will experience adverse events 
that are "suspected-related to HSCT" (e.g. historical rate of GI toxicity of myeloablative 
HSCT itself is 90%, not to mention myelosuppression (100% of patients) and other 
common adverse events related to HSCT).  
 
Definitions:  An adverse event is any untoward medical occurrence associated with the 
use of a drug in humans, whether or not considered drug related. 
 
A serious adverse event (SAE): an adverse event or suspected adverse reaction is 
considered "serious" if, in the view of either the investigator, it results in any of the 
following outcomes: 
• Death 
• A life-threatening adverse event in the view of the investigator its occurrence 
places the patient at immediate risk of death 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, "reasonable possibility" means there is evidence to suggest a causal 
relationship between the drug and the adverse event. Suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug. 
 


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Unexpected adverse event or unexpected suspected adverse reaction. An adverse 
event or suspected adverse reaction is considered "unexpected" if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been 
observed; or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the 
current application. 
 
Any SAE will be reported to Duke, Novartis, and the FDA as soon as possible, but in no 
case later than 7 calendar days after receipt of the information.  Each notification to 
FDA will be transmitted to the review division in the Center for Drug Evaluation and 
Research or in the Center for Biologics Evaluation and Research that has responsibility 
for review of the IND 
 
This study will utilize the NCI Common Toxicity Criteria for Adverse Events (CTCAE) 
version 4.0 to determine the severity of the reaction for adverse event reporting. Any 
reaction that is reportable (serious, unexpected and related/possibly related to the 
study) must be reported using the FDA #3500 MedWatch form and the Novartis SAE 
coversheets (Appendix H).  All AEs reported will be recorded on an electronic AE Case 
Report Form (CRF).    
 
14.1.2 SAE Reporting 
The principal investigator has the obligation to report all serious adverse events to the 
FDA, IRB, and Novartis Pharmaceuticals Drug Safety and Epidemiology Department 
(DS&E). 
 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 
3500A (MedWatch Form) and the Novartis SAE coversheets (Appendix H).  
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after 
the patient has provided informed consent and until at least 30 days after the patient 
has stopped pasireotide must be reported to Duke (Fax: 919-668-1091) and Novartis 
within 24 hours of learning of its occurrence (Fax: 1-877-778-9739) using the 
coversheets found in Appendix H. This includes serious, related, labeled (expected) and 
serious, related, unlabeled (unexpected) adverse experiences. All deaths during 
treatment or within 30 days following completion of active protocol therapy must be 
reported within 5 working days. 
 
Any SAEs experienced after this 30 day period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the 
original episode within 24 hours of the investigator receiving the follow-up information. A 
SAE occurring at a different time interval or otherwise considered completely unrelated 
to a previously reported one should be reported separately as a new event.  The end 
date of the first event must be provided. 
 


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The original copy of the SAE Report and the fax confirmation sheet must be kept within 
the Trial Master File at the study site. 
 
Follow-up information is sent to the same fax number as the original SAE Report Form 
was sent, using a new fax cover sheet, stating that this is a follow-up to the previously 
reported SAE, and giving the date of the original report. Each re-occurrence, 
complication, or progression of the original event should be reported as a follow-up to 
that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the 
blind was broken or not (if applicable), and whether the patient continued or withdrew 
from study participation. 
 
If the SAE is not previously documented in the SOM230 Investigator Brochure or 
Package Insert (new occurrence) and is thought to be related to the Novartis study 
drug, a DS&E associate may urgently require further information from the investigator 
for Health Authority reporting. Novartis may need to issue an Investigator Notification 
(IN), to inform all investigators involved in any study with the same drug that this SAE 
has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will 
be collected and reported to the competent authorities and relevant ethics committees 
in accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries. 
 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious 
adverse experiences will be forwarded to the comparator drug company by the 
investigator. 
 
14.1.3 Pregnancy 
The potential reproductive risk for humans is unknown.  Women of childbearing 
potential should be advised to use highly effective contraception methods while they are 
receiving SOM230 and up to 8 weeks after treatment has been stopped.   
 
To ensure patient safety, each pregnancy occurring while the patient is on study 
treatment must be reported to Duke and Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence 
of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. The newborn will be followed for at least 12 months. 
 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to Duke and to the oncology Novartis Drug Safety and Epidemiology 
Department (DS&E). Pregnancy follow-up should be recorded on the same form and 
should include an assessment of the possible relationship to the study treatment and 
any pregnancy outcome. Any SAE experienced during pregnancy must be reported on 
the SAE Report Form. 
 


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14.2 Data Monitoring:  
This clinical research study will be monitored both internally by the PI and externally by 
the Duke University Medical Center Cancer Center’s Protocol Review and Monitoring 
system in accord with their NCI- approved “Institutional Protocol Monitoring Procedures 
and Guidelines for NIH-Sponsored Research Involving Human Subjects.” 
 
In terms of internal review, the PI and the Co-PI will continuously monitor and tabulate 
adverse events. Appropriate reporting to the Duke University Medical Center IRB will be 
made.  If an unexpected frequency of grade III or IV events occur, depending on their 
nature, action appropriate to the nature and frequency of these adverse events will be 
taken.  This may require a protocol amendment, or potential closure of the study.  The 
severity of adverse events will be classified according to the NCI CTC.   
 
The DCI Monitoring Team will conduct monitoring visits to ensure subject safety and to 
ensure that the protocol is conducted, recorded, and reported in accordance with the 
protocol, standard operating procedures, good clinical practice, and applicable 
regulatory requirements.  As specified in the DCI Data and Safety Monitoring Plan, the 
DCI Monitoring Team will conduct routine monitoring after the third subject is enrolled, 
followed by annual monitoring of 1 – 3 subjects until the study is closed to enrollment 
and subjects are no longer receiving study interventions that are more than minimal 
risk.   
 
The DCI Safety Oversight Committee (SOC) will perform annual reviews on findings 
from the DCI Monitoring Team visit and additional safety and toxicity data submitted by 
the Principal Investigator. 
 
Additional monitoring may be prompted by findings from monitoring visits, unexpected 
frequency of serious and/or unexpected toxicities, or other concerns and may be 
initiated upon request of DUHS and DCI leadership, the CPC, the Safety Oversight 
Committee (SOC), the Duke University Office of Audit, Risk, and Compliance- Human 
Subjects Research Compliance Office, the sponsor, the Principal Investigator, or the 
IRB.  All study documents must be made available upon request to the DCI Monitoring 
Team and other authorized regulatory authorities, which may include but is not limited to 
the National Institute of Health, National Cancer Institute, and the FDA.  Every 
reasonable effort will be made to maintain confidentiality during study monitoring. 
 
The Duke University Office of Audit, Risk, and Compliance – Human Subjects Research 
Compliance (OARC HSRC) office may conduct confidential audits to evaluate 
compliance with the protocol and the principles of GCP. The PI agrees to allow the 
OARC HSRC auditor(s) direct access to all relevant documents and to allocate his/her 
time and the time of the study team to the OARC HSRC auditor(s) in order to discuss 
findings and any relevant issues. 
 
 
15 STATISTICAL CONSIDERATIONS 
 


09/20/2017 
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15.1  Objectives 
 
15.1.1 Primary Objective:  
To evaluate the efficacy and safety of pasireotide in mitigating GI toxicity from the 
preparatory regimens of allogeneic stem cell transplantation compared to historical 
controls.   
 
The control group will be selected from about 400 existing patients who did not enroll on 
this study. This group will be matched based on age, disease, GVHD prophylaxis, 
preparatory regimen (TBI or busulfan), graft source, and number of prior therapies.  
 
Efficacy will be assessed as the incidence of all Grade III-IV gastrointestinal toxicities 
occurring from the baseline visit through transplant day +30. Toxicities will be graded 
according to CTCAE v. 4.0 and labeled using CTCAE criteria found under the heading 
of “Gastrointestinal disorders”.  This will include symptoms of nausea, vomiting, 
diarrhea, abdominal pain, distention, mucositis, and the like. It will be noted if the toxicity 
arose from a preexisting or grade 1 toxicity. 
 
15.1.2 Secondary Objectives:   
To evaluate the efficacy of pasireotide in reducing the incidence and severity of acute 
GVHD at 100 days post-transplant compared to historical controls.   
 
To evaluate the efficacy of pasireotide in reducing the incidence and severity of chronic 
GVHD at 1 year post-transplant. 
 
To compare the rate of overall survival in patients treated with pasireotide at 1 year 
post-transplant to historical controls.  
 
To compare the rate of disease free survival in patients treated with pasireotide at 1 
year post-transplant to historical controls.  
 
15.2  Exploratory Objectives:  
To evaluate plasma citrulline and fecal calprotectin levels as biomarkers of GI tract 
health and function in SCT patients and the correlation between these biomarkers and 
GI toxicity.  The control population would consist of bone marrow transplant patients, 
being seen concurrently and who also consented to participate in Pro00006268. 
 
To evaluate GI toxicity assessment by video capsule endoscopy.  We will enroll 10 
subjects who take pasireotide and 5 controls who do not receive pasireotide.   
 
15.3  Endpoints:   
 
15.3.1 Primary Endpoint 
The primary endpoint for the study will be the incidence of grades III-IV GI toxicity in 
SCT patients who are treated with pasireotide. 


09/20/2017 
Page 39 of 61 
 
 
We plan to enroll 40 patients in the trial and select 40 matched controls. After collecting 
data, we will use the Chi-square test to test for the hypothesis H0: p0≤p1 versus H1: 
p0>p01, where p0 and p1 are the rates of GI toxicity for SCT patients who don’t take 
pasireotide and who take pasireotide, respectively. Historical data show that the rate of 
GI toxicity without the drug is about 90%, and we expect that the GI toxicity rate in 
patients who receive pasireotide will decrease to about 50%. With this number of 
patients, the power of the test is close about 0.99 with a type I error rate 0.05 under our 
expected rates of GI toxicity. We can still achieve 80% power under a very conservative 
estimate of GI toxicity rate for those who take drug of 0.65. 
 
15.3.2 Secondary Endpoints 
The incidence and severity of acute or chronic GVHD in SCT patients who receive 
pasireotide. We will test for the hypothesis H0: q0=q1 versus H1: q0>q1 using the Chi-
square test, where q1 and q0 are the rates of GVHD in patients with and without 
pasireotide respectively. 
 
We will compare GVHD incidence rates between treatment group versus historical 
control group using survival type regression modeling that takes competing risks into 
account. We will examine cause-specific Cox proportional hazards models as well as 
the proportional subdistribution hazard regression model developed by Fine and Gray. 
While the primary treatment comparison will be unadjusted, adjustment for covariates to 
explore the impact of various risk factors will also be performed. 
 
Survival outcomes will be analyzed in a similar fashion to GVHD, as described above. 
 
15.3.3 Exploratory Endpoints 
 
As exploratory endpoints, citrulline and fecal calprotectin levels will be measured at 
baseline and transplant day 0, +7, and +14 and descriptive statistics such as means 
and standard deviations will be calculated. Logistic regression analysis will be 
performed to evaluate the correlation between the highest measured biomarker level 
and the incidence of GI toxicity.   
 
Video Capsule  
The means of mucositis in the video endoscopy group and the control group will be 
compared using the Student’s t test. 
15.4  Stopping Rules 
We will monitor 6-month treatment related mortality (TRM) in two stages. At DUMC, the 
TRM rate has been 0.2 with standard care (consistent with rates in the literature of 16-
30%). We will consider a rate of .35 or higher to be unacceptable.  We will use the 
following sequential rules to determine early stopping due to excessive TRM.  
Stage 
Number of patients accrued 
Stop trial if 6-month TRM 
≥ 
1 
15 
6 
2 
30 
11 


09/20/2017 
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This rule will have probability of 0.13 of stopping if the actual TRM rate is at the 
acceptable rate of 0.20 and a probability of 0.86 of stopping early if the true TRM rate is 
at the unacceptable rate of 0.35. 
 
 
 
 


09/20/2017 
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16  
REFERENCES 
 
1. 
Dainiak, N., et al., The hematologist and radiation casualties. Hematology Am 
Soc Hematol Educ Program, 2003: p. 473-96. 
2. 
Hauer-Jensen, M., et al., Radiation damage to the gastrointestinal tract: 
mechanisms, diagnosis, and management. Curr Opin Support Palliat Care, 2007. 
1(1): p. 23-9. 
3. 
Nejdfors, P., et al., Intestinal permeability in humans is increased after radiation 
therapy. Dis Colon Rectum, 2000. 43(11): p. 1582-1587; discussion 1587-8. 
4. 
Morgenstern, L. and N. Hiatt, Injurious effect of pancreatic secretions on 
postradiation enteropathy. Gastroenterology, 1967. 53(6): p. 923-9. 
5. 
Hauer Jensen, M., et al., Influence of pancreatic secretion on late radiation 
enteropathy in the rat. Acta Radiol Oncol, 1985. 24(6): p. 555-60. 
6. 
Morgenstern, L., et al., Prolongation of survival in lethally irradiated dogs by 
pancreatic duct ligation. Arch Surg, 1970. 101(5): p. 586-9. 
7. 
Shinozaki, H., et al., Effect of somatostatin on pancreatic enzyme secretion. 
Gastroenterol Jpn, 1988. 23(6): p. 673-9. 
8. 
Williams, S.T., et al., Effect of octreotide acetate on pancreatic exocrine function. 
Am J Surg, 1989. 157(5): p. 459-62. 
9. 
Wang, J., et al., The synthetic somatostatin analogue, octreotide, ameliorates 
acute and delayed intestinal radiation injury. Int J Radiat Oncol Biol Phys, 1999. 
45(5): p. 1289-96. 
10. 
Yavuz, M.N., et al., The efficacy of octreotide in the therapy of acute radiation-
induced diarrhea: a randomized controlled study. Int J Radiat Oncol Biol Phys, 
2002. 54(1): p. 195-202. 
11. 
Ma, P., et al., Pharmacokinetic-pharmacodynamic comparison of a novel 
multiligand somatostatin analog, SOM230, with octreotide in patients with 
acromegaly. Clin Pharmacol Ther, 2005. 78(1): p. 69-80. 
12. 
Fu, Q., et al., The somatostatin analog SOM230 (pasireotide) ameliorates injury 
of the intestinal mucosa and increases survival after total-body irradiation by 
inhibiting exocrine pancreatic secretion. Radiat Res, 2009. 171(6): p. 698-707. 
13. 
Lutgens, L.C., et al., Monitoring myeloablative therapy-induced small bowel 
toxicity by serum citrulline concentration: a comparison with sugar permeability 
tests. Cancer, 2005. 103(1): p. 191-9. 
14. 
Gupta, P.K., et al., Development of high-throughput HILIC-MS/MS methodology 
for plasma citrulline determination in multiple species. Analytical Methods, 2011. 
3(8): p. 1759-1768. 
15. 
Hille, A., et al., A prospective study of faecal calprotectin and lactoferrin in the 
monitoring of acute radiation proctitis in prostate cancer treatment. Scand J 
Gastroenterol, 2008. 43(1): p. 52-8. 
16. 
Larsen, A., et al., Faecal calprotectin and lactoferrin as markers of acute 
radiation proctitis: a pilot study of eight stool markers. Scand J Gastroenterol, 
2004. 39(11): p. 1113-8. 
17. 
Blood and Marrow Transplant Clinical Trials Network, Technical Manual of 
Procedures. 2013. 3: p. 6-7. 


09/20/2017 
Page 42 of 61 
 
18. 
Jagasia, M., et al., National Institutes of Health Consensus Development Project 
on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 
Diagnosis and Staging Working Group report. Biology of Blood and Marrow 
Transplant. 2015 Mar; 21(3): p389-401.e1. doi:10.1016/j.bbmt.2014.12.001. 
Epub 2014 Dec 18.  
19. 
P.A. Harris, R. Thielke, R. Taylor, J. Payne, N. Gonzalez, J.G. Conde. Research 
Electronic Data Capture (REDCap) - A metadata-driven methodology and 
workflow process for providing translational research informatics support. Journal 
of Biomedical Informatics, 2008 (doi:10.1016/j.jbi.2008.08.010). 
 
 
 


09/20/2017 
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APPENDIX A: Study Calendar for Special Studies  
 
Assessments solely related to the stem cell transplant will be done per institutional standards and are not included below. 
Studies 
specific for 
pasireotide  
 Screening10 
Baseline/Start 
of Study Drug 
(day before 
conditioning) 
Day 
06 
Day 
+4 
Day 
+7 
Day 
+14 
Weekly 
through 
Day 
+100 
Day 
+30 
+/-7 
days 
Day 
+60 
+/-7 
days 
Day 
+100 
+/-14 
days 
Day 
+180 
+/-14 
days 
Day 
+270 
+/-14 
days 
Day 
+365 
+/-14 
days 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Conditioning 
Regimen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
GVHD 
Medications11 
 
 
x 
 
x 
x 
 
x 
x 
x 
x 
 
x 
Liver function 
tests1, 3 
x 
x 
x 
 
x 
x 
x 
 
 
x 
 
 
 
Routine blood 
tests4 
x 
x 
x 
 
x 
x 
x 
 
 
x 
 
 
 
ECG 
x 
x5 
 
 
 
 
 
 
 
 
 
 
 
Qualitative 
Serum HcG 
pregnancy test 
for FCBP 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting plasma 
glucose or 
HbA1c 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
Thyroid function 
tests: TSH/free 
T4, GH/IGF-1 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
Gallbladder 
ultrasound 
 
X8 
 
x7 
 
 
 
 
 
 
 
 
 
Citrulline assay 
[12.3.1] 
 
x 
x 
 
x 
x 
 
 
 
 
 
 
 
Calprotectin 
assay [12.3.2]9 
 
x 
x 
 
x 
x 
 
 
 
 
 
 
 
Video Capsule 
Endoscopy 
[12.2]2 
 
 
 
x 
 
 
 
 
 
 
 
 
 
Toxicity 
Assessments 
 
x 
x 
 
x 
X12 
 
 
 
 
 
 
 


09/20/2017 
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1ALT, aspartate aminotransferase, alkaline phosphatase, and total bilirubin, should be done weekly, or more frequently, if any value exceeds 5 
times the baseline value in case of abnormal baselines or 5 times the ULN in case of normal baselines. 
2 For subset of 10 subjects; only performed at Duke site. To be performed between transplant Day +4 and +6. 
3 LFTs will occur at baseline and weekly starting Day 0 through day +100. 
4 CBC, Chemistry profile, PT/PTT, INR. At baseline/start of study drug visit, labs are to be performed prior to first dose of pasireotide. 
5 ECG will be done at 1, 1.5, and 2 hrs after first infusion of Pasireotide. 
6 Day 0 = the day of transplant. 
7 Gallbladder ultrasound to be completed between Transplant Day +4 and +6 
8 To be performed within 30 days prior to start of pasireotide. 
9 Baseline calprotectin sample to be collected within 72 hours prior to start of pasireotide. All other calprotectin samples may be collected +/- 1 
day from expected assessment day. 
10 All screening assessments should be completed within 30 days prior to the start of pasireotide.  
11 Medications used for GVHD prophylaxis and all information regarding any GVHD treatment received during each study period will be recorded 
at each time point.   
12 Toxicity assessments to be completed at baseline, daily while on pasireotide, and then weekly through Transplant Day +35.  Maximum grade of 
each toxicity to be recorded at Baseline, Days 0, +7, +14, +21, +28, and +35. 
 
Acute GVHD 
Assessments 
 
 
x 
 
x 
x 
x 
 
 
x 
x 
 
x 
Chronic GVHD 
assessments 
 
 
 
 
 
 
 
 
 
x 
x 
 
x 
Survival 
Analysis 
 
 
 
 
 
 
 
 
 
x 
x 
 
x 


09/20/2017 
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APPENDIX B: CAPSULE ENDOSCOPY PREPARATION INSTRUCTIONS 
 
Your doctor has ordered a Video Capsule Endoscopy to evaluate your small intestines 
for conditions such as ulcers and bleeding. This procedure involves swallowing a 
capsule the size of a large vitamin pill. The capsule will pass through your small 
intestines taking pictures. The pictures will be transmitted to a small computer which 
you will wear on a belt around your waist. The test lasts 6 to 8 hours, during which time 
you may leave and go about your daily activities. At the end of that time, you will be 
asked to return the recording computer to the Gastroenterology (GI) Clinic, where the 
images will be downloaded for analysis. The video capsule is disposable and will 
usually pass naturally in your bowel movement within 24-48 hours. You will be asked to 
sign a consent form prior to the procedure because of the rare possibility that the 
capsule may not pass. 
 
Please read and follow the directions below prior to your procedure.  There will be a 
change to diabetic medications the DAY OF the procedure.  If you are diabetic, call the 
GI Resource Nurse at 919-684-6437 to assist you with this. Call the GI Scheduling Hub 
at 919-684-6437 if you need to reschedule your appointment or for any other questions. 
 
Three (3) Days Before the Procedure : stop taking iron supplements 
 
One (1) Day Before The Procedure: 
Stop taking antacids (Tums, Rolaids), Pepto-Bismol, or Carafate, which coats the 
camera lens. 
AM :    You may eat a regular breakfast. 
11am:  After breakfast, CONSUME ONLY CLEAR LIQUIDS for the remainder of the day 
and evening. No more solid food.  Avoid anything that is colored red or purple.    See 
below for list of clear liquids. 
 
7pm:   TAKE ONE DOSE (17 grams) OF MIRALAX over-the-counter laxative, mixed in 
water. (**Note: It is NOT necessary to move your bowels after this dose!) 
 
12 Midnight :  DO NOT  EAT OR DRINK ANYTHING ELSE .  If you have any 
medications due, you may take them with sips of water. 
 
Day of the Procedure: 
6am :   You may take your morning medications with small sips of water.  Do not take 
anything further by mouth. 
 
o Diabetics:   check blood sugar.  Alter diabetic medications as discussed with GI 
Resource Nurse 
 
Wear loose, comfortable 2-piece clothing.  Avoid belts, dresses, pantyhose, or anything 
else restrictive around your waist. Men are no longer required to shave the chest or 
abdomen. 
 


09/20/2017 
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8 - 9am : Arrive at assigned (GI) Clinic.  Location and time will be specified on your 
appointment letter. After meeting with the nurse and doctor, the recording computer will 
be attached to you with a belt and suspenders.  You will then swallow the capsule with a 
glass of water. 
 
Once the capsule is swallowed, specific instructions on diet and care of recording 
equipment will be given to you.  A general guideline to the diet is as follows: 
0-2 hours after swallowing capsule:        Do not eat or drink. 
2 hours after swallowing capsule:           Clear liquids and medications. 
4 hours after swallowing capsule:           Light snacks. 
6 hours after swallowing capsule:           Regular diet. 
 
The Capsule Endoscopy will last 6 to 8 hours.  You will be allowed to leave, drive, and 
go about your daily activities (with some exceptions). 
 
4 - 5pm : Return the equipment to the GI Clinic.  Resume regular diet and activities. 
 
Clear Liquid Diet List :       (avoid anything that is colored Red or Purple) 
Beverages: Soft Drinks ± orange, ginger ale, cola, Sprite, 7-Up, Gatorade G/G2, Kool-
Aid, Strained fruit juices without pulp ± apple, white grape, orange, lemonade, Water, 
tea, coffee (no milk or non-dairy creamer) 
 
Soups: 
Low-sodium chicken or beef bouillon/broth (broth may be strained off 
regular soup) 
 
Desserts: 
Jell-O (lemon, lime, or orange; no fruit or toppings), Popsicles (no sherbet 
or fruit bars) 
 
 
 


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APPENDIX C: Guidance for hyperglycemia management 
 
Hyperglycemia is known to be associated with the treatment with somatostatin 
analogues (SSA).  Clinical studies of pasireotide in healthy volunteers and in patients 
with Cushing’s disease, acromegaly or carcinoid syndrome have reported transient, 
asymptomatic increases in fasting and postprandial glucose levels.   
 
Novartis has conducted 2 clinical studies ([SOM230B2216] and [SOM230B2124]) to 
further understand the mechanism of pasireotide-induced hyperglycemia and to 
evaluate the clinical utility of anti-diabetes agents in the management of pasireotide-
induced hyperglycemia.  Preliminary results suggest that pasireotide induces insulin 
suppression, particularly in the postprandial period, as being the key mechanistic driver 
of hyperglycemia.   
 
Based on the mechanisms of pasireotide-induced hyperglycemia and findings from the 
[SOM230B2124] 
study, 
appropriate 
management 
for 
the 
pasireotide-induced 
hyperglycemia includes the use of oral anti-diabetic agents for mild to moderate 
hyperglycemia, such as incretin enhancers (e.g. GLP-1analogues or DPP4 inhibitors or 
insulin secretagogues).  Metformin is not recommended.  Insulin should be used for 
moderate to severe hyperglycemia.  
 
Taking the above into account, hyperglycemia should be monitored and managed 
according to institutional practice. 
 
 
 
 
 
 


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APPENDIX D: QT Prolonging Medications  
 
The following drugs are generally recognized to have an association with QT 
prolongation.  This list is not conserved to be all inclusive. 
 
Drugs that are generally accepted by the QTdrug.org Advisory Board of the 
Arizona CERT to have a risk of causing torsade de pointes are listed below 
 
Generic Name 
Brand Name 
Class 
Bepridil  
Vascor® 
Anti-anginal / heart pain 
Amiodarone  
Cordarone® 
Anti-arrhythmic / abnormal heart 
rhythm 
Amiodarone  
Pacerone® 
Anti-arrhythmic / abnormal heart 
rhythm 
Disopyramide  
Norpace® 
Anti-arrhythmic / abnormal heart 
rhythm 
Dofetilide  
Tikosyn® 
Anti-arrhythmic / abnormal heart 
rhythm 
Ibutilide 
Corvert® 
Anti-arrhythmic / abnormal heart 
rhythm 
Procainamide  
Pronestyl® 
Anti-arrhythmic / abnormal heart 
rhythm 
Procainamide  
Procan®  
Anti-arrhythmic / abnormal heart 
rhythm 
Quinidine 
Cardioquin®  
Anti-arrhythmic / abnormal heart 
rhythm 
Quinidine 
Quinaglute® 
Anti-arrhythmic / abnormal heart 
rhythm 
Sotalol  
Betapace®  
Anti-arrhythmic / abnormal heart 
rhythm 
Clarithromycin 
Biaxin® 
Antibiotic / bacterial infection 
Sparfloxacin  
Zagam®  
Antibiotic / bacterial infection 
Erythromycin  
Erythrocin® 
Antibiotic;GI stimulant / bacterial 
infection; increase GI motility 
Erythromycin  
E.E.S.®  
Antibiotic;GI stimulant / bacterial 
infection; increase GI motility 
Arsenic trioxide  
Trisenox® 
Anti-cancer / Leukemia 
Astemizole  
Hismanal® 
Antihistamine / Allergic rhinitis 
Terfenadine 
Seldane® 
Antihistamine / Allergic rhinitis 
Pentamidine  
Pentam® 
Anti-infective 
/ 
pneumocystis 
pneumonia 
Pentamidine  
NebuPent® 
Anti-infective 
/ 
pneumocystis 
pneumonia 
Probucol 
Lorelco® 
Antilipemic 
/ 
Hypercholesterolemia 
Chloroquine 
Aralen® 
Anti-malarial / malaria infection 
Halofantrine  
Halfan® 
Anti-malarial / malaria infection 
Domperidone 
Motilium® 
Anti-nausea / nausea 
Mesoridazine 
Serentil® 
Anti-psychotic / schizophrenia 
Thioridazine 
Mellaril®  
Anti-psychotic / schizophrenia 


09/20/2017 
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Haloperidol  
Haldol® 
Anti-psychotic / schizophrenia, 
agitation 
Pimozide 
Orap®  
Anti-psychotic / Tourette's tics 
Chlorpromazine  
Thorazine® 
Anti-psychotic/ 
Anti-emetic 
/ 
schizophrenia/ nausea 
Cisapride 
Propulsid® 
GI stimulant / heartburn 
Levomethadyl 
Orlaam® 
Opiate agonist / pain control, 
narcotic dependence 
Methadone 
Dolophine® 
Opiate agonist / pain control, 
narcotic dependence 
Methadone 
Methadose® 
Opiate agonist / pain control, 
narcotic dependence 
Droperidol  
Inapsine® 
Sedative;Anti-nausea 
/ 
anesthesia adjunct, nausea 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX E: Study Drugs and Example Preparatory Regimens 
 
The following is only an example of transplant preparatory regimen that can be used on 
this trial, however, any regimen that meets the definition of myeloablative as defined in 
this protocol is acceptable (TBI ≥ 1200 cGy, or Busulfan ≥ 12.8mg/kg). Similarly, GVHD 
prophylaxis (e.g. cyclosporine) may be as per institutional standard. 
 
E1.  
Total Body Irradiation 
Source: Total body irradiation will be delivered in a fractionated fashion over four days 
in a total of 8 fractions at 150 cGy per fraction to a total of 12 Gy using a Varian Linear 
Accelerator. 
 
Toxicity:  Acute - myelosuppression, complete ablation is expected in the setting of 
bone marrow transplantation.  Severe nausea and vomiting, anorexia, diarrhea, 
alopecia, fever and mucositis, are common. Pulmonary fibrosis has also been reported. 
LFTs elevation can also be observed. 
 
E2. 
Busulfan (Myerlan) NSC #750 
Source and Pharmacology: Alkylating agent utilized intravenously.  The drug is 
metabolized to several metabolites that are excreted into the urine.  Approximately 25% 
to 35% of busulfan is eliminated via the kidneys as methanesulfonic acid.  Busulfan has 
an elimination half-life around 2.5 hours. 
 
Formulation:  IV formulation. 
 
 
Storage and Stability:  Check manufacturer's expiration date.  Store at room 
temperature. 
 
Supplier: Commercially available from Otsuka. 
 
Toxicity:  Acute DLT - myelosuppression, primarily leukopenia, with a nadir of 8-14 
days; complete ablation is expected in the setting of bone marrow transplantation.  
Nausea and vomiting, anorexia, diarrhea, alopecia, fever, mucositis, and 
hyperpigmentation are common.  Liver dysfunction (increased LFTs) and renal or 
bladder dysfunction (increased BUN, creatinine, necrosis) may be seen.  Pulmonary 
fibrosis has also been reported.  Peripheral neuropathies and paresthesias have been 
occasionally observed.  Seizures may occur in patients receiving busulfan therapy; all 
patients in this study should be prophylaxed with phenytoin (diphenylhydantoin).   
 
Route of Administration: IV preparation 
 
E3. 
Cyclophosphamide (Cytoxan, CTX) NSC #26271 
Source and Pharmacology:  An alkylating agent, related to nitrogen mustard, which is 
biochemically inert until it is metabolized to its active components by the liver 
phosphamidases.  It is non-phase-specific.  The drug is excreted exclusively by the 
kidney after parenteral administration.  The plasma half-life ranges from 4-6.5 hours.   


09/20/2017 
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Formulation and Stability:  A freeze-dried powder available in 100 mg and 500 mg vials 
with diluent which contains 0.9% benzyl alcohol in water.  The unreconstituted form of 
the drug is stable at room temperature for at least 2 years.  Reconstitute with 5 ml of 
diluent to 100 mg vial and 10 ml to the 500 mg vial.  Also available as 1 g and 2 g vials 
without diluent.  Reconstitute with 10 ml and 20 ml sterile water or bacteriostatic water.  
The reconstituted solution is stable at room temperature for 48 hours.  Solutions that 
have a slight haze should be discarded.   
 
Supplier: Commercially available. 
 
Toxicity:  Acute DLT - myelosuppression, primarily leukopenia, with a nadir of 8-14 
days; complete ablation is expected in the setting of bone marrow transplantation.  
Hemorrhagic cystitis is a potential complication, especially of high-dose therapy.  All 
patients receiving high-dose CTX should have a three-way foley catheter with 
continuous irrigation in place for the duration of CTX therapy and 24 additional hours 
after the last dose.  If the patient is too small for a three-way foley catheter, a regular 
foley catheter should be used and continuous bladder irrigation can be omitted.  Other 
adverse reactions include anorexia, nausea and vomiting, alopecia, fluid retention, 
hyponatremia, inappropriate ADH, immunosuppression, and gonadal suppression with 
associated sterility.  Pulmonary fibrosis is rare.  Very high doses over a short period of 
time may be associated with myocardial necrosis, transiently blurred vision, and cardiac 
toxicity with arrhythmias.  Consideration to holding a dose of CTX should be given for 
patients who develop otherwise unexplained tachycardia or a drop in QRS voltage of 
>25% during cyclophosphamide administration. 
 
Route of Administration:  The total daily dose will be given as a 1-hour IV infusion in 
D5NS.  Patients should receive additional hydration with 3000 ml/m2/day of appropriate 
maintenance IV fluids.   
 
E4. 
Cyclosporine (Sandimmune) 
Source and Pharmacology:  A cyclic polypeptide immunosuppressant agent consisting 
of 11 amino acids.  The exact mechanism of action of cyclosporine is not known, but 
experimental evidence suggests that its effectiveness is due to specific and reversible 
inhibition of immuno-competent lymphocytes in the G0 or G1-phase of the cell cycle.  T-
lymphocytes are preferentially inhibited.  The T-helper cell is the main target, although 
the T-suppressor cell may also be suppressed.  Absorption of cyclosporine from the 
gastrointestinal tract is incomplete and variable.  Peak concentrations (Cmax) in blood 
and plasma are achieved at about 3.5 hours.  The disposition of cyclosporine from 
blood is biphasic with a terminal half-life of approximately 19 hours (range: 10-27 
hours).  Elimination is primarily biliary with only 6% of the dose excreted in the urine. 
 
Formulation and Stability:  Oral solution in 50 ml bottles (100 mg/ml), soft gelatin 
capsules (25 mg and 100 mg/capsule), and IV 5 ml ampoules (50 mg/ml).  Store at 
room temperature.  The oral cyclosporine is in an olive oil solution which should be 
utilized within two months after the bottle is opened.  It may be mixed in whole milk, 


09/20/2017 
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chocolate milk, or fruit juice to mask the taste and should be taken immediately after 
mixing.  The IV solution should be mixed in D5W to a concentration of 2.5-10 mg/ml and 
should be used within 24 hours after mixing. 
 
Supplier:  Commercially available from Sandoz Pharmaceuticals. 
 
Toxicity:  Renal dysfunction; increased blood pressure; hirsutism; tremors or seizures; 
paresthesias; liver toxicity; hyperkalemia or hypokalemia; low serum magnesium; 
gastrointestinal complaints including anorexia, nausea, and ileus; pancytopenia; gingival 
hyperplasia; skin pigmentation changes; mental depression; capillary leak syndrome; 
lymphoproliferative disorders (malignant lymphoma) 
 
Route of Administration:  Continuous IV infusion, or PO at treating physician’s 
discretion.   
 
Precautions:  Nephrotoxicity is felt to be related to whole blood drug level and for that 
reason whole blood samples will be obtained at least 3 times weekly (Monday, 
Wednesday, and Friday) throughout the first 21 days post-transplant (or until switched 
to PO therapy) for the determination of cyclosporine levels.  Blood samples must be 
obtained from a line which is not in use for constant infusion of cyclosporine.  The whole 
blood cyclosporine level should not be <100 ng/ml and/or >300 ng/ml.  Another guide to 
cyclosporine dosing can be assessed by the serum creatinine level.  The cyclosporine 
dose should be reduced by 25% if the serum creatinine is between 1.5-1.7 mg%.  The 
dose should be further reduced 50% if the creatinine is 1.8-2.0 mg% and the drug held if 
the serum creatinine is >2.0 mg%.  Furthermore the drug dose may need to be modified 
in patients with liver disease, significant grand mal tremors, significant pancytopenia, 
and poorly-controlled hypertension.  Cyclosporine therapy may be restarted when the 
whole blood drug level is <300 ng/ml and the serum creatinine returns to treatable 
levels. 
E5. 
Methotrexate (MTX) 
MTX is an analog of aminopterin, the folic acid antagonist introduced in 1948 for the 
treatment of acute leukemia. As one of the antimetabolites, it functions as a decoy 
substrate for critical biochemical reactions leading to cell death. The amino group 
substitution found in MTX results in a less potent antifolate but a drug with more 
predictable toxicity profile and equivalent clinical results. The precise mechanism by 
which MTX prevents GVHD is not understood; however, it is likely related to MTX’s 
ability to inhibit cellular growth and division. Therefore, antigen activated T cells that are 
rapidly proliferating would be particularly sensitive to this antimetabolite. MTX can 
induce tolerance following marrow transplantation. In canine transplantation, MTX given 
after the graft was effective in controlling GVHD and in inducing tolerance when donor 
and recipient were matched for the dog leukocyte antigen system. 
 
Pharmacology 
MTX was one of the first chemotherapy agents introduced for the therapy of 
malignancies. Studies have detailed its pharmacokinetics and mechanisms of action at 
the intracellular level. How these mechanisms translate to its in vivo effects and how it 


09/20/2017 
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functions in the prevention of GVHD, facilitation of engraftment, and induction of 
tolerance are not well understood. At the cellular level, MTX exerts its cytotoxic effect by 
inhibiting dihydrofolate reductase (DHFR). DHFR is the intracellular enzyme responsible 
for converting folic acid to reduced folate cofactors. The reduced state of the folates, 
namely the tetrahydrofolates are responsible for the transport of single carbon groups 
that are required for purine and thymidylate synthesis. Once the single carbon group is 
delivered, the oxidized folates must be converted back to tetrahydrofolates by DHFR. 
MTX binds to DHFR, thereby preventing its ability to reduce the oxidized folates to 
tetrahydrofolate and blocking further purine or thymidylate synthesis. 
 
Administration 
Following the administration of MTX approximately 50% is bound to plasma proteins, 
especially albumin, with the highest tissue-plasma equilibrium reported in the kidney, 
liver, GI tract and muscle. The GI tract is an important site of distribution and 
metabolism of MTX, perhaps accounting for one of the primary sites of toxicity. One 
concern in using MTX is its clearance in those patients who have pleural or ascitic fluid 
since these reservoir spaces can have a substantial impact on the disposition of MTX. 
These spaces can be a reservoir from which MTX can be continuously released, 
leading to severe toxicity. At the low IV doses, MTX clearance correlates with 
glomerular filtration and renal excretion of unmetabolized drug is the major route for 
elimination. 
 
Polyglutamate formation is also important to MTX metabolism. The formation of MTX 
polyglutamates intracellularly may account for its retention within the cell and its 
cytotoxic effects. The enzyme folyl polyglutamate synthetase adds glutamate residues 
to folates or antifolates such as MTX. These polyglutamate moieties are then retained 
inside the cell leading to prolonged antifolate activity. The polyglutamate derivatives of 
MTX appear to be as toxic to DHFR as the native compound. If the retained MTX 
polyglutamates are produced differentially in lymphocytes compared to other normal 
cells, the effective concentrations of the drug would differ. For example, these 
differences in intracellular concentrations may account for selective toxicities and may 
selectively inhibit certain subpopulations of cells. 
 
Toxicity 
The most common adverse effects of MTX when used for GVHD prophylaxis are 
hematopoietic, renal, hepatic, and GI mucosal toxicity. Patients may have an elevation 
in creatinine and elevation of bilirubin levels following the administration of MTX. As 
many of these are also the side-effects of CSP or tacrolimus, dose attenuation of MTX 
and CSP or tacrolimus may be necessary. Full target doses may not be achievable in 
patients with grade III-IV mucositis resulting from the preparatory regimen because of 
airway obstruction and severe oropharyngeal bleeding. 
 
Clinical use 
The use of MTX following allogeneic BMT has been exclusively with the IV formulation. 
The drug doses administered have been relatively small given the inability to dose 
escalate MTX significantly. Initial studies in Seattle tested MTX as a single agent on a 


09/20/2017 
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weekly basis up to day +100 but, because of the toxicity of weekly administration of 
MTX, the dose was changed to four doses and combined with CSP. MTX, when used 
with CSP or tacrolimus, generally is injected IV on days +1, +3, +6 and +11 following 
BMT.  
E6. Example Schedule 
 
TBI/Cytoxan 
Busulfan/Cytoxan 
Day 
Treatment 
Treatment 
-8 
Hickman at 0700 
TBI X 1 (150 cGy) 
Admit 9200 
Start Busulfan 12 am 
0.8 mg/kg IV Q6hrs X 16 doses 
-7 
TBI X 2 (150 cGy each) 
Busulfan Q6hrs 
-6 
TBI X 2 (150 cGy each) 
Busulfan Q6hrs 
-5 
TBI X 2 (150 cGy each) 
Busulfan Q6hrs last dose 6 pm 
-4 
TBI X 2 (150 cGy each) 
Cyclophosphamide 60/mg/kg 
-3 
Cytoxan 60 mg/kg 
Cyclophosphamide 60 mg/kg 
-2 
Cytotoxan 60 mg/kg 
Rest 
-1 
Rest 
Rest 
0 
Stem Cell Infusion 
Stem cells infused 
 
 
 


09/20/2017 
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APPENDIX F: Acute GVHD Scoring 
 
Acute GVHD Scoring (BMT CTN, 2013) 
 
 
 
 
 
 


09/20/2017 
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APPENDIX G: Chronic GVHD Scoring 
 
Chronic GVHD: 2014 NIH Consensus Criteria (Jagasia et. al., 2014) 
 
Organ Scoring 
                                           SCORE 0  
SCORE 1  
SCORE 2  
SCORE 3  
PERFORMANCE 
SCORE: _____ 
 KPS  
 ECOG  
 LPS  
  Asymptomatic 
and 
fully 
active 
(ECOG 0; KPS or 
LPS 100%)  
 
Symptomatic, 
fully 
ambulatory, 
restricted 
only 
in 
physically strenuous 
activity 
(ECOG 
1, 
KPS or LPS 80-90%)  
 
Symptomatic, 
ambulatory, 
capable 
of self-care, >50% of 
waking hours out of 
bed (ECOG 2, KPS or 
LPS 60-70%)  
 
Symptomatic, 
limited 
self-care, 
>50% 
of 
waking 
hours in bed (ECOG 
3-4, KPS or LPS 
<60%)  
SKIN†  
SCORE % BSA:  _____ 
GVHD features to be 
scored  
by BSA:  
Check 
all 
that 
applies:  
  Maculopapular 
rash/erythema  
 Lichen planus-like 
features  
  Sclerotic features  
  Papulosquamous 
lesions or  
ichthyosis  
  Keratosis pilaris-
like GVHD  
  No BSA involved  
  1-18% BSA  
  19-50% BSA  
  >50% BSA  
SKIN FEATURES  
SCORE: _____ 
 
 
No 
sclerotic 
features  
  Superficial  
sclerotic features “not 
hidebound” (able to 
pinch)  
Check 
all 
that 
applies:  
  Deep sclerotic 
features  
 
 
“Hidebound” 
(unable to pinch)  
  Impaired mobility  
  Ulceration  
Other skin GVHD features (NOT scored by BSA)  
Check all that applies:  
  Hyperpigmentation  
 Hypopigmentation  
  Poikiloderma  
  Severe or generalized pruritus  
  Hair involvement  
  Nail involvement  
 
Abnormality 
present 
but 
explained 
entirely 
by 
non-GVHD 
documented 
cause 
(specify):_____________________________  
 
† Skin scoring should use both percentage of BSA involved by disease signs and the cutaneous features scales. When a 
discrepancy exists between the percentage of total body surface (BSA) score and the skin feature score, OR if superficial 
sclerotic features are present (Score 2), but there is impaired mobility or ulceration (Score 3), the higher level should be 
used for the final skin scoring.  
 


09/20/2017 
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SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
MOUTH  
Lichen 
planus-like 
features present:  
  Yes  
  No  
  No symptoms  
  Mild symptoms 
with disease signs but 
not 
limiting 
oral 
intake significantly  
 
 
Moderate 
symptoms 
with 
disease 
signs 
with 
partial limitation of 
oral intake  
  Severe symptoms 
with disease signs on 
examination 
with 
major limitation of 
oral intake  
 
 
Abnormality 
present 
but 
explained 
entirely 
by 
non-GVHD 
documented 
cause 
(specify):_____________________________  
 
                                        SCORE 0  
SCORE 1  
SCORE 2  
SCORE 3  
EYES  
Keratoconjunctivitis 
sicca 
(KCS) 
confirmed 
by 
Ophthalmologist:  
  Yes  
  No  
  No symptoms  
  Mild dry eye 
symptoms 
not 
affecting 
ADL 
(requirement 
of 
lubricant eye drops < 
3 x per day)  
  Moderate dry eye 
symptoms 
partially 
affecting 
ADL 
(requiring 
lubricant 
eye drops > 3 x per 
day or punctal plugs), 
WITHOUT 
new 
vision 
impairment 
due to KCS  
  Severe dry eye 
symptoms 
significantly affecting 
ADL (special eyeware 
to relieve pain) OR 
unable 
to 
work 
because 
of 
ocular 
symptoms OR loss of 
vision due to KCS  
 
 
Abnormality 
present 
but 
explained 
entirely 
by 
non-GVHD 
documented 
cause 
(specify):_____________________________  
 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
GI Tract  
Check 
all 
that 
applies:  
   Esophageal web/ 
proximal stricture or 
ring  
  Dysphagia  
  Anorexia  
  Nausea  
  Vomiting  
  Diarrhea  
  Weight loss*  
  Failure to thrive  
  No symptoms  
 
 
Symptoms 
without 
significant 
weight loss* (<5%)  
 
 
 
 
 
 
 
 
*within last 3 months 
 
 
Symptoms 
associated with mild 
to moderate weight 
loss* (5-15%)  
 
 
 
 
 
 
 
*within last 3 months 
 
 
Symptoms 
associated 
with 
significant 
weight 
loss* >15%, requires 
nutritional supplement 
for most calorie needs 
or esophageal dilation  
 
 
 
*within last 3 months 
 
 
Abnormality 
present 
but 
explained 
entirely 
by 
non-GVHD 
documented 
cause 
(specify):_____________________________  
 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
LIVER  
  Normal total 
bilirubin and ALT < 2 
x NUL  
  Normal total 
bilirubin and ALT >2 
x NUL  
  Elevated total 
Bilirubin 
but 
<3 
mg/dL NUL  
  Elevated total 
bilirubin > 3 x NUL  
 
Abnormality 
present 
but 
explained 
entirely 
by 
non-GVHD 
documented 
cause 
(specify):_____________________________  
 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
LUNGS**  
Symptoms score:___ 
  No symptoms  
  Mild symptoms 
(shortness of breath 
after 
climbing 
one 
flight of steps)  
 
 
Moderate 
symptoms (shortness 
of 
breath 
after 
walking 
on 
flat 
ground)  
  Severe symptoms 
(shortness of breath at 
rest; requiring 02)  
Lung 
obstructive 
function score: ____ 
FEV1: ____ 
  FEV1≥80%  
  FEV1 60-79  
  FEV1 40-59%  
  FEV1 <39%  
Pulmonary function tests: ____ 


09/20/2017 
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  Not performed  
 
 
Abnormality 
present 
but 
explained 
entirely 
by 
non-GVHD 
documented 
cause 
(specify):_____________________________  
**Lung scoring should be performed using both the symptoms and FEV1 scores whenever possible. FEV1 should be used 
in the final lung scoring where there is discrepancy between symptoms and FEV1 scores.  
 
                                       SCORE 0  
SCORE 1  
SCORE 2  
SCORE 3  
JOINTS AND FASCIA  
P-ROM score   
Shoulder (1-7):___  
Elbow (1-7): ____  
Wrist/finger 
(1-
7):___  
Ankle (1-4):___  
 
P-ROM Chart 
  No symptoms  
  Mild tightness of 
arms or legs, normal 
or 
mild 
decreased 
range 
of 
motion 
(ROM) 
AND 
not 
affecting ADL  
 
Tightness 
of 
arms or legs OR 
joint 
contractures, 
erythema 
thought 
due 
to 
fasciitis, 
moderate 
decrease 
ROM AND mild to 
moderate limitation 
of ADL  
  Contractures WITH 
significant 
decrease 
of 
ROM AND significant 
limitation of ADL (unable 
to tie shoes, button shirts, 
dress self etc.)  
 
 
Abnormality 
present 
but 
explained 
entirely 
by 
non-GVHD 
documented 
cause 
(specify):__________________________  
 
 SCORE 0  
SCORE 1 
SCORE 2 
SCORE 3 
GENITAL TRACT  
(See 
Supplemental 
table‡)  
Check 
all 
that 
applies  
 Not examined  
Currently 
sexually 
active  
  Yes  
  No  
  No signs  
  Mild signs‡ and 
females 
with 
or 
without 
discomfort 
on exam  
  Moderate signs‡ 
and may have signs* 
of 
discomfort 
on 
exam  
  Severe signs‡ with or 
without symptoms  


09/20/2017 
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Check all signs that apply:  
 Lichen planus-like features  
 Lichen sclerosis-like features  
 Vaginal scarring (female)  
 Clitoral/labial agglutination (female)  
 Labial resorption (female)  
 Erosions  
 Fissures  
 Ulcers  
 Phimosis (male)  
 Urethral meatus scarring/ stenosis (male)  
Female genitalia: Severity of signs:  
1) Mild (any of the following); erythema on vulvar mucosal surfaces, vulvar lichen-planus or vulvar lichen-sclerosis 
2) Moderate (any of the following); erosive inflammatory changes of the vulvar mucosa, fissures in vulvar folds  
3) Severe (any of the following); labial fusion, clitoral hood agglutination, fibrinous vaginal adhesions,
circumferential  
fibrous vaginal banding, vaginal shortening, synechia, dense sclerotic changes, and complete vaginal stenosis  
Male genitalia: Diagnostic features include lichen planus-like or lichen sclerosis-like features and phymosis or
urethral scarring or stenosis. Severity of signs: Mild – lichen planus-like feature; Moderate – lichen sclerosis-like
feature or moderate erythema; Severe – phimosis or urethral/meatal scarring  
 Abnormality present but NOT thought to represent GVHD  
(specify cause):________________________________  
 Abnormality thought to represent GVHD PLUS other causes 
(specify cause):_______________________________  
 
Other indicators, clinical features or complications related to chronic GVHD (check all that apply and assign a 
score to its severity (0-3) based on its functional impact where applicable none – 0,mild -1, moderate -2, severe – 3)  
  Ascites (serositis)___  
  Myasthenia Gravis___  
  Pericardial Effusion___  
  Peripheral Neuropathy___  
  Eosinophilia > 500μl___  
  Pleural Effusion(s)___  
  Polymyositis___  
  Platelets <100,000/μl ___  
  Nephrotic syndrome___  
  Weight loss* without GI 
symptoms  
 
 
Others 
(specify):_________________  
Overall GVHD 
Severity  
(Opinion 
of 
the 
evaluator)  
 
 No GVHD  
 
 
 Mild 
 
 
 Moderate  
 
 
 Severe  
 
 
Mild chronic GVHD 
Moderate chronic GVHD  
Severe chronic GVHD  
1or 2 organs involved (not lung) 
plus  
Score in involved organs 1 plus  
Lung score 0  
3 or more organs involved plus  
Score of 1 in each organ  
OR  
At least 1 organ (not lung) with a 
score of 2  
OR  
Lung score 1  
At least 1 organ with a score of 3  
OR  
Lung score of 2 or 3  
 
 
 
 


09/20/2017 
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Appendix H: SAE Report Coversheets 
 
 
 
 
 
 
Interventional Clinical Trial SAE Fax Cover Sheet 
 
To: Local Novartis Drug Safety and Epidemiology Safety Desk 1-877-778-9739 
 
Investigator contact details: 
Fax number : ______________________________ 
Phone number : ____________________________ 
 
Study Name 
 
Centre Number 
 
Patient Number 
 
 
 
Relationship between study treatment and event(s) is: 
 
Suspected/Unknown 
 
  
Investigator Signature 
 
 
This document contains important safety information. 
If fax is received in error, please forward to  1 877 778 9739 
 


09/20/2017 
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Version 1.0, 01_Jul_2010 
 
 
 
 
 
Interventional Clinical Trial SAE Fax Cover Sheet 
 
To: Local Novartis Drug Safety and Epidemiology Safety Desk 1-877-778-9739 
 
Investigator contact details: 
Fax number : ______________________________ 
Phone number : ____________________________ 
 
Study Name 
 
Centre Number 
 
Patient Number 
 
 
 
Relationship between study treatment and event(s) is: 
 
Not Suspected 
 
  
Investigator Signature 
 
This document contains important safety information. 
If fax is received in error, please forward to  1 877 778 9739