Conditions: Stage III Intrahepatic Cholangiocarcinoma AJCC v7 Stage IIIA Gallbladder Cancer AJCC v7 Stage IIIB Gallbladder Cancer AJCC v7 Stage IVA Gallbladder Cancer AJCC v7 Stage IVA Intrahepatic Cholangiocarcinoma AJCC v7 Stage IVB Gallbladder Cancer AJCC v7 Stage IVB Intrahepatic Cholangiocarcinoma AJCC v7 Unresectable Extrahepatic Bile Duct Carcinoma Unresectable Gallbladder Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 62
Healthy volunteers: no

Brief summary:
This phase II trial studies how well gemcitabine hydrochloride, cisplatin, and nab-paclitaxel (paclitaxel albumin-stabilized nanoparticle formulation) work in treating patients with biliary cancers (which includes the gallbladder and bile ducts inside and outside the liver) that have spread to other places in the body and usually cannot be cured or controlled with treatment. Drugs used in chemotherapy, such as gemcitabine hydrochloride, cisplatin, and paclitaxel albumin-stabilized nanoparticle formulation, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) may kill more tumor cells.

Detailed description:
PRIMARY OBJECTIVES:

I. Determine the progression-free survival (PFS) of gemcitabine hydrochloride (gemcitabine), cisplatin, and nab-paclitaxel in advanced, untreated biliary cancers (intrahepatic cholangiocarcinomas, extrahepatic cholangiocarcinomas, and gallbladder cancers).

SECONDARY OBJECTIVES:

I. Determine the response rate (RR) and disease control rate (partial response + complete response + stable disease) of gemcitabine, cisplatin, and nab-paclitaxel in advanced biliary cancers.

II. Determine overall survival (OS) of gemcitabine, cisplatin, and nab-paclitaxel in advanced biliary cancers.

III. Evaluate the toxicity of gemcitabine, cisplatin, and nab-paclitaxel in advanced biliary cancers.

EXPLORATORY OBJECTIVES:

I. Correlate the carbohydrate antigen (CA) 19-9 response (defined as \>50% decrease from baseline) with tumor response, PFS and OS.

II. Assess ribonucleotide reductase subunit MI (RRMI), excision repair cross-complementation group 1 (ERCC1) pre-treatment status and correlate with tumor response, PFS and OS on an exploratory basis.

III. Collect optional blood and tissue at the start of treatment and at progression to explore mechanisms of resistance.

OUTLINE:

Patients receive paclitaxel albumin-stabilized nanoparticle formulation intravenously (IV) over 30 minutes, cisplatin IV over 60 minutes, and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months thereafter.

Arms:
arm 1: Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes, cisplatin IV over 60 minutes, and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Cisplatin intervention 2: Gemcitabine Hydrochloride intervention 3: Laboratory Biomarker Analysis intervention 4: Nab-paclitaxel
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Correlative studies intervention 4: Given IV

Protocol document:
Prot_SAP_000.pdf: 
2014-0524 
March 16, 2016 
Page 1 
THE UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER 
DIVISION OF CANCER MEDICINE 
 
Protocol 2014-0524: A Phase II Study of Gemcitabine, Cisplatin, and Nab-Paclitaxel 
in Advanced Biliary Cancers 
 
 
Principal Investigator:  Rachna T. Shroff, M.D., M.S. 
The University of Texas MD Anderson Cancer Center 
Department of Gastrointestinal Medical Oncology 
1515 Holcombe Blvd. 
Unit 0426 
(713) 745-9280 
(713) 563-0180 (fax) 
(713) 606-4162 (pager) 
rshroff@mdanderson.org 
 
MD Anderson Cancer Center Collaborators:  
Milind M. Javle, M.D.  
Robert A. Wolff, M.D. 
Gauri Varadhachary, M.D. 
Kanwal Raghav, M.D. 
Ahmed Kaseb, M.D. 
Linus Ho, M.D. 
Lianchun Xiao, M.S. 
Xuemei Wang, M.S. 
 
Mayo Clinic  Phoenix Collaborators: 
Mitesh Borad, M.D. 
Michael Barrett, Ph.D. 
5777 East Mayo Boulevard 
Phoenix, AZ 85054 
480-342-4800 
480-301-4675 (fax)  
 
Mayo Clinic Rochester Collaborator: 
Joleen Hubbard, M.D. 
200 First St, SW  
Rochester, MN 55901  
507-284-8318  
 
 
 
Dose level  


2014-0524 
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Page 2 
 
 
 
TABLE OF CONTENTS 
 
 
1.0 
Study Rationale 
2.0 
Background 
3.0 
Drug Information 
4.0 
Objectives 
5.0 
Patient Eligibility 
6.0 
Treatment Plan 
7.0 
Evaluation during Study 
8.0 
Criteria for Removal from the Study 
9.0 
Response Evaluation 
10.0 
Statistical Methods 
11.0     Registration Process 
12.0     Data and Protocol Management 
13.0  Correlative Studies 
14.0     Safety Reporting of Adverse Events  
15.0 
References 
 
 
 
APPENDICES 
 
 
 
Appendix 1 – ECOG Performance Status 
Appendix 2 – Nab-Paclitaxel- Additional Information 
Appendix 3 – Statistical Simulation 
Appendix 4 – Registration Process 
Appendix 5 – Multicenter Data Management Process 
 
 
 
 
 
 
 
 
 
 
 
 
 


2014-0524 
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1. STUDY RATIONALE 
 
Biliary cancers are a heterogeneous group of malignancies with a limited number of 
chemotherapeutic options in advanced disease. The current standard of care for palliative 
treatment of biliary cancers is the combination of gemcitabine and cisplatin1. Nab-
Paclitaxel is FDA-approved for treatment of metastatic pancreatic cancer, and is 
presumed to enhance delivery of chemotherapy by modifying the dense stromal barrier 
that is thought to surround pancreatic cancer cells2. Given the presence of a strong 
desmoplastic response in biliary cancers as well, we hypothesize that the combination of 
gemcitabine, cisplatin, and Nab-Paclitaxel in advanced biliary cancers will improve drug 
delivery and enhance response and progression-free survival in these deadly 
malignancies. 
 
 
2. BACKGROUND 
 
2.1 Biliary Cancers 
 
Biliary cancers are comprised of intrahepatic cholangiocarcinoma, extrahepatic 
cholangiocarcinoma, and gallbladder carcinoma. They are an aggressive group of 
malignancies but heterogeneous in their presentations and clinical pictures. The majority 
of patients present at an advanced stage, and median survival of locally-advanced or 
metastatic biliary tract cancers is less than one year. These malignancies are characterized 
by lymph node involvement and distant metastases3.  
 
Gallbladder cancer (GBC) is the most common form of biliary tract cancers. 
Internationally, Israel has the highest incidence worldwide, with 7.5 cases per 100,000 
men and 13.8 cases per 100,000 women. Other countries with significant incidence rates 
include Mexico, Bolivia, Chile, and northern Japan4. In the US, about five thousand new 
cases are reported every year. The incidence has been on the decline owing to the 
increase in the number of cholecystectomies for other reasons like acute or chronic 
symptomatic cholecystitis.  Less than 10 percent of patients with GBC live more than 
five years after diagnosis. The mortality is very high and is attributed to the late diagnosis 
and an advanced stage of the disease5. 
 
At the same time, cholangiocarcinoma is a highly fatal cancer of the biliary tree.  In the 
United States, approximately 5,000 new cases of cholangiocarcinoma are diagnosed 
annually; these cases are equally distributed between intra-hepatic cholangiocarcinoma 
(ICC) and extrahepatic cholangiocarcinoma (ECC)6. Data from the National Cancer 
Institute’s Surveillance, Epidemiology and End Results (SEER) indicate that the 
incidence of ICC is increasing7. The incidence of ICC in the US almost tripled between 
1975 and 19998. The reasons behind this increase are not clear. 
 
 


2014-0524 
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Chemotherapy for biliary cancers 
 
Biliary cancers are often treated similarly to pancreatic cancers given their equally strong 
desmoplastic response creating dense stromal barriers that play a role in the 
chemoresistance seen in these malignancies9. Furthermore, like pancreatic cancers, 
gemcitabine has been the mainstay of chemotherapy in these diseases. The ABC-01 study 
was a phase II trial that examined the combination of gemcitabine and cisplatin in 
advanced biliary cancers. 86 patients were randomized to gemcitabine alone versus the 
doublet regimen. The primary endpoint of 6-month progression-free survival was 45.5% 
vs. 57.1% in the two arms with median time to progression being 8 months with the 
gemcitabine and cisplatin combination10. The benefit of the addition of cisplatin to 
gemcitabine was verified with the ABC-02 study, a randomized phase III trial of 410 
patients with overall survival as the primary endpoint. The authors found that the 
combination of gemcitabine and cisplatin significantly improved median overall survival 
(11.7 months vs. 8.1 months) and progression-free survival (8.0 months vs. 5.0 months) 
compared to gemcitabine alone1. 
 
Taxanes in biliary cancers 
 
The efficacy of taxanes in biliary cancers has been reported in the literature. A phase II 
study of single-agent docetaxel in twenty-five untreated, advanced biliary cancer patients 
demonstrated a response rate of 20% and a median overall survival of 8.0 months11. The 
combination of erlotinib and docetaxel was investigated in refractory hepatobiliary 
cancers. 64% of the patients with biliary cancers achieved the primary endpoint of 16-
week progression-free survival12. In another study, 43 patients were treated with the 
combination of gemcitabine and docetaxel with a disease control rate of 67.4% and a 
median survival of 11 months13. Reports of the efficacy of paclitaxel have also been 
published14,15. 
 
Stromal interactions in biliary cancers and the role of Nab-Paclitaxel 
 
Tumor progression and growth has been previously linked to dynamic interactions 
between tumor cells and the surrounding stromal tissue. Cancers with a “reactive” stroma 
are associated with a high density of alpha-smooth muscle actin (-SMA)-positive 
fibroblasts, hypovascularity, and activated stellate cells16-19. The presence of -SMA-
positive fibroblasts within the cholangiocarcinoma stroma has been associated with a 
poor prognosis18,20.  
 
Preclinical studies in pancreatic cancer have demonstrated that Nab-Paclitaxel enhances 
delivery of gemcitabine to pancreatic tumors by depleting the desmoplastic stroma that 
surrounds them and by enhancing the microvasculature21. In a study of potentially 
resectable pancreatic cancer patients treated with Nab-Paclitaxel and gemcitabine, 
surgical specimens of patients with a marked pathologic response demonstrated stromal 
disruption, characterized by collagen disorganization, and a lower density of -SMA-


2014-0524 
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Page 5 
positive fibroblasts suggesting a role for this combination in other stromal-rich 
malignancies like biliary cancers22.  
 
A Phase IB/II study was conducted with gemcitabine/Nab-Paclitaxel in metastatic 
pancreatic cancer and significant efficacy (RECIST response rate of 48%, PFS of 7.9 
months and overall survival of 12.2 months at the MTD) was observed23. These findings 
led to a phase III study involving 861 patients with metastatic pancreatic cancer who 
were randomized to gemcitabine alone versus gemcitabine and Nab-Paclitaxel. The 
combination arm demonstrated a significant improvement in overall survival from 6.7 
months to 8.5 months (p<0.001). Median progression-free survival was 5.5 months with 
gemcitabine and Nab-Paclitaxel compared to 3.7 months with gemcitabine alone 
(p<0.001). Response rates, similarly, were higher with the combination (23% versus 7%, 
p<0.001)2.  The most common adverse events included neutropenia, fatigue, and 
neuropathy, however, overall the combination was relatively well-tolerated with no 
difference in serious adverse events between the two arms. 
 
The combination of gemcitabine and Nab-Paclitaxel is currently being investigated with 
the PrECOG study, a phase II trial as first-line therapy in cholangiocarcinoma. This 
multi-institutional trial will be looking at progression-free survival as the primary 
endpoint with a maximum of 70 patients enrolled 
(http://clinicaltrials.gov/show/NCT02181634).   
 
Safety of combining gemcitabine, cisplatin, and Nab-Paclitaxel 
The safety of combining gemcitabine and cisplatin and gemcitabine and Nab-Paclitaxel 
has been previously described in biliary cancers and pancreatic cancers, respectively1,2. 
The tolerability of the combination of gemcitabine, cisplatin, and Nab-Paclitaxel is 
currently being investigated by the Pancreatic Cancer Research Team in a phase IB/II 
pilot study of previously untreated, metastatic pancreatic cancer patients.  3 patients were 
enrolled with gemcitabine at 1000 mg/m2, Nab-Paclitaxel at 125 mg/m2, and cisplatin at 
25 mg/m2 on days 1 and 8 of a 21-day cycle with no dose-limiting toxicities. The first 
patient enrolled on the cohort of cisplatin at 50 mg/m2 was hospitalized with febrile 
neutropenia, and thus the first cohort of cisplatin at 25 mg/m2 has now been expanded. 2 
additional patients have been treated to date in this expanded cohort of cisplatin at 25 
mg/m2 with toxicities being manageable and no dose-limiting toxicities seen (personal 
communication with research team).  
 
3.  DRUG INFORMATION 
 
3.1 NAB-PACLITAXEL 
1. The Product 
NAB-PACLITAXEL for Injectable Suspension (also known as ABI-007, nab-
paclitaxel, paclitaxel protein-bound particles for injectable suspension) is an albumin-
bound form of paclitaxel with a mean particle size of approximately 130 nanometers. 
Paclitaxel exists in the particles in a non-crystalline, amorphous state. NAB-
PACLITAXEL is supplied as a white to yellow, sterile, lyophilized powder for 


2014-0524 
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reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to 
intravenous infusion. Each single-use vial contains 100 mg of paclitaxel and 
approximately 900 mg of human albumin. Each milliliter (mL) of reconstituted 
suspension contains 5 mg paclitaxel. NAB-PACLITAXEL is free of solvents.   The 
active agent in NAB-PACLITAXEL is paclitaxel.  
 
2. Indication 
In the United States, NAB-PACLITAXEL for Injectable Suspension (paclitaxel 
protein-bound particles for injectable suspension) is indicated for the treatment of 
metastatic adenocarcinoma of the pancreas as first-line treatment, in combination 
with gemcitabine. 
 
3. Introduction 
NAB-PACLITAXEL is a biologically interactive albumin-bound paclitaxel 
combining a protein with a chemotherapeutic agent in the particle form. This 
composition provides a novel approach of increasing intra-tumoral concentrations of 
the drug by a receptor-mediated transport process allowing transcytosis across the 
endothelial cell. This albumin-specific receptor mediated process involves the 
binding of albumin to a specific receptor (gp60) on the intraluminal endothelial cell 
membrane, resulting in activation of a protein (caveolin-1), which initiates an 
internalization process in the endothelial cell through the formation of caveolae, with 
transport of the intact albumin-bound chemotherapeutic complex via these caveolae 
to the underlying tumor interstitium24.  Other postulated mechanisms of action for the 
combination of gemcitabine with nab-paclitaxel include downregulation of cytidine 
deaminase by paclitaxel resulting in higher/sustained concentrations of gemcitabine, 
macropinocytosis of proteins such as albumin by Ras-transformed cells which would 
allow for enhanced uptake of paclitaxel loaded albumin nanoparticles into pancreatic 
cancer tumor cells25,26. 
 
4. Preclinical Studies with NAB-PACLITAXEL  
Preclinical studies comparing NAB-PACLITAXEL to Taxol® (paclitaxel 
Cremophor® EL solvent-based, BMS) demonstrated lower toxicities, with an MTD 
approximately 50% higher for NAB-PACLITAXEL compared to Taxol.  At equal 
doses there was less myelosuppression and improved efficacy in a xenograft tumor 
model of human mammary adenocarcinoma.  At equitoxic doses of paclitaxel, NAB-
PACLITAXEL treated groups showed more complete regressions, longer time to 
recurrence, longer doubling time, and prolonged survival. At equal dose, tumor 
paclitaxel area under the curve was 33% higher for NAB-PACLITAXEL versus 
solvent based paclitaxel, indicating more effective intratumoral accumulation of 
NAB-PACLITAXEL27.  
 
5. Clinical Studies with NAB-PACLITAXEL 
A multicenter, multinational, randomized, open-label study was conducted in 861 
patients comparing NAB-PACLITAXEL plus gemcitabine versus gemcitabine 


2014-0524 
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Page 7 
monotherapy as first-line treatment of metastatic adenocarcinoma of the pancreas. 
Key eligibility criteria were Karnofsky Performance Status (KPS) ≥70, normal 
bilirubin level, transaminase levels ≤ 2.5 times the upper limit of normal (ULN) or ≤ 
5 times the ULN for patients with liver metastasis, no prior cytotoxic chemotherapy 
in the adjuvant setting or for metastatic disease, no ongoing active infection requiring 
systemic therapy, and no history of interstitial lung disease. Patients with rapid  
decline in KPS (≥10%) or serum albumin (≥20%) during the 14 day screening period 
prior to study randomization were ineligible. 
 
 
A total of 861 patients were randomized (1:1) to the NAB-
PACLITAXEL/gemcitabine arm (N=431) or to the gemcitabine arm (N=430). 
Randomization was stratified by geographic region (Australia, Western Europe, 
Eastern Europe, or North America), KPS (70 to 80 versus 90 to 100), and presence of 
liver metastasis (yes versus no). Patients randomized to NAB-
PACLITAXEL/gemcitabine received NAB-PACLITAXEL 125 mg/m2 
as an intravenous infusion over 30-40 minutes followed by gemcitabine 1000 mg/m2 
as an intravenous infusion over 30-40 minutes on Days 1, 8, and 15 of each 28-day 
cycle. Patients randomized to gemcitabine received 1000 mg/m2 as an intravenous 
infusion over 30-40 minutes weekly for 7 weeks followed by a 1-week rest period in 
Cycle 1 then as 1000 mg/m2 on Days 1, 8 and 15 of each subsequent 28-day cycle. 
Patients in both arms received treatment until disease progression or  
unacceptable toxicity. The major efficacy outcome measure was overall survival 
(OS). Additional outcome measures were progression-free survival (PFS) and overall 
response rate (ORR), both assessed by independent, central, blinded radiological  
review using RECIST (version 1.0). 
 
In the intent to treat (all randomized) population, the median age was 63 years (range 
27-88 years) with 42% ≥ 65 years of age; 58% were men; 93% were White and KPS 
was 90-100 in 60%. Disease characteristics included 46% of patients with 3 or more  
metastatic sites; 84% of patients had liver metastasis; and the location of the primary 
pancreatic lesion was in the head of pancreas (43%), body (31%), or tail (25%). 
 
The median overall survival of the NAB-PACLITAXEL/gemcitabine group was 8.5 
months compared to 6.7 months in the gemcitabine alone group (HR 0.72, p<0.0001). 
PFS was similarly improved in the combination arm (5.5 vs. 3.7 months, HR 0.69, 
p<0.0001). Overall response rate by central review was 23% with NAB-
PACLITAXEL/gemcitabine and 7% with gemcitabine alone (p<0.0001). 
 
6. Potential Risks of NAB-PACLITAXEL Toxicities  
The most common toxicities reported with NAB-PACLITAXEL when given with 
gemcitabine in the pancreatic cancer studies include myelosuppression (neutropenia: 
73%, thrombocytopenia: 38%), fatigue (59%), peripheral edema (46%), pyrexia 
(41%), nausea (54%) vomiting (36%), diarrhea (44%), sensory neuropathy (54%), 
alopecia (50%), arthralgia (11%), myalgia (10%). During post marketing 


2014-0524 
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surveillance, rare cases of severe hypersensitivity reactions have occurred.  
 
 
7.   Further Information 
      See Appendix 2 
      Nab paclitaxel (Nab-PaclitaxelTM) Prescribing Information (Updated 1/2012) –  
Accessed via Nab-Paclitaxel Website: http://www.Nab-Paclitaxel.com/docs/Nab-   
Paclitaxel_PrescribingInformation.pdf 
 
3.2 GEMCITABINE 
The most common toxicities reported for gemcitabine include myelosuppression, 
transient elevations in serum transaminases (approximately 70%), nausea and vomiting 
(69%), fever (41%), rash (30%), diarrhea (19%), flu syndrome, (19%), infection (16%), 
alopecia (15%), edema (13%), stomatitis (11%),) neurotoxicity (mild 10%, severe <1%), 
mild proteinuria and hematuria; Hemolytic Uremia Syndrome (HUS) reported rarely 
(0.25%), dyspnea (0.2%) and serious pulmonary toxicity (0.06%). Also reported include 
constipation and pruritus. 
Gemcitabine (GemzarTM) Prescribing Information (Updated 2/2011) – Accessed via 
Gemzar Website: http://pi.lilly.com/us/gemzar.pdf 
3.3 CISPLATIN 
The most common toxicities of cisplatin include nephrotoxicity (28-36%; acute renal 
failure and chronic renal insufficiency), peripheral neuropathy (dose and duration 
dependent), nausea and vomiting (76% to 100%), myelosuppression (25% to 30%; nadir: 
day 18-23; recovery: by day 39; mild with moderate doses, mild-to-moderate with high-
dose therapy), liver enzymes increased (especially SGOT and bilirubin), ototoxicity (10% 
to 30%; manifested as high frequency hearing loss; ototoxicity is especially pronounced 
in children), tissue irritation (extravasation). 
Other toxicities (<1%) include alopecia (mild), anaphylactic reaction, arrhythmias, 
arterial vasospasm (acute), blurred vision, bradycardia, diarrhea, heart block, heart 
failure, hemolytic anemia (acute), hemolytic uremic syndrome, hypercholesterolemia, 
hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, limb 
ischemia (acute), mesenteric ischemia (acute), myocardial infarction, myocardial 
ischemia, mouth sores, neutropenic typhlitis, optic neuritis, orthostatic hypotension, 
pancreatitis, papilledema, phlebitis, reversible posterior leukoencephalopathy syndrome 
(RPLS), SIADH, stroke, thrombophlebitis, thrombotic thrombocytopenic purpura. 
Cisplatin Prescribing Information (updated 2012) – Accessed via Daily Med (National 
Library of Medicine) http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a440f077-
46f6-4688-a209- 65bce38d1c92 
 


2014-0524 
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4.     OBJECTIVES 
 
PRIMARY 
Determine the progression-free survival (PFS) of gemcitabine, cisplatin, and Nab-
Paclitaxel in advanced, untreated biliary cancers (intrahepatic cholangiocarcinomas, 
extrahepatic cholangiocarcinomas, and gallbladder cancers). 
 
SECONDARY 
• Determine the response rate (RR) and disease control rate (partial response + 
complete response + stable disease) of gemcitabine, cisplatin, and Nab-
Paclitaxel in advanced biliary cancers 
• Determine overall survival (OS) of gemcitabine, cisplatin, and Nab-Paclitaxel 
in advanced biliary cancers 
• Evaluate the toxicity of gemcitabine, cisplatin, and Nab-Paclitaxel in 
advanced biliary cancers 
 
EXPLORATORY 
• Correlate the carbohydrate antigen (CA) 19-9 response (defined as >50% 
decrease from baseline) with tumor response, PFS and OS 
• Assess RRMI, ERCC1 pre-treatment status and correlate with tumor response, 
PFS and OS on an exploratory basis   
• Collect optional *blood and tissue at the start of treatment and at progression 
to explore mechanisms of resistance. 
▪ *Blood collection is mandatory at screening/baseline, however, it is      
 optional at progression/end of treatment. 
 
 
 
5. 
PATIENT ELIGIBILITY 
Patients will be included in the study based on the following inclusion and exclusion 
criteria.    
INCLUSION CRITERIA 
1. Patient must have histologically or cytologically confirmed intrahepatic 
cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer or 
may undergo a repeat biopsy for histologic confirmation if pre-existing biopsy is 
not sufficient for diagnosis. 
 
2. Metastatic or unresectable disease documented on diagnostic imaging studies. 
 
3. May not have received prior chemotherapy. If patient has received prior adjuvant 
therapy, must be > 6 months from treatment.  


2014-0524 
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4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1 
(Appendix 1).   
 
5. Adequate organ function including: 
 
Absolute 
neutrophil count 
(ANC) 
 
≥1,500 cells/mm3 
Platelets 
 
≥100,000/ul 
Hemoglobin 
>9.0 g/dL 
Total bilirubin 1 
≤1.5mg/dL 
AST and ALT  
 ≤5 x ULN 
Creatinine 
≤1.5 gm/dL 
1 In patients with known Gilbert’s syndrome direct bilirubin ≤1.5 x ULN 
will be used as organ function criteria, instead of total bilirubin  
6. Negative serum or urine pregnancy test in women with childbearing potential 
(WOCBP) defined as not post-menopausal for 12 months or no previous surgical 
sterilization, within one week prior to initiation of treatment.  WOCBP must be 
using an adequate method of contraception to avoid pregnancy throughout the 
study and for up to 12 weeks after the last dose of study drug to minimize the risk 
of pregnancy. 
 
7. A male subject of fathering potential must use an adequate method of 
contraception to avoid conception throughout the study and for up to 12 weeks 
after the last dose of study drug to minimize the risk of pregnancy. If the partner 
is pregnant or breastfeeding, the subject must use a condom. 
 
8. Patients must sign an Informed Consent and Authorization indicating that they are 
aware of the investigational nature of this study and the known risks involved. 
 
9.  Patient is ≥ 18 years of age on the day of consenting to the study. 
 
EXCLUSION CRITERIA 
 
1. Peripheral neuropathy of grade 2 or greater by Common Terminology Criteria for 
Adverse Events (CTCAE) 4.0. In CTCAE version 4.0 grade 2 sensory neuropathy 
is defined as “moderate symptoms; limiting instrumental activities of daily living 
(ADLs)” 
 


2014-0524 
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Page 11 
2. Concurrent severe and/or uncontrolled medical conditions which could 
compromise participation in the study such as unstable angina, myocardial 
infarction within 6 months, unstable symptomatic arrhythmia, uncontrolled 
diabetes, serious active or uncontrolled infection. 
3. Pregnancy (positive pregnancy test) or lactation.  
 
4. Known CNS disease, except for treated brain metastasis.  Treated brain 
metastases are defined as having no evidence of progression or hemorrhage after 
treatment and no ongoing requirement for dexamethasone, as ascertained by 
clinical examination and brain imaging (MRI or CT) during the screening period.  
Anticonvulsants (stable dose) are allowed.  Treatment for brain metastases may 
include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, 
LINAC, or equivalent) or a combination as deemed appropriate by the treating 
physician.  Patients with CNS metastases treated by neurosurgical resection or 
brain biopsy performed within 3 months prior to Day 1 will be excluded 
 
6. 
 TREATMENT PLAN 
 
 
This is a multi-center, open-label phase II study.  Patients with advanced biliary cancers 
will be enrolled.  All patients must be registered on the M. D. Anderson Cancer Center 
Clinical Oncology Research (CORe) system prior to initiation of treatment and patients 
from Mayo Clinic will have their information sent to MD Anderson for registration into 
the system.  
This study will enroll up to 50 patients to at MD Anderson Cancer Center and the Mayo 
Clinic hospitals.  Accrual is projected to be 2 to 2.5 subjects per month. 
 
This will be an open-label, single arm study with each cycle being 21 days. All three 
drugs will be administered intravenously on day 1 and day 8 of the cycle. Dosing will be 
calculated using body surface area (BSA) based on the actual weight of the patient. Nab-
Paclitaxel will be given at 100 mg/m2, followed by cisplatin at 25 mg/m2 and then 
gemcitabine at 800 mg/m2 for 2 weeks in a row followed by a week of rest. Restaging 
will be done every 3 cycles (+/- 1week).  Treatment will be continued until progression 
unless other reasons for study discontinuation occur as listed in section 8 “Criteria for 
Removal from the Study.” Additionally, patients who have therapy interrupted for 
consolidative therapies (including, but not limited to radiation therapy, 
radioembolization, and chemoembolization) or at the physician’s discretion, will remain 
on study for survival analyses. 
 
Table 2: Starting Dose Level 
Drug 
Dose 
Infusion Time 
Schedule (in 21-day 
cycle 
IV Nab-
Paclitaxel 
100 mg/m2 
30 min (+/- 5 min) 
Day 1 and 8 
IV Cisplatin 
25 mg/m2 
60 min (+/- 5 min) 
Day 1 and 8 


2014-0524 
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IV Gemcitabine 
800 mg/m2 
30 min (+/- 5 min) 
Day 1 and 8 
 
Dosing and Administration 
The study drugs will be stored according to package inserts. They will be administered in 
the following order with the specified pre-medications and hydration: 
o Pre cisplatin hydration: 0.9% Sodium Chloride Injection 1000 mL with 
Mannitol 18.5 grams and Magnesium Sulfate 2 grams IV infusion over 2 
hours on days 1 and 8 repeated every 21 days.  
o Aloxi (palonosetron) 0.25 mg IV, Emend (fosaprepitant) 150 mg IV and 
dexamethasone 12 mg IV within 30 minutes prior to treatment on days 1 
and 8, repeated every 21 days. Patients will continue oral antiemetic 
prophylaxis at home with dexamethasone 4 mg bid for 2 days after 
chemotherapy.  
o Nab-paclitaxel 100mg/m2 in NS dilute to a total concentration of 5 
mg/mL (DO NOT FILTER) over 30 minute IV infusion on days 1 and 8 
repeated every 21 days, followed by:  
o Cisplatin 25mg/m2 in 500 mL of NS over 60 minute IV infusion on days 1 
and 8 repeated every 21 days, followed by:  
o Gemcitabine 800 mg/m2 in 500ml over 30 minute IV infusion on days 1 
and 8 repeated every 21 days  
o Post-cisplatin hydration: 0.9% Sodium Chloride Injection 1000 mL IV 
infusion over 3 hours on days 1 and 8 repeated every 21 days. May start at 
the same time as the gemcitabine infusion.  
Dose Modifications and Toxicity Management 
Dose modifications and treatment delays based on observed drug-related toxicity will be 
performed as described below. Any toxicity associated or possibly associated with 
gemcitabine, cisplatin, and Nab-Paclitaxel treatment should be managed according to 
standard medical practice. 
A cycle of therapy may be delayed up to 3 weeks to allow for weather events, patient’s 
personal emergencies, observation of holidays, or other unforeseen delays that the 
Investigator deems to be in the best interest of the patient. For any dose interruptions, re-
initiation of therapy may be delayed for a maximum of 21 days to allow recovery from 
any toxicity. In exceptional cases where subjects are responding, re-initiation of therapy 
after missing > 21 consecutive days of treatment may be done on a case-by-case basis 
after confirmation with the Primary Investigator. Day 8 of cycle can be delayed up to 2 
weeks or a treating physician’s discretion. 
 


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Toxicity will be graded according to the NCI CTCAE, Version 4.0 (which is available at: 
http://ctep.info.nih.gov/protocolDevelopment/electronic_applications/ctc.htm). For any 
event which is apparent at baseline, the dose modification will apply according to the 
corresponding shift in toxicity grade if the investigator feels this is appropriate, (e.g. if a 
patient has grade 1 asthenia at baseline which increases to grade 2 during treatment, this 
will be considered as a shift of 1 grade and treated as a grade 1 toxicity for dose 
modification purposes).   
 
Dose modifications of gemcitabine and Nab-Paclitaxel will be done based on the specific 
toxicity. Once a dose of any study drug has been reduced, it should not be increased at a 
later time.  Reasons for dose modifications or delays, the supportive measures taken, and 
the outcome will be documented in progress notes. Growth factors may be used to treat 
hematologic toxicity and will not constitute a dose reduction. A maximum of a 3-week 
treatment delay is permitted to allow recovery of toxicities. 
Table 3: Dose Levels 
Dose Level Nab-Paclitaxel (mg/m2) Cisplatin (mg/m2) Gemcitabine (mg/m2) 
0 – baseline 
100 
25 
800 
-1 
75 
25 
600 
-2 
50 
25 
600 
-3 
50 
20 
600 
 
Hematologic Toxicity 
In the event dose modifications are required at the beginning of a cycle or within a cycle 
due to hematologic toxicities, doses of nab-paclitaxel, cisplatin, and gemcitabine may be 
adjusted as detailed below. In the event that patients must have treatment delayed within 
a treatment cycle due to hematologic toxicities, those doses held during a cycle will not 
be made up.  
Table 4: Dose Modifications for Day 1 of Each Cycle (Hematologic Toxicity) 
ANC 
 
Platelets 
Timing 
≥ 1,500 cells/mm3 
AND 
≥ 100,000/uL 
Treat on time 
< 1,500 cells/mm3 
OR 
< 100,000/uL 
Delay by 1 week 
intervals until 
recovery 
 
 
Table 5: Dose Modifications for Day 8 of Each Cycle (Hematologic Toxicity)* 
Day 8 
Laboratory 
Results 
Day 8 Nab-Paclitaxel 
Day 8 
Cisplatin 
Day 8 Gemcitabine 
ANC > 1000 
100% 
100% 
100% 


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and Platelets ≥ 
100,000 
ANC 500-1000a 
or Platelets 
50,000-99,000 
Decrease dose by 1 level 
(treat on time) 
100% 
Decrease dose by 1 level 
(treat on time) 
ANC < 500 or 
Platelets < 
50,000 
HOLD 
HOLD 
HOLD 
Febrile 
Neutropenia 
(Grade 3 or 4)b 
HOLD. Upon resuming 
dosing, decrease to next 
lower dose level and do 
not re-escalate throughout 
the rest of treatment. 
HOLD 
HOLD. Upon resuming 
dosing, decrease to next 
lower dose level and do not 
re-escalate throughout the 
rest of treatment. 
Recurrent 
Febrile 
Neutropenia 
(Grade 3 or 4) 
Decrease 2 dose levels (to 
75 mg/m2) and do not re-
escalate throughout the 
rest of treatment. 
HOLD 
Decrease 2 dose levels (to 
600 mg/m2) and do not re-
escalate throughout the rest 
of treatment. 
* See Table 3 for dose reductions guidelines. 
 
a If patients do not experience resolution of neutropenia within 21 days, despite 
 
uninterrupted G-CSF treatment, study treatment will be discontinued.  
 
b Febrile neutropenic should have their chemotherapy treatment interrupted. A full sepsis 
diagnostic work-up should be performed while continuing broad spectrum antibiotics. If 
cultures are positive, the antibiotic may or may not be changed, depending on the sensitivity 
profile of the isolated organism. Patients with persisting fever after 3 weeks, despite 
uninterrupted antibiotic treatment, will discontinue study treatment. Patients can also receive 
G-CSF, in addition to antibiotic treatment, to hasten the resolution of their febrile neutropenia 
(following current institutional guidelines). In all cases, blood counts must have returned to 
non-neutropenic levels before resuming chemotherapy treatment.  
Special Instructions Regarding Treatment of Chemotherapy-related Toxicity 
Dose modification or delay may occur in the setting of lower Grade toxicity if the 
treating physician believes that it is in the interest of a subject’s safety.  Alopecia and 
nausea and/or vomiting that can be controlled by antiemetics do not require dose 
modification or interruption.  No dose reduction or interruption will be required for 
anemia as it can be satisfactorily managed by transfusions. Dose reductions for non-
hematologic toxicity should be as below. Nab-Paclitaxel and Gemcitabine and specific 
exceptions are listed separately below Tables 6 and 7. 
 
Table 6: Dose Modifications for Nab-Paclitaxel and Gemcitabine on Day 1 of 
Each Cycle (Non-Hematologic Toxicity)* 
Toxicity/Dose Held 
Nab-Paclitaxel+Gemcitabine dose this cycle 
Grade 0-2 toxicity 
Same as Day 1 previous cycle (except for Grade 2 cutaneous 
toxicity where doses of nab-paclitaxel and gemcitabine 
should be reduced to next lower dose level – see below) 
Grade 3 toxicitya,c 
Decrease Nab-Paclitaxel and gemcitabine 
to next lower dose levela 


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Grade 4 toxicityb 
Off protocol treatmentb 
Dose held in 2 
previous consecutive 
cycles 
Decrease Nab-Paclitaxel and gemcitabine to next lower dose 
level and continue throughout the rest of treatment 
   * Except peripheral neuropathy and nephrotoxicity (see below) 
 aIf the toxicity only affects neuropathy, then only nab-paclitaxel should be reduced (see 
below). 
 bPulmonary embolism (a Grade 4 toxicity in the CTCAE tables) if mild or asymptomatic, will 
be exempt from this requirement (see below).  
 cExcluding electrolyte abnormalities per judgment of the physician/investigator.  
 
Table 7: Dose Modifications for Nab-Paclitaxel and Gemcitabine on Day 8 of Each 
Cycle (Non-Hematologic Toxicity) 
CTC Grade % of Day 1 Nab-Paclitaxel+Gemcitabine Dose 
0-2 
100%a 
3+ 
Hold treatment until resolution to ≤ 
Grade 1b,c 
 aExcept for cutaneous toxicity (see below).  
 bPulmonary embolism (a Grade 4 toxicity in the CTCAE tables) if mild or asymptomatic, 
willbe exempt from this requirement. 
 cExcluding electrolyte abnormalities per judgment of the physician/investigator.  
 
6.1 G-CSF Administration 
The exact dosage amount and schedule for G-CSF support will be left to the 
treating physician’s discretion.  A recommended approach would be to administer 
G-CSF 5 mcg/kg/day (rounded to the nearest vial size per investigator’s standard 
of care) 24 hours after chemotherapy until recovery to the predetermined 
neutrophil count. 
 
6.2 Sensory Neuropathy 
Cisplatin and nab-paclitaxel treatment should be withheld in patients who 
experience ≥ Grade 3 peripheral neuropathy. Gemcitabine administration can 
continue during this period. Cisplatin may be resumed at the same dose and nab-
paclitaxel treatment may be resumed at the next lower dose level in subsequent 
cycles after the peripheral neuropathy improves to ≤ Grade 2. Patients 
experiencing peripheral neuropathy that requires a delay in scheduled cisplatin 
and nab-paclitaxel dosing for ≥ 21 days will discontinue study treatment. The 
time to resolution to Grade ≤ 2 should be the adverse event duration used for 
adverse event reporting. In those patients who experience Grade 4 sensory 
neuropathy, both drugs should be withheld, and treatment resumed at a reduction 
of 2 dose levels (Dose Level -2) in subsequent cycles after the sensory neuropathy 


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improves to  Grade 2.  Note: the investigator may elect to dose modify for Grade 
2 sensory neuropathy. 
 
6.3 Nephrotoxicity 
Cisplatin (cisplatin injection) produces cumulative nephrotoxicity. The serum 
creatinine, BUN, creatinine clearance, and magnesium, sodium, potassium, and 
calcium levels should be measured prior to initiating therapy, and prior to each 
subsequent course. Cisplatin should not be given unless adequate renal function is 
confirmed with a calculated creatinine clearance of  ≥ 45 mL/min. 
 
6.4 Cutaneous Toxicity 
Patients who develop Grade 2 or 3 cutaneous toxicity should have their dose 
reduced to the next lower dose level as per Table 3. If the patient continues to 
experience these reactions, despite dose reduction, treatment should be 
discontinued. Patients who develop Grade 4 cutaneous toxicity should have 
treatment discontinued. 
 
6.5 Gastrointestinal Toxicity 
 
If Grade 3 mucositis or diarrhea occurs, all 3 study drugs should be withheld until 
resolution to ≤ Grade 1, then reinstituted at the next lower dose level as per Table 
3. Patients who develop Grade 4 mucositis or diarrhea should have treatment 
discontinued. 
 
     6.6  Pulmonary Embolism  
 
Asymptomatic or clinically mild pulmonary embolism can be treated with low-
molecular weight heparin without interruption of therapy. Moderate to severe 
pulmonary embolism will require permanent discontinuation of treatment.  
 
6.7 Interstitial Pneumonitis 
Pulmonary toxicity has been reported for both gemcitabine and paclitaxel. 
Epidemiology reports show that gemcitabine monotherapy is weakly associated 
with lung toxicity. A retrospective review of pooled clinical trial data of 4,448 
patients with mixed cancer indications reported an incidence of dyspnea of 0.2% 
and serious pulmonary toxicity of 0.06%.  
During study participation, patients should be carefully monitored for signs and 
symptoms of pneumonitis (i.e. episodes of transient or repeated dyspnea with 
unproductive persistent cough or fever) and, if observed, immediate clinical 
evaluation and timely institution of appropriate management (emphasizing the 


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need for corticosteroids if an infectious process has been ruled out as well as 
appropriate ventilation and oxygen support when required). Administration of 
study drugs will be permanently discontinued upon making a diagnosis of 
interstitial pneumonitis. 
Prevention, Surveillance and Management of Interstitial Pneumonitis 
• During study treatment, episodes of transient or repeated dyspnea with 
unproductive persistent cough or fever should be paid attention to. Radiographic 
evaluation with chest X-rays and CT scans (normal or high resolution) may be 
indicated to look for infiltrates, ground-glass opacities or honeycombing patterns. 
Pulse oximetry and pulmonary function tests can show respiratory and ventilation 
compromise. 
• Infections should be ruled out with routine immunological/ microbiological 
methods. Transbronchial lung biopsy is not recommended, given its limited value 
and risk of pneumothorax and hemorrhage, and should be reserved for cases with 
unclear etiology.  
• Study drug administration should be interrupted upon diagnosis of interstitial 
pneumonitis and patients permanently discontinued from further study drug 
treatment. After ruling out an infectious etiology, intravenous high-dose 
corticosteroid therapy and secondary pathogen coverage should be instituted 
without delay. Patients with an added immunological component may also require 
immune modulation with azathioprine or cyclophosphamide. Appropriate 
ventilation and oxygen support should be used when required.  
 
6.8 Sepsis 
 
Sepsis has been reported in less than 1% during Nab-Paclitaxel monotherapy and 
fatalities attributed to these events have been rare. However, the risk was 
appreciably higher in patients with advanced or metastatic pancreatic cancer 
receiving Nab-Paclitaxel in combination with gemcitabine with a rate of 5% in 
patients in patients with or without neutropenia receiving Nab-
Paclitaxel/gemcitabine. Complications due to the underlying pancreatic cancer, 
especially biliary obstruction or presence of biliary stent, were identified as 
significant contributing factors. The increased risk of sepsis in the setting of 
advanced or metastatic cancer in combination with gemcitabine could be managed 
with prophylactic antibiotic treatment in febrile patients (regardless of neutrophil 
count) and dose reduction, and with G-CSF treatment in neutropenic patients. If a 
patient becomes febrile (regardless of neutrophil count), initiate treatment with 
broad spectrum antibiotics. For febrile neutropenia, withhold Nab-Paclitaxel and 
gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at 
reduced dose levels. 
Prophylaxis Against Sepsis 
Due to the incidences of non-neutropenic sepsis, at the first occurrence of fever ≥ 


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38.5°C (regardless of neutrophil count), institution of ciprofloxacin (500 mg 
orally, twice daily) or amoxicillin/clavulanate (500 mg orally, 2-3 times daily) in 
patients with allergy to fluoroquinolones should be initiated. On their first visit, 
patients should be provided with enough ciprofloxacin (or the alternative 
antibiotic) for use at home, and they should be instructed to begin taking it when 
they first record a temperature of ≥ 38.5 °C (or if they feel they are developing a 
fever and a thermometer is not available). They should also immediately contact 
their physician for guidance on where to go for blood counts and to be evaluated 
for sepsis as soon as possible. Hospitalization or evaluation in the emergency 
room may be required depending on the clinical presentation. If hospitalization is 
required, this should be reported as a Serious Adverse Event (SAE). 
 
6.9 Hypersensitivity Reactions 
 
Hypersensitivity reactions rarely occur.  If they do occur, minor symptoms such 
as flushing, skin reactions, dyspnea, lower back pain, hypotension, or tachycardia 
may require temporary interruption of the infusion.  However, severe reactions, 
such as hypotension requiring treatment, dyspnea requiring bronchodilators, 
angioedema or generalized urticaria require immediate discontinuation of study 
drug administration and aggressive symptomatic therapy.  Patients who 
experience severe hypersensitivity reactions to Nab-Paclitaxel should not be re-
challenged.  It is not recommended to administer Nab-Paclitaxel to patients with 
prior hypersensitivity to a taxane. If mild to moderate cisplatin hypersensitivity 
develops (per NCI CTCAE), the patient may be desensitized using the standard 
desensitization protocol of the institution. In the setting of a severe 
hypersensitivity reaction, cisplatin should be discontinued. 
Nab-Paclitaxel Premedication 
Patients do not require premedication prior to Nab-Paclitaxel administration, as 
hypersensitivity reactions are rare. Although the solubilizing agents Cremophor® 
EL and Tween® 80 have long been implicated in adverse events including 
hypersensitivity reactions due to their detergent-like nature and known ability to 
induce histamine release (Ten Tije et al, 2003), the administration of solvent-
based taxanes (Taxol and Taxotere) requires premedication with 
corticosteroids and histamine receptor blocking agents to prevent the occurrence 
of hypersensitivity reactions. However, the hypersensitizing role of the taxane 
molecules themselves cannot be ruled out.   
 
In the unlikely event of a mild hypersensitivity reaction, premedication may be 
administered using the premedication regimen the institution typically uses for 
solvent based paclitaxel.  In the rare event of a severe hypersensitivity reaction, 
discontinue Nab-Paclitaxel. 
 
Concomitant Medications 


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Supportive care, including but not limited to anti-emetic medications, may be 
administered at the discretion of the Investigator.  Erythropoietin and G-CSF may 
be administered at the discretion of the investigator, consistent with institutional 
guidelines.  
 
 
 
7.  EVALUATION DURING STUDY 
Patients must begin Cycle 1 within 30 days of signing the informed consent document 
and after the screening assessments. Treatment will be administered by qualified and 
trained site personnel in a hospital, clinic, or other out-patient setting appropriate for 
chemotherapeutic infusions. All assessments should be performed within 24 hours of 
each specified time parameter, with the exception of Cycle 1 in which assessments 
must be conducted within  7 days  or if medical or scheduling conditions require a 
delay. Request of 20 unstained tumor slides of 5 to 10 microns thick will be sent at 
enrollment. 
 
 Day 1 of each cycle (except where noted) 
• 
Inclusion/exclusion review (Cycle 1 only)  
• 
Directed physical exam with neuropathy assessment 
• 
Vital Signs  
• 
Measurement of weight (kg) and BSA calculation prior to dosing   
• 
ECOG Performance Status (see Appendix 1)  
• 
Hematology: CBC with differential and platelet count  
• 
Serum chemistries: glucose, creatinine, BUN, total bilirubin, AST, ALT, alkaline 
phosphatase albumin, LDH, total protein, and electrolytes (sodium, potassium, 
phosphorus, chloride, C02, magnesium, calcium).   In patients with known 
Gilbert’s syndrome, it is recommended to perform a direct bilirubin and indirect 
bilirubin. Calculate creatinine clearance.  
• 
CA 19-9, CA 125, and CEA 
• 
Urinalysis (at Screening only)  
• 
Serum Pregnancy (at Screening only) 
• 
AEs using the NCI CTCAE (http://ctep.info.nih.gov) 
• 
Concomitant medication notation   
  Day 8 of each cycle   
• 
Directed physical exam with neuropathy assessment 
• 
Vital Signs 
• 
Measurement of weight (kg)  
• 
ECOG Performance Status (see Appendix 1)  
• 
Hematology: CBC with differential and platelet count  
• 
Serum chemistries 
• 
AEs using the NCI CTCAE (http://ctep.info.nih.gov)   
• 
Concomitant medication notation 


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 Prior to Cycles 4, 7, 10, etc.  
• 
In order to more precisely determine time to progression, the investigator is 
encouraged to obtain radiological assessments earlier if there is a strong clinical 
suspicion of disease progression, in order to either confirm or refute the clinical 
impression.  
• 
Reassessment of the extent of tumor should be made by the same imaging methods  
used to establish baseline tumor measurements.  
Table 8: Study Assessments (treatment cycle is 21 days) 
 
1. Informed consent must be obtained before any evaluations are initiated.  Diagnostic 
imaging studies must be completed within 28 days prior to first day of study 
treatment. All other baseline evaluations, except for height (which can be obtained at 
any time prior to enrollment), must be completed within 7 days prior to first dose of 
study drug. 
2. Archival tissue will be collected for correlative studies. Patients may initiate study 
treatment prior to the receipt of the archival tissue.  The collection of archival tumor 
tissue is not an absolute requirement for study enrollment and if no prior tissue is 
available than patients may still be enrolled and undergo study treatment. Additional 
tumor and unaffected liver tissue may be collected at the time of standard of care 
biopsy for diagnostic confirmation if a clear histologic diagnosis is unable to be made 
Evaluation or Procedure 
Screening1 
Study Treatment  
End of 
Treatment 
Evaluation11 
30-day Post-
Treatment 
Evaluation12/Long 
Term Follow-up 
 
 
On or before Day 
1 and day 8 of 
each cycle 
 
 
Informed consent 
X 
 
 
 
Medical History 
X 
 
 
 
Physical Examination 
X 
X3,4 
X 
 
Inclusion/Exclusion criteria 
X 
 
 
 
Height 
X 
 
 
 
Weight 
X 
X3,4 
X 
 
Vital Signs (Blood Pressure) 
X 
X3,4 
X 
 
ECOG Performance Status 
X 
X 3,4 
X 
 
Hematology
10 
X 
X
3,4 
X 
 
Biochemistry10 
X 
X
3,4 
X 
 
Urinalysis 
X 
 
 
 
Serum or urine pregnancy test (for females 
of child-bearing potential)  
X 
 
 
 
Tumor Tissue Collection 
X
2 
 
X2 
 
Blood Collection for exploratory analysis 
X13 
 
X 
 
Toxicity assessment 
X 
X3.4 
X 
X
8 
Diagnostic Imaging for Tumor 
Assessment7 
X 
Every 3 cycles
5 
X
6  
X6 
Survival  
 
 
 
X
9 


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with archival tissue. At time of disease progression, if a biopsy for routine clinical 
molecular profiling (using commercial assays such as Foundation One or Caris) is 
done, again, additional tumor and liver tissue may be obtained. For both time points 
(at time of standard of care diagnostic confirmation and at time of progression when 
performing routine clinical molecular profiling), additional preferably fresh frozen 2-
3 cores of tumor tissue using an 18 gauge needle should be collected. Tissue will be 
flash frozen and stored in a -80 degree freezer or shipped on dry ice to the Borad 
laboratory. If fresh frozen tissue is not available, archival tissue may be used. 
Preferably tissue should be sent as 3 scrolls of 50 micron thickness. If not available in 
this format, up to 20 unstained, standard 5 to 10 micron slides can be sent.  Collection 
of additional tissue at time of standard of care biopsies at screening and progression 
likewise is optional. 
3. For Cycle 1, baseline evaluations will suffice as they are performed within 7 days 
prior to first dose of study drug (except for imaging studies which are performed 
within 28 days prior). 
4.  Within 48 hours prior to start of day 1 and day 8 of each cycle (except for Cycle 1 as 
noted above). 
5.  Imaging should be obtained every 3 cycles (+/- 1week).  After a tumor demonstrates a 
tumor response (partial or complete), confirmation of the response will be obtained 
by a second evaluation to be performed 3 cycles later (+/- 1week). Evaluations earlier 
than every 3 cycles are allowed if, in the investigator’s opinion, this evaluation is in 
the patient’s best interest.    
6. The end of treatment imaging does not have to be repeated if recent imaging has been 
completed within 4 weeks.  For patients discontinued from the study for reasons other 
than progression, it is recommend to perform every 12 weeks (+/- 5 week) after the 
End of Treatment Evaluation visit until documentation of progression or for 12 
months after their first dose of study drug, whichever comes first, if no other anti-
cancer treatment is given.   
7. CT of the chest, abdomen, and pelvis. MRI may be used in cases where it is felt to be 
unsafe to perform CT secondary to patient's history of dye allergy, or if the tumor is 
not adequately seen on CT for the purposes of this study. 
8. Treatment-related adverse events occurring during study treatment or within 30 days 
(window of 28-35 days allowed) after the last administration of study drug(s) will be 
followed until resolution or stabilization.  If the patient is unable or unwilling to 
return to M. D. Anderson or Mayo Clinic for this assessment, the patient will be 
contacted by phone for this assessment.   
9. Every 3 months (+/- 5 weeks) from Post-Treatment Evaluation. 
10. Hematology: complete blood count with differential. Chemistry:  glucose, creatinine, 
BUN, total bilirubin, AST, ALT, alkaline phosphatase, albumin, LDH, total protein, 
and electrolytes (sodium, potassium, phosphorus, chloride, C02, magnesium, 
calcium).  Tumor markers (CEA, CA19-9, and CA-125) as indicated. Tumor markers 
are performed every 3 cycles. If starting a new cycle is delayed, no need to repeat 
tumor markers. In patients with known Gilbert’s syndrome, it is recommended to 
perform a direct bilirubin and indirect bilirubin. 
11. Within 10 days of decision to discontinue study treatment.  


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12. At 28-45 days from last dose of study medication. 
13. 10 cc of blood will be collected at the same time as standard of care labs in an EDTA 
tube. Buffy coat will be separated after centrifugation and sample will be shipped 
over dry ice or stored at -80 degrees Celsius. 
 
7.1 End of treatment evaluations  
Within 10 days of decision to discontinue treatment 
• The investigator will evaluate the results of the following clinical and 
laboratory assessments to be conducted at the time the patient discontinues 
study treatment: 
• Physical examination with neuropathy assessment 
• ECOG Performance Status 
• Weight 
• Vital signs (blood pressure) 
• Hematology:  complete blood count with differential 
• Biochemistry:  glucose, creatinine, BUN, total bilirubin, AST, ALT, alkaline 
phosphatase albumin, LDH, total protein, and electrolytes (sodium, potassium, 
phosphorus, chloride, C02, magnesium, calcium).  Tumor markers (CEA, 
CA19-9, and CA-125) as indicated.  In patients with known Gilbert’s 
syndrome, it is recommended to perform a direct bilirubin and indirect 
bilirubin. 
 
• Concomitant medication notation 
• Toxicity (adverse events) assessment (including neurologic toxicities) using 
NCTCTCAE Version 4.0 
• Tumor evaluations including CT scan or MRI of the chest, abdomen, and 
pelvis (if recent imaging within 4 weeks, tumor evaluation does not need to be 
repeated) 
7.2 Follow-up (off-treatment)   
Follow-up/observation for all treatment related adverse events will be through Day 30 
(Day 28 to Day 45 allowed) following the last dose of study drug or until resolution 
or stabilization of the toxicity or start of another treatment regimen. If it is not 
feasible for the patient to return to M. D. Anderson or Mayo Clinic for the Day 30 
toxicity assessment, the patient will be contacted by phone for this assessment.  
 
Patients with documented (radiological) disease progression at any point during the 
study will discontinue treatment with study drugs under this protocol. Objective 
evidence of progressive disease will be recorded at the time of progression.  Patients 
without evidence of progression while on study, regardless of the number of 
treatment cycles received, will be followed for progression until it is documented.  If 
a patient is off treatment with no documented disease progression and no subsequent 
anti-cancer treatment is received, he/she should be followed every 12 weeks (+/- 5 
weeks) after the End of Treatment Evaluation visit with tumor evaluations until 


2014-0524 
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disease progression is documented or for 12 months after their first dose of study 
drug, whichever comes first. 
 
 
7.3     Long-term follow-up 
 
All patients will be followed for survival status approximately every 3 months 30-day 
post-treatment evaluation.  Survival status may be obtained by checking the electronic 
medical record or by telephone call.   
 
 
 
8. 
 CRITERIA FOR REMOVAL FROM THE STUDY  
 
      Subjects who meet the following criteria should be discontinued from study    
      treatment:  
• Disease progression 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s) as determined by the treating physician 
• Patient decides to withdraw from the study  
• General or specific changes in the patient’s condition render the patient      
      unacceptable for further treatment in the judgment of the investigator.   
 
 
 
9. 
RESPONSE EVALUATION 
 
9.1 Measurement of effect  
Response and progression will be evaluated in this study using the new international 
RECIST criteria (version 1.1, 2009) proposed by the RECIST committee28.  All 
patients who have measurable disease according to the RECIST criteria and who have 
their disease re-evaluated will be evaluable for response.  For the purposes of this 
study, patients should be reevaluated for response approximately every 3 cycles.  
Note:  Lesions are either measurable or non-measurable using the criteria provided 
below. The term “evaluable” in reference to measurability will not be used because it 
does not provide additional meaning or accuracy. 
 
9.2 Definitions 
All sites of disease should be followed as either target or non-target lesions, as 
categorized at baseline.  All measurable lesions up to a maximum of 2 lesions per 
organ or 5 lesions in total, representative of all involved organs should be identified 
as target lesions, while all other lesions (either additional measurable lesions or non-
measurable lesions) should be classified as non-target lesions. In cases where a target 
lesion is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned. To ensure comparability, the baseline 


2014-0524 
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radiology/scans and subsequent radiology/scans to assess response should be 
performed using identical techniques (eg, scans performed immediately following 
bolus contrast administration should be made with a standard volume of contrast, the 
identical contrast agent, and preferably the same scanner). The same method, 
radiological or physical, should be employed and assessed by the same individual on 
each occasion, when possible.  
 
9.3 Measurable disease 
Measurable lesions are defined as those that can be accurately measured in at least 
one dimension (longest diameter to be recorded) as >10 mm with CT scan (with 
minimum slice thickness no greater than 5mm, or 10mm caliper measurement by 
clinical exam, or 20mm by chest X-ray).  All tumor measurements must be recorded 
in millimeters (or decimal fractions of centimeters). 
Pathological lymph nodes may also be considered as target or non-target lesions.  To 
be considered pathologically enlarged and measurable (target lesion), a lymph node 
must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). Lymph nodes with a short axis ≥ 10 mm 
but < 15 mm should be considered non-target lesions. Lymph nodes that have a short 
axis < 10 mm are considered non-pathologic and should not be recorded. The short 
axis measurement of any lymph node that is considered a target lesion should 
continue to be recorded regardless if the node progresses to below 10 mm. This may 
prevent the sum of lesions from being zero even if complete response criteria are met, 
since a normal lymph node is defined as having a short axis of < 10 mm.  In rare 
circumstances, when a target lymph node is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned.  
 
9.4 Non-measurable disease 
All other lesions (or sites of disease), including small lesions (longest diameter <10 
mm or pathological lymph nodes with ≥ 10 to <15mm short axis) as well as truly non-
measurable lesions.  Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by CT 
or MRI).  For bone and cystic lesions, please refer to the RECIST criteria (version 
1.1, 2009). 
 
9.5 Target lesions 
All measurable lesions up to a maximum of five lesions total (and a maximum of two 
lesions per organ) representative of all involved organs should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on 
the basis of their size (lesions with the longest diameter) and their suitability for 
accurate repeated measurements (either by imaging techniques or clinically).  A sum 
of the diameters for all target lesions (longest for non-nodal lesions, short axis for 
nodal lesions) will be calculated and reported as the baseline sum diameters (LD).  
The baseline sum diameters will be used as reference by which to characterize the 
objective tumor response. 
 


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9.6 Non-target lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline.  Non-target lesions include measurable lesions 
that exceed the maximum numbers per organ or total of all involved organs as well as 
non-measurable lesions. It is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (e.g. “multiple enlarged 
pelvic lymph nodes” or “multiple liver metastases”).   Measurements of these lesions 
are not required, but the presence or absence of each should be noted throughout 
follow-up.  
 
9.7 Guidelines for evaluation of measurable disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.  
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor effect of a treatment. 
Clinical lesions.  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended.  
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and Magnetic Resonance Imaging.  Conventional CT and MRI 
should be performed to obtain images of 5 mm or less slice thickness. 
Tumor markers.  Tumor markers alone cannot be used to assess response.  If markers 
are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
Cytology, Histology.  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in 
tumor types, such as germ cell tumors, where known residual benign tumors can 
remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
9.8 Response Criteria 
 
Evaluation of target lesions  
▪ Complete Response (CR): 
 Disappearance of all target and non-target lesions 
including normalization of elevated tumor marker level. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. All non-


2014-0524 
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target lymph nodes must be non-pathological in size (< 10 mm short axis). Complete 
response must be confirmed at a second tumor assessment not less than 4 weeks apart 
from the assessment at which CR was observed. 
▪ Partial Response (PR):  At least a 30% decrease in the sum of LD of target 
lesions taking as reference the baseline sum LD. Partial response must be 
confirmed at a second tumor assessment not less than 4 weeks apart from the 
assessment at which PR was observed. 
▪ Progressive Disease (PD): At least a 20% increase (and an absolute increase of 
at least 5 mm) in the sum of LD of measured lesions taking as references the 
smallest sum LD recorded since the treatment started. Appearance of new 
lesions will also constitute PD. In exceptional circumstances, unequivocal 
progression of non-target lesions may be accepted as evidence of disease 
progression. 
▪ Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum LD 
since the treatment started 
▪ Non-CR/Non-PD:  Persistence of 1 or more non-target lesions and/or 
maintenance of tumor marker level above the normal limits. 
 
Evaluation of non-target lesions 
▪ Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level 
▪ Incomplete Response/ Stable Disease (SD): Persistence of one or more non-
target lesion(s) and/or maintenance of tumor marker level above the normal 
limits 
▪ Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions 
▪ Although a clear progression of “non-target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail, and the 
progression status should be confirmed at a later time by the study chair. 
▪ Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
9.9 Time point evaluation 
At each protocol specified time point, a response assessment occurs. Table 9 
provides a summary of this for patients who have measurable disease at baseline. 
Table 10 provides a summary of this for patients with non-measurable (therefore 
non-target) disease. 
 
Table 9: Response for Measurable Disease 
Target 
Lesions 
Non-target Lesions  New Lesions  
Overall 
Response  
Best Response for this 
Category also Requires  
CR 
CR 
No 
CR 
≥ 4 weeks Confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
≥ 4 weeks Confirmation 


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CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Documented at least once ≥ 6 
weeks from baseline 
Not All 
Evaluated 
Non-PD 
No 
NE 
NE 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. NE = inevaluable Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment.  
 
Table 10: Response for Non-measurable Disease 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
NE = inevaluable a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as endpoint for assessment of efficacy in some trials so to assign this category when no 
lesions can be measured is not advised.  
 
9.10  Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria. 
 
Table 11: Response Assignment 
Overall Response First Time 
Point 
Overall Response Subsequent 
Time Point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR 
CR 
SD 
SD provided minimum criteria 
for SD duration met, otherwise, 
PD 


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CR 
PD 
SD provided minimum criteria 
for SD duration met, otherwise, 
PD 
CR 
NE 
SD provided minimum criteria 
for SD duration met, otherwise, 
NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria 
for SD duration met, otherwise, 
PD 
PR 
NE 
SD provided minimum criteria 
for SD duration met, otherwise, 
NE 
NE 
NE 
NE 
NE = inevaluable.  If a CR is truly met at first time point, then any disease seen at a subsequent time 
point, even disease meeting PR criteria relative to baseline, makes the disease PD at that point (since 
disease must have reappeared after CR).  Best response would depend on whether minimum duration for 
SD was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions 
were likely still present and in fact, the patient had PR, not CR at the first time point. Under these 
circumstances, the original CR should be changed to PR and the best response is PR.  
 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as 
having “symptomatic deterioration.”  Every effort should be made to document the 
objective progression, even after discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
 
9.11 
Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessment at a minimum follow-up interval of 6 weeks after the 
criteria for response are first met.  In the case of SD, follow-up measurements must 
have met the SD criteria at least once after study entry at a minimum interval of 6 
weeks. 
 
 
9.12 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are 
met for CR or PR (whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented. 


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9.13 
Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the 
treatment started.  
 
 
 
10. 
STATISTICAL METHODS 
 
10.1 
STUDY DESIGN AND SAMPLE SIZE                                                    
This is a single arm, open label, phase II trial to assess the efficacy and toxicity of 
Nab-Paclitaxel when added to gemcitabine and cisplatin in patients with advanced 
bile duct cancer. The primary objective is to evaluate the efficacy of the combination 
therapy. The primary endpoint is the progression-free survival (PFS).  A maximum of 
50 patients will be enrolled in the study at an estimated accrual rate of 2-3 patients per 
month. The study will monitor for futility and safety. 
 
10.2 
Futility monitoring: 
The Bayes factor single arm time-to-event model by Johnson & Cook will be used to 
monitor the PFS time29. Based on historical data, the median PFS time for the 
standard of care (gemcitabine and cisplatin) is 8 months (mean PFS = 11.54 months), 
and we expect that the combination treatment proposed in this study would prolong 
the median PFS time to 10 months (mean PFS = 14.43 months).  Thus, using this 
Bayesian hypothesis test-based design, we assume the median PFS time is 8 months 
under the null hypothesis (H0), and the median PFS time is 10 months under the 
alternative hypothesis (H1).  
We assume that the sample distribution of PFS time follows an exponential 
distribution, and use an inverse moment prior for mean PFS time under the alternative 
hypothesis. 
 
10.3  
Futility Stopping Rules: 
We implement the following futility stopping rule during the trial, that is, we will stop 
the trial for futility if the posterior probability of the alternative hypothesis is less than 
0.15, i.e. Pr(H1|Data) < 0.15.  
  
10.4 
Operating Characteristics: 
The operating characteristics of the design were produced using the M.D. Anderson 
Cancer Center Department of Biostatistics software Bayes Factor TTE, version1.1.0.   
 
Table 12: Operating characteristics for Futility monitoring 
Scenario True median (mean) 
PFS in months 
Pr(Stopping for 
H0) 
Average # patients treated 
(10%, 25%, 50%, 75%, 90%) 


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1 
6 ( 8.66 ) 
0.842 
36.18 (23, 28, 36, 45, 50 ) 
2 
8 ( 11.54 ) 
0.36 
45.39 (33, 43, 50, 50, 50 ) 
3 
10 ( 14.43 ) 
0.082 
49.04 (50, 50, 50, 50, 50 ) 
4 
12 ( 17.31 ) 
0.019 
49.71 (50, 50, 50, 50, 50 ) 
 
Based on simulations, if the true median PFS time is 6.0 months (Scenario 1), the trial 
will stop with a probability of 84.2% in favor of the null hypotheses. The average 
number of patients (10%, 90%) treated is 36.18 (23, 50). if the true median PFS time 
is 8.0 months (Scenario 2, the null hypothesis), the trial will stop with a probability of 
36% in favor of the null hypotheses.  The average number of patients (10%, 90%) 
treated is 45.39 (33, 50).  If the true median PFS time is 10 months (Scenario 3, the 
alternative hypothesis), the trial will stop with a probability of 8.2% in favor of the 
null hypotheses.  The average number of patients (10%, 90%) treated is 49.71 (50, 
50). 
 
10.5 
Futility Stopping Boundaries: 
The entire simulation output from Bayes Factor TTE is attached as Appendix 3, 
including boundaries of stopping for futility. 
 
10.6 
Safety monitoring: 
Toxicity will be monitored closely using the method of Thall et al30. Denote the 
probability of toxicity by PE, where toxicity is defined as any Grade 4 or higher 
hematologic and Grade 3 or higher non-hematologic toxicities related to the 
treatment.  We assume PE ~ beta (0.6, 1.4).  We will stop the trail if at any point Pr(PE 
> 0.30 | data)  >0.90. That is, we will stop the trial if, at any time during the study, we 
determine that there is more than 90% chance that the toxicity rate is more than 30%. 
The trial will be stopped if (the number of patients with toxicities /number of patients) 
≥6/10, 7/13, 8/15, 9/18, 10/21, 11/23, 12/26, 13/29, 14/32, 15/35, 16/38, 17/41, 18/43, 
19/46 and 20/49.  We will implement this monitoring rule continuously during the 
trial, starting from the 10th patient.  The operating characteristics are listed in table 13 
below. 
Table 13: The operating characteristics for toxicity monitoring are summarized in 
the following table 
True toxicity 
probability  
Probability 
of early 
stop 
Sample size 
percentiles (10, 25, 
50, 75, 90) 
0.2 
0.033  
50  50  50  50  50  
0.3 
0.265  
12  40  50  50  50  


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0.4 
 0.739 
10  12  22  50  50  
0.5 
0.974  
    10  10  11  19  31 
 
The stopping probabilities shown in Table 12 and Table 13 are based on marginal 
probabilities. The early termination of the study can be caused by either lack of 
efficacy or excessive toxicity. If the efficacy and toxicity are considered jointly, the 
stopping probabilities will be higher than the probabilities shown in Table 12 and 
Table 13.  
Table 14 shows several scenarios of the joint stopping probabilities assuming the 
efficacy and toxicity is independent. 
 
Table 14: Operating characteristics considering efficacy and 
toxicity jointly 
True Median PFS 
(Months) 
True probability of toxicity 
Stop 
Probability 
6 
0.2 
0.847 
8 
0.2 
0.381 
8 
0.3 
0.53 
10 
0.2 
0.112 
10 
0.3 
0.325 
12 
0.4 
0.975 
 
All calculations were performed using Bayes Factor TTE v1.1 and Multc99 v2.1. 
 
10.7 Futility monitoring in CTC website  
The Department of Biostatistics will provide and maintain a website (“Clinical Trial 
Conduct”:  https://biostatistics.mdanderson.org/ClinicalTrialConduct/) to monitor 
futility for patients enrolled on this study. The Clinical Trial Conduct website resides 
on a secure server, and access is gained through usernames and passwords provided 
to personnel responsible for enrolling patients and updating patient data.  The website 
is accessed through a browser using secure socket layer (SSL) technology. Personnel 
responsible for enrolling patients on trials, which includes the principal 
investigator(s), research nurse(s), and data coordinator(s), will be trained by members 
of the Department of Biostatistics in the use of the trial website; the importance of 
timely updating of follow-up times and recording of events will be emphasized in 
training. 
 
           10.8 
Statistical analysis:  
SAS software V9.3 (SAS Institute Inc., Cary, NC) will be used for statistical analysis. 
 
Patients demographic, clinical and adverse events observe during the trial will 
summarized using descriptive statistics, including means, frequencies and graphs. All 


2014-0524 
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patients who receive one cycle of therapy will be reported for final toxicity analysis, 
while efficacy will be reported for both an intent to treat population (all patients who 
received one dose of study drug) and for the efficacy evaluable population (all 
patients who received 3 cycles of therapy).   
 
For the primary analysis, we will calculate the Bayes factor, which represents the 
odds in favor of the alternative hypothesis. We will also use the Kaplan-Meier 
method to estimate the PFS probability, OS probability, and duration of response. In 
addition, we will tabulate toxicities and adverse events by frequency and percentage, 
and estimate response rate and its 95% confidence interval. For exploratory purpose, 
we will use Fisher’s exact test and logistic regression analysis to evaluate the 
association between biomarkers and response, and use log rank test and Cox 
proportional hazards regression analysis to evaluate the association between 
biomarkers and OS or PFS. Paired t test and McNemar’s test will be used to compare 
marker expressions at baseline and at the time of disease progression in blood and 
tissue (if available). 
 
 
 
11. 
REGISTRATION PROCESS 
Please see Appendix 4 for a detailed description of the registration process for all 
sites. 
 
 
 
12. 
DATA AND PROTOCOL MANAGEMENT 
Designated research personnel must enter the information required by the protocol 
onto electronic Case Report Forms (CRFs). The University of Texas MD Anderson 
Cancer Center’s Clinical Oncology Research (CORE) system, and the University of 
Texas MD Anderson Cancer Center’s Protocol Data Management System ©(PDMS) 
CRF system will be used for this study.  PDMS is a clinical research information 
management system. The PDMS CRF is an electronic document designed to record 
all the protocol-required information to be reported on each trial subject. 
PDMS provides data entry templates as defined in the protocol. Laboratory results are 
automatically transferred from MD Anderson Cancer Center Laboratory Medicine’s 
server to PDMS each morning. Users must have clearance through the MD Anderson 
Cancer Center Information Services Security Department in order to access PDMS. 
PDMS login is password protected.   The Investigator is responsible for verifying and 
providing source documentation for all adverse events and assigning attribution for 
each event for all subjects enrolled on the trial.  
 
For details regarding the process for data collection among all centers involved in the 
study (MD Anderson and Mayo Clinic), please see Appendix 5. 
 


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13. 
CORRELATIVE STUDIES 
All patients who sign consent for this study will provide consent for the collection of 
previously collected paraffin embedded tissue.  Up to 20 unstained slides of 5 to 10 
microns thick will be requested from the outside institution or prepared from the 
patient’s tumor block, if applicable.  Any residual tumor tissue above what is 
specified here will be returned to the sending institution.  Collected paraffin 
embedded tissue will be handled by GI Medical Oncology research personnel.  Only 
the PI and her authorized research staff will have access to the identifiable 
information from this study.  All the samples extracted from the paraffin tissue used 
in this study will be coded and identifiers (name, medical record number) will not be 
present on any material that is undergoing analysis.  Patient information and relevant 
data will be stored on password –protected institution computers behind the 
institution firewall.  At the closure of this study all unused material will be either 
returned to the sending institution or destroyed. 
 
When patients are enrolled, we will collect their pre-existing tissue biopsies, if 
available, for testing for protein expression using IHC for RRM1 and ERCC1. If a 
clear pathologic diagnosis is not able to be made with pre-existing biopsies, a repeat 
biopsy will be performed for histologic confirmation. From this additional tissue, as 
an optional part of the study, 2-3 cores using an 18 gauge needle and 1 core of 
unaffected liver tissue, will be flash frozen and stored in a -80 degree freezer or 
shipped over dry ice, to the address below. About 10% of each biopsy should be cut 
at the time of sampling and submitted for routine pathological evaluation.  
 
Similarly, an optional biopsy will be done at the time of disease progression in the 
context of routine clinical molecular profiling (e.g. Foundation One or Caris) for 
consideration of further lines of therapy, including clinical trials with targeted 
inhibitors. Tissue will be obtained from tumor using 2-3 cores of 18-gauge needle and 
tissue will be obtained from normal liver using 1 core of 18-gauge needle. Samples 
will preferably be flash frozen and stored in -80 degree freezer or shipped to the 
address below. About 10% of each biopsy end should be cut at the time of sampling 
and submitted for routine pathological evaluation.  
 
If fresh frozen samples are not available in the instances described above, FFPE tissue 
may be utilized. Preferably this would be in the form of up to 3, 50-micron scrolls or 
more standard 5 micron slides (up to 20).  
 
We will also collect blood samples at the start of therapy (mandatory) and at 
progression (optional). Genomic analyses would include RNASeq, flow sorting 
enabled whole exome sequencing and whole methylome analysis at both timepoints. 
These analyses would be performed in the laboratory of Dr. Mitesh Borad at Mayo 
Clinic Phoenix. Samples should be shipped to: 
 


2014-0524 
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Mayo Clinic PRC/Biobank 
ATTN:  Leslie Dixon 
13400 E. Shea Blvd. 
SCJ 3-308 
Scottsdale, AZ  85259 
Telephone: (480) 301-6867 
Lab Telephone: (480) 301-6379 
Fax: (480) 301- 9241 
Email: Dixon.Leslie@mayo.edu 
 
Baseline and at progression blood samples will be collected in the following 
vacutainers: 
o One-10ml Lavender Top EDTA vacutainer tube 
 
Buffy coat should be separated from sample and blood samples should be shipped 
over dry ice (or stored in -80 degree freezer if stored for later shipment) to the address 
listed above and should be obtained at the same time standard of care labs are being 
drawn. 
 
 
 
14. 
SAFETY REPORTING OF ADVERSE EVENTS 
14.1 
Adverse Event Reporting and Definitions  
An adverse event is the appearance or worsening of any undesirable sign, symptom, 
or medical condition occurring after starting the study drug even if the event is not 
considered to be related to study drug. Medical conditions/diseases present before 
starting study drug are only considered adverse events if they worsen after starting 
study drug. Abnormal laboratory values or test results constitute adverse events only 
if they induce clinical signs or symptoms, are considered clinically significant, or 
require therapy. 
 
Information about all adverse events, whether volunteered by the subject, discovered 
by investigator questioning, or detected through physical examination, laboratory test 
or other means, will be collected and recorded and followed as appropriate.  Adverse 
events will be collected from the signing of the informed consent until 30 days after 
the last dose of study drug, or any time after that if the PI determines the event is 
related to the study drug. 
 
The occurrence of adverse events should be sought by non-directive questioning of 
the patient at each visit during the study. Adverse events also may be detected when 
volunteered by the patient during or between visits or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine: 


2014-0524 
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• The severity grade (mild, moderate, severe or grade 1-5) 
• 
Its relationship to the study drug(s) (suspected/not suspected) 
• Its duration (start and end dates or if continuing at final exam) 
• Action taken (no action taken; study drug dosage adjusted/temporarily 
interrupted; study drug permanently discontinued due to this adverse event; 
concomitant medication taken; non-drug therapy given; 
hospitalization/prolonged hospitalization) 
• Whether it constitutes a serious adverse event (SAE) 
All adverse events should be treated appropriately. Such treatment may include 
changes in study drug treatment including possible interruption or discontinuation, 
starting or stopping concomitant treatments, changes in the frequency or nature of 
assessments, hospitalization, or any other medically required intervention. Once an 
adverse event is detected, it should be followed until its resolution, and assessment 
should be made at each visit (or more frequently, if necessary) of any changes in 
severity, the suspected relationship to the study drug, the interventions required to 
treat it, and the outcome. 
Information about common side effects already known about drug can be found in the 
Investigators’ Brochure or will be communicated between IB updates in the form of 
Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
14.2 Adverse event attribution 
• 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
Adverse events for this protocol will be recorded using the Recommended 
Adverse Event Recording Guidelines for phase II protocols.   
 
Recommended Adverse Event Recording Guidelines  
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
Phase II 
Phase II 
Phase II 
Unlikely 
 
 
Phase II 
Phase II 
Phase II 
Possible 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
Probable 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 


2014-0524 
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Definitive 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
 
The Investigator is responsible for verifying and providing source documentation 
for all adverse events and assigning attribution for each event for all subjects 
enrolled on the trial. 
 
14.3 Serious adverse event (SAE) reporting  
A serious adverse event is one that at any dose (including overdose): 
• Results in death 
• Is life-threatening
1 
• Requires inpatient hospitalization or prolongation of existing 
hospitalization 
• Results in persistent or significant disability or incapacity
2 
• Is a congenital anomaly or birth defect 
• Is an important medical event
3 
1“Life-threatening” means that the subject was at immediate risk of death at the time of 
the serious adverse event; it does not refer to a serious adverse event that hypothetically 
might have caused death if it were more severe. 
2“Persistent or significant disability or incapacity” means that there is a substantial 
disruption of a person’s ability to carry out normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in situations where none of the outcomes listed above occurred.  
Important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above should also usually be considered 
serious.  Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse.  
A new diagnosis of cancer during the course of a treatment should be considered as 
medically important.   
 
Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event 
reporting.  A copy of the CTCAE Version 4.0 can be downloaded from the CTEP 
homepage (http://ctep.info.nih.gov).  All appropriate treatment areas should have access 
to a copy of the CTCAE Version 4.0.  All adverse clinical experiences, whether observed 
by the investigator or reported by the patient, must be recorded, with details about the 
duration and intensity of each episode, the action taken with respect to the test drug, and 
the patient’s outcome.  The investigator must evaluate each adverse experience for its 
relationship to the test drug and for its seriousness. 
 
 


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Pregnancies 
Pregnancies occurring while the subject (or female partner of a male subject) is on study 
or within 30 days after the subject’s last dose of Nab-Paclitaxel are considered expedited 
reportable events.  If the subject is on Nab-Paclitaxel, it is to be discontinued 
immediately.  The pregnancy must be reported to Celgene Drug Safety immediately on a 
Pregnancy Reporting Form. 
The Investigator will follow the subject until completion of the pregnancy, and must 
notify Celgene Drug Safety of the outcome on a Pregnancy Follow-Up Reporting Form. 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE 
(i.e., spontaneous abortion [any congenital anomaly detected in an aborted fetus is to be 
documented], stillbirth, neonatal death, or congenital anomaly), the Investigator should 
follow the procedures for Expedited Reporting of SAEs to Celgene (i.e., report the event 
to Celgene Drug Safety by facsimile within 24 hours of the Investigator’s knowledge of 
the event). 
Any suspected fetal exposure to Nab-Paclitaxel must be reported to Celgene within 24 
hours of being made aware of the event.  The patient should be referred to an 
obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and 
counseling. 
All neonatal deaths that occur within 30 days of birth should be reported, without regard 
to causality, as SAEs.  In addition, any infant death after 30 days that the Investigator 
suspects is related to the in utero exposure to Nab-Paclitaxel should also be reported. 
In the case of a live “normal” birth, Celgene Drug Safety should be advised as soon as the 
information is available. 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax: (908) 673-9115 
E-mail:drugsafety@celgene.com 
Investigator Reporting Responsibilities 
The conduct of the study will comply with all FDA safety reporting requirements.   
IND Annual Reports - (If Applicable) 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an 
annual report is provided to the FDA within 60-days of the IND anniversary date.  21 
CRF 312.33 provides the data elements that are to be submitted in the report.  The 
Annual Report should be filed in the study's Regulatory Binder, and a copy provided to 
Celgene Corporation as a supporter of this study as follows. 
 


2014-0524 
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Celgene Corporation 
Attn: Medical Affairs Operations 
Connell Corporate Park  
400 Connell Drive Suite 700 
Berkeley Heights, NJ  07922 
 
All adverse experience reports must include the patient number, age, sex, weight, severity 
of reaction (mild, moderate, severe), relationship to drug (probably related, unknown 
relationship, definitely not related), date and time of administration of test medications 
and all concomitant medications, and medical treatment provided.   The investigator is 
responsible for evaluating all adverse events to determine whether criteria for “serious” 
and as defined above are present.  The investigator is responsible for reporting adverse 
events to Celgene as described below. 
Expedited reporting by investigator to Celgene 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene 
in writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 
24 hours of being aware of the event.  The written report must be completed and supplied 
to Celgene by facsimile within 24 hours.  The initial report must be as complete as 
possible, including an assessment of the causal relationship between the event and the 
investigational product.  Information not available at the time of the initial report (e.g., an 
end date for the adverse event or laboratory values received after the report) must be 
documented on a follow-up report.  A final report to document resolution of the SAE is 
required.  The Celgene tracking number (AX-CL-OTHER-PI-003908) and the 
institutional protocol number should be included on SAE reports (or on the fax cover 
letter) sent to Celgene.  A copy of the fax transmission confirmation of the SAE report to 
Celgene should be attached to the SAE and retained with the patient records. 
Participating study sites must report SAEs to Celgene as described and within 24 hours of 
awareness.  Participating sites should also report SAEs to MD Anderson Cancer Center, 
the primary study site. 
 
Report of Adverse Events to the Institutional Review Board 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) 
of a serious adverse event according to institutional policy.   
Investigator Reporting to the FDA 
Serious adverse events (SAEs) that are unlisted/unexpected, and at least possibly 
associated to the drug, and that have not previously been reported in the Investigators 
brochure, or reference safety information document should be reported promptly to the 
Food and Drug Administration (FDA) by telephone or by fax.  Fatal or life threatening 
SAEs that meet the criteria for reporting to the FDA must be reported to the FDA within 
7 calendar days after awareness of the event.  All other SAEs that meet the criteria for 
reporting to the FDA must be reported to the FDA within 15 calendar days after 
awareness of the event.  A clear description of the suspected reaction should be provided 
along with an assessment as to whether the event is drug or disease related.    


2014-0524 
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Page 39 
Adverse event updates/IND safety reports 
Celgene shall notify the Investigator via an IND Safety Report of the following 
information: 
• Any AE associated with the use of drug in this study or in other studies that is 
both serious and unexpected. 
• Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
 
The Investigator shall notify his/her IRB/EC promptly of these new serious and 
unexpected AE(s) or significant risks to subjects. The Investigator must keep copies of all 
AE information, including correspondence with Celgene and the IRB/EC, on file. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2014-0524 
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Page 40 
 
15.  
REFERENCES 
 
 
1. 
Valle J, Wasan H, Palmer DH, et al: Cisplatin plus gemcitabine versus 
gemcitabine for biliary tract cancer. N Engl J Med 362:1273-81, 2010 
2. 
Von Hoff DD, Ervin T, Arena FP, et al: Increased survival in pancreatic cancer 
with nab-paclitaxel plus gemcitabine. N Engl J Med 369:1691-703, 2013 
3. 
Zhu AX, Hezel AF: Development of molecularly targeted therapies in biliary tract 
cancers: reassessing the challenges and opportunities. Hepatology 53:695-704, 
2011 
4. 
Lazcano-Ponce EC, Miquel JF, Munoz N, et al: Epidemiology and molecular 
pathology of gallbladder cancer. CA Cancer J Clin 51:349-64, 2001 
5. 
Augustine MM, Fong Y: Epidemiology and risk factors of biliary tract and 
primary liver tumors. Surg Oncol Clin N Am 23:171-88, 2014 
6. 
Jemal A, Murray T, Samuels A, et al: Cancer statistics, 2003. CA Cancer J Clin 
53:5-26, 2003 
7. 
Shaib Y, El-Serag HB: The epidemiology of cholangiocarcinoma. Semin Liver 
Dis 24:115-25, 2004 
8. 
Shaib YH, Davila JA, McGlynn K, et al: Rising incidence of intrahepatic 
cholangiocarcinoma in the United States: a true increase? J Hepatol 40:472-7, 
2004 
9. 
Mertens JC, Fingas CD, Christensen JD, et al: Therapeutic effects of deleting 
cancer-associated fibroblasts in cholangiocarcinoma. Cancer Res 73:897-907, 
2013 
10. 
Valle JW, Wasan H, Johnson P, et al: Gemcitabine alone or in combination with 
cisplatin in patients with advanced or metastatic cholangiocarcinomas or other 
biliary tract tumours: a multicentre randomised phase II study - The UK ABC-01 
Study. Br J Cancer 101:621-7, 2009 
11. 
Papakostas P, Kouroussis C, Androulakis N, et al: First-line chemotherapy with 
docetaxel for unresectable or metastatic carcinoma of the biliary tract. A 
multicentre phase II study. Eur J Cancer 37:1833-8, 2001 
12. 
Chiorean EG, Ramasubbaiah R, Yu M, et al: Phase II trial of erlotinib and 
docetaxel in advanced and refractory hepatocellular and biliary cancers: Hoosier 
Oncology Group GI06-101. Oncologist 17:13, 2012 
13. 
Kuhn R, Hribaschek A, Eichelmann K, et al: Outpatient therapy with gemcitabine 
and docetaxel for gallbladder, biliary, and cholangio-carcinomas. Invest New 
Drugs 20:351-6, 2002 
14. 
Law LY: Dramatic response to trastuzumab and paclitaxel in a patient with 
human epidermal growth factor receptor 2-positive metastatic 
cholangiocarcinoma. J Clin Oncol 30:e271-3, 2012 
15. 
Tajima H, Ohta T, Shinbashi H, et al: Successful treatment of unresectable 
gallbladder cancer with low-dose paclitaxel as palliative chemotherapy after 
failure of gemcitabine and oral S-1: A case report. Oncol Lett 4:1281-1284, 2012 
16. 
Claperon A, Mergey M, Aoudjehane L, et al: Hepatic myofibroblasts promote the 
progression of human cholangiocarcinoma through activation of epidermal 
growth factor receptor. Hepatology 58:2001-11, 2013 


2014-0524 
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17. 
Coulouarn C, Clement B: Stellate cells and the development of liver cancer: 
Therapeutic potential of targeting the stroma. J Hepatol 60:1306-9, 2014 
18. 
Sirica AE, Gores GJ: Desmoplastic stroma and cholangiocarcinoma: Clinical 
implications and therapeutic targeting. Hepatology, 2013 
19. 
Sulpice L, Rayar M, Desille M, et al: Molecular profiling of stroma identifies 
osteopontin as an independent predictor of poor prognosis in intrahepatic 
cholangiocarcinoma. Hepatology 58:1992-2000, 2013 
20. 
Sirica AE: The role of cancer-associated myofibroblasts in intrahepatic 
cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 9:44-54, 2012 
21. 
Ma WW, Hidalgo M: The winning formulation: the development of paclitaxel in 
pancreatic cancer. Clin Cancer Res 19:5572-9, 2013 
22. 
Alvarez R, Musteanu M, Garcia-Garcia E, et al: Stromal disrupting effects of nab-
paclitaxel in pancreatic cancer. Br J Cancer 109:926-33, 2013 
23. 
Von Hoff DD, Ramanathan RK, Borad MJ, et al: Gemcitabine plus nab-paclitaxel 
is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. 
J Clin Oncol 29:4548-54, 2011 
24. 
Desai N, et al.: Increased endothelial transcytosis of nanoparticle albumin-bound 
paclitaxel (ABI-007) by gp60-receptors: a pathway inhibited by taxol. . 
Proceedings of San Antonio Breast Cancer Symposium, 2004 
25. 
Commisso C, Davidson SM, Soydaner-Azeloglu RG, et al: Macropinocytosis of 
protein is an amino acid supply route in Ras-transformed cells. Nature 497:633-7, 
2013 
26. 
Frese KK, Neesse A, Cook N, et al: nab-Paclitaxel potentiates gemcitabine 
activity by reducing cytidine deaminase levels in a mouse model of pancreatic 
cancer. Cancer Discov 2:260-9, 2012 
27. 
Desai N, Trieu V, Yao Z, et al: Increased antitumor activity, intratumor paclitaxel 
concentrations, and endothelial cell transport of cremophor-free, albumin-bound 
paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res 
12:1317-24, 2006 
28. 
Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 
2009 
29. 
Johnson VE, Cook JD: Bayesian design of single-arm phase II clinical trials with 
continuous monitoring. Clin Trials 6:217-26, 2009 
30. 
Thall P ea: Bayesian sequential monitoring designs for single-arm clinical trials 
with multiple outcomes, Statistics in Medicine, 1995, pp 357-379 
 
 
 
 
 
 
 
 
 


2014-0524 
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Page 42 
 
Appendix 1 – Eastern Cooperative Oncology Group Performance Status 
 
 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2014-0524 
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Page 43 
 
Appendix 2 - Nab-Paclitaxel – Additional Information 
 
 
  
 
 
Contacts:      
 
For Celgene International Sàrl 
Investors: 
+41 32 729 8303 ir@celgene.com 
 
Media: 
+41 32 729 8304 media@celgene.com 
 
 
NAB-PACLITAXEL® DEMONSTRATES STATISTICALLY SIGNIFICANT 
IMPROVEMENT IN OVERALL SURVIVAL FOR PATIENTS WITH 
ADVANCED PANCREATIC CANCER IN PHASE III STUDY  
 
BOUDRY, Switzerland – (November 9, 2012) – Celgene International Sàrl, a subsidiary 
of Celgene Corporation (NASDAQ: CELG) today announced that its phase III study of 
NAB-PACLITAXEL® (paclitaxel protein-bound particles for injectable suspension) 
(albumin-bound) in combination with gemcitabine in treatment-naïve patients with 
advanced pancreatic cancer met its primary endpoint of overall survival. In the study, 
NAB-PACLITAXEL in combination with gemcitabine demonstrated a statistically 
significant improvement in overall survival compared to patients receiving gemcitabine 
alone.   
 
In the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) study, a Celgene-
sponsored, open-label, randomized, international study 861 metastatic pancreatic cancer 
patients were randomized to receive either NAB-PACLITAXEL plus gemcitabine (125 
mg/m2 followed by 1000 mg/m2 gemcitabine for 3 weeks followed by a week of rest) or 
gemcitabine alone (1000 mg/m2 administered weekly for 7 weeks followed by a week of 
rest followed by cycles of weekly administration for 3 weeks followed by one week of 
rest).  
 
The primary endpoint for the study is improvement in overall survival. Secondary 
endpoints include evaluation of progression-free survival, objective tumor response and 
the safety and tolerability of this combination in this patient population. 
 


2014-0524 
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Page 44 
The safety profile of NAB-PACLITAXEL in combination with gemcitabine observed in 
the study is comparable with other NAB-PACLITAXEL clinical trials in pancreatic 
cancer. A late-breaker placeholder abstract for this study has been submitted to the 
American Society of Clinical Oncology’s (ASCO) 2013 Gastrointestinal Cancers 
Symposium being held in San Francisco on January 24-26, 2013.  
 
Based on the results of the MPACT study, the company plans to submit dossiers for 
registration  in the US, Europe and other markets.  
These results are from an investigational phase III study. NAB-PACLITAXEL is not 
currently approved for the treatment of advanced pancreatic cancer. 
 
About Advanced Pancreatic Cancer 
Advanced pancreatic cancer is a difficult-to-treat cancer with the lowest survival rates 
among all cancer types.  Across all patients with pancreatic cancer, relative 5-year 
survival is 5.5%.  There are two main types of pancreatic cancer - adenocarcinomas, 
which accounts for approximately 95% of all pancreatic cancer, and neuroendocrine 
tumors.  Pancreatic cancer is relatively uncommon with new cases accounting for only 
2.1% of all newly diagnosed cancers. However, pancreatic cancer is the fourth most 
common cause of cancer death in the United States and throughout the world.  
About NAB-PACLITAXEL®    
NAB-PACLITAXEL is an albumin-bound form of paclitaxel that is manufactured using 
patented nab® technology.  NAB-PACLITAXEL is formulated with albumin, a human 
protein, and is free of solvents. 
 
In the United States, NAB-PACLITAXEL was first approved in January 2005 for the 
treatment of breast cancer after failure of combination chemotherapy for metastatic 
disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have 
included an anthracycline unless clinically contraindicated.  NAB-PACLITAXEL is also 
available in Europe, Canada, Russia, Australia, New Zealand, India, Japan, South Korea, 
Bhutan, Nepal, United Arab Emirates and China for the treatment of metastatic breast 
cancer. 
 
In October 2012, NAB-PACLITAXEL was approved by the U.S. Food and Drug 
Administration for the first-line treatment of locally advanced or metastatic non-small 
cell lung cancer, in combination with carboplatin, in patients who are not candidates for 
curative surgery or radiation therapy. 
 
For 
the 
full 
prescribing 
information 
for 
NAB-PACLITAXEL 
please 
visit 
http://www.Nab-Paclitaxel.com.  
 
NAB-PACLITAXEL is currently in various stages of investigation for the treatment of 
the following cancers: pancreatic, metastatic melanoma, bladder, ovarian, and expanded 
applications for breast cancer. 
 


2014-0524 
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Page 45 
NAB-PACLITAXEL® for Injectable Suspension (paclitaxel protein-bound particles 
for injectable suspension) (albumin bound) is indicated for the treatment of breast 
cancer after failure of combination chemotherapy for metastatic disease or relapse 
within 6 months of adjuvant chemotherapy. Prior therapy should have included an 
anthracycline unless clinically contraindicated.   
 
NAB-PACLITAXEL is indicated for the first-line treatment of locally advanced or 
metastatic non-small cell lung cancer, in combination with carboplatin, in patients 
who are not candidates for curative surgery or radiation therapy. 
 
Important Safety Information 
 
WARNING - NEUTROPENIA 
 
• Do not administer NAB-PACLITAXEL therapy to patients who have baseline 
neutrophil counts of less than 1,500 cells/mm3. In order to monitor the 
occurrence of bone marrow suppression, primarily neutropenia, which may be 
severe and result in infection, it is recommended that frequent peripheral blood 
cell counts be performed on all patients receiving NAB-PACLITAXEL 
 
• Note: An albumin form of paclitaxel may substantially affect a drug’s functional 
properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR 
OR WITH OTHER PACLITAXEL FORMULATIONS 
 
CONTRAINDICATIONS 
Neutrophil Counts 
• NAB-PACLITAXEL should not be used in patients who have baseline neutrophil 
counts of < 1,500 cells/mm3  
 
Hypersensitivity 
• Patients who experience a severe hypersensitivity reaction to NAB-PACLITAXEL 
should not be rechallenged with the drug 
 
WARNINGS AND PRECAUTIONS 
Hematologic Effects 
• Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-
limiting toxicity of NAB-PACLITAXEL 
• Monitor for myelotoxicity by performing complete blood cell counts frequently, 
including prior to dosing on Day 1 for metastatic breast cancer (MBC) and Days 1, 8, 
and 15 for non-small cell lung cancer (NSCLC) 
• Do not administer NAB-PACLITAXEL to patients with baseline absolute neutrophil 
counts (ANC) of less than 1,500 cells/mm3 
• In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a 
course of NAB-PACLITAXEL therapy, reduce the dose of NAB-PACLITAXEL in 
subsequent courses in patients with either MBC or NSCLC 


2014-0524 
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Page 46 
• In patients with MBC, resume treatment with every-3-week cycles of NAB-
PACLITAXEL after ANC recovers to a level >1,500 cells/mm3 and platelets recover 
to >100,000 cells/mm3 
• In patients with NSCLC, resume treatment if recommended at permanently reduced 
doses for both weekly NAB-PACLITAXEL and every-3-week carboplatin after ANC 
recovers to at least 1,500 cells/mm3 and platelet count of at least 100,000 cells/mm3 
on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 
cells/mm3 on Days 8 or 15 of the cycle 
 
Nervous System 
• 
Sensory neuropathy is dose- and schedule-dependent 
• 
The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose 
modification 
• 
If ≥ Grade 3 sensory neuropathy develops, treatment should be withheld until 
resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade1 for NSCLC 
followed by a dose reduction for all subsequent courses of NAB-PACLITAXEL 
 
Hypersensitivity 
• Severe and sometimes fatal hypersensitivity reactions, including anaphylactic 
reactions, have been reported 
• Patients who experience a severe hypersensitivity reaction to NAB-PACLITAXEL 
should not be re-challenged with this drug 
 
Hepatic Impairment 
• 
Because the exposure and toxicity of paclitaxel can be increased with hepatic 
impairment, administration of NAB-PACLITAXEL in patients with hepatic 
impairment should be performed with caution 
• 
The starting dose should be reduced for patients with moderate or severe hepatic 
impairment 
 
Albumin (Human) 
• NAB-PACLITAXEL contains albumin (human), a derivative of human blood 
 
Use in Pregnancy: Pregnancy Category D 
• 
NAB-PACLITAXEL can cause fetal harm when administered to a pregnant woman  
• 
If this drug is used during pregnancy, or if the patient becomes pregnant while 
receiving this drug, the patient should be apprised of the potential hazard to the fetus 
• 
Women of childbearing potential should be advised to avoid becoming pregnant 
while receiving NAB-PACLITAXEL 
 
Use in Men 
• 
Men should be advised not to father a child while receiving NAB-PACLITAXEL 
 
 


2014-0524 
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Page 47 
ADVERSE REACTIONS  
 
Randomized Metastatic Breast Cancer (MBC) Study 
• The most common adverse reactions (≥20%) with single-agent use of NAB-
PACLITAXEL in the MBC study  were alopecia (90%), neutropenia (all cases 80%; 
severe 9%), sensory neuropathy (any symptoms 71%; severe 10%), abnormal ECG 
(all patients 60%; patients with normal baseline 35%), fatigue/asthenia (any 47%; 
severe 8%), myalgia/arthralgia (any 44%; severe 8%), AST elevation (any 39%), 
alkaline phosphatase elevation (any 36%), anemia (all cases 33%; severe 1%), nausea 
(any 30%; severe 3%), diarrhea (any 27%; severe <1%) and infections (24%)  
• Sensory neuropathy was the cause of NAB-PACLITAXEL discontinuation in 7/229 
(3%) patients  
• Other adverse reactions of note included vomiting (any 18%; severe 4%), renal 
dysfunction (any 11%; severe 1%), fluid retention (any 10%; severe 0%); mucositis 
(any 7%; severe <1%), hepatic dysfunction (elevations in bilirubin 7%),  
hypersensitivity reactions (any 4%; severe 0%), thrombocytopenia (any 2%; severe 
<1%), and injection site reactions (<1%). In all NAB-PACLITAXEL treated patients 
(n=366) ocular/visual disturbances were reported (any 13%; severe 1%). Dehydration 
and pyrexia were also reported 
• Severe cardiovascular events possibly related to single-agent NAB-PACLITAXEL 
occurred in approximately 3% of patients and included cardiac ischemia/infarction, 
chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, 
pulmonary thromboembolism, pulmonary emboli, and hypertension  
• Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been 
reported  
 
Non-Small Cell Lung (NSCLC) Cancer Study 
• Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use 
of NAB-PACLITAXEL and carboplatin in NSCLC were: anemia (28%); neutropenia 
(47%); thrombocytopenia (18%), and peripheral neuropathy (3%) 
• The most common adverse reactions (≥ 20%) of NAB-PACLITAXEL in combination 
with carboplatin for NSCLC were anemia, neutropenia, thrombocytopenia, alopecia, 
peripheral neuropathy, nausea, and fatigue 
• The most common serious adverse reactions of NAB-PACLITAXEL in combination 
with carboplatin for NSCLC were anemia (4%) and pneumonia (3%) 
• The most common adverse reactions resulting in permanent discontinuation of NAB-
PACLITAXEL were neutropenia (3%), thrombocytopenia (3%), and peripheral 
neuropathy (1%) 
• The most common adverse reactions resulting in dose reduction of NAB-
PACLITAXEL were neutropenia (24%), thrombocytopenia (13%), and anemia (6%) 
• The most common adverse reactions leading to withholding or delay in NAB-
PACLITAXEL dosing were neutropenia (41%), thrombocytopenia (30%), and 
anemia (16%) 
• The following common (≥10% incidence) adverse reactions were observed at a 
similar incidence in NAB-PACLITAXEL plus carboplatin-treated and paclitaxel 


2014-0524 
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Page 48 
injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, 
decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 
12%, dyspnea 12%, and rash 10% (incidence rates are for the NAB-PACLITAXEL 
plus carboplatin treatment group) 
 
Post-Marketing Experience with NAB-PACLITAXEL and other Paclitaxel 
Formulations 
• 
Severe and sometimes fatal hypersensitivity reactions have been reported with NAB-
PACLITAXEL. The use of NAB-PACLITAXEL in patients previously exhibiting 
hypersensitivity to paclitaxel injection or to human albumin has not been studied 
• 
There have been reports of congestive heart failure and left ventricular dysfunction 
with NAB-PACLITAXEL, primarily among individuals with underlying cardiac 
history or prior exposure to cardiotoxic drugs 
• 
There have been reports of extravasation of NAB-PACLITAXEL. Given the 
possibility of extravasation, it is advisable to monitor closely the NAB-
PACLITAXEL infusion site for possible infiltration during drug administration 
 
DRUG INTERACTIONS 
• 
Caution should be exercised when administering NAB-PACLITAXEL concomitantly 
with medicines known to inhibit or induce either CYP2C8 or CYP3A4 
 
USE IN SPECIFIC POPULATIONS 
Nursing Mothers 
• 
It is not known whether paclitaxel is excreted in human milk. Because many drugs 
are excreted in human milk and because of the potential for serious adverse reactions 
in nursing infants, a decision should be made to discontinue nursing or to discontinue 
the drug, taking into account the importance of the drug to the mother 
 
Pediatric 
• The safety and efficacy of NAB-PACLITAXEL in pediatric patients have not been 
evaluated 
 
Geriatric 
• No toxicities occurred notably more frequently among patients ≥ 65 years of age who 
received NAB-PACLITAXEL for MBC 
• Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in 
patients ≥65 years of age treated with NAB-PACLITAXEL and carboplatin in 
NSCLC 
 
Renal Impairment 
• The use of NAB-PACLITAXEL has not been studied in patients with renal 
impairment 
 
 


2014-0524 
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Page 49 
DOSAGE AND ADMINISTRATION 
• Dose adjustment is recommended for patients with moderate and severe hepatic 
impairment and patients who experience severe neutropenia or severe sensory 
neuropathy during treatment with NAB-PACLITAXEL  
• Withhold NAB-PACLITAXEL if AST >10 x ULN or bilirubin > 5 x ULN 
• Dose reductions or discontinuation may be needed based on severe hematologic or 
neurologic toxicities  
• Monitor patients closely 
 
Please see full Prescribing Information, including Boxed WARNING, 
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE 
REACTIONS. 
 
About Celgene International Sàrl 
Celgene International Sàrl, located in Boudry, in the Canton of Neuchâtel, Switzerland, is 
a wholly owned subsidiary and international headquarters of Celgene Corporation. 
Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global 
pharmaceutical company engaged primarily in the discovery, development and 
commercialization of innovative therapies for the treatment of cancer and inflammatory 
diseases through gene and protein regulation. For more information, please visit the 
Company's website at www.celgene.com. 
 
Forward-Looking Statements 
 
This press release contains forward-looking statements, which are generally statements 
that are not historical facts. Forward-looking statements can be identified by the words 
"expects," "anticipates," "believes," "intends," "estimates," "plans," "will," “outlook” 
and similar expressions. Forward-looking statements are based on management’s 
current plans, estimates, assumptions and projections, and speak only as of the date they 
are made. We undertake no obligation to update any forward-looking statement in light 
of new information or future events, except as otherwise required by law. Forward-
looking statements involve inherent risks and uncertainties, most of which are difficult to 
predict and are generally beyond our control. Actual results or outcomes may differ 
materially from those implied by the forward-looking statements as a result of the impact 
of a number of factors, many of which are discussed in more detail in our Annual Report 
on Form 10-K and our other reports filed with the Securities and Exchange Commission.  
#  #  # 
 
 
 
 
 
 
 
 


2014-0524 
March 16, 2016 
Page 50 
 
Appendix 3 – Statistical Simulation 
 
The software BayesFactorTTE V1.1 for single arm TTE  trial monitoring with Bayes 
factors was used for simulation of futility monitoring. This software implements the 
clinical trial monitoring method proposed by Valen Johnson and John Cook in "Bayesian 
Design of Single-Arm Phase II Clinical Trials with Continuous Monitoring," Clinical 
Trials 2009; 6(3):217-26.  The software was downloaded from the software download 
site in the department of Biostatistics MDACC 
https://biostatistics.mdanderson.org/SoftwareDownload/SingleSoftware.aspx?Software_I
d=89 
 
Output Report 
BayesFactorTTE (version 1.1.0) 
Bayes Factor One-arm Time-to-event Outcome  
Random seed for simulation: 12345 
Design input parameters: 
Parameter 
Value 
Maximum number of patients  
50 
Null hypothesis of median (mean) TTE in month 
8 ( 11.54 ) 
Alternative hypothesis of median (mean) TTE in month  10 ( 14.43 ) 
Cutoff to stop for futility if Pr(H1|Data)     <  
0.15 
Cutoff to stop for superiority if Pr(H1|Data)   >  
1 
Accrual rate per month  
3 
Number of repetitions for the simulation  
1000 
Do you need to print out the stopping boundaries  
Yes  
 
Note: H1 = alternative hypothesis 
Simulation Results 
Scenario True median 
(mean) TTE 
Pr(Stopping for 
H0) 
Average # patients treated (10%, 
25%, 50%, 75%, 90%)  
1 
6 ( 8.66 ) 
0.842 
36.18 (23, 28, 36, 45, 50 ) 
2 
8 ( 11.54 ) 
0.36 
45.39 (33, 43, 50, 50, 50 ) 


2014-0524 
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Page 51 
3 
10 ( 14.43 ) 
0.082 
49.04 (50, 50, 50, 50, 50 ) 
4 
12 ( 17.31 ) 
0.019 
49.71 (50, 50, 50, 50, 50 ) 
 
Note:H0 = null hypothesis; H1 = alternative hypothesis 
Stopping Boundaries 
Number Events 
Max total time-on-test in days (months) to claim futility 
0 
0 ( 0 )  
1 
0 ( 0 )  
2 
0 ( 0 )  
3 
0 ( 0 )  
4 
0 ( 0 )  
5 
0 ( 0 )  
6 
98 ( 3.2 )  
7 
502 ( 16.5 )  
8 
905 ( 29.7 )  
9 
1309 ( 43 )  
10 
1711 ( 56.2 )  
11 
2114 ( 69.5 )  
12 
2516 ( 82.7 )  
13 
2917 ( 95.8 )  
14 
3319 ( 109 )  
15 
3720 ( 122.2 )  
16 
4120 ( 135.4 )  
17 
4521 ( 148.5 )  
18 
4921 ( 161.7 )  
19 
5320 ( 174.8 )  


2014-0524 
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Page 52 
20 
5720 ( 187.9 )  
21 
6119 ( 201 )  
22 
6518 ( 214.1 )  
23 
6917 ( 227.3 )  
24 
7316 ( 240.4 )  
25 
7714 ( 253.4 )  
26 
8112 ( 266.5 )  
27 
8510 ( 279.6 )  
28 
8908 ( 292.7 )  
29 
9305 ( 305.7 )  
30 
9703 ( 318.8 )  
31 
10100 ( 331.8 )  
32 
10497 ( 344.9 )  
33 
10894 ( 357.9 )  
34 
11290 ( 370.9 )  
35 
11687 ( 384 )  
36 
12083 ( 397 )  
37 
12479 ( 410 )  
38 
12875 ( 423 )  
39 
13271 ( 436 )  
40 
13667 ( 449 )  
41 
14062 ( 462 )  
42 
14458 ( 475 )  
43 
14853 ( 488 )  
44 
15248 ( 501 )  
45 
15643 ( 513.9 )  


2014-0524 
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46 
16038 ( 526.9 )  
47 
16433 ( 539.9 )  
48 
16828 ( 552.9 )  
49 
17222 ( 565.8 )  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2014-0524 
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Appendix 4 -  Registration Process for Mayo Clinic Sites 
 
Centralized Registrations  
 
A centralized registration procedure will be used. Subjects who are considered candidates 
for the study will be evaluated for eligibility by the participating investigator. There will 
be a 2-part registration procedure:  
 
1) Participating Institution Registration  
Subjects at participating institutions should be registered with their institutional central 
registration following each institution’s established policies.  
 
2) MD Anderson GI Medical Oncology Registration  
Participating institutions must register subjects with GI Medical Oncology in accordance 
with project specific procedures. All participating institution subjects must be registered 
with GI Medical Oncology before protocol treatment is initiated. Late registrations will 
not be accepted.  
 
Registrations will be completed by GI Medical Oncology within 1 business day after the 
date the registration is received from the participating site.  
 
Subject ID Number  
At the time of registration, the participating institution’s subject will be assigned an MD 
Anderson subject number. This number is unique to the subject and must be used for 
registrations onto subsequent protocols and written on all data and correspondence for 
that subject prior to submission to GI Medical Oncology.  
 
MD Anderson Cancer Center subjects will be registered using their MD Anderson subject 
number.  
 
Registration Verification Letter  
A Registration Verification Letter will be created by GI Medical Oncology and then 
faxed or emailed to the participating institution after the registration is completed.  
 
Initiation of Therapy  
Subjects must be registered with GI Medical Oncology before receiving study treatment. 
Treatment may not be initiated until the participating institution receives the subject’s 
Registration Verification Letter from GI Medical Oncology.   GI Medical Oncology must 
be notified of any exceptions to this policy.  
 
Eligibility Exceptions  
The MD Anderson Cancer Center policy regarding exceptions to eligibility will be 
applied unless eligibility exceptions (also known as PI Overrides) are specifically 
prohibited by the project or protocol. The Clinical Research Support Center (CRSC) 


2014-0524 
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policy on Multicenter Eligibility Exceptions describes the inclusion of subjects from 
participating sites in this process.  
 
Eligibility Exceptions will be processed within 1 business day from the time the Lead 
Principal Investigator’s written approval and the rationale for allowing the exemption is 
received in GI Medical Oncology.    
 
The subject registration will not be completed until after the Exception has been 
approved by all parties.  
 
Confidentiality  
All documents, investigative reports, or information relating to the subject are strictly 
confidential. Any subject specific data or reports (i.e. Pathology Reports, MRI Reports, 
Operative Reports, etc.) that the site submits to GI Medical Oncology will adhere to the 
CRSC’s Multicenter Subject Confidentiality Policy. 
 
 
Patient registration process flowchart below (next page). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2014-0524 
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Patient Registration Process Flowchart 
 
 
Participating Site
Consent 
Eligibility Checklist
Source Documents
Send by e-mail to: 
2014-0524@mdanderson.org
 and copy   
MultiCenterSupport@mdanderson.org
GI Med Onc
Verify Eligibility
Patient not 
Eligible
Inform site that 
participation 
has been 
registered “or” 
is ineligible
Patient Eligible
Register in 
CORe
Send registration 
documents
CRSC
(Coordinating Center)
A protocol email 
address makes it easy 
for the site to register as 
well as send messages.
The email group 
includes everyone 
involved with the 
management of the 
protocol including the 
PI. 
 
 
 
 
 
 


2014-0524 
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APPENDIX 5 
 
 
PROTOCOL 2014-0524 
DATA QUALITY MANAGEMENT PLAN 
Multicenter Project 
 
 
TABLE OF CONTENTS 
 
1.0    Introduction 
 
2.0 General Roles and Responsibilities 
 
2.1 Protocol Principal Investigator 
 
2.2 Coordinating Center 
 
2.3 Participating Institution Principal Investigator 
 
3.0 Coordinating Center 
 
3.1 Correspondence Information 
 
3.2    Hours of Operation 
 
4.0 Protocol Management 
 
4.1  Protocol Distribution 
 
4.2 Protocol Revisions and Closures 
 
4.3  Informed Consent Requirements 
 
4.4  Regulatory Documents 
 
4.5  Participating Institution Site Initiation 
 
4.6  IRB Annual Review 
 
4.7  Participant Confidentiality and Authorization Statement 
 
4.8  Patient Registration 
 
4.9  Schedule of Data Entry and Source Document Submission 
 
4.10  Data Form and Source Document Review 
 
4.11 Missing and Deficient Memorandum 
 
5.0 Study Drug Requisition 
 
    
 


2014-0524 
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6.0   
Safety Assessments and Toxicity Monitoring 
 
6.1  Serious Adverse Events 
 
6.2 Oversight for Safety Assessment and Toxicity Monitoring 
 
6.3  Reporting Serious Adverse Events 
 
 
7.0 Protocol Violations, Deviations and Unanticipated Problems 
 
7.1  Definitions 
 
7.2  Reporting Procedures 
 
8.0 Quality Assurance 
 
8.1 Ongoing Monitoring of Protocol Compliance 
 
8.2  Verification of Study Data 
     
8.3  On-Site Audit 
     
9.0    Evaluation of Participating Institution Performance                                                                                 
 
9.1   Sub-Standard Performance                                                                                                        
 
9.2   Corrective Actions                                                                                                                            
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2014-0524 
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1.0 
INTRODUCTION 
 
The purpose of the Data Quality Management Plan (DQMP) is to establish 
standards which will ensure that the conduct of an MD Anderson Cancer Center 
(MD Anderson) multicenter protocol complies with institutional guidelines, 
Federal regulations (21 CFR Part 11), Good Clinical Practice (GCP) Guidelines, 
and Health Insurance Portability and Accountability Act (HIPAA) requirements. 
 
The DQMP outlines the procedures required for participating institutions in the 
conduct of a MD Anderson multicenter protocol. 
 
 
2.0 
GENERAL ROLES AND RESPONSIBILITIES 
 
Being the lead institution, MD Anderson and its Institutional Review Board (IRB) 
are responsible for the coordination, development, submission, and approval of a 
protocol as well as its subsequent amendments.   
 
The MD Anderson Protocol Principal Investigator, Coordinating Center, and the 
Participating Institution Principal Investigator will all agree to the general 
responsibilities as follows: 
 
2.1 Protocol Principal Investigator (Protocol PI) 
Being charged with the administrative responsibilities of the MD Anderson 
multicenter protocol, the Protocol PI will accept the following:  
 
▪ Obtain initial approval of the protocol and approval of any subsequent 
amendments from the MD Anderson IRB, and/or sponsor or supporting 
entity (if applicable). 
▪ Identify participating institutions and investigators, and obtain accrual 
commitments. 
▪ Include the list of participating institutions and responsible investigators in 
the abstract or protocol appendix. 
▪ Coordinate contractual agreements with sponsor or supporters (when 
applicable), and with each participating institution.   
▪ Assure that all participating institutions are using the correct version of the 
protocol. 
▪ Assure that all participating institutions obtain IRB (or equivalent) 
approval of the protocol prior to performing any study related activities 
with potential subjects. 
▪ Review Adverse Events/Serious Adverse Events from all participating 
institutions on a timely basis to assure participant safety. 


2014-0524 
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▪ Review deviations, violations or unanticipated problems that are reported 
from all participating institutions on a timely basis to assure participant 
safety and protocol integrity. 
▪ Ensure timely submission of protocol data from all participating 
institutions. 
▪ Review and assess protocol data from all participating institutions for 
study analysis in a timely fashion. 
▪ Submit all required reports to the MD Anderson IRB, Sponsor or 
Supporter, and any other relevant regulatory agencies. 
▪ Monitor the overall conduct and progress of the study at all participating 
institutions. 
 
2.2 Coordinating Center  
To assist the Protocol PI in fulfilling these responsibilities, the study teams in 
the Department of Gastrointestinal Medical Oncology and the Clinical 
Research Support Center (CRSC) at MD Anderson, will provide the 
administrative support and assume the following responsibilities to ensure 
data quality and protocol compliance at all participating institutions. 
 
▪ Act as liaison between MD Anderson and the participating institutions.  
▪ Implement quality assurance and quality control systems to ensure quality 
data and protocol compliance. 
▪ Distribute MD Anderson IRB approved protocol and its amendments to all 
participating institutions.     
▪ Collect and maintain regulatory documents for all participating 
institutions.  
▪ Collaborate with the Department of Gastrointestinal Medical Oncology in 
providing protocol and database trainings to ensure that all investigators 
and staff are given instructions on following the protocol, on complying 
with a uniform set of standards for the assessment of clinical and 
laboratory findings, and on completing the CRFs/eCRFs.  
▪ Review, process, and maintain records of Adverse Events/Serious Adverse 
Events from all participating institutions on a timely basis to assure 
participant safety.  
▪ Review, process, and maintain records of Deviations, Violations or 
Unanticipated problems, that are reported from all participating 
institutions on a timely basis to assure participant safety and protocol 
integrity.  
▪ Distribute Safety Reports (External Adverse Events), if applicable, to all 
participating institutions. 
▪ Ensure timely submission and accuracy of protocol data from all 
participating institutions.  
▪ Assist in the submission of all required reports to the Protocol PI, MD 
Anderson IRB and any other relevant regulatory agencies.  
 


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2.3 Participating Institution Principal Investigator (Participating PI) 
▪ Commit to accrual to the MD Anderson protocol. 
▪ Submit the MD Anderson IRB approved protocol and its 
amendments to the institution’s local or central IRB (or equivalent) 
for approval prior to performing any study related activities with 
potential subjects.  
▪ Assume overall responsibility for the trial at his/her institution.  
▪ Oversee the conduct of the clinical trial at his/her institution.  
▪ Identify study collaborators from that institution who agree to 
participate.  
▪ Assure that all involved research personnel are aware of the effort 
required to oversee and conduct the trial.  
▪ Balance the trial needs with other commitments.  
▪ Assure adequate staff with adequate research and protocol training.  
▪ Assure adequate facilities to conduct the trial.  
▪ Provide, and update as needed, a list of contact information of 
involved staff and Delegation Authority Log for the protocol to the 
Coordinating Center.  
▪ Ensure that the multicenter trial procedures are performed at 
his/her institution in compliance with the protocol and the DQMP. 
 
 
3.0    COORDINATING CENTER 
 
3.1 Correspondence Information   
  
Department of Gastrointestinal Medical Oncology at MD Anderson  
(Patient Registrations to be performed by the GI Medical Oncology team) 
▪ Phone: 713/794-4869 
Fax:  713/745-3662 
Email: 2014-0524@mdanderson.org 
 
▪ Mailing address: for all U.S. Mail excluding express mail: 
The University of Texas  
MD Anderson Cancer Center, Unit 426 
Department of Gastrointestinal Medical Oncology 
1515 Holcombe Blvd. 
Houston, Texas 77030-4009 
▪ Mailing address for Federal Express, Airborne, and UPS: 
The University of Texas 
MD Anderson Cancer Center 
Department of Gastrointestinal Medical Oncology 
1515 Holcombe Blvd, Unit 426 
Houston, Texas 77030 
 
Clinical Research Support Center at MD Anderson 


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(Regulatory oversight, study monitoring and auditing, and general 
correspondence) 
   
▪ Mailing address for all U.S. Mail excluding express mail: 
The University of Texas 
MD Anderson Cancer Center 
Clinical Research Support Center, Unit 1635P.O. Box 301407 
7007 Bertner Avenue 
Houston, Texas 77230-1407 
 
▪ Mailing address for Federal Express, Airborne, and UPS: 
The University of Texas 
MDAnderson Cancer Center 
Clinical Research Support Center 
7007 Bertner, Suite 12.2152  
Houston, Texas 77030 
▪ Email:  MultiCenterSupport@mdanderson.org 
Facsimile:  713-563-5468 
 
 
            3.2  Hours of Operation 
The staff at both the Department of Gastrointestinal Medical Oncology and 
Clinical research Support Center (Coordinating Center) at MD Anderson are 
available between the hours of 8:00 a.m. and 5:00 p.m. Central Standard 
Time, Monday through Friday, excluding holidays.  On designated 
University of Texas holidays, the office will be closed. 
 
Transactions (i.e. participant registration, correspondences) will not take 
place on holidays.  Occasionally, the Coordinating Center may close due to 
hurricanes or other inclement weather conditions.  Each participating 
institution will be notified of office closures by phone, fax, or e-mail. 
 
Night, Weekend, and Holiday Emergencies:  
If participant-related emergencies or questions arise when the Coordinating 
Center is closed, please email the Protocol PI and confirm receipt by 
contacting the PI the next business day at the telephone number listed in the 
protocol. 
 
 
4.0 
PROTOCOL MANAGEMENT 
 
            The Coordinating Center is responsible for assuring that each participating 
institution has the appropriate assurance on file with the Office of Human 


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Research Protection (OHRP).  Additionally, the Coordinating Center will 
maintain copies of all IRB approvals from each participating institution.  
 
4.1    Protocol Distribution 
  The Coordinating Center will distribute the final M.D. Anderson IRB 
approved protocol and any subsequent amended protocols to all 
participating institutions within thirty (30) days of approval.  
 
4.2    Protocol Revisions and Closures  
 The Participating Institutions will receive fax or e-mail notification of 
protocol revisions from the Coordinating Center.  Protocol revisions will be 
submitted in pdf format to participating institutions.  It is the responsibility 
of each participating institution to notify its IRB of these revisions within 
the timeline set forth below.  
 
 
 
Major Amendment: A substantive change in the study which may increase or 
decrease the risk to study subjects.  Major revisions require full IRB approval.   
Participating institutions shall provide its IRB approval of the revision within 90 
days after notice.  If more than 90 days, participant enrollment shall be 
temporarily suspended at participating institution until its IRB approval is 
submitted to the Coordinating Center.   
 
The following are examples of major amendments: 
▪ Change of eligibility (inclusion/exclusion) criteria  
▪ Change in design of protocol  
▪ Change in statistical section  
▪ Change in sample size/accrual (e.g., doubling the sample size)  
▪ Change in informed consent  
▪ Change of estimated dropout rate  
▪ Change of treatment or intervention  
▪ Change of device  
▪ Change in primary objective evaluation process  
 
Non-life-threatening Revisions: Participating institutions will receive written 
(faxed or emailed) notification of revisions regarding non-life-threatening events 
from the Coordinating Center. Non-life-threatening revisions must be submitted 
to the participating institution’s IRB within fourteen (14) days from the date of 
notification.  
 
Revisions for Life-threatening Causes: Participating institutions will receive a 
phone notification followed by the written (faxed or emailed) notification from 
the Coordinating Center concerning protocol revisions required to protect lives.  
Life-threatening protocol revisions must be submitted to the local IRB within one 
business day from date of notification.   Immediate closure of the protocol will be 


2014-0524 
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required until the protocol amendment is approved. 
 
Once the participating institution’s IRB has approved the amendment, notification 
of IRB approval should be sent to the Coordinating Center within fourteen (14) 
business days of approval. 
 
Protocol Closures and Temporary Holds: Participating institutions will receive 
written (fax or e-mail) notification of protocol closures and temporary holds from 
the Coordinating Center. Closures and holds will be effective immediately.  In 
addition, the Coordinating Center will update the Participating institutions on an 
ongoing basis about protocol accrual data so that they will be aware of imminent 
protocol closures.  
 
            4.3    Informed Consent Requirements  
 The Protocol PI or designee will ensure review and approval of the 
participating institution’s Informed Consent Document (ICD) prior to its 
submission to the institution’s IRB. 
 
 The Participating PI will identify members of the study team who will be 
obtaining participants’ signed ICD for protocols, as per the delegation of 
authority log and the institution’s Informed Consent Policy. 
 
            4.4   Regulatory Documents  
                    The following must be on file with the Coordinating Center prior to      
                    participant registration:  
 
Participating Institution 
▪ 
Federal Wide Assurance 
▪ 
Participating institution's IRB approval memo/letter of the protocol 
and ICD 
▪ 
IRB approval for all amendments within the predetermined timelines 
▪ 
CLIA, CAP, and Normal Lab Values (if applicable) 
 
Participating Institution Research Personnel 
▪ 
Certification of Human Subjects Protection Training 
▪ 
FDA 1572  
▪ 
Current Medical License (Participating PI and co-investigators) 
▪ 
Curriculum Vitae 
▪ 
Delegation of Authority Log 
▪ 
Application Access Authorization Request Form (AAAR Form) 
 
            4.5    Participating Institution Site Initiation 
Before an institution begins participating in a MD Anderson multicenter 
protocol, the following steps must be completed:  
 


2014-0524 
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Page 65 
▪ 
Submit all required regulatory documents to the Coordinating Center  
▪ 
Participate in a site initiation visit, webcast, or conference call  
▪ 
Receive training regarding study specific CRFs/eCRFs 
▪ 
Execute all required contractual agreements 
 
After these requirements have been fulfilled, the participating institution 
will receive a written Site Activation Notification by fax or e-mail.  Once 
the Site Activation Notification has been received, the participating 
institution may begin to register patients to the protocol.  
 
            4.6    IRB Annual Review 
Annual IRB review from the participating institution is required in order to 
register participants onto a protocol.  There is no grace period for annual 
reviews.  
 
Protocol registrations will be suspended if an annual review letter is not 
received by the Coordinating Center from the participating institutions 
within thirty (30) days of the anniversary of the previous approval date.    
 
      4.7    Participant Confidentiality and Authorization Statement 
In order for covered entities to use or disclose protected health information 
during the course of this trial, the participant in the trial must sign an 
authorization. This authorization may or may not be separate from the 
Informed Consent.  
 
MD Anderson will attempt to limit its use of protected health information 
in its Multicenter Project trials.  However, portions of a participant’s 
protected health information may be collected. In order for MD Anderson 
to collect this information on any participant enrolled, the participant must 
have signed an informed consent document, which includes an 
authorization for the release of protected personal health information 
(IC/A). The authorization that each institution obtains to use and disclose 
protected health information must include MD Anderson as an entity with 
whom they will share data.  Each institution should also list study sponsor 
or supporter in their authorization form.   
 
All documents, investigative reports, or information relating to the 
participant are strictly confidential. Any participant specific reports (i.e. 
Pathology Reports, MRI Reports,  etc.) submitted to the Coordinating 
Center must have the participant’s full name & social security number de-
identified and the assigned MD Anderson participant ID number , 
accession number and protocol number written in. Participant initials need 
to be included or retained for cross verification of identification.  
 


2014-0524 
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The de-identification process can be waived only when the following 
criteria are met: 
1) The participating institution provides the Coordinating Center an 
IRB policy or a written statement that the de-identification process is 
not required on all documents submitted to MD Anderson. 
2) The study participants give their authorization to MD Anderson for 
the use and disclosure of their Protected Health Information in either 
the protocol specific Informed Consent or HIPAA Authorization 
Form.  
 
            4.8    Patient Registration  
The Department of Gastrointestinal Medical Oncology at MD Anderson is 
responsible for central patient registration and randomization.  
  
All participants must be registered centrally before a protocol treatment is 
initiated. Late registrations will not be accepted.   
 
Fax:  713-745-3662      
Phone:  713-794-4869 
Email:  2014-0524@mdanderson.org 
 
Registration hours are 8:00 a.m. to 5:00 p.m. Central Standard Time, 
Monday through Friday, except holidays. 
 
      4.8.1 Registration Information 
The following are required for registration. All subject related 
information sent via fax or email should be encrypted or password 
protected. 
▪ 
Copy of the signed ICD and HIPAA authorization 
▪ 
Completed and signed Eligibility Checklist 
▪ 
Source documents supporting each eligibility requirement 
 
4.8.2 Multicenter Project Participant Number 
Once eligibility has been established, non MD Anderson patients will be 
assigned a ten character patient number. This number is unique to the patient 
and must be written on all correspondence related to the patient. 
 
4.8.3 Eligibility Exceptions:  There will be no eligibility exceptions.  
 
All documents submitted to MD Anderson must be identified with: 
1. MD Anderson protocol number 
2. Assigned multicenter protocol participant ID number 
3. Participant initials 
 


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All participants must be registered in the Clinical Oncology Research 
(CORe) system at MD Anderson with the correct corresponding 
institution and investigator. 
 
           4.9   Schedule of Data Entry and Source Document Submission 
All documents, except for those sent at the time of registration, are to be 
forwarded to the Department of Gastrointestinal Medical Oncology via 
EDMS or other systems as agreed.  Case Report Form/s (CRF), will be used 
for data collection for this protocolThe schedule for data submission (CRF) 
and submission of source documents into the EDMS or other systems as 
agreed is specified in this document.  
 
COMMON FORMS & DOCUMENTS 
▪ Signed Informed Consent/Patient Authorization for the Release of Personal 
Health Information 
▪ Eligibility Checklist 
▪ Baseline Medical History  
▪ Treatment Data (Chemotherapy documentation -  Medication Administration 
Record, Laboratory Results, administration of any blood products)) 
▪ Evaluation Data (Protocol Response)  
▪ Adverse Events  
▪ Off-Treatment Update  
▪ Follow-Up Update Off Study Update  
▪ Source Documents (e.g. Pathology, Radiology, Operative, Laboratory Reports; 
History and Physical, Progress Notes) 
 
PROTOCOL 2014-0524 DATA AND SOURCE SUBMISSION SCHEDULE 
                   (See table below) 
 
 
 
 
DATA 
CASE REPORT 
FORM 
SOURCE 
DOCUMENT 
EVENT 
INTERVAL 
SUBMISSION 
SCHEDULE 
1.  Informed 
Consent with 
HIPAA 
Authorization 
 
N/A 
Copy of signed/initialled 
Informed Consent 
w/HIPAA 
Authorization 
Baseline  
On or before 
registration date. 
2. Demographics  
 
Pre-registration 
Form 
 
Baseline History & 
Physical Note or 
Demographic Form 
Baseline  
On or before 
registration date. 
3. Eligibility Checklist  
 
Inclusion-Exclusion 
Form 
History and Physical 
Progress Note that 
Baseline 
On or before 
registration date. 


2014-0524 
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includes prior treatment 
history 
(medical/surgical/ and 
other treatments such us 
chemotherapy, 
radiotherapy), pathology 
report, and laboratory 
report (to include tumor 
markers). 
 
4. Baseline History and 
Evaluation Data 
 
Medical History 
Form, Physical 
Exam Form, Vital 
Signs Form, 
Concomitant 
Medication Form, 
Laboratory Results 
Form, Other Data 
Submission Form, 
Research Specimen 
Status Form 
History and Physical 
Progress Note that 
includes prior treatment 
history 
(medical/surgical/ and 
other treatments such us 
chemotherapy, 
radiotherapy), pathology 
report, and laboratory 
report (to include tumor 
markers). 
 
Baseline 
On or before 
registration date. 
5. Disease Evaluation 
Data  
  
Disease Evaluation 
Form (Target and 
Non Target Tumor 
Measurements), 
Other Data 
Submission Form 
 
CT (or MRI) Scan 
Report of the chest, 
abdomen and pelvis.  
 
 
Baseline 
On or before 
registration date. 
6. Treatment Data 
 
Treatment Form, 
Physical Exam 
Form, Vital Signs 
Form, Concomitant 
Medication Form, 
Laboratory Results 
Form, Adverse 
Event Form, 
Multicenter SAE 
Form (if applicable).  
 
Serious Adverse Event 
source (if applicable), 
physician treatment 
orders, and 
chemotherapy 
MAR/infusion records. 
 
Treatment 
Phase 
Within 14 days 
after end of each 
of cycle. 
7. Disease Evaluation 
Data 
 
 
Disease Evaluation 
Form (Target and 
Non Target Tumor 
Measurements), 
Other Data 
Submission Form 
 
To include clinical 
evaluations to determine 
response (CT or MRI 
reports of the chest, 
abdomen and pelvis 
every 3 cycles).  
 
Continue to submit 
report until first 
Treatment 
Phase 
Within 14 days 
after event date. 


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Progressive Disease 
(PD) event. 
 
8. End of Treatment 
Summary Data 
 
End of Treatment 
Form, Physical 
Exam Form, Vital 
Signs Form, 
Concomitant 
Medication Form, 
Laboratory Results 
Form, Adverse 
Event Form, Disease 
Evaluation/Target 
and Non Target 
Tumor 
Measurements 
Form, Other Data 
Submission Form, 
Research Specimen 
Status Form. 
 
N/A 
Off-treatment 
Phase 
Within 14 days 
after the end of 
treatment date. 
9. Disease Evaluation 
Data  
 
N/A 
CT scan or MRI report 
of the chest, abdomen 
and pelvis (off treatment 
patients  who met first 
PD at this interval) 
 
Off Treatment 
Phase 
Within 14 days 
after event date. 
10. Follow-Up  
▪ Off Treatment Data 
▪ Survival Status  Data 
(Long term follow-
up) 
 
Survival Follow-up 
Form, Adverse 
Event Form  
 
N/A 
Follow-up 
Phase 
Within 59 days 
after end of 
treatment date. 
11. Off Study Data 
 
  
Off Study Form 
Off Study Note 
Off Study 
Phase 
Within 14 days 
after off study 
date. 
 
4.10  Data Form and Source Document Review 
The data entered in the CRFs and source document submitted via EDMS or 
other systems as agreed are reviewed by the Coordinating Center for:  
 
▪ 
Timeliness: Did the form arrive on time as specified in the protocol? 
▪ 
Completeness: Is all the information provided as required per 
protocol? 
▪ 
Patient Eligibility: Does the patient meet the eligibility 
requirements for the study? 


2014-0524 
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▪ 
Treatment Compliance: Are the body surface area (BSA) and drug 
dosage calculations correct? The dose must be within 10% of the 
calculated protocol dose. 
▪ 
Adverse Events: Did the patient experience adverse events 
attributed to protocol treatment? Was the treatment delayed due to an 
adverse event? What were the maximum grade, duration, and 
attribution of the event?Notations concerning adverse events will 
contain grade, start and stop date, and attribution. 
▪ 
Response:  Response will be assessed using the RECIST Criteria 
(version 1.1, 2009).  Responses must be verified, documented, and 
signed in the local medical record by the local PI. 
 
4.11 Missing and Deficient Memorandum 
Data submissions are monitored for timeliness and completeness of 
submission.  Participating institutions are notified of their data submission 
delinquencies in accordance with the following policies and procedures: 
 
Incomplete or Questionable Data 
If data entered in the CRFs is incomplete, or if there is a conflict between 
data entered and source documents reviewed, queries will be generated. 
Responses to any queries generated are due within 14 days.  Source 
documents are also expected to be available within 14 days of occurrence. 
 
Missing Source Documents 
If source documents are not submitted or available for viewing on schedule, 
the participating institution will receive a “Missing and Deficient Report” 
from the coordinating center noting the missing source document (s). These 
reports are distributed on a monthly basis. If source documents are 30 or 
more days late, the site will be contacted by telephone for assistance in 
obtaining delinquent forms. If forms are > 60 days late, the Protocol Chair 
will contact the participating institution’s Principal Investigator for 
assistance.   
 
Missing Query Responses: 
If replies to Queries are not received on schedule, the institution will receive 
a “Missing and Deficient Query Report” from the coordinating center noting 
the missing Query.  These reports are compiled and distributed on a monthly 
basis. If responses are 30 or more days late, the coordinating center will 
communicate with the participating institution’s Research staff for 
assistance in obtaining the forms.  If responses are 60 or more days late, the 
Protocol PI and the Participating PI will be notified via email.  All 
delinquencies will also be discussed in the monthly consortia meetings. 
 


2014-0524 
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5.0  
STUDY DRUG REQUISITION 
 
Gemcitabine and Cisplatin are FDA approved and commercially available drugs 
for the treatment of biliary cancer.    The study will not provide these 2 study 
agents and the patient and/or insurance will be charged for the drugs. 
 
Nab-Paclitaxel is provided by Celgene. To order study supplied drugs contact: 
Ralph F. Petruzzi 
Contractor - US Medical Affairs IIT Management 
Celgene Corporation 
86 Morris Avenue 
L2-804E 
Summit, NJ 07901 
(908) 219-0978 (O) 
(908) 673-2779 (F) 
rpetruzzi@celgene.com 
 
 
 
6.0  
SAFETY ASSESSMENTS AND TOXICITY MONITORING 
 
6.1 Serious Adverse Events 
A serious adverse event (SAE) is any adverse drug experience at any dose 
that results in any of the following outcomes: Death, a life-threatening 
adverse drug experience, inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant disability/incapacity, or 
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 participant or may 
require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  
 
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions in a participant who has never had seizure activity in the past 
that do not result in inpatient hospitalization, or the development of drug 
dependency or abuse (21 CFR 312.32). 
 
6.2 Oversight for Safety Assessments and Toxicity Monitoring 
 
6.2.1 Participating Institution 
 


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The MD Anderson multicenter protocol which outlines the methods 
to be used for data safety monitoring will be submitted by the 
participating institution to its own IRB.  The participating institution 
IRB will be responsible for reviewing and approving the protocol, 
as well as, monitoring the conduct of the study at its institution.  
Data and safety monitoring at the participating institution must be 
consistent with the data and safety monitoring guidelines delineated 
in the MD Anderson protocol.  The participating institution will 
ensure that all safety information related to their study site has been 
forwarded to the Coordinating Center. 
 
6.2.2 Coordinating Center 
 
All patients receiving study drugs will be evaluated for safety. 
The safety parameters include all laboratory and hematologic 
abnormalities, CNS observations, physical examination findings, 
and spontaneous reports of adverse events reported to the 
investigator by patients.  All toxicities encountered during the 
study will be evaluated according to the NCI Clinical Toxicity 
Criteria Scale (0-5) using the NCI’s CTCAE Criteria Version 4.0 
and recorded prior to each course of therapy.  A copy of the 
CTCAE Criteria can be downloaded from the CTEP home page 
(http://ctep.cancer.gov).   
 
Life- threatening toxicities should be reported immediately to the 
Protocol PI and MD Anderson IRB. 
 
6.3 Reporting Serious Adverse Events 
 
The MD Anderson Department of Gastrointestinal Medical Oncology will 
report SAEs in accordance with MD Anderson IRB policies and 
procedures and this protocol. 
 
Participating Multicenter Institution SAE reporting requirements will be 
as follows: 
 
• Any Serious Adverse Event (SAE) will be reported to the local 
institution’s 
IRB and the Coordinating Center as specified below. The circulation of 
unexpected and related SAEs to the participating institutions will be 
performed by the coordinating center in accordance with the study 
agreement. 
• Any adverse event falling under the definition of serious will be 
reported immediately to the Protocol PI who, in turn, must notify MD 
Anderson IRB per IRB policy.  


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• Symptoms related to progressive disease will not be reported as 
toxicity or as Serious Adverse Events.   
• Participating institutions will notify the Coordinating Center of all 
life-threatening serious adverse events or Deaths within 24 hours of 
knowledge of the event.  
• SAEs that do not result in death but are serious and unexpected and 
related, are to be reported within 5 working days from the time the 
research team becomes aware of the event. 
• SAEs that do not result in death and unrelated, are to be reported 
within 5 working days from the time the research team becomes aware 
of the event. 
• The Coordinating Center will notify the Protocol PI or his designee of 
the SAE per MD Anderson policy for reporting serious adverse events.  
• The initial SAE report from the participating institution will be 
forwarded to the Protocol PI or his designee for review and signature.  
• The MD Anderson Multicenter Serious Adverse Event Report form will 
be used for the study by all participating institutions, and the 
Coordinating Center will maintain documentation of all Adverse Event 
Reporting. 
• Serious adverse events will be captured from the time the patient signs 
consent until 30 days after the last dose of drug.  Serious adverse events 
must be followed until clinical recovery is complete and laboratory tests 
have returned to baseline, progression of the event has stabilized or there 
has been acceptable resolution of the event. 
 
Multicenter SAE forms are to be submitted via EDMS: 
 
Clinical Research Support Center Multicenter Support 
EDMS: https://iview.mdanderson.org 
E-mail: multicentersupport@mdanderson.org    
                  
 
Follow up Information: 
Additional information may be added to a previously submitted report by any 
of the following methods: 
 
• Adding to the original  Multicenter SAE report and submitting it as 
follow-up 
• Adding supplemental summary information and submitting it as follow-up 
with the original  Multicenter SAE form  
• Summarizing new information and faxing it with a cover letter including 
subject identifiers (i.e. D.O.B. initial, subject number), protocol 


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description and number, if assigned, suspect drug, brief adverse event 
description, and notation that additional or follow-up information is being 
submitted  (The subject identifiers are important so that the new 
information is added to the correct initial report) 
 
6.4  Additional Adverse Event Reporting by the Coordinating Center 
(CRSC) 
MDACC and the participating centers will ensure that investigators 
will comply with all safety reporting regulations as set forth in the 
Code of Federal Regulations and the protocol.  The Coordinating 
Center at MD Anderson will notify Celgene of the occurrence of;  
• Serious Adverse Events (SAE) within twenty four (24) hours of 
becoming aware of a confirmed adverse event.   
• Any correspondence to the FDA regarding adverse events or other 
safety issues will be simultaneously submitted to Celgene. 
• The MedWatch 3500A form should be utilized to report serious 
adverse events to the FDA. 
• Non-serious adverse drug reactions are to be reported as required 
in the protocol and in accordance with the procedures outlined in 
the protocol (Adverse Event [AE] data capture via AE CRF) and 
this DQMP.    
             
Celgene’s contact information for submitting SAEs: 
Facsimile: 908-673-9115 
 
            
 
  7.0  PROTOCOL VIOLATIONS, DEVIATIONS AND UNANTICIPATED 
PROBLEMS 
 
Neither the FDA nor the ICH GCP guidelines define the terms “protocol 
violation” or “protocol deviation.” The definition is often left to the lead 
institution IRB.  Accordingly, since MD Anderson is the lead institution and the 
Protocol PI must adhere to those policies set by the MD Anderson IRB, the 
definitions for protocol violation and deviation as described by the MD 
Anderson IRB will be applied for reporting purposes for all institutions 
participating in the MD Anderson Multicenter Project.  
 
7.1 Definitions 
 
Protocol Deviation: Noncompliance with the required elements of the 
protocol that does not have a significant effect on the subject’s rights, safety, 
welfare, and/or the integrity of the data.  Deviations may be caused by the 
action of, or the omission of, the subject, the investigator, the research team, 


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or natural events.  Continuing non-compliance of the protocol may be 
considered a violation. 
 
Protocol Violation: Changes to protocol procedures without prior approval of 
the IRB/Sponsor.  These changes may have a significant effect on the 
subject’s rights, safety, welfare, and/or the integrity of the data, and may cause 
an unanticipated problem to the subject or others.  Violations may 
significantly alter the clinical effectiveness of the treatment or the evaluation 
of its toxicity and adversely affect patient’s safety and rights. 
 
Examples include but are not 
limited to:  
 
Informed Consent Document 
• 
ICD not signed and dated by the participant 
• 
Protocol specific procedures conducted prior to obtaining informed 
consent 
• 
ICD used was not current IRB-approved version at the time of 
participant registration 
• 
Participant not re-consented within timelines described in IRB policy 
 
Eligibility 
• 
Enrollment of ineligible participant 
 
Treatment and Procedures 
• 
Incorrect agent/treatment/procedure used 
• 
Additional agent/treatment/procedure used which is excluded by protocol 
• 
Errors in dosing (error greater than +/- 10%) 
• 
Dose modifications not followed per protocol or unjustified 
• 
Unjustified continuation of treatment 
 
Disease Outcome and Response 
• 
Tumor measurements/evaluation of status or disease not 
performed or documented adequately to assess baseline or 
interpret response 
• 
Documented response status cannot be verified 
 
Adverse Events 
• 
Serious or Unexpected Adverse Events not reported as required by 
protocol and IRB policy 
 
Evaluations 
• 
Protocol- specified laboratory, diagnostic tests, or evaluations to assess 
participant eligibility, safety, or response not completed 


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Unanticipated Problems (UAPs): An incident, experience or outcome, that is 
unexpected, related or possibly related to participation in the research and 
suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) that was previously 
known or recognized. These incidents do not meet the definition of an adverse 
event. Unanticipated problems are not limited to study participants, and may also 
include others such as family members and research staff. 
Examples include but are not limited to:  
• Participant complaints  
• Breach of confidentiality of research data  
• Lost, stolen or destruction of confidential information 
• Disqualification or suspension of investigators 
• Change in FDA labeling or withdrawal from marketing of a drug, device 
or biologic agent 
• Injury to research staff or others while conducting study-related 
procedures 
• Expected events not reported in a timely manner as required by the 
protocol or IRB policy 
• New information becomes available that may affect the participant's 
willingness to participate 
• Issues with preparation, storage or handling of a study drug or device 
• Unaccounted for study drug 
• Drug stability issues 
• Changes made to the research without prior IRB approval in order to 
eliminate apparent immediate harm 
 
7.2  Reporting Procedures 
 
The Protocol Principal Investigator: The Protocol PI will be responsible 
for ensuring that all protocol violations/deviations/UAPs are promptly 
reported to the IRB per MD Anderson institutional guidelines.  
 
Participating Institutions: Protocol violations/deviations/UAPs occurring 
at a participating institution will be promptly reported to the coordinating 
center at MD Anderson even if they do not meet local IRB reporting 
requirements. Participating institutions should also report to their IRB 
according to their local policies and procedures. A copy of the participating 
institution’s violation/deviation report and the local IRB response will be 
included in the site’s protocol regulatory file. The local IRB response to the 
report will be forwarded to the Coordinating Center upon receipt. 
 


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Coordinating Center:  Upon receipt of the violation/deviation report from 
the participating institution, the Coordinating Center will submit the report 
to the Protocol PI for review before the submission to the MD Anderson 
IRB.  
 
    8.0  QUALITY ASSURANCE 
 
The quality assurance process for a clinical trial research study requires verification 
of protocol compliance and data accuracy.  MD Anderson provides quality 
assurance oversight for the protocol with three basic mechanisms:  
1) Ongoing monitoring of protocol compliance 
2) Verification of study data  
3) On-Site Audit  
 
8.1 Ongoing Monitoring of Protocol Compliance 
The Coordinating Center will perform the ongoing protocol compliance 
monitoring based on the data provided in the CRF and source documents 
submitted via EDMS or other systems as agreed with the support of the Protocol 
PI, Participating PI and research staff. Monitoring will begin at the time of 
participant registration and will continue during protocol performance and 
completion.  
 
8.2 Verification of Study Data 
All data submitted to the Coordinating Center will be monitored for timeliness 
of submission, completeness, and adherence to protocol requirements. If study 
documents/data are submitted with missing pages, inaccurate or illegible 
data, the site will be notified and is required to resubmit the corrected 
document/data within 14 calendar days. 
 
If study documents/data are not submitted on schedule, the Coordinating 
Center will notify the participating institution regarding the delinquency and 
describe a corrective action that includes deadline for bringing the data 
current. 
 
Failure to comply with the delinquency notification will be communicated 
to the Protocol PI and/or MD Anderson IRB for further decision regarding 
the participating institution’s study participation. 
 
8.3 On-Site Audit  
 
As part of the quality assurance process, the Clinical Research Support Center 
(CRSC) is authorized by the M.D. Anderson IRB to conduct on-site 
audits/inspections on multicenter human subject research projects for which 
MD Anderson is the lead institution. 
 


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The CRSC auditing staff will notify the IRB immediately of any findings that 
may suggest intentional misrepresentation of data or disregard for regulatory 
safeguards for any component of the audit. Documentation of all findings will 
be included in the final audit report submitted to the IRB.  
 
 
9.0   
EVALUATION OF PARTICIPATING INSTITUTION PERFORMANCE 
 
The MD Anderson Coordinating Center and Clinical Research Support Center are 
bound by institutional and federal regulations in the conduct of cancer research 
trials. Protocol performance concerns are reported to the Protocol PI.  
 
 
9.1  Sub-Standard Performance   
 
The Protocol Principal Investigator is charged with considering the totality 
of an institution’s performance when evaluating each institution. 
 
9.2 
Corrective Actions:  Institutions that fail to meet the performance goals 
of accrual, submission of timely accurate data, and adherence to protocol 
requirements may be recommended for a probationary period.  Such 
institutions must respond with a corrective action plan and must 
demonstrate during the probationary period that deficiencies have been 
corrected, as evidenced by improved performance.  Institutions that fail to 
demonstrate significant improvement may be subject to reduced funding 
(if applicable) or revocation of participation as determined by the Protocol 
Principal Investigator and/or the MD Anderson IRB.