Conditions: Bladder Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
Patients with invasive bladder cancer will be given 3-6 treatments (based on treatment response) BCG intravesically followed by a cystectomy.

Detailed description:
Patients with muscle invasive (≥T1) bladder cancer will be given 3-6 treatments (based on treatment response) intravesical TICE® BCG. BCG is an attenuated, live culture preparation of the Bacillus of Calmette and Guerin (BCG) strain of Mycobacterium bovis.

After completion of BCG treatments the patient will undergo a cystectomy. A portion of bladder tumor tissue and lymph nodes will be collected for research purposes during the cystectomy.

Arms:
arm 1: Invasive bladder cancer treated with 3-6 weeks of intravesical BCG

Interventions: intervention 1: BCG strain of Mycobacterium bovis
Intervention descriptions: intervention 1: Invasive bladder cancer treated with 3-6 weeks of intravesical BCG

Protocol document:
Prot_SAP_000.pdf: 
14-002H, Svatek, Form BB, 01-23-17 AMD 
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Official Protocol Title: Evaluating Local and Regional Immune Responses 
to Intravesical BCG administration to Patients with Invasive Bladder Cancer  
 
 
Protocol #: HSC20140002H 
 
Version: 4.0  
 
IRB Approval Date: January, 23. 2017 
 
NCT number: NCT02365207 
 
 
 
 
 


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TABLE of Contents 
 
STUDY SCHEMA....................................................................................................................3 
1.0 OBJECTIVES....................................................................................................................4 
2.0 BACKGROUND ................................................................................................................4 
3.0 DRUG INFORMATION .....................................................................................................5 
4.0 STAGING CRITERIA.........................................................................................................10 
5.0 ELIGIBILITY CRITERIA ....................................................................................................11 
6.0 STUDY PLAN………..........................................................................................................11 
7.0 STUDY CALENDAR ........................................................................................................ 15 
8.0 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS ....................................15 
9.0 STATISTICAL CONSIDERATIONS................................................................................  15 
10.0 REGISTRATION GUIDELINES ......................................................................................16 
11.0 ETHICAL AND REGULATORY CONSIDERATIONS..................................................... 16 
12.0 DATA SAFETY MONITORING .......................................................................................16 
REFERENCES………………………………………………………………………………………..20 
 
 
 
 
Principle Investigator: 
 
Robert S. Svatek, MD, MSCI 
Department of Urology 
Division of Urologic Oncology 
University of Texas Health Science Center San Antonio 
Office:  210-567-5676 
Fax: 210-567-8095 
Email: Svatek@uthscsa.edu 
 
 
Co-investigators: 
 
Tyler Curiel, MD 
Department of Medicine and Cancer Immunology 
University of Texas Health Science Center San Antonio 
Office: 210 450 5882 
Email: curielt@uthscsa.edu 
 


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Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient with known 
invasive (> T1) bladder 
cancer diagnosed  
Visit 1 
Informed Consent; 
Research blood/urine 
(optional); Symptoms 
Questionnaires 
(Visit 1 may occur on same 
day as BCG week 1) 
 
Neoadjuvant Intravesical BCG (weekly for approximately 3 to 6 
weeks); 
Symptoms questionnaire weekly; 
Research urine before and after each BCG instillation 
Radical Cystectomy 
Research blood, urine, and 
tissue, tissue blocks 
Post Cystectomy 
Routine Follow-up 
(within 90 days post- 
surgery); Research 
blood  


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1.0  
Objectives 
 
1.1 The primary objectives of the study are to determine: 
a. 
the ability of intravesical BCG immunotherapy to enhance tumor-specific immunity as 
measured by autologous T cells proliferation following co-culture with autologous 
monocyte-derived dendritic cells pulsed with autologous tumor lysate 
 
1.2 Secondary objectives of the study are to determine: 
a.  the immune effects of BCG in the tumor microenvironment and tumor-draining lymph 
nodes 
b. 
the extent to which BCG is processed and presented by tumors cells and/or antigen-
presenting cells 
c. 
the ability of BCG to elicit tumor necrosis/apoptosis  in invasive disease 
d.   the pathologic stage of disease following BCG treatment  
e. 
to determine if immune changes elicited by BCG in patients with bladder cancer will 
provide an opportunity for benefit from mTOR inhibition in tumor milieu 
 
 
 
 
2.0 
Background 
 
2.1 
Overview 
Urothelial carcinoma of the bladder (UCB) accounted for 70,530 new cases of cancer and 14,680 
cancer-related deaths in the United States during 20101.  Of these new cases, approximately 25% 
presented as invasive tumors involving the muscular wall of the bladder. Transurethral resection of 
bladder tumor (TURBT) is an endoscopic procedure that allows for histopathologic assessment and 
disease staging.  TURBT is the primary diagnostic procedure for new and recurrent bladder tumors.  
TURBT can also be therapeutic for small or non-muscle invasive tumors. However, when muscle-
invasive disease is detected, the standard of care involves bladder removal or radical cystectomy 
(RC) and urinary diversion.   
 
Despite aggressive surgical treatment with bladder removal, up to 50% of patients undergoing RC 
will experience disease recurrence2,3.  Chemotherapy given both before and after surgery has been 
investigated to improve survival for these patients4-10.  Neoadjuvant chemotherapy renders only a 
modest improvement in survival- approximately 5-7% absolute benefit in 5-year recurrence free 
survival4,11.  Nevertheless neoadjuvant chemotherapy has not been widely adopted due to 
concerns of toxicity for a modest benefit11.  In addition, many consider that giving adjuvant 
chemotherapy for only those patients with high risk pathologic features is a better alternative than 
treating all patients with neoadjuvant chemotherapy11.  Current research efforts, therefore, are 
aimed towards identifying less toxic regimens for use in the neoadjuvant setting. Such effective 
therapies, especially using those agents with low to moderate toxicity that are easily administered, 
would be a significant advance in the treatment of invasive bladder cancer.  The development of 
novel, effective therapies, remains an area of unmet need. 
 
2.2 
Pre-surgical trial 
 
Pre-surgical drug testing is an excellent venue in which paired tumor tissue can be evaluated 
before and after exposure to a drug to address target specificity, drug delivery, physiologic effects 
on tumor growth and apoptosis, and correlation of biomarkers with clinical activity12-15.  Pre-surgical 
trials have been conducted in radical cystectomy populations were patients were given drugs for 4-
7 weeks prior to surgery12,13.  This approach has been acceptable given the evidence that delaying 
cystectomy for more than 3 months is not associated with a worse clinical outcome16-18.  In our 
protocol, we will seek to characterize the immune effects of intravesical administration in patients 
undergoing radical cystectomy to help elucidate the anticancer immune mechanisms of BCG in 
patients with bladder cancer. 
 
2.3 
BCG immunotherapy 
 
BCG immunotherapy is the mainstay treatment for high-risk non-muscle invasive bladder cancer.  
BCG specifically, and Mycobacteria generally, have long been known to be potent immune 
stimulators but the mechanism of action of BCG in cancer remains incompletely understood.  BCG 
reduces bladder cancer relapse by 50%19-21 and without it, the risk for cancer relapse is extremely 


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high (45-80% in non-muscle invasive disease)22-24. In animal models, it has been established that 
BCG could be effective to treat bladder cancer through immune mechanisms mediating anti-cancer 
immunity against other cancers, including T cells25, NK cells26 and IFN-γ27. Nevertheless, many 
mechanistic details are lacking, notably to what extent BCG generates BCG-specific and tumor-
specific immunity and whether BCG affects tumor tolerance. Recently, it was demonstrated that 
BCG efficacy is mediated, at least in part, through stimulation and recruitment of T cells into peri-
tumoral draining lymph nodes28.  This finding has important implications for the utilization of BCG 
as discussed below.   
 
Currently BCG is principally used to manage non-muscle invasive bladder cancer and has not been 
employed to treat muscle-invasive disease, since muscle-invasive disease requires bladder 
removal.  However, to date, BCG is the most immunostimulant utilized in bladder cancer there is 
increasing evidence that BCG could improve tumor-specific immunity28,29.  If BCG can improve 
tumor-specific immunity, then it could be used as an adjuvant therapy in the management of 
bladder cancers of all stages, including muscle-invasive disease.  For example, BCG given to 
patients with muscle-invasive disease prior to cystectomy could improve tumor-specific immunity 
and enable patients to improve tumor clearance in cases of nodal or distant metastasis.  By 
increasing tumor-specific immunity and memory T cell responses, BCG could also enable 
sustained long-term protection from recurrent disease.    
 
2.4 
Rapamycin and immune modulation.  
mTOR is a protein kinase that regulates cell growth, proliferation, and other key elements of cell 
survival. Rapamycin (sirolimus) has long been used in combination with immunosuppressive 
agents to prevent organ allograft rejection. However, there is no published human study of normal 
subjects that shows that rapamycin alone is immune suppressive30. In fact, recent publications 
specifically looking at rapamycin immune effects demonstrate that rapamycin boosts immunity to 
infections31-33, accelerates memory CD8+ T cell differentiation33, and improves antigen-specific 
immunity33. Further, rapamycin fed to mice prolongs lifespan34, which is inconsistent with significant 
immunosuppression. Finally, immune modulating properties of mTOR inhibition include effects on T 
cells, interferon (IFN)-γ and other immune mediators critical to anti-cancer immune defenses33,35-38.  
In preclinical studies, we found rapamycin to improve immune responses and improve the activity 
of BCG.  In secondary objectives, we aim to clarify the effect of BCG in the tumor milieu to 
determine mTOR inhibition could be beneficial.  Specifically, we aim to measure the quantity of 
regulatory immune activity including PD-1 expression and Treg cells which could negatively 
influence BCG’s activity.  If these populations are elevated, mTOR inhibition may be beneficial, as 
we have observed rapamycin to decrease PD-1 T cells. 
 
 
3.0 
Drug Information (TICE® BCG) 
3.1 
Description: TICE® BCG for intravesical use, is an attenuated, live culture preparation of the 
Bacillus of Calmette and Guerin (BCG) strain of Mycobacterium bovis. The TICE® strain was 
developed at the University of Illinois from a strain originated at the Pasteur Institute. The medium 
in which the BCG organism is grown for preparation of the freeze-dried cake is composed of the 
following ingredients: glycearin, asparagine, citric acid, potassium phosphate, magnesium sulfate, 
and iron ammonium citrate. The final preparation prior to freeze drying also contains lactose. The 
freeze-dried BCG preparation is delivered in glass vials, each containing 1 to 8 x 108 colony 
forming units (CFU) of TICE® BCG which is equivalent to approximately 50 mg wet weight. 
Determination of in-vitro potency is achieved through colony counts derived from a serial dilution 
assay. A single dose consists of 1 reconstituted vial (see DOSAGE AND ADMINISTRATION). For 
intravesical use the entire vial is reconstituted with sterile saline. TICE® BCG is viable upon 
reconstitution. No preservatives have been added. 
3.2 
Mechanism of Action:  TICE® BCG induces a granulomatous reaction at the local site of 
administration. Intravesical TICE® BCG has been used as a therapy for, and prophylaxis against, 
recurrent tumors in patients with carcinoma in situ (CIS) of the urinary bladder, and to prevent 
recurrence of Stage TaT1 papillary tumors of the bladder at high risk of recurrence. The precise 
mechanism of action is unknown but is thought to be related to immune stimulation and subsequent 
immune-mediated cytotoxicity. 
3.3 
Toxicology: Symptoms of bladder irritability, related to the inflammatory response induced, are 
reported in approximately 60% of patients receiving TICE® BCG. The symptoms typically begin 4–
6 hours after instillation and last 24–72 hours. The irritative side effects are usually seen following 
the third instillation, and tend to increase in severity after each administration.  


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3.4 
Clinical Studies: To evaluate the efficacy of intravesical administration of TICE® BCG in the 
treatment of carcinoma in situ, patients were identified who had been treated with TICE® BCG 
under six different Investigational New Drug (IND) applications in which the most important shared 
aspect was the use of an induction plus maintenance schedule. Patients received TICE® BCG (50 
mg; 1 to 8 x 108 CFU) intravesically, once weekly for at least 6 weeks and once monthly thereafter 
for up to 12 months. A longer maintenance was given in some cases. The study population 
consisted of 153 patients, 132 males, 19 females, and 2 unidentified as to gender. Thirty patients 
lacking baseline documentation of CIS and four patients lost to follow-up were not evaluable for 
treatment response. Therefore, 119 patients were available for efficacy evaluation. The mean age 
was 69 years (range: 38–97 years). There were two categories of clinical response: (1) Complete 
Histological Response (CR), defined as complete resolution of carcinoma in situ documented by 
cystoscopy and cytology, with or without biopsy; and (2) Complete Clinical Response Without 
Cytology (CRNC), defined as an apparent complete disappearance of tumor upon cystoscopy. The 
results of a 1987 analysis of the evaluable patients are shown in Table I. 
 
There was no significant difference in response rates between patients with or without prior 
intravesical chemotherapy. The median duration of response, calculated from the Kaplan-Meier 
curve as median time to recurrence, is estimated at 4 years or greater. The incidence of 
cystectomy for 90 patients who achieved a complete response (CR or CRNC) was 11%. The 
median time to cystectomy in patients who achieved a complete response (CR or CRNC) exceeded 
74 months. The efficacy of intravesical TICE® BCG in preventing the recurrence of a TaT1 bladder 
cancer after complete transurethral resection of all papillary tumors was evaluated in two open-
label randomized phase III clinical trials. Initial diagnosis of patients included in the studies was 
determined by cystoscopic biopsies. One was conducted by the Southwestern Oncology Group 
(SWOG) in patients at high risk of recurrence39. High risk was defined as two occurrences of tumor 
within 56 weeks, any stage T1 tumor, or three or more tumors presenting simultaneously. The 
second study was conducted at the Nijmegen University Hospital; Nijmegen, The Netherlands. In 
this study patients were not selected for high risk of recurrence. In both studies treatment was 
initiated between 1 and 2 weeks after TUR. In the SWOG trial (study 8795) patients were 
randomized to TICE® BCG or mitomycin C (MMC)39. Both drugs were given intravesically weekly 
for 6 weeks, at 8 and 12 weeks, and then monthly for a total treatment duration of 1 year. 
Cystoscopy and urinary cytology were performed every 3 months for 2 years. Patients with 
progressive disease or residual or recurrent disease at or after the 6 month follow-up were 
removed from the study and were classified as treatment failures. 
 
A total of 469 patients was entered into the study: 237 to the TICE® BCG arm and 232 to the MMC 
arm. Twenty-two patients were subsequently found to be ineligible, and 66 patients had concurrent 
CIS, and were analyzed separately. Four patients were lost to follow-up, leaving 191 evaluable 
patients in the TICE® BCG arm and 186 in the MMC arm. Of the patients, 84% were male and 16% 
were female. The average age of these patients was 65 years old. The Kaplan-Meier estimates of 2 
year disease-free survival are shown in Table III. The difference in disease-free survival time 
between the two groups was statistically significant by the log rank test (p=0.03). The 95% 
confidence interval of the difference in 2 year disease-free survival was 12% ± 10%. No statistically 
significant differences between the groups were noted in time to tumor progression, tumor invasion, 
or overall survival. 


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In the Nijmegen study, the efficacy of three treatments was compared: TICE substrain BCG, 
Rijksinstituut voor Volksgezondheid en Milieuhygiene substrain BCG (BCG-RIVM), and MMC. 
TICE® BCG and BCG-RIVM were given intravesically weekly for 6 weeks. In contrast to the SWOG 
study, maintenance BCG was not given. Mitomycin C was given intravesically weekly for 4 weeks 
and then monthly for a total duration of treatment of 6 months. Cystoscopy and urinary cytology 
were performed every 3 months until recurrence. A total of 469 patients was enrolled and 
randomized. Thirty-two patients were not evaluable, 17 were ineligible, 15 were withdrawn before 
treatment, and 50 had concurrent CIS and were analyzed separately, leaving 387 evaluable 
patients: 117 in the TICE® BCG arm, 134 in the BCG-RIVM arm, and 136 in the MMC arm. 
Twenty-eight patients (24%) in the TICE® BCG arm, 32 patients (24%) in the BCG-RIVM arm and 
24 patients (18%) in the MMC arm had TaG1 tumors. The median duration of follow-up was 22 
months (range 3–54 months). The Kaplan-Meier estimates of 2 year disease-free survival are 
shown in Table IV. The differences in disease-free survival among the three arms were not 
statistically significant by the log-rank test (p=0.08). 
 
In both the SWOG 8795 study and the Nijmegen study, acute toxicity was more common, and 
usually more severe, with TICE® BCG than with MMC (see ADVERSE REACTIONS). 
 
3.5 
Warnings:  BCG LIVE (TICE® BCG) is not a vaccine for the prevention of cancer. BCG Vaccine, 
U.S.P., not BCG LIVE (TICE® BCG), should be used for the prevention of tuberculosis. For 
vaccination use, refer to BCG Vaccine, U.S.P. prescribing information. TICE® BCG is an infectious 
agent. Physicians using this product should be familiar with the literature on the prevention and 
treatment of BCG-related complications, and should be prepared in such emergencies to contact 
an infectious disease specialist with experience in treating the infectious complications of 
intravesical BCG. The treatment of the infectious complications of BCG requires long-term, 
multiple-drug antibiotic therapy. Special culture media are required for mycobacteria, and 
physicians administering intravesical BCG or those caring for these patients should have these 
media readily available.  
3.5.1 
Instillation of TICE® BCG with an actively bleeding mucosa may promote systemic BCG infection. 
Treatment should be postponed for at least one week following transurethral resection, biopsy, 
traumatic catheterization, or gross hematuria.  
3.5.2 
Deaths have been reported as a result of systemic BCG infection and sepsis.2,3 Patients should be 
monitored for the presence of symptoms and signs of toxicity after each intravesical treatment. 
Febrile episodes with flu-like symptoms lasting more than 72 hours, fever ≥103°F, systemic 
manifestations increasing in intensity with repeated instillations, or persistent abnormalities of liver 
function tests suggest systemic BCG infection and may require antituberculous therapy. Local 
symptoms (prostatitis, epididymitis, orchitis) lasting more than 2–3 days may also suggest active 
infection. 
3.5.3 
The use of TICE® BCG may cause tuberculin sensitivity. Since this is a valuable aid in the 
diagnosis of tuberculosis, it is advisable to determine the tuberculin reactivity by PPD skin testing 
before treatment.  
3.5.4 
Intravesical instillations of BCG should be postponed during treatment with antibiotics, since 
antimicrobial therapy may interfere with the effectiveness of TICE® BCG (see PRECAUTIONS). 
TICE® BCG should not be used in individuals with concurrent infections.  
Small bladder capacity has been associated with increased risk of severe local reactions and 
should be considered in deciding to use TICE® BCG therapy. 
3.6 Management of Serious BCG Complications: Acute, localized irritative toxicities of TICE® BCG may be 
accompanied by systemic manifestations, consistent with a “flu-like” syndrome. Systemic adverse 


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effects of 1–2 days’ duration such as malaise, fever, and chills often reflect hypersensitivity reactions. 
However, symptoms such as fever of ≥38.5°C (101.3°F), or acute localized inflammation such as 
epididymitis, prostatitis, or orchitis persisting longer than 2–3 days suggest active infection, and 
evaluation for serious infectious complication should be considered.  
3.6.1 
In patients who develop persistent fever or experience an acute febrile illness consistent with BCG 
infection, two or more anti-mycobacterial agents should be administered while diagnostic 
evaluation, including cultures, is conducted and BCG treatment should be discontinued. Negative 
cultures do not necessarily rule out infection. Physicians using this product should be familiar with 
the literature on prevention, diagnosis, and treatment of BCG-related complications and, when 
appropriate, should consult an infectious disease specialist or other physician with experience in 
the diagnosis and treatment of mycobacterial infections. TICE® BCG is sensitive to the most 
commonly used antituberculous agents (isoniazid, rifampin and ethambutol). TICE® BCG is not 
sensitive to pyrazinamide. 
3.7 PRECAUTIONS:  
3.7.1 
TICE® BCG contains live mycobacteria and should be prepared and handled using aseptic 
technique (see Preparation of Agent subsection of DOSAGE AND ADMINISTRATION). BCG 
infections have been reported in health care workers preparing BCG for administration. Needle 
stick injuries should be avoided during the handling and mixing of TICE® BCG. Nosocomial 
infections have been reported in patients receiving parenteral drugs which were prepared in areas 
in which BCG was prepared.4  
3.7.2 
BCG is capable of dissemination when administered by intravesical route and serious reactions, 
including fatal infections, have been reported in patients receiving intravesical BCG.3 Care should 
be taken not to traumatize the urinary tract or to introduce contaminants into the urinary system. 
Seven to 14 days should elapse before TICE® BCG is administered following TUR, biopsy, or 
traumatic catheterization.  
3.7.3 
TICE® BCG should be administered with caution to persons in groups at high risk for HIV infection 
 
3.8 Drug Interactions 
3.8.1 
Drug combinations containing immunosuppressants and/or bone marrow depressants and/or 
radiation interfere with the development of the immune response and should not be used in 
combination with TICE® BCG. Antimicrobial therapy for other infections may interfere with the 
effectiveness of TICE® BCG. There are no data to suggest that the acute, local urinary tract toxicity 
common with BCG is due to mycobacterial infection and antituberculosis drugs (e.g., isoniazid) 
should not be used to prevent or treat the local, irritative toxicities of TICE® BCG. 
3.8.2 
Carcinogenesis, Mutagenesis, Impairment of Fertility: TICE® BCG has not been evaluated for its 
carcinogenic, mutagenic potentials or impairment of fertility.  
3.9 Pregnancy  
3.9.1 
Teratogenic Effects – Pregnancy Category C: Animal reproduction studies have not been 
conducted with TICE® BCG. It is also not known whether TICE® BCG can cause fetal harm when 
administered to a pregnant woman or can affect reproductive capacity. TICE® BCG should not be given 
to a pregnant woman except when clearly needed. Women should be advised not to become pregnant 
while on therapy.  
3.10 Nursing Mothers:It is not known whether TICE® BCG is excreted in human milk. Because many drugs 
are excreted in human milk and because of the potential for serious adverse reactions from TICE® BCG 
in nursing infants, it is advisable to discontinue nursing or to discontinue the drug, taking into account 
the importance of the drug to the mother.  
3.11 Pediatric Use: Safety and effectiveness of TICE® BCG for the treatment of superficial bladder cancer in 
pediatric patients have not been established.  
3.12 Geriatric Use: Of the total number of subjects in clinical studies of TICE® BCG, the average age was 66 
years old. No overall difference in safety or effectiveness was observed between older and younger 
subjects. Other reported clinical experience has not identified differences in response between elderly 
and younger patients, but greater sensitivity of some older individuals to BCG cannot be ruled out. 
 
3.13 
ADVERSE REACTIONS  
Symptoms of bladder irritability, related to the inflammatory response induced, are reported in approximately 
60% of patients receiving TICE® BCG. The symptoms typically begin 4–6 hours after instillation and last 24–
72 hours. The irritative side effects are usually seen following the third instillation, and tend to increase in 
severity after each administration.  
The irritative bladder adverse effects can usually be managed symptomatically with products such as 


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pyridium, propantheline bromide, oxybutynin chloride and acetaminophen. The mechanism of action of  
the irritative side effects has not been firmly established, but is most consistent with an immunological 
mechanism.3 There is no evidence that dose reduction or antituberculous drug therapy can prevent or 
lessen the irritative toxicity of TICE® BCG. “Flu-like” symptoms (malaise, fever, and chills) which may 
accompany the localized, irritative toxicities often reflect hypersensitivity reactions which can be treated 
symptomatically. Antihistamines have also been used.5 Adverse reactions to TICE® BCG tend to be 
progressive in frequency and severity with subsequent instillation. Delay or postponement of subsequent 
treatment may or may not reduce the severity of a reaction during subsequent instillation. Although 
uncommon, serious infectious complications of intravesical BCG have been reported.2,3,6 The most serious 
infectious complication of BCG is disseminated sepsis with associated mortality. In addition, M. bovis 
infections have been reported in lung, liver, bone, bone marrow, kidney, regional lymph nodes, and prostate 
in patients who have received intravesical BCG. Some male genitourinary tract infections 
(orchitis/epididymitis) have been resistant to multiple drug antituberculous therapy and required orchiectomy. 
If a patient develops persistent fever or experiences an acute febrile illness consistent with BCG 
infection, BCG treatment should be discontinued and the patient immediately evaluated and treated 
for systemic infection (see WARNINGS). The local and systemic adverse reactions reported in a review of 
674 patients with 
 
 
 
 
 


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3.14 
OVERDOSAGE Overdosage occurs if more than one vial of TICE® BCG is administered per 
instillation. If overdosage occurs, the patient should be closely monitored for signs of active local or systemic 
BCG infection. For acute local or systemic reactions suggesting active infection, an infectious disease 
specialist experienced in BCG complications should be consulted.  
 
3.15 
DOSAGE AND ADMINISTRATION  
The dose for the intravesical treatment of carcinoma in situ and for the prophylaxis of recurrent papillary 
tumors consists of one vial of TICE® BCG suspended in 50 ml preservative-free saline. 
 
3.16 
Preparation of Agent  
The preparation of the TICE® BCG suspension should be done using aseptic technique. To avoid cross-
contamination, parenteral drugs should not be prepared in areas where BCG has been prepared. A separate 
area for the preparation of the TICE® BCG suspension is recommended. All equipment, supplies and 
receptacles in contact with TICE® BCG should be handled and disposed of as biohazardous. The 
pharmacist or individual responsible for mixing the agent should wear gloves and take precautions to avoid 
contact of BCG with broken skin. If preparation cannot be performed in a biocontainment hood, then a mask 
and gown should be worn to avoid inhalation of BCG organisms and inadvertent exposure to broken skin.  
Option-1 (Using Syringe Method)  
Draw 1 ml of sterile, preservative-free saline (0.9% Sodium Chloride Injection U.S.P.) at 4–25°C, into a small 
syringe (e.g., 3 ml) and add to one vial of TICE® BCG to resuspend. Gently swirl the vial until a 
homogenous suspension is obtained. Avoid forceful agitation which may cause clumping of the 
mycobacteria. Dispense the cloudy TICE® BCG suspension into the top end of a catheter-tip syringe which 
contains 49 ml of saline diluent, bringing the total volume to 50 ml. To mix, gently rotate the syringe.  
Option-2 (Using Reconstitution Accessories)  
Reconstitution Accessories may be provided with each TICE® BCG product order. Please refer to the 
Instructions For Use provided with the accessories for a full description of the product reconstitution 
procedures using these accessories.  
The reconstituted TICE® BCG should be kept refrigerated (2–8°C), protected from exposure to direct 
sunlight, and used within 2 hours. Unused solution should be discarded after 2 hours.  
Note: DO NOT filter the contents of the TICE® BCG vial. Precautions should be taken to avoid exposing the 
TICE® BCG to direct sunlight. Bacteriostatic solutions must be avoided. In addition, use only sterile 
preservative-free saline, 0.9% Sodium Chloride Injection U.S.P. as diluent.  
3.17 
HOW SUPPLIED  
TICE® BCG is supplied in a box of one vial of TICE® BCG. Each vial contains 1 to 8 x 108 CFU, which is 
equivalent to approximately 50 mg (wet weight), as lyophilized (freeze-dried) powder. NDC 0052-0602-02.  
3.18 
STORAGE  
The intact vials of TICE® BCG should be stored refrigerated, at 2–8°C (36–46°F).  
This agent contains live bacteria and should be protected from direct sunlight. The product should not be 
used after the expiration date printed on the label.  
 
 
 
4.0 
Staging Criteria 
Bladder cancer 
Primary Tumor (T) 
Clinical Stage 
cT1 
Invades subepithelial connective tissue (lamina propria) 
cT2 
Muscle-invasive 
cT3 
Residual mass on exam under anesthesia following TURBT 
cT4 
Clinically fixed disease on exam under anesthesia  
 
Pathologic Stage 
 
pT1 
Invades subepithelial connective tissue (lamina propria) 
pT2 
Muscle-invasive 
pT3 
Invades perivesicle fat 
pT4 
Invades adjacent organs (prostate, vagina, uterus, bone, etc…) 
 
Histiologic subtypes 
 
 
Urothelial cell carcinoma (Transitional cell carcinoma) 
 
Squamous cell carcinoma 
 
Adenocarcinoma or glandular carcinoma 


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Sarcomatoid carcinoma 
 
Micropapillary carcinoma 
 
Histiologic grade 
 
 
High-grade 
Poorly- or un-differentiated 
 
5.0 
Eligibility Criteria   
 
Inclusion Criteria: 
5.1 
Have suspected or known invasive (≥T1) bladder cancer  
5.2 
Not be in an immunosuppressed state (e.g. HIV +, use of chronic steroids (>1 month)) 
5.3 
Be able to give informed consent 
5.4 
Be age 18 or older 
 
 
 
 
Exclusion Criteria: 
5.1.1 
Have non-invasive (<T1) bladder cancer  
5.1.2 
Is in an immunosuppressed state (e.g. HIV +, use of chronic steroids (>1 month)) 
5.1.3 
Unable to give informed consent 
5.1.4 
< 18 or older 
 
 
6.0 
Study Plan 
 
 
6.0 
Study Design 
 
This is a one-arm, open label, interventional study.  For the purposes of enrollment “study 
procedure” refers to intravesical BCG instillation.  See below for a description of study 
procedure. 
 
 
6.1 
Recruitment 
 
Participants will be recruited through the urology outpatient clinics at the Medical Arts and 
Research Center (MARC).  Attending physicians in the Department of Urology, and 
selected other personnel who also serve as research staff for this study, will identify 
prospective study participants.  To eliminate selection bias, any patient who presents with 
invasive bladder cancer and meets the inclusion/exclusion criteria will be given an option 
to participate in the study. The inclusion of participants or refusal to participate by patients 
eligible for this study will in no way compromise the quality of health care they will receive.  
 
Study eligibility will be determined by investigators and study staff with legitimate access 
to patient PHI due to their clinical role and/or as members of the research team.  Patients 
who meet the eligibility criteria will be approached by one of the investigators or other 
members of the study staff to determine whether they are willing to participate in the 
study.  Prior to study entry, the study staff will explain to each potential subject the 
research objectives, risks and benefits of study participation, alternative treatments 
available, and the subjects’ rights and responsibilities.  If the patient agrees to participate, 
informed consent will be obtained.  Research blood and urine may be obtained-
OPTIONAL (details in 6.2).  Baseline symptoms questionnaires will be administered. 
 
Patients will be approached in a private consult room located within the GU clinic at the 
MARC.  Usual privacy policy practices will be followed.  The study procedures and 
objectives will be described to them and they will be given a copy of the consent 
document. Participants will also be given contact information for someone they can call 
with any questions that may arise. 
 
 
6.2 
Visit 1 
 
Routine medical history and demographics and physical exam will be performed during 
the visit (standard care). 
 
6.2.1 Research blood and urine collection & handling OPTIONAL 


14-002H, Svatek, Form BB, 01-23-17 AMD 
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Research blood and urine may be collected after signing informed consent (OPTIONAL). 
Approximately 50 mL or 3.5 tablespoons of blood will be taken from a peripheral vein or 
an indwelling catheter if present and functional specifically for research studies.   Study 
staff will then provide a urine specimen cup and self-catch instruction to the participant.  
The participant will be able to do this in the privacy of the clinic restroom. 
 
If collected, research blood and urine specimens will be transported to our lab in the STRF 
in approved containers by qualified personnel. Additional blood will be collected as 
needed for initial eligibility screening. Urine will be processed by centrifugation and the 
supernatant will be stored separately from the pellet.  Both blood and urine samples are 
de-identified in the lab per HIPAA protocol.   
 
Baseline symptoms questionnaires will also be administered. 
 
 
 
6.3  
 Neoadjuvant Intravesical BCG Instillation 
 
Prior to undergoing routine radical cystectomy (standard care), participant will receive 3 to 
6 weeks of neoadjuvant intravestical BCG instillation weekly as part of the research study 
procedure.  The instillation will be scheduled roughly one week apart pending on the 
clinic’s and participant’s schedules, and also participant’s reaction to the BCG instillation. 
BCG Week 1 may occur on the same day as Visit 1. 
 
Intravesical BCG will be given as the intervention measure for treatment of bladder 
cancer.  In brief, following sterile preparation, a Foley catheter is introduced into the 
bladder thru the urethral meatus.  The BCG is instilled through gravity drainage and held 
in the bladder for approximately 2 hours.  Instructions are provided to the patient regarding 
the proper disposal of the BCG. The duration of BCG treatment is allowed to fluctuate 
between 3-6 weeks for two reasons: (1) This allows for flexibility in scheduling participants 
for radical cystectomy as the time from enrollment to cystectomy would vary based on 
surgeon and patient preferences and on operative room availability.  In this manner, the 
surgery date can be established first and then duration of treatment would be based on 
amount of time available between enrollment and cystectomy date.  In our experience, this 
“time period” is usually 4-6 weeks; (2) The number of BCG treatments needed to elicit 
expected immune responses is not known.  In fact the current paradigm of 6 weekly 
treatments has little scientific justification but was based on a rather arbitrary dosing 
schedule;  (3) Allowing for multiple durations of therapy, could provide us with the 
opportunity to explore differences in immune responses across different dosing duration 
regimens.   
 
6.3.1 Research Urine Collection and Handling Pre and Post-BCG Instillation (research  
only) 
 
We will collect a urine sample pre-BCG treatment. We will also collect urine samples post-
BCG instillations, specifically the second void, which typically occur 4-6 hours post 
Intravesical BCG treatment.  Participants will be given the following options for collection 
of urine sample post intravesical BCG treatments: 
a) 
Participant may remain in the clinic for urine collection 
-OR- 
b) 
Participant may leave the clinic with a urine sample collection cup and biohazard 
bag.  Participant will be given specific instruction to collect second void post 
intravesical BCG therapy, and return the sample to the clinic. . 
 
 
Study team member will  work with participant on how post BCG therapy urine will be 
collected and returned to the team.  Post-BCG urine collection will take place at weekly 
during the 3-6 weeks of intravesical BCG treatments. Urine will be processed by 
centrifugation and the supernatant will be stored separately from the pellet.  
 
 
 
6.3.2 Dose Modification and Toxicity 


14-002H, Svatek, Form BB, 01-23-17 AMD 
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BCG at a dose of 1 to 8 x 108 is given intravesically for 2 hours, irrespective of weight or 
age.  This dose was chosen because previous experience and standard care with BCG.  
 
Adjustments (1/2 strength or ¼ strength) are allowed for participants demonstrating poor 
toleration of treatment as is done in the course of usual standard care. 
 
*Note: Due to the nationwide shortage of BCG, the entire vial (1 full dose) may not be 
used for the treatment.  Patients may elect to receive BCG treatments at standard of care 
physician.   
 
BCG treatment may be held by the treating physician for clinical reasons such as active 
urinary tract infection or gross bleeding from the bladder as per standard care.  
Regardless of dose or amount of BCG given, patients will be allowed to continue with 
study procedures. 
 
6.3.3 Monitoring during BCG Instillation 
 
At each visit (including baseline) symptom questionnaires will be administered prior to any 
procedures.  The symptom questionnaires will assess irritative LUTS present. If BCG 
Grade 3 bladder toxicity occurs it will result in postponing combined therapy by 1 week, 
provided that the patient’s symptoms resolved.  
 
Participant-reported side effect questionnaires will be administered prior to each weekly 
instillation to ascertain the previous instillation’s effects.  Patients will be monitored in the 
clinic during instillation of BCG.    
 
Adverse event (AE) monitoring will be assessed at each clinic visit, during BCG 
treatments, and on the day of cystectomy.  Safety will be assessed by a urologist with 
training in administration of intravesical BCG.  
 
Dose-Limiting Toxicity (DLT) - Dose-limiting toxicity (DLT) is defined as any grade 3 or 4 
systemic toxicities or evidence of grade 4 bladder toxicity using the National Cancer 
Institute common toxicity criteria. 
 
6.4 
Research Blood, urine, & tissue collection (research only) at the time of Radical 
Cystectomy (standard care)  
 
Research blood and urine will be collected at radical cystectomy..  Approximately 50 mL 
or 3.5 tablespoons of blood will be taken from a peripheral vein or an indwelling catheter if 
present and functional specifically for research studies.   The handling method can be 
found in Section 6.2.1. Voided urine or urine from an indwelling catheter will be collected. 
 
 
At the time of radical cystectomy, a section of tumor tissue, normal adjacent bladder 
tissue, and adjacent lymphatic tissue will be taken for immune studies. A small section of 
the tissue from the bladder (approximately 5 mm x 5 mm x 5 mm) will be taken.  Most 
patients with muscle invasive tumors have large tumors so taking a small section does not 
compromise pathologic assessment of stage. This research tissue would be excess tumor 
and would not compromise the ability of the pathologist to stage or grade the tumor, and 
poses no additional meaningful risk to the patient.  To ensure this we clarify that the tumor 
tissue taken for research represents a small (10% of the tumor volume or less) component 
of the tumor.  If sufficient excess tumor is not available for research purposes, then no 
research bladder tissue would be removed.  We have experience with such post-treatment 
tumor acquisition for research in bladder cancer studies here at UTHSCSA.  For benign 
adjacent bladder mucosa, we will also take a small section (approximately 5 mm x 5 mm x 
5 mm) of tissue.  Normally for lymph node dissections, we typically remove 20-60 lymph 
nodes during a cystectomy.  We will isolate several (2-8) lymph nodes to be used for 
research purposes.  The lymph node will removed and then surgically split in half.  One 
half will be sent for pathologic processing and the other half will be used for research.  In 
this way, we do not compromise the ability to pathologically examine the lymph nodes. 


14-002H, Svatek, Form BB, 01-23-17 AMD 
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We will also obtain the tissue blocks from cystectomy on all subjects from pathology 
where surgery was done. 
 
 
 
6.5 
Post-Radical Cystectomy Follow-up Visit (standard care) 
 
As per routine care, participants will return to clinic approximately within 90 days following 
surgery for a follow-up visit.  During this visit, research blood will be collected.   
 
Approximately 50 mL or 3.5 tablespoons of blood will be taken from a peripheral vein or 
an indwelling catheter if present and functional specifically for research studies. The 
research blood specimens will be transported to our lab in the STRF in approved 
containers by qualified personnel. The blood sample will be de-identified in the lab per 
HIPAA protocol.   
 
 
  
 


14-002H, Svatek, Form BB, 01-23-17 AMD 
15 
 
7.0 
 Study Calendar 
Study 
Component/Procedures 
Visit 
1 
BCG 
Week 
1 
(may 
be 
same 
day as 
Visit 
1) 
BCG 
Week 
2 
BCG 
Week 
3 
BCG 
Week 
4a 
BCG 
Week 
5a 
BCG 
Week 
6a 
Cystectomy 
Post 
Cystectomy 
(~within 90 
days post 
cystectomy) 
Informed Consent 
R 
 
 
 
 
 
 
 
 
Medical History, 
Demographics, Physical 
Exam 
S 
 
 
 
 
 
 
 
 
Assessment of AEs 
 
R 
R 
R 
R 
R 
R 
 
 
Urinary symptoms 
questionnaires 
R 
R 
R 
R 
R 
R 
R 
 
 
Blood Collection 
R* 
 
 
 
 
 
 
R 
R 
Urine Collection  
(pre and post treatment 
urine collected on BCG 
weeks) 
R* 
R 
R 
R 
R 
R 
R 
R 
 
Tissue collection 
 
 
 
 
 
 
 
R 
 
 
Tissue blocks from 
cystectomy procedure  
 
 
 
 
 
 
 
R 
 
 “R” indicates performed only for research purposes and “S” indicates performed for standard  care practice 
 a- Additional BCG treatments beyond week 3 will be given selectively to participants based on time interval 
between study enrollment and scheduled cystectomy date  
* Optional blood and urine collection 
 
 
 
8.0 
Criteria for Evaluation and Endpoint Definitions 
 
8.1  The primary end-point is taken as difference in tumor-specific immune response (comparing 
before and after treatment with BCG).   Tumor-specific immune response will be measured 
using a standard T cell proliferation assay. T cell response to autologous tumor will be 
measured using a paired analysis by utilizing PBMCs collected before and after BCG therapy.  
Autologous monocyte-derived dendritic cells (moDCs) and autologous T cells will be co-
cultured following pulsation of moDCs with whole tumor lysates.   
 
8.2 Secondary endpoints are exploratory and will not be considered for determining sample size.  
Secondary endpoints include (1) description of tumor infiltrating lymphocyte populations 
following BCG (examining 3 weeks of treatment versus 4,5, or 6 weeks as available); (2) 
determination of the presence/absence of BCG in lymph nodes following treatment; (3) 
examining extent of necrosis/apoptosis in tumor following BCG treatment; (4) pathologic 
assessment of tumor stage following BCG treatment; (5) characterization of systemic immune 
populations before treatment, at time of cystectomy,   
 
9.0 
Statistical Considerations 
 
9.1 
Sample Size Determination 
 
This is a one-arm open label study of the tumor-specific immune effect of BCG in 
participants undergoing radical cystectomy for bladder cancer.  The sample size 
calculation is based on one-sided testing on the proportion of subjects who experience an 
increase in T cell proliferation (≥100% increase in proliferative index during the 
proliferation assay) in post treatment assessment compared to pretreatment assessment 
with power=90% and target alpha=5%.  The null proportion responding is taken to be 0.10 
and the desired proportion responding is specified as greater than or equal to 0.50.  The 
estimated sample size, under these assumptions, is 10.  In order to achieve this number 


14-002H, Svatek, Form BB, 01-23-17 AMD 
16 
 
we would need to consent 25 participants to account for completion rate and assay 
variability. 
 
Sample size calculations were run using Stata 10.1 (College Station, Texas). 
 
Data analysis 
Descriptive graphs will be developed to describe immune subpopulations and 
immunodynamic end points on paired samples on an intraindividual basis.  For all other 
immune analyses, comparisons between groups will be conducted using the 
nonparametric Wilcoxon rank-sum test and comparison within groups will be conducted 
using the Wilcoxon signed-rank test.  Correlation will be analyzed with the Spearman rank 
test.   
 
 
10.0  
Registration Guidelines 
 
Participants will be registered on to IDEAS. 
 
11.0 
Ethical and regulatory 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review  
 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) 
and the Office for Protection from Research Risks Reports: Protection of Human Subjects (Code of 
Federal Regulations 45 CFR 46). 
 
12.0 
Data and Safety Monitoring Oversight 
 
A Data and Safety Monitoring Plan (DSMP) is required for all an individual protocols conducted at CTRC. All 
protocols conducted at CTRC are covered under the auspices of the CTRC Institutional Data Safety 
Monitoring Plan.   
 
The CTRC Institutional DSMP global policies provide individual trials with:  
• 
institutional policies and procedures for institutional data safety and monitoring,  
• 
an institutional guide to follow, 
• 
monitoring of protocol accrual by the CTRC Protocol Review Committee, 
• 
review of study forms and orders by the Forms Committee, 
• 
tools for monitoring safety events, 
• 
monitoring of UPIRSO’s by the Director of Quality Assurance and DSMC, 
• 
determining level of risk (Priority of Audit Level Score – PALS) ,  
• 
oversight by the Data Safety Monitoring Committee (DSMC),  and 
• 
verification of protocol adherence via annual audit for all Investigator Initiated Studies by the CTRC 
Quality Assurance Division. 
 
Monitoring Safety: 
Due to the low risk associated with participation in this protocol, the Principal Investigator will perform 
primary assessment of adverse events, adverse event trends and treatment effects on this study.  The PI 
will conduct independent review and report findings yearly to the CTRC Data Safety Monitoring Committee 
(DSMC) and the UTHSCSA IRB.  
 


14-002H, Svatek, Form BB, 01-23-17 AMD 
17 
 
Baseline events and adverse events will be captured using the CTRC Master Adverse Events Document for 
each patient using CTCAE V. (specify version you will use in this protocol) for the grading and attribution of 
adverse events. Usage of the CTRC Master Adverse Events Document centrally documents: 
• 
the event and grades the seriousness of it,  
• 
if the event was a change from baseline,   
• 
determines the relationship between the event and study intervention,  
• 
if the event was part of the normal disease process, and  
• 
what actions were taken as a result of the event.  
 
 
Safety Definitions: 
 
For this study, the following safety definitions will be applicable: 
 
Adverse Event Definition: An adverse event (AE) is defined as any untoward or unfavorable medical 
occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the 
research, whether or not considered related to the subject’s participation in the research For this study, all 
adverse events will be documented starting with specify here when you want to start collecting adverse 
event information, generally this would be with the first dose of the study drug  and ending 30 days after the 
last dose of study drug is received.  
 
Serious Adverse Event Definition: is any adverse event that: 
1. results in death; 
2. is life-threatening (places the subject at immediate risk of death from the event as it occurred); 
3. results in inpatient hospitalization or prolongation of existing hospitalization; 
4. results in a persistent or significant disability/incapacity; 
5. results in a congenital anomaly/birth defect; or 
6. based upon appropriate medical judgment, may jeopardize the subject’s health and may require 
medical or surgical intervention to prevent one of the other outcomes listed in this definition  
 
Unanticipated Problems Involving Risks to Subjects or Others Definition: Unanticipated problem involving 
risk to subjects or others includes any incident, experience or outcome that meets all of the following criteria: 
 
A. unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the subject population being studied 
(note: the unfounded classification of a serious adverse event as “anticipated” constitutes serious 
non-compliance); 
B. definitely related or probably related to participation in the research; and 
C. suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized 
 
Reporting Requirements 
 
For this study, all Master Adverse Events Documents collected on participants for this protocol will be 
reviewed by the Principal Investigator at each study visit/as they occur to determine if a serious safety 
problem has emerged that result in a change or early termination of a protocol such as: 
• 
dose modification, 
• 
suspending enrollment due to safety or efficacy, or 
• 
termination of the study due to a significant change in risks or benefits.   
 
The PI will use clinical judgment to make dose reduction and dose delay in BCG as per standard of care. 
Since these adjustments are very patient-specific, this will be done on a case-by-case basis. 
 
As per the CTRC DSMP, any protocol modifications, problematic safety reports, unanticipated problems, 
and suspension or early termination of a trial must be reported to all members of the research team 
Suspension and early termination of a trial must also be reported immediately to the Director of Quality 
Assurance (DQA) who will promptly notify the sponsor and the UTHSCSA IRB.  
 
The PI will review the Master Adverse Events documents to determine the significance of the reported 
events and will file the Investigator Initiated Study Quarterly DSMC Report Form on a yearly basis with the 
CTRC DSMC.  The Investigator Initiated Study Quarterly DSMC Report Form includes information on 
adverse events, current dose levels, number of participants enrolled, significant toxicities per the protocol, 


14-002H, Svatek, Form BB, 01-23-17 AMD 
18 
 
patient status (morbidity and mortality), dose adjustments with observed response, and any interim findings.  
Any trend consisting of three or more of the same event will be reported to the CTRC DSMP for independent 
review outside of the quarterly reporting cycle, which begins three months following protocol start up. 
Conflict of interest is avoided by the independent review of the CTRC DSMC and by ongoing independent 
review of adverse events trends by the Director of Quality Assurance.  
 
All SAE and UPRISO’s will be reported following CTRC and UTHSCSA institutional guidelines. 
UTHSCSA SAE/UPRISO REPORTING REQUIREMENTS 
Type Event 
Report to 
Timeframe 
All AE, SAE and UPIRSO 
Regulatory Affairs and DQA 
Same as other notification timeframes except for 
SAE/AE which should be reported on Monday 
for the prior week of PI being made aware 
SAE 
Clinical Trial Sponsor 
within 24 hours of PI being made aware 
AE/SAE 
UTHSCSA IRB 
Annually 
UPIRSO - all 
Clinical Trial Sponsor 
within 24 hours of the PI determining a UPIRSO 
exists 
UPIRSO - life threatening 
UTHSCSA IRB 
within 48 hours of the PI determining a UPIRSO 
exists 
UPIRSO - non-life threatening 
UTHSCSA IRB 
within 7 days of the PI determining a UPIRSO 
exists 
 
Include the following adverse event reporting requirement tables for NCI Trials supported by Grant or 
Contract Funding: 
TABLE A: Expedited Reporting for Phase I Studies (including hospitalization* to NCI Investigational 
Drug Branch (IDB) 
UNEXPECTED EVENT 
EXPECTED EVENT 
GRADES 2 - 3 Attribution of 
Possible, Probable or Definite 
GRADES 4 - 5 Regardless of 
Attribution 
GRADES 1 – 3 
GRADES 4 - 5 Regardless of 
Attribution 
Grade 2 - Expedited report 
within 10 working days 
Grade 3 - Report by phone to 
IDB within 24 hrs. Expedited 
report to follow within 10 
working days. 
(Grade 1 - Adverse Event 
Expedited Reporting NOT 
required.) 
Report by phone to IDB within 
24 hrs. Expedited report to 
follow within 10 working days. 
This includes all deaths within 
30 days of the last dose of 
treatment with an 
investigational agent 
regardless of attribution. 
Any late death attributed to 
the agent (possible, probable, 
or definite) should be reported 
within 10 working days. 
Adverse Event 
Expedited Reporting 
NOT required. 
Report by phone to IDB within 
24 hrs. Expedited report to 
follow within 10 working days. 
This includes all deaths within 
30 days of the last dose of 
treatment with an 
investigational agent 
regardless of attribution. 
Any late death attributed to 
the agent (possible, probable, 
or definite) should be reported 
within 10 working days. 
* For Hospitalization Only — Any medical event equivalent to CTC Grade 3, 4, 5 which precipitated 
hospitalization (or prolongation of existing hospitalization) must be reported regardless of requirements for 
Phase of study, expected or unexpected and attribution. 
Expedited reporting may not be appropriate for specific expected adverse events for certain later Phase II 
and Phase III protocols. In those situations the adverse events that will not have expedited reporting must be 
specified in the text of the approved protocol. An expected Grade 3 event that is definitely related to the 
investigational agent is only to be reported if the patient is hospitalized using the generic reporting criteria. 
For instance, in a trial of an investigational agent where Grade 3 diarrhea requiring hospitalization is 
expected, only diarrhea requiring ICU care (Grade 4) might be designated for expedited reporting. 


14-002H, Svatek, Form BB, 01-23-17 AMD 
19 
 
Serious adverse events on NCI sponsored trials utilizing a commercially available agent (with no IND’s 
involved) will additionally be reported via the FDA’s Medwatch program.   
 
Assuring Compliance with Protocol and Data Accuracy 
As with all studies conducted at CTRC, the PI has ultimate responsibility for ensuring protocol compliance, 
data accuracy/integrity and responding to recommendations that emanate from monitoring activities.    
(Please write in here any specific monitoring functions such as source verification etc that are either 
conducted by the sponsor’s monitor or newly implemented CTRC monitoring plan –for example, source 
verification of data will be performed routinely at each visit/as they occur). Protocol compliance, data 
accuracy and reporting of events is further ensured by an annual audit conducted by the Data Safety Officer, 
whose audit report is shared with the PI, the research team, and will be reviewed by the CTRC DSMC.  
 
DSMB #2 (for Solid Tumors) 
Kevin Kelly, MD 
Ting Lu, MD 
Wendy Crabbe, PA, MSN, RN 
Melissa Nashawati, MPA 
Yuanyuan Liang, PhD 
 
 


14-002H, Svatek, Form BB, 01-23-17 AMD 
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