Clinical trial NCT01215136
Conditions: Transitional Cell Carcinoma Bladder Carcinoma Urothelial Carcinoma
Sponsor: Matthew Galsky
Start date: 2010-12-01; Completion date: 2018-04-24
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this trial is to explore the activity and safety of everolimus +/- paclitaxel as first-line therapy for cisplatin-ineligible patients with advanced urothelial carcinoma.

Detailed description:
OUTLINE: This is a multi-center study

Patients will be enrolled into one of two parallel cohorts:

* Cohort 1: impaired renal function AND poor performance status (cycle length = 28 days). Everolimus 10 mg orally daily
* Cohort 2: impaired renal function OR poor performance status (cycle length = 28 days). Everolimus 10 mg orally daily + IV Paclitaxel 80 mg/m2 on D1, 8, 15

Restaging evaluations will be performed after every 2 cycles.

Treatment will continue until disease progression or unacceptable toxicity.

Karnofsky performance status 60-70%

Life Expectancy: Not specified

Hematopoietic:

* Absolute neutrophil count (ANC) ≥ 1.5 K/mm3
* Hemoglobin (Hgb) ≥ 9 g/dL
* Platelets ≥ 100 K/mm3
* INR ≤ 1.5 (Anticoagulants are allowed if target INR ≤ 1.5 on a stable dose of warfarin or on a stable dose of Low molecular weight (LMW) heparin for at least 2 weeks prior to registration for protocol therapy).
* Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L
* Fasting triglycerides ≤ 2.5 x ULN.
* Fasting serum glucose \< 1.5 x ULN

Hepatic:

* Bilirubin ≤ 1.5 x ULN
* Aminotransferases (AST and ALT) ≤ 2.5 x ULN (unless liver metastases, then ≤ 5 x ULN)

Renal:

* Calculated creatinine clearance of \< 60 using the Cockcroft-Gault formula

Cardiovascular:

* No symptomatic congestive heart failure of New York heart Association Class III or IV.
* No unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease.

Arms: arm 1: Single-agent everolimus (enrollment limited to patients with patients with creatinine clearance \< 60 ml/min AND Karnofsky performance status of 60-70%) arm 2: Everolimus plus paclitaxel (enrollment limited to patients with creatinine clearance \< 60 ml/min OR Karnofsky performance status of 60-70%)
Interventions: intervention 1: Everolimus intervention 2: Everolimus intervention 3: Paclitaxel
Intervention descriptions: intervention 1: 10 mg PO daily (continuously, without scheduled treatment interruptions). The cycle length will last 28 days. Everolimus will be dispensed on Day 1 of each cycle by the study center personnel on an outpatient basis. intervention 2: 10 mg PO daily (continuously, without scheduled treatment interruptions). The cycle length will last 28 days. Everolimus will be dispensed on Day 1 of each cycle by the study center personnel on an outpatient basis. intervention 3: Paclitaxel 80 mg/m2 IV as a 1 hour infusion on days 1, 8, and 15, of a 28-day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
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Protocol Title 
Phase II Trial of Everolimus or Everolimus plus Paclitaxel as First-line Therapy in 
Cisplatin-ineligible Participants with Advanced Urothelial Carcinoma: Hoosier 
Oncology Group GU10-147 
 
 
Sponsor Investigator 
Matthew Galsky, MD 
Mount Sinai Medical Center/Tisch Cancer Institute 
 
 
Co-Investigators 
Noah Hahn, MD 
Indiana University Melvin and Bren Simon Cancer Center 
Guru Sonpavde, MD 
The University of Alabama at Birmingham 
 
 
Statistician 
Ziyue Liu, PhD 
Indiana University, School of Medicine 
 
 
 
Trial Supported by 
Novartis 
 
 
Investigational New Drug (IND) Application #: Exempt 
 
 
 
 
Version Date: 10JAN2014 
 
 


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PROTOCOL SIGNATURE PAGE 
 
Phase II Trial of Everolimus as First-line Therapy in Cisplatin-ineligible 
Participants with Advanced Urothelial Carcinoma: Hoosier Oncology Group 
GU10-147 
 
VERSION DATE: 10JAN2014 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, or the applicable laws and regulations of the country of the 
study site for which I am responsible, whichever provides the greater protection of the individual.  
I will accept the monitor’s overseeing of the study.  I will promptly submit the protocol to 
applicable ethical review board(s). 
 
 
 
 
 
 
 
 
____________________________________ 
________________________ 
 Signature of Investigator 
 
 
 
 
 
       Date 
 
 
____________________________________ 
 Investigator Name (printed) 
 
 
____________________________________ 
 Investigator Title 
 
 
____________________________________ 
 Name of Facility 
 
 
____________________________________ 
 Location of Facility (City and State) 
 
____________________________________ 
 Not Submitting to IRB 
 Expected IRB Approval Date 
 
PLEASE COMPLETE AND EMAIL TO HOOSIER ONCOLOGY GROUP 
Instructions to the investigator:  Please SIGN and DATE this signature page.  
PRINT your name and title, the name and location of the facility in which the 
study will be conducted, and the expected IRB approval date.  Scan and email 
the completed form to Hoosier Oncology Group and keep a record for your 
files. 


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STUDY SYNOPSIS 
 
 
TITLE 
Phase II Trial of Everolimus as First-line Therapy in Cisplatin-ineligible 
Participants with Advanced Urothelial Carcinoma: Hoosier Oncology 
Group GU10-147 
STUDY PHASE  
Phase II 
OBJECTIVES 
Primary Objective: 
To evaluate clinical benefit rate (complete response, partial response, and 
stable disease) at 4 months from initiation of treatment. 
 
Secondary Objective: 
To determine the: 
 Safety of everolimus and everolimus plus paclitaxel in this participant 
population. 
 Progression-free survival. 
 Survival at 1-year from the initiation of treatment. 
 
STUDY DESIGN 
Participants will be enrolled into one of two parallel cohorts: : 
Cohort 1 (single agent everolimus) 
 Calculated creatinine clearance (Cockroft-Gault) < 60 ml/min 
AND Karnofsky performance status 60-70%. 
 
Cohort 2 (everolimus plus paclitaxel) 
 If participants have a calculated creatinine clearance (Cockroft-
Gault)    < 60 ml/min then their Karnofsky performance status 
must to be >70%. 
OR 
 If participants have a Karnofsky performance status of 60-70% 
then their calculated creatinine clearance (Cockroft-Gault) must 
be  ≥ 60ml/min. 
 
Participants in cohort 1 will take everolimus 10 mg PO daily 
(continuously, without scheduled treatment interruptions). The cycle 
length will last 28 days. Everolimus will be dispensed on Day 1 of each 
cycle by the study center personnel on an outparticipant basis. Participants 
will be provided with an adequate supply of everolimus for self 
administration at home. 
 
Participants in Cohort 2 will take everolimus 10 mg daily continuously as 
described above for Cohort 1 participants. Participants in cohort 2 will 
also receive paclitaxel 80 mg/m2 IV as a 1 hour infusion on days 1, 8, and 
15, of a 28-day cycle. 
TOTAL NUMBER OF 
PARTICIPANTS FOR 
ACCRUAL 
A total of 68 participants will be enrolled in this study.  


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ELIGIBILITY CRITERIA 
 
Written informed consent and HIPAA authorization for release of 
personal health information. 
 
Age > 18 years at the time of consent. 
 
Must be ineligible for cisplatin, based on  the following, within 30 
days prior to registration for protocol therapy: 
Cohort 1 (single agent everolimus) 
 
Calculated creatinine clearance (Cockroft-Gault) < 60 
ml/min AND 
 
Karnofsky performance status 60-70% 
Cohort 2 (everolimus plus paclitaxel) 
 
Calculated creatinine clearance (Cockroft-Gault) < 60 
ml/min OR 
 
Karnofsky performance status 60-70% 
 Histological or cytological proof of transitional cell carcinoma 
(TCC) of the bladder, urethra, ureter, or renal pelvis (urothelial 
carcinoma). Histology may be mixed, but still requires a 
component of TCC.  
 Measurable disease according to RECIST and obtained by imaging 
within 30 days prior to registration for protocol therapy.  
 
NOTE:  If the participant has had previous radiation to the marker 
lesion(s), there must be evidence of progression since the 
radiation. 
 Women of childbearing potential (WOCBP) and males of 
childbearing potential and their sexual partner(s) who are WOCBP 
must be willing to use a highly effective method of contraception 
from the time consent is signed until 8 weeks after treatment 
discontinuation. Examples of highly effective contraception 
methods include a combination of any two of the following: 
o Use of oral, injected or implanted hormonal methods of 
contraception 
o Placement of an intrauterine device (IUD) or intrauterine 
system (IUS) 
o Barrier methods of contraception: condom or occlusive 
cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/vaginal suppository 
o Total abstinence 
o Male/female sterilization 
 
 WOCBP must have a negative pregnancy test within 7 days prior 
to prior to registration for protocol therapy.    
 
NOTE:  Females are considered not of child bearing potential if 
they are surgically sterile (they have undergone a hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy) or they are 
postmenopausal (defined as amenorrhea for at least 12 consecutive 
months).                                                                                                
 Females must not be breastfeeding. 
 No prior chemotherapy for metastatic disease. Prior chemotherapy 


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in the neoadjuvant/adjuvant setting is allowed if completed at least 
12 months prior to registration for protocol therapy. 
 No active CNS metastases or leptomeningeal metastases.  
Participants with neurological symptoms must undergo a head CT 
scan or brain MRI to exclude brain metastasis.  
 
NOTE:  A participant with prior brain metastasis may be 
considered if they have completed their treatment for brain 
metastasis, 
no 
longer 
require 
corticosteroids, 
and 
are 
asymptomatic.  
 
 
No prior malignancy is allowed except for adequately treated basal 
cell or adequately treated squamous cell skin cancer, in situ 
cervical cancer, Gleason ≤ grade 7 prostate cancers (treated 
definitively with no evidence of PSA progression). Patients with 
other localized malignancies, definitively treated, and estimated at 
low risk of recurrence (<30%) based on available risk prediction 
tools, are eligible if approved by the sponsor investigator. 
 
No treatment with any anticancer therapy or investigational agent 
within 30 days prior to registration for protocol therapy.  
 
No known hypersensitivity to any protocol treatment. 
 
No prior treatment with mTOR inhibitor (sirolimus, temsirolimus, 
everolimus).  
 
No history of immunization with attenuated live vaccines within 
one week prior to registration for protocol therapy or during study 
period. 
 
No history of any severe and/or uncontrolled medical conditions 
or other conditions that   could affect their participation in the 
study such as: 
o Symptomatic congestive heart failure of New York heart 
Association Class III or IV. (Please refer to the SPM). 
o Unstable angina pectoris, symptomatic congestive heart 
failure, myocardial infarction within 6 months of start of 
study drug, serious uncontrolled cardiac arrhythmia or any 
other clinically significant cardiac disease. 
o Severely impaired lung function as defined as spirometry 
and DLCO that is 50% of the normal predicted value 
and/or 02 saturation that is 88% or less at rest on room air. 
o Uncontrolled diabetes as defined by fasting serum glucose 
>1.5 x ULN. 
o Active (acute or chronic) or uncontrolled severe 
infections. 
o Liver disease such as cirrhosis, chronic active hepatitis or 
chronic persistent hepatitis. 
o A known history of HIV seropositivity. 
o Impairment of gastrointestinal function or gastrointestinal 
disease that may significantly alter the absorption of 
everolimus (e.g., ulcerative disease, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome or small 


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bowel resection). 
o An active, bleeding diathesis. 
 
 No history of major surgery (defined as requiring general 
anesthesia) or significant traumatic injury within 30 days prior to 
registration for protocol therapy.      
        
NOTE: Must have recovered from the side effects of any major 
surgery. 
 Prior radiation therapy is allowed to < 25% of the bone marrow 
[see bone marrow radiation chart in the study procedure manual 
(SPM)].   
 
NOTE:  No radiation therapy within 30 days prior to registration 
for protocol therapy. 
 
Laboratory values must be obtained within 7 days prior to 
registration for protocol therapy.   
 
  Absolute neutrophil count (ANC) > 1.5 K/mm3 
 
Hemoglobin (Hgb) > 9 g/dL 
 
Platelets > 100 K/mm3 
 
Calculated creatinine clearance of  < 60 using the Cockcroft-Gault 
formula: 
 
 
Males:  (140 – Age in years) × Actual Body Weight in kg 
 72 × Serum Creatinine (mg/dL) 
 
             Females:  Estimated creatinine clearance for males × 0.85 
 
 
Bilirubin < 1.5 x ULN 
 
Aminotransferases (AST and ALT) < 2.5 x ULN (unless liver 
metastases, then < 5  ULN) 
 
INR ≤ 1.5 (Anticoagulants are allowed if target INR ≤ 1.5 on a 
stable dose of warfarin or on a stable dose of Low molecular 
weight (LMW) heparin for at least 2 weeks prior to registration for 
protocol therapy). 
 Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L  
 
Fasting triglycerides ≤ 2.5 x ULN.  
 
Random serum glucose ≤ 1.5 x ULN 
 
NOTE:  If random serum glucose is > 1.5 x ULN then a fasting 
serum glucose must be performed and must be ≤ 1.5 x ULN. 
 
STATISTICAL 
CONSIDERATIONS 
Sample Size Considerations 
This study will involve two parallel cohorts. The study is not designed 
for statistical comparisons of the cohorts. Each cohort will employ a 
separate Simon’s 2-stage MinMax design.  
 


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For cohort 1 (single agent everolimus), the sample size is based on the 
assumption that a clinical benefit rate of ≤ 10% is not worthy of further 
evaluation while a clinical benefit rate of ≥ 30% warrants additional 
testing. In the first stage, more than 1 participant with an objective 
response or stable disease (at 4 months) out of 15 evaluable participants is 
needed.  In the second stage, an additional 10 evaluable participants  will 
be required and more than 5 participants with an objective response or 
stable disease (at 4 months) are needed to consider the treatment 
successful with alpha = 0.05 and 80% power. The probability of early 
termination is 55% when the clinical benefit rate is ≤ 10%.  
For cohort 2 (single agent everolimus plus paclitaxel), the sample size is 
based on the assumption that a clinical benefit rate of ≤ 25% is not worthy 
of further evaluation while a clinical benefit rate of ≥ 45% warrants 
additional testing. In the first stage, more than 4 participants with an 
objective response or stable disease (at 4 months) out of 17 evaluable 
participants are needed.  In the second stage, an additional 19 evaluable 
participants (for a total of 36 evaluable participants) will be required and 
more than 13 participants with an objective response or stable disease (at 4 
months) are needed to consider the treatment successful with alpha = 0.05 
and 80% power. The probability of early termination is 57% when the 
clinical benefit rate is ≤ 25%.  
For both cohorts, the primary endpoint is clinical benefit rate which 
includes response (defined as partial and complete response) and stable 
disease (at 4 months). It will be reported with 95% confidence intervals 
(CI).   
 
Survival which is part of the secondary endpoints will be calculated from 
the date of initiation of treatment to the death or last date of contact. 
Survival at 1 year will be estimated from a Kaplan-Meier analysis. 
Progression-free survival will be calculated from the date of initiation of 
therapy until progressive disease or death due to any cause.  If the 
participant did not progress nor die, the participant will be censored on the 
date of the last disease assessment performed. Progression-free survival 
will be analyzed using the method of Kaplan and Meier. Toxicities will be 
graded according to the NCI Common Toxicity Criteria (version 4.0). 
Participants enrolled in this study will be carefully monitored during the 
entire treatment phase and will be followed as is appropriate, with safety 
evaluations. All participants receiving at least 1 dose of the study regimen 
will be included in the safety analysis. Incidence and type of grades 3 and 
4 adverse events, including serious adverse events, will be tabulated and 
summarized using descriptive statistics.  
The participant is evaluable for efficacy if the participant receives at least 
one dose of treatment and at least one post-baseline disease evaluation. 
Dosage adjustments or interruptions will be based on treatment-related 
toxicity.  Early discontinuation of treatment (<2 cycles) secondary to 
toxicity will be considered a treatment failure.   
 
Assume 10% of the cohorts are nonevaluable or dropout, we plan to 
accrue 68 (28+40) participants. Accrual rate of 2-4 participants per month 
is anticipated, and thus the trial accrual time will be approximately 17-34 


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months. 
 
Potential biomarkers will be assessed by repeating the analysis of each 
clinical outcome with the level of each individual marker included as 
factor or covariate as appropriate.  Markers with a continuous, rather than 
a discrete, measurement will also be evaluated as a discrete factor by 
dividing participants into low and high expression classes at the point of 
the distribution that maximizes the association between the marker and 
each clinical outcome.  Significance of this association will be evaluated 
using a test for maximal chi-square values. 
 
Archival tissue samples will be submitted to a CLIA-certified lab for 
transcriptional profiling. The Co-Expression Extrapolation algorithm will 
be utilized to generate scores for sensitivity to paclitaxel and/or 
everolimus. The scores will be correlated with clinical outcomes. The 
correlation will be explored using Kendall’s tau statistic. 
Baseline comorbidity scores will be calculated using the Charlson index 
and correlated with adverse events and clinical outcomes, which also be 
quantified using Kendall’s tau statistic 
 
 
 


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Phase II Trial of Everolimus or Everolimus plus Paclitaxel as First-line Therapy in 
Cisplatin-ineligible Participants with Advanced Urothelial Carcinoma: Hoosier Oncology 
Group GU10-147 
 
 
INDEX  
 
SECTION                                                                                                                 
PAGE 
 
SCHEMA ........................................................................................................................................ 10 
1 
BACKGROUND & RATIONALE ....................................................................................... 11 
2 
OBJECTIVES ........................................................................................................................ 13 
3 
ELIGIBILITY CRITERIA ................................................................................................... 13 
4 
PARTICIPANT REGISTRATION ...................................................................................... 17 
5 
TREATMENT PLAN ............................................................................................................ 17 
6 
DOSE MODIFICATIONS .................................................................................................... 22 
7 
STUDY CALENDAR & EVALUATIONS .......................................................................... 37 
8 
CRITERIA FOR DISEASE EVALUATION ...................................................................... 43 
9 
BIOLOGICAL CORRELATIVES ...................................................................................... 46 
10 CTM INFORMATION & ADVERSE EVENTS MANAGEMENT ................................. 47 
11 ADVERSE EVENTS ............................................................................................................. 51 
12 STATISTICAL CONSIDERATIONS ................................................................................. 56 
13 TRIAL MANAGEMENT ...................................................................................................... 57 
14 REFERENCES ....................................................................................................................... 60 
15 APPENDIX A ......................................................................................................................... 63 
 
 
 
 
 
 


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SCHEMA 
 
Phase II Trial of Everolimus or Everolimus plus Paclitaxel as First-line Therapy in 
Cisplatin-ineligible Participants with Advanced Urothelial Carcinoma:  
Hoosier Oncology Group GU10-147 
Evaluation of 
Eligibility Criteria 
Participant Registration 
Cohort 1 (cycle length = 28 days)     
Everolimus 10 mg orally daily 
Cohort 2 (cycle length = 28 days) 
Everolimus 10 mg orally daily 
+ IV Paclitaxel 80 mg/m2 on D1, 8, 
15 
Discontinue protocol 
therapy  
PD or unacceptable toxicity 
Continue protocol 
therapy  
Continue protocol 
therapy  
Non-PD 
and/or 
acceptable 
toxicity 
Non-PD 
and/or 
acceptable 
toxicity 
The cycle length = 28 days. 
Restaging evaluations will be performed after every 2 cycles. 
Participants will be enrolled into one of two parallel cohorts: 
Cohort 1: impaired renal function AND poor performance status 
Cohort 2: impaired renal function OR poor performance status 


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1 
BACKGROUND & RATIONALE 
 
Transitional cell carcinoma (TCC) of the urinary bladder is the second most common 
genitourinary malignancy. Each year in the United States, more than 60,000 participants will 
develop TCC and over 12,000 will die of their disease 1. While TCC is a chemosensitive 
neoplasm, current therapeutic approaches are inadequate. Response durations are short and the 
median survival of participants with metastatic disease is slightly over 1 year 2. These findings 
highlight the need for novel approaches to the treatment of metastatic TCC. 
 
A large proportion of participants with TCC are ineligible for cisplatin-based therapy.  
 
Cisplatin-based combination chemotherapy is considered the standard of care for participants with 
metastatic TCC. However, a large proportion of participants are ineligible for such treatment 
based on renal function or disease/functional status. In a retrospective study of 512 participants 
with pathologic stage ≥ T3 and/or node positive TCC being considered for adjuvant 
chemotherapy, approximately 40% were ineligible for cisplatin-containing therapy based on a 
calculated creatinine clearance of < 60 ml/min – in participants over 60 years old, 63% were 
ineligible 3. The median age of diagnosis of advanced bladder cancer is 70, and the proportion of 
‘cisplatin-ineligible’ participants is expectedly higher in the metastatic disease population. There is 
no standard treatment for cisplatin-ineligible participants with advanced urothelial carcinoma.  
 
A recently reported randomized phase II study explored gemcitabine plus carboplatin versus 
methotrexate, vinblastine, plus carboplatin in cisplatin-ineligible participants with metastatic TCC. 
Cisplatin-ineligibility in this study was defined as a World Health Organization Performance 
Status of 2 and/or a creatinine clearance of < 60 ml/min 4. Notably, this trial demonstrated that the 
severe acute toxicity rate was approximately 25% in participants with both impaired renal function 
and that these participants were the least likely to experience a response to treatment. The study of 
“new drugs with alternative mechanisms of action” in this participant population was 
recommended by the authors. 
 
“Targeted” therapies as first-line treatment for cisplatin-ineligible participants. 
 
Bellmunt et al explored the activity of sunitinib as a first-line treatment in participants with 
advanced urothelial carcinoma who were ineligible for cisplatin therapy 5. Preliminary results 
indicated that of the 16 participants evaluable for efficacy, there were 2 partial responses, and 8 
participants achieved stable disease lasting greater than 3 months for a clinical benefit rate of 64%. 
Notably, the median time to progression of 6 months compared favorably to chemotherapy in this 
population. This study demonstrates the feasibility of exploring “targeted” agents as first-line 
therapy in cisplatin-ineligible participants. 
 
 
Rationale for mTOR inhibition in urothelial carcinoma 
 
 
Multiple lines of evidence support targeting mTOR in participants with urothelial carcinoma: 
1. 
PTEN mutations are present in approximately 30% of participants with urothelial carcinoma. 
2. 
The PI3Kinase pathway is a key mediator of urothelial carcinoma invasion and prognosis 6-7. 


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3. 
mTOR pathway markers, including pS-6 and p-4E BP1, are overexpressed in the majority of 
participants with invasive urothelial carcinomas 8. 
4. 
Inactivation of p53 and PTEN promotes tumorigenesis in human bladder cells and is 
correlated with poor survival in human tumors. The synergistic effects of p53 and PTEN 
deletion are mediated by deregulation of mTOR signaling 9.  
 
Clinical experience with everolimus 
Everolimus is an oral inhibitor of mTOR which has shown activity in a variety of hematologic 
malignancies and solid tumors. A randomized phase III trial of everolimus versus placebo in 
participants with renal carcinoma that had previously progressed on sunitinib, sorafenib, or both 
demonstrated an improvement in progression free survival with everolimus relative to placebo (4 
vs. 19 months, P < 0.001)10. Everolimus was well tolerated with stomatitis, rash, and fatigue as the 
most common adverse events. This study led to the approval of everolimus by the US Food and 
Drug Administration for the treatment of renal carcinoma. Several ongoing studies are exploring 
mTOR inhibitors in a variety of tumor types. 
 
Combination therapy with everolimus and paclitaxel 
Paclitaxel is among the most active single agents in the treatment of urothelial carcinoma 11. 
Furthermore, paclitaxel has demonstrated safety in the treatment of cisplatin-ineligible participants 
with metastatic urothelial carcinoma 12. Preclinical data suggest that the PI3 kinase/Akt/mTOR 
signalling pathways may be associated with resistance to taxanes. Inhibition of mTOR has been 
shown to counteract Akt-mediated resistance to drugs inhibiting tubulin and to restore apoptosis in 
cancer cells 13-14. In vivo combinations of everolimus and paclitaxel have demonstrated additive 
and synergistic effects in tumor models. The combination of paclitaxel plus everolimus has shown 
safety in a phase I trial, without apparent pharmacokinetic drug interactions 15. A phase Ib/II study 
(study J2101) has explored weekly paclitaxel in combination with trastuzumab and everolimus in 
participants with metastatic breast cancer 16. Trastuzumab (2mg/kg on day 1, 8, 15 and 22) and 
paclitaxel (80mg/m2 on day 1, 8 and 15) were administered in combination with 3 schedules of 
everolimus (5mg daily, 10mg daily, and 30mg weekly) in 4-week cycles. In this study, the 10mg 
daily was felt to demonstrate the most promising preliminary efficacy results. In addition, a 
pharmacodynamic model, supported by a clinical tumor pharmacodynamic study showed that the 
10mg daily dosage achieved more profound and sustained suppression of mTOR activity than 
could be achieved with weekly dosing. Therefore, the 10mg daily dose of everolimus in 
combination with weekly paclitaxel and trastuzumab was selected for further development.  
 
Given the safety and activity of weekly paclitaxel in cisplatin-ineligible participants with 
metastatic urothelial carcinoma, the preclinical evidence of synergy combining paclitaxel plus 
everolimus, and the safety of combination therapy in phase I testing, the combination of paclitaxel 
plus everolimus warrants evaluation in cisplatin-ineligible participants with advanced urothelial 
carcinoma. 
 
Rationale for the current study 
 
Several lines of evidence support the current study: 
1. A large proportion of participants with advanced urothelial carcinoma are ineligible for 
cisplatin-based chemotherapy. There is no standard treatment for this participant population. 


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Furthermore, combination cytotoxic chemotherapy regimens are poorly tolerated by many of 
these participants 4.  
2. Preclinical studies support targeting PI3K/AKT/mTOR signaling in urothelial carcinoma. 
3. Everolimus is a well tolerated orally bioavailable inhibitor of mTOR with activity in multiple 
tumor types. 
4. Prelinical studies have demonstrated synergistic antitumor activity when combining 
everolimus and paclitaxel supporting evaluation of this combination in cisplatin-ineligible 
participants with advanced urothelial carcinoma. 
 
Rationale for treatment options: 
There is no standard treatment for cisplatin-ineligible participants with metastatic bladder cancer 
and many participants in this subset tolerate combination chemotherapy poorly. Furthermore, a 
recent randomized phase II study of combination chemotherapy regimens in this participant 
population revealed that participants with both a poor performance status and impaired renal 
function had a high rate of severe acute toxicity with combination chemotherapy and were least 
likely to respond to therapy. Therefore, in the current study, participants with either poor 
performance status or impaired renal function will be assigned to treatment with paclitaxel plus 
everolimus while participants with both poor performance status and impaired renal function will 
be assigned to treatment with single-agent everolimus. 
 
2 
OBJECTIVES 
 
 
2.1 
Primary Objective: 
To evaluate clinical benefit rate (complete response, partial response, and stable disease) at 
4 months from initiation of treatment. 
 
2.2 
Secondary Objectives: 
To determine the: 
 Safety of everolimus and everolimus plus paclitaxel in this participant population. 
 Progression-free survival. 
 Survival at 1-year from the initiation of treatment. 
 
2.3 
Exploratory Objectives: 
 To correlate mTOR pathway markers in archived tumor samples with clinical benefit 
rate. 
 To correlate gene expression models derived from archived tumor samples using the 
Co-Expression Extrapolation Algorithm with clinical benefit rate.  
 To correlate baseline Charlson comorbidity score with adverse events and clinical 
outcomes. 
 
3 
ELIGIBILITY CRITERIA 
 
3.1 
Written informed consent and HIPAA authorization for release of personal health 
information. 
 
3.2 
Age > 18 years at the time of consent. 


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3.3 
Must be ineligible for cisplatin, based on the following, within 30 days prior to 
registration for protocol therapy: 
 
Cohort 1 (single agent everolimus) 
 
Calculated creatinine clearance (Cockroft-Gault) < 60 ml/min AND 
Karnofsky performance status 60-70%. 
 
Cohort 2 (everolimus plus paclitaxel) 
 
If participants have a calculated creatinine clearance (Cockroft-Gault) < 60 ml/min then 
their  
Karnofsky performance status must to be >70%. 
 
 
OR 
 
If participants have a Karnofsky performance status of 60-70% then their calculated 
creatinine clearance (Cockroft-Gault) must be  ≥ 60ml/min. 
 
NOTE: Calculated creatinine clearance using the Cockcroft-Gault formula: 
 
 
Males:  (140 – Age in years) × Actual Body Weight in kg 
 72 × Serum Creatinine (mg/dL) 
 
Females:  Estimated creatinine clearance for males × 0.85 
 
 
3.4 
Histological or cytological proof of transitional cell carcinoma (TCC) of the bladder, 
urethra, ureter, or renal pelvis (urothelial carcinoma). Histology may be mixed, but still 
requires a component of TCC.  
 
3.5 
Measurable disease according to RECIST and obtained by imaging within 30 days prior 
to registration for protocol therapy.  
 
NOTE:  If the participant has had previous radiation to the marker lesion(s), there must 
be evidence of progression since the radiation. 
 
3.6 
Women of childbearing potential (WOCBP) and males of childbearing potential and 
their sexual partner(s) who are WOCBP must be willing to use a highly effective method 
of contraception from the time consent is signed until 8 weeks after treatment 
discontinuation. Highly effective contraception methods include a combination of any 
two of the following: 
a. Use of oral, injected or implanted hormonal methods of contraception 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 
d. Total abstinence 
e. Male/female sterilization 
 


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3.7 
WOCBP potential must have a negative pregnancy test within 7 days prior to prior to 
registration for protocol therapy.    
 
NOTE:  Women are considered not of child bearing potential if they are surgically 
sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or they are postmenopausal (defined as amenorrhea for at least 12 
consecutive months).                                                                                                                                   
 
3.8 
Females must not be breastfeeding. 
 
3.9 
No prior chemotherapy for metastatic disease. Prior chemotherapy in the 
neoadjuvant/adjuvant setting is allowed if completed at least 12 months prior to 
registration for protocol therapy. 
 
3.10 
No active CNS metastases or leptomeningeal metastases.  Participants with neurological 
symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis.  
 
NOTE:  A participant with prior brain metastasis may be considered if they have 
completed their treatment for brain metastasis, no longer require corticosteroids, and are 
asymptomatic.  
 
3.11 
No prior malignancy is allowed except for adequately treated basal cell or adequately 
treated squamous cell skin cancer, in situ cervical cancer, Gleason ≤ grade 7 prostate 
cancers (treated definitively with no evidence of PSA progression). Patients with other 
localized malignancies, definitively treated, and estimated at low risk of recurrence 
(<30%) based on available risk prediction tools, are eligible if approved by the sponsor 
investigator. 
 
3.12 
No treatment with any anticancer therapy or investigational agent within 30 days prior to 
registration for protocol therapy.  
 
3.13 
No known hypersensitivity to any protocol treatment. 
 
3.14 
   No prior treatment with mTOR inhibitor (sirolimus, temsirolimus, everolimus). 
 
3.15 
No history of immunization with attenuated live vaccines within one week prior to 
registration for protocol therapy or during study period. 
 
3.16 
No history of any severe and/or uncontrolled medical conditions or other conditions that   
could affect their participation in the study such as: 
 
 Symptomatic congestive heart failure of New York heart Association Class III or 
IV. (Please refer to the SPM). 
 Unstable angina pectoris, symptomatic congestive heart failure, myocardial 
infarction within 6 months of start of study drug, serious uncontrolled cardiac 
arrhythmia or any other clinically significant cardiac disease. 


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 Severely impaired lung function as defined as spirometry and DLCO that is 50% of 
the normal predicted value and/or 02 saturation that is 88% or less at rest on room 
air. 
 Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN. 
 Active (acute or chronic) or uncontrolled severe infections. 
 Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent 
hepatitis. 
 A known history of HIV seropositivity. 
 Impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of everolimus (e.g., ulcerative disease, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel 
resection). 
 An active, bleeding diathesis. 
 
3.17 
No history of major surgery (defined as requiring general anesthesia) or significant 
traumatic injury within 30 days prior to registration for protocol therapy.             
 
NOTE: Must have recovered from the side effects of any major surgery. 
 
3.18 
Prior radiation therapy is allowed to < 25% of the bone marrow [see bone marrow 
radiation chart in the study procedure manual (SPM)].   
 
NOTE:  No radiation therapy within 30 days prior to registration for protocol therapy. 
 
Laboratory values must be obtained within 7 days prior to registration for protocol therapy.   
 
3.19 
Absolute neutrophil count (ANC) > 1.5 K/mm3 
 
3.20 
Hemoglobin (Hgb) > 9 g/dL 
 
3.21 
Platelets > 100 K/mm3 
 
 
3.22 
Bilirubin < 1.5 x ULN 
 
3.23 
Aminotransferases (AST and ALT) < 2.5 x ULN (unless liver metastases, then 
< 5  ULN) 
 
3.24 
INR ≤ 1.5 (Anticoagulants are allowed if target INR ≤ 1.5 on a stable dose of warfarin or 
on a stable dose of Low molecular weight (LMW) heparin for at least 2 weeks prior to 
registration for protocol therapy). 
 
3.25 
Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L  
 
3.26 
Fasting triglycerides ≤ 2.5 x ULN.  


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3.27 
Random serum glucose ≤ 1.5 x ULN 
Note:  If random serum glucose is > 1.5 x ULN then a fasting serum glucose must be performed 
and must be ≤ 1.5 x ULN. 
 
4 
PARTICIPANT REGISTRATION  
 
All participants must be registered through Hoosier Oncology Group’s electronic data capture 
(EDC) system. 
  
Detailed guidelines for participant registration and electronic case report form (eCRF) completion 
can be found in the Study Procedures Manual (SPM) associated with this protocol.   
 
Participants must be registered prior to starting protocol therapy and begin therapy within 5 
business days of registration. 
 
4.1 
Randomization 
 
There will be no randomization in this protocol. 
 
4.2 
Blinding 
 
 
The study treatment is not blinded to the participant or the investigator. 
 
 
 
5 
TREATMENT PLAN 
 
5.1 
Treatment Plan   
 
Participants will be enrolled into one of two parallel cohorts based on the following: 
 
Cohort 1 (single agent everolimus) 
 Calculated creatinine clearance (Cockroft-Gault) < 60 ml/min AND 
 Karnofsky performance status 60-70% 
Cohort 2 (everolimus plus paclitaxel) 
 Calculated creatinine clearance (Cockroft-Gault) < 60 ml/min OR 
 Karnofsky performance status 60-70% 
 
Participants in cohort 1 will take everolimus 10 mg PO daily (continuously, without 
scheduled treatment interruptions). The cycle length will last 28 days. Everolimus will be 
dispensed on Day 1 of each cycle by the study center personnel on an outparticipant basis. 
Participants will be provided with an adequate supply of everolimus for self administration 
at home. All dosages prescribed and dispensed to the participant and all dose changes 
during the study will be recorded. 
 


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Participants are to bring their unused everolimus to the clinic on Day 1 of each cycle, and 
a new supply of everolimus will be dispensed on Day 1 of each cycle. Compliance 
should be verified by the investigator’s staff by counting the number of tablets consumed 
between visits. 
 
The participant will continue to take everolimus until disease progression (by RECIST 
criteria), unacceptable toxicity, death or discontinuation for any other reason (i.e. 
withdrawal of consent, administrative reasons). The participant will be asked to return all 
unused everolimus at the end-of-treatment visit. 
 
Participants in Cohort 2 will take everolimus 10 mg daily continuously as described 
above for Cohort 1 participants. Participants in cohort 2 will also receive paclitaxel 80 
mg/m2 IV as a 1 hour infusion on days 1, 8, and 15, of a 28-day cycle. 
 
5.1.1 
Pre-medication  
 
There will be no standard pre-medications prior to administration of everolimus. 
 
All participants in cohort 2 should receive premedication with corticosteroids, 
antihistamines and H2 antagonists prior to paclitaxel administration in order to prevent 
severe hypersensitivity reactions. Pre-medications for paclitaxel administration should be 
used per institutional guidelines.  
 
5.1.2   
Drug Administration 
 
Medication labels will comply with US legal requirements and be printed in English. 
They will supply no information about the patient. The storage conditions for Everolimus 
will be described on the medication label. Everolimus is supplied by Novartis. 
Everolimus is formulated as tablets for oral administration of 2.5mg, 5mg, and 10mg 
strength. Tablets are blister-packed under aluminum foil, which should be opened only at 
the time of administration as drug is both hygroscopic and light-sensitive. 
 
The extent of absorption of everolimus through topical exposure is not known.  
Therefore, caregivers are advised to avoid contact with suspensions of Afinitor Tablets.  
Wash hands thoroughly before and after preparation of either suspension. 
 
 
Participants will be instructed to take the study drug exactly as prescribed and by stating 
that compliance is necessary for the patient’s safety and the validity of the study.  The 
patient should be instructed to contact the investigator if he/she is unable for any reason 
to take the study drug as prescribed.  Patients will be instructed to take 10 mg tablets of 
everolimus orally with a glass of water, once daily at the same time each day. Everolimus 
may be taken with or without food; however, any dietary habits around the time of intake 
should be as consistent as possible throughout the study. The tablets should be 
swallowed whole with a glass of water and should not be chewed or crushed. For patients 
unable to swallow tablets, the tablet(s) should be dispersed completely in a glass of water 


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(containing approximately 30 mL) by gently stirring until the tablet(s) is fully 
disintegrated (approximately 7 minutes), immediately prior to drinking. The glass should 
be rinsed with the same volume of water and the rinse completely swallowed to ensure 
the entire dose is administered. If vomiting occurs, no attempt should be made to replace 
the vomited dose. Patients should be instructed that if they miss a dose on one day, they 
must not take any extra dose the next day, but instead to immediately contact the study 
center as soon as possible to ask for advice. Everolimus should not be taken with 
grapefruit, star fruit, Seville oranges or juices containing those ingredients. 
 
Table 1: Drug administration 
Cohort 
Drug 
Dose                    
Frequency 
of 
administration 
Length 
of 
the 
cycle 
1 
Everolimus 
10 mg PO 
Daily 
28 days 
2 
Everolimus  
+               
Paclitaxel 
10 mg PO         
+                  
80 mg/m2 IV 
Daily  
+    
Days 1, 8 and 
15  
 28 days 
NOTE: * IV Paclitaxel may be given ± 3 days for reasons such as observed holidays, 
inclement weather, scheduling conflicts, etc. It should be clearly documented in 
participant’s chart and case report forms. 
 
NOTE: Drug dose may be recalculated only if participant’s weight changes by > 10% 
during the course of the study. 
 
5.1.3 
Missed doses  
 
Missed doses of either Everolimus or Paclitaxel will not be made up on subsequent days. 
Patients that meet criteria to proceed with treatment will resume with the next scheduled 
treatment. 
 
5.2 
Supportive Care 
 
Administration of other chemotherapy or immunotherapy, or hormonal therapy (with the 
exception of contraceptives and replacement steroids), or experimental medications during 
the study is not allowed. Participants cannot receive radiation therapy while on study. 
Supportive care may be administered at the discretion of the treating Physician. Granulocyte 
colony stimulating factors may be used at the direction of the Treating Physician but should 
not be used prophylactically during cycle #1 or in lieu of a recommended dose reduction. 
 
5.3 
Concomitant Medications 
 


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Participants should be instructed not to take any additional medications (over-the-counter or 
other products including nutritional supplements) during the study without prior consultation 
with/approval from the treating physician.  
 
Everolimus is metabolized primarily by the cytochrome P450 isoenzyme, CYP3A4, to 
produce its primary active metabolite. Drugs or substances known to be inhibitors, inducers 
or substrates of the isoenzyme CYP3A4 should be avoided unless use of the drug is essential 
and no substitute is available (strong inhibitors should not be used). Refer to Table 2 below 
for concomitant treatments to avoid. For a complete list of drugs which are substrates for 
CYP3A4, please refer to this website: http://medicine.iupui.edu/flockhart/clinlist.htm. 
 
A strong inhibitor is one that causes a > 5-fold increase in the plasma AUC values or more 
than 80% decrease in clearance. A moderate inhibitor is one that causes a > 2-fold increase 
in plasma AUG valued or 50-80% decrease in clearance. A weak inhibitor is one that causes 
a > 1.25-fold increase in plasma AUC values or 20-50% decrease in clearance. (Distinction 
is not always categorical as interaction can vary according to conditions). 
 
Table 2: Clinically relevant drug interaction: substrates, inducers, and inhibitors of 
isoenzyme CYP3A4 
Substrates (competitive inhibition) 
Antibiotics1: 
clarithromycin* 
erythromycin 
telithromycin* 
Anti-arrhythmics: 
quinidine 
Benzodiazepines: 
alprazolam 
diazepam 
midazolam 
triazolam 
 
Immune Modulators: 
cyclosporine 
tacrolimus (FK506) 
 
HIV Protease Inhibitors: 
indinavir* 
ritonavir* 
saquinavir* 
Prokinetic: 
cisapride 
 
Antihistamines: 
astemizole 
chlorpheniramine 
 
Calcium Channel Blockers: 
amlodipine 
diltiazem 
felodipine 
nifedipine 
nisoldipine 
nitrendipine 
verapamil 
 
HMG CoA Reductase Inhibitors2: 
cerivastatin 
lovastatin 
simvastatin 
 
Miscellaneous: 
aripiprazole 
aprepitant 
buspirone 
gleevec* 
haloperidol 
methadone 
pimozide 
quinine 
sildenafil 
tamoxifen 
trazodone 
vincristine 
 
Inducers 
Carbamazepine 
Dexamethasone 
Primidone 
Progesterone 


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Ethosuximide 
Glucocorticoids 
Griseofulvin 
Nafcillin 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenylbutazone 
Phenytoin* 
 
Rifabutin* 
Rifampicin* 
Rifapentin 
Roxfecoxib 
St John’s Wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
 
Inhibitors 
Primidone 
Progesterone 
Rifabutin* 
Rifampicin* 
Rifapentin 
Roxfecoxib 
St John’s Wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
Cannabinoids 
Cimetidine 
Cisapride 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delaviridine 
Dexamethasone 
Diethyldithiocarbamate 
Diltiazem 
Dirithromycin 
Disulfiram 
Entacapone (high dose) 
Erythromycin 
Ethinyl estradiol 
Fluconazole 
Ketoconazole* 
Mibefradil 
Nefazodone* 
Nelfinavir* 
Norfloxacin 
Norfluoxetine 
Fluoxetine 
Fluvoxamine* 
Gestodene 
Grapefruit juice 
Indinavir 
Isoniazid 
Itraconazole* 
Omeprazole 
Oxiconazole 
Paroxetine 
Posaconazole* 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin and dalfopristin 
Ranitidine 
Ritonavir* 
Saquinavir* 
Sertindole 
Sertraline 
Sevilla orange 
Telithromcyin* 
Troglitazone 
Troleandomycin 
Valproic acid 
Verapamil 
Voriconazole* 
Zafirlukast 
Zileuton 
 
Based on: Ingelman-Sunderberg, 2004 Human drug metabolising cytochrome P450 enzymes: 
properties and polymorphisms, Naunyn Schmiedebergs Arch Pharmacol. 2004 Jan; 369(1):89-104 and 
[http://www.medicine.iupui.edu/flockhart/clinlist.htm as of February 15, 2007] 
* Asterisk denotes strong inhibition/ induction. These strong inhibitors are not allowed during the study. 
1Macrolide antibiotics: Azithromycin is not a CYP3A4 substrate. It may therefore be employed where 
antibiotic therapy with a macrolide is desirable in a participant being treated with everolimus 
2Statins: Atorvastatin OR Pravastatin may be co-administered with everolimus, since a PK interaction 
study has shown that there is no relevant PK interaction. 
 


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Strong inhibitors should not be co-administered with everolimus. Drugs or substances known 
to be inhibitors, inducers or substrates of the isoenzyme CYP3A4 should be avoided unless 
use of the drug is essential and no substitute is available. 
 
The following concomitant treatments are not allowed during the study: 
 Co-administration with strong CYP3A inhibitors (e.g., ketoconazole, itraconazole,  
ritonavir), and strong inducers (e.g., rifampin, rifabutin). 
 Seville oranges, grapefruit, star fruit and their juices affect cytochrome P450 and 
PgP activity. 
 
 Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, 
fluconazole, calcium channel blockers, benzodiazepines) and moderate inducers 
(e.g., carbamazepine, phenobarbital, and phenytoin) should also be avoided if 
possible or otherwise subject to caution (e.g., increased frequency of safety 
monitoring). If a patient requires co-administration of moderate CYP3A4 inhibitors 
or PgP inhibitors, reduce the dose of everolimus by approximately 50%. Additional 
dose reductions to every other day may be required to manage toxicities. If the 
inhibitor is discontinued, the Everolimus dose should be returned to the dose used 
prior to initiation of the moderate CYP3A4/PgP inhibitor after a washout period of 
2 to 3 days. 
 
Everolimus may affect the response to vaccinations making the response to the vaccination, 
less effective. Live vaccines (BCG, varicella, Zoster, typhoid, small pox, rubella, rotavirus, 
measles and mumps) should be avoided while a participant is treated with everolimus.  
 
 
6 
DOSE MODIFICATIONS  
 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 will be used to 
grade adverse events. 
   
Participants enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in Section 7. 
 
Participants will be evaluated for adverse events (all grades), serious adverse events, and adverse 
events requiring study drug interruption or discontinuation at each study visit for the duration of 
their participation in the study.   
 
Participants discontinued from the treatment phase of the study for any reason will be evaluated at 
least 30 days after the last dose of study drug. 
 
6.1 
Treatment-Limiting Adverse Event 
 
 
A treatment-limiting adverse event is any adverse event related to protocol therapy 
experienced during the study resulting in treatment termination.   
 


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6.2 
Dose Modifications  
 
  
For participants who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted. The guidelines set forth in this section should be followed. If 
treatment is interrupted due to toxicity, Everolimus should not be resumed until recovery to 
baseline or ≤ Grade 1, then reintroduce Everolimus at the initial dose or lower dose level 
depending on toxicity type and grade. The maximum allowed time of interruption of 
Everolimus is 4 weeks. 
 
Patients enrolled in Cohort 2 who are unable to tolerate paclitaxel, may continue on protocol 
and receive Everolimus alone. In that instance, the schedule of events will be as per the 
schedule outlined for Cohort 1.  
 


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Table 3: Dose reduction for Everolimus 
Dose Level 
Dose and Schedule 
0 (starting dose) 
10 mg po daily 
Decrease 1 dose level 
5 mg po daily 
Decrease 2 dose levels 
5 mg po every other day 
Note: If a participant has already decreased 2 dose levels, no further dose reduction is 
permitted. Participants requiring a third dose reduction must discontinue everolimus. 
 
 
Table 4: Dose reduction for Paclitaxel 
Dose Level 
Dose and Schedule 
0 (starting dose) 
80 mg/m2 
Decrease 1 dose level 
60 mg/m2 
Note: If a participant has already decreased 1 dose level, no further dose reduction is 
permitted. Participants requiring an additional dose reduction will be required to 
discontinue paclitaxel. 


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Table 5: Dosing guidelines for hematologic toxicities 
AE 
Grade 
Required Dose Reduction 
Thrombocytopenia 
Grade 2 (platelets 
< 75-50 x 109/L) 
Everolimus: 
No action. 
Paclitaxel: 
Hold until improvement to ≥ 75 x109/L. Reintroduce at the same dose 
level. 
Grade 3 (platelets 
< 50-25 x 109/L) 
Everolimus: 
Hold until improvement to grade ≤ 1. 
If resolution occurs ≤ 7 days, reintroduce at the dose level prior to 
interruption. If resolution occurs > 7 days, or event occurs within 4 weeks, 
reintroduce at one dose lower if available. 
Paclitaxel: 
Hold until improvement to ≥ 75 x109/L. 
Reintroduce at the same dose level. 
If significant bleeding is associated, reintroduce at the next lowest dose 
level. 
Grade 4 (platelets 
< 25 x 109/L) 
Everolimus: 
Hold until improvement to grade ≤ 1. 
Reintroduce at the next lowest dose level if available. 
Paclitaxel: 
Hold until improvement to ≥ 75 x109/L. 
Reintroduce at the next lowest dose level. 
Neutropenia or 
anemia 
Grade 3 
(neutrophil <1-
0.5 x109/L) 
 
Everolimus: 
Hold until improvement to grade ≤ 1 or baseline value 
If AE resolution occurs ≤ 7 days, reintroduce at the same dose level. If AE 
occurs > 7 days, or event occurs within 4 weeks, reintroduce at the next 
lowest dose level if available. 
Paclitaxel: 
Hold until improvement to ≥ 1.5 x109/L. 
If improvement occurs ≤ 7 days, reintroduce paclitaxel at the same dose 
level. 
If improvement occurs ≥ 7 days, or event recurs within the same cycle, 
reintroduce at the next lowest dose level. 
Grade 4  
(neutrophil < 0.5 
x109/L) 
Everolimus: 
Hold until improvement to grade ≤ 1 or baseline value. 
Reintroduce at the next lowest dose level if available.* 
Paclitaxel: 
Hold until improvement to grade ≤ 1 or baseline value. 
Reintroduce at the next lowest dose level if available. 
Febrile neutropenia 
 
Everolimus: 
Hold until improvement to grade ≤ 1 (or baseline value) and no fever. 
Reintroduce at the next lowest dose level if available.* 
If febrile neutropenia recurs, discontinue. 
Paclitaxel: 
Hold until improvement to neutrophils to grade ≤ 1  and no fever. 
Reintroduce at the next lowest dose level. 


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Recurrence of 
grade 3 toxicity 
after dose 
reduction 
 
Everolimus: 
Reduce dose to the next lower dose level, if available. The lowest possible 
dose level of Everolimus is 5 mg every other day (2.5 mg daily). Below 
this level Everolimus must be discontinued. 
Paclitaxel: 
Reduce dose to the next lower dose level, if available. 
* Recurrence of 
grade 4 toxicity 
(including febrile 
neutropenia) after 
dose reduction 
 
Everolimus/Paclitaxel: 
Permanently discontinue treatment. 
 
Toxicity requiring 
interruption for > 
4 weeks 
Any 
Everolimus/Paclitaxel: 
Permanently discontinue treatment. 
 
 
 
 
Table 6: Dosing guidelines for non-hematologic toxicities 
 
AE 
Grade 
Required Dose Reduction 
Recommended Management 
Non-infection 
Pneumonitis 
 
 
Please refer to Section 6.3.5 
Reactivation of HBV or 
HCV flare 
 
 
Please refer to Section 6.3.6 
AST or ALT elevation 
 
Grade 1 (> 
ULN – 3.0 x 
ULN) 
 
Grade 2 (> 3.0 
– 5.0 x ULN) 
Everolimus: 
Maintain current dose level 
Paclitaxel: 
Maintain current dose level 
Medical management at  
investigator’s discretion 
AST or ALT elevation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST or ALT elevation 
 
Grade 3 (> 5.0 
– 20.0 x 
ULN)* 
Everolimus: 
Interrupt Everolimus 
administration until resolution to 
grade ≤ 1 (or ≤ grade 2 if 
baseline values were within range 
of grade 2). If resolution occurs ≤ 
7 days, Everolimus should be 
restarted at the dose level prior to 
interruption. If resolution takes > 
7 days, or if event recurs within 4 
weeks, hold Everolimus until 
recovery to grade ≤ 1 or baseline 
value and reintroduce Everolimus 
at one dose level lower, if 
available.  
Paclitaxel: 
Hold Paclitaxel until symptoms 
improve to grade ≤ 1 or baseline 
value. Reintroduce at the next 
lowest dose level if available. 
 
Grade 4 (>20.0 
x ULN)* 
Everolimus: 
Interrupt Everolimus 
administration until resolution to 
grade ≤ 1 (or ≤ grade 2 if 
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of grade 2). If resolution occurs ≤ 
7 days, Everolimus should be 
restarted at the dose level prior to 
interruption. If resolution takes > 
7 days, or if event recurs within 4 
weeks, hold Everolimus until 
recovery to grade ≤ 1 or baseline 
value and reintroduce Everolimus 
at one dose level lower, if 
available.  
Paclitaxel: 
Hold Paclitaxel until symptoms 
improve to grade ≤ 1 or baseline 
value. Reintroduce at the next 
lowest dose level if available. 
Neurotoxicity 
≥ 2 
Everolimus: 
If intolerable to participant, hold 
until improvement to grade ≤ 1. 
Reintroduce Everolimus at the 
same dose level. 
Paclitaxel: 
Hold until improvement to grade 
≤ 1. 
Reintroduce at the next lowest 
dose level. 
Medical management at  
investigator’s discretion 
 
Stomatitis 
 
 
 
 
 
 
2*/3 
*For intolerable grade 2 AE 
Everolimus: 
Hold until improvement to grade 
≤ 1or baseline value. If resolution 
occurs within ≤ 7 days, 
Everolimus should be 
reintroduced at the dose level 
prior to interruption.  If 
resolution takes > 7 days, or if 
event recurs within 4 weeks, hold 
Everolimus until recovery to 
grade ≤ 1 or baseline value and 
reintroduce Everolimus at next 
lowest dose level if available. 
Paclitaxel: 
No action. 
Please refer to section 6.3.2.3 
 
Medical management at 
investigator’s discretion 
and as per protocol 
suggestions 
 
Patients will be withdrawn from 
study if they fail to recover to grade 
≤ 1 or baseline within 4 weeks. 
 
Recurrence of 
intolerable 
grade 2 or 
grade 3 event 
after dose 
reduction 
Everolimus: 
Reduce dose to next lower dose 
level, if available. The lowest 
possible dose level of Everolimus 
is 2.5 mg daily. Below this level, 
Everolimus must be 
discontinued. If toxicity recurs at 
Grade 3, consider discontinuation 
4 
Everolimus: 
Discontinue treatment. 
Paclitaxel: 
No action. 
Other toxicities 
(except specific 
3 
Everolimus: 
Hold until improvement to grade 
Medical management at 
investigator’s discretion 


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AEs above and 
hyperglycemia or 
hypertriglyceridemia or 
hypercholesterolemia 
(see Section 6.3.4) 
 
≤ 1 or baseline value. If 
resolution occurs within ≤ 7 days, 
Everolimus should b 
reintroduced at the dose level 
prior to interruption. If resolution 
takes > 7 days, or if AE recurs 
within 4 weeks, hold Everolimus 
until recovery to grade ≤ 1 or 
baseline value and reintroduce 
Everolimus at the next lowest 
dose level if available. 
Paclitaxel: 
Hold Paclitaxel until symptoms 
improve to grade ≤ 1 or baseline 
value. 
Reintroduce at the next lowest 
dose level if available. 
and as per protocol 
suggestions 
 
Patients will be withdrawn from 
study if they fail to recover to grade 
≤ 1 or baseline within 4 weeks. 
Any other non-
hematologic toxicity 
4 
Everolimus: 
Hold until improvement to grade 
≤ 1 or baseline value. 
Reintroduce at the next lowest 
dose level if available. 
Paclitaxel: 
Hold Paclitaxel until symptoms 
improve to grade ≤ 1 or baseline 
value. 
Reintroduce at the next lowest 
dose level if available. 
 
Any non-hematologic 
toxicity recurrence after 
dose reduction 
4 
Everolimus/Paclitaxel: 
Permanently discontinue 
treatment. 
Medical management at 
investigator’s discretion 
 
Clinical liver failure 
(asterixis or 
encephalopathy/coma) 
3 / 4 
Everolimus/Paclitaxel: 
Permanently discontinue 
treatment. 
Medical management at 
investigator’s discretion 
Any non-hematologic 
toxicity requiring 
interruption for 
> 4 weeks 
 
 
Everolimus/Paclitaxel: 
Permanently discontinue 
treatment. 
 
Medical management at 
investigator’s discretion 
 
* Should HCV flare be confirmed, the guidelines for flare must take precedence (see Section 6.3.6) 
 
6.3 
Management of Specific Everolimus related toxicities 
Overall, safety data available from completed, controlled and uncontrolled studies indicate 
that Everolimus is generally well tolerated at weekly or daily dose schedules. The safety 
profile is characterized by manageable adverse events (AEs). These AEs are generally 
reversible and non-cumulative. 
Adverse events most frequently observed with Everolimus are stomatitis, rash, diarrhea, 
fatigue, infections, asthenia, nausea, peripheral edema, decreased appetite, headache, 
dysgeusia, epistaxis, mucosal inflammation, pneumonitis, weight decreased, vomiting, 
pruritus, cough, dyspnea, dry skin, nail disorder, and pyrexia. Overall, the most frequently 
observed laboratory abnormalities include decreased hematology parameters including 
hemoglobin, lymphocytes, platelets, and neutrophils (or collectively as pancytopenia); 


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increased clinical chemistry parameters including cholesterol, triglycerides, glucose, 
aspartate transaminases,creatinine, alanine transaminases, and bilirubin; and decreased 
clinical chemistry parameters including phosphate and potassium. The majority of these AEs 
have been of mild to moderate severity (NCI CTC grade 1-2).  
 
6.3.1 Management of infections 
 
Everolimus has immunosuppressive properties and may predispose patients to bacterial, 
fungal, viral or protozoal infections, including infections with opportunistic pathogens. 
Localized and systemic infections, including pneumonia, other bacterial infections, 
invasive fungal infections, such as aspergillosis or candidiasis and viral infections 
including reactivation of hepatitis B virus, have been described in patients taking 
Everolimus Some of these infections have been severe (e.g. leading to respiratory or 
hepatic failure) and occasionally have had a fatal outcome. 
 
Physicians and patients should be aware of the increased risk of infection with Everolimus 
Treat pre-existing infections prior to starting treatment with Everolimus. While taking 
Everolimus, be vigilant for symptoms and signs of infection; if a diagnosis of infection is 
made, institute appropriate treatment promptly and consider interruption or discontinuation 
of Everolimus. 
 
If a diagnosis of invasive systemic fungal infection is made, discontinue Everolimus and 
treat with appropriate antifungal therapy. 
 
6.3.2 Management of skin toxicity 
 
For patients with grade 1 toxicity, no specific supportive care is usually needed or 
indicated. Rash must be reported as an AE. Patients with grade 2 or higher toxicity may be 
treated with the following suggested supportive measures at the discretion of the 
investigator: oral minocycline, topical tetracycline, topical clindamycin, topical silver 
sulfadiazine, diphenhydramine, oral prednisolone (short course), topical corticosteroids, or 
pimecrolimus. 
 
 
6.3.2.1 
Hypersensitivity reactions 
Hypersensitivity reactions manifested by symptoms including, but not limited to, 
anaphylaxis, dyspnea, flushing, chest pain or angioedema (e.g. swelling of the airways or 
tongue, with or without respiratory impairment) have been observed with everolimus. 
 
6.3.2.2 
Renal Failure Events 
Cases of renal failure (including acute renal failure), some with fatal outcome, occurred in 
patients treated with everolimus. Renal function of patients should be monitored 


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particularly where patients have additional risk factors that may further impair renal 
function. 
Elevations of serum creatinine, usually mild, and proteinuria have been reported in patients 
taking everolimus. Monitoring of renal function, including measurement of blood urea 
nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of 
everolimus therapy and periodically thereafter. 
 
6.3.2.3 Management of stomatitis/oral mucositis/mouth ulcers 
Adverse Drug Reaction 
Severity 
Everolimus 
Dose 
Adjustment 
and 
Management 
Recommendations 
Stomatitis 
Grade 1 
(Minimal 
symptoms, 
normal diet) 
No dose adjustment required.  
Manage with non-alcoholic or salt water (0.9%) mouth 
wash several times a day. 
 
Grade 2 
(Symptomatic 
but can eat and 
swallow 
modified diet) 
Temporary dose interruption until recovery to grade ≤1.  
Re-initiate study drug at the same dose. 
If stomatitis recurs at grade 2, interrupt dose until recovery 
to grade ≤1. Re-initiate study drug at a lower dose. 
Manage with topical analgesic mouth treatments (e.g. 
benzocaine,butyl aminobenzoate, tetracaine hydrocholoride, 
menthol or phenol)with or without topical corticosteroids 
(i.e. triamcinolone oral paste)*. 
 
Grade 3 
(Symptomatic 
and unable to 
adequately 
eat 
or 
hydrate 
orally) 
Temporary dose interruption until recovery to grade ≤1.  
Re-initiate study drug at lower dose. 
Manage with topical analgesic mouth treatments (i.e. 
benzocaine,butyl aminobenzoate, tetracaine hydrocholoride, 
menthol or phenol) with or without topical corticosteroids 
(i.e. triamcinolone oral paste)* 
 
Grade 4 
(Symptoms 
associated with 
life-threatening 
consequences) 
Discontinue study drug and treat with appropriate medical 
therapy. 
* using agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives in management of stomatitis as they may 
worsen mouth ulcers. 
Patients with a clinical history of stomatitis/mucositis/mouth ulcers and those with 
gastrointestinal morbidity associated with mouth/dental infections, irritation of esophageal 
mucosa e.g. gastroesophageal reflux disease (GERD) and pre-existing stomatitis/mucositis 
must be monitored even more closely. Patients should be instructed to report the first onset 
of buccal mucosa irritation/reddening to their study physician immediately. 
 
Stomatitis/oral mucositis/mouth ulcers due to Everolimus should be treated using local 
supportive care. Please note that investigators in earlier trials have described the oral 
toxicities associated with Everolimus as mouth ulcers, rather than mucositis or stomatitis. 
If your examination reveals mouth ulcers rather than a more general inflammation of the 
mouth, please classify the adverse event as such. Please follow the paradigm below for 
treatment of stomatitis/oral mucositis/mouth ulcers:  


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1. 
For mild toxicity (Grade 1), no dose adjustment required. Manage with non-
alcoholic mouth wash or salt water (0.9%) mouth wash several times a day until 
resolution. 
 
2. 
For more severe toxicity (Grade 2 in which case participants have pain but are able to 
maintain adequate oral alimentation, or Grade 3 in which case participants cannot 
maintain adequate oral alimentation), the suggested treatments are topical analgesic 
mouth 
treatments 
(i.e., 
local 
anesthetics 
such 
as 
benzocaine, 
butyl 
aminobenzoate, tetracaine hydrochloride, menthol, or phenol) with or without 
topical corticosteroids, such as triamcinolone oral paste 0.1% (Kenalog in 
Orabase®). 
 
3. 
Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to 
worsen mouth ulcers. It is preferable to avoid these agents.  
 
4.  
Antifungal agents should be avoided unless a fungal infection is diagnosed. In 
particular, systemic imidazole antifungal agents (ketoconazole, fluconazole, 
itraconazole, etc.) should be avoided in all participants due to their strong inhibition 
of Everolimus metabolism, thereby leading to higher Everolimus exposures. 
Therefore, topical antifungal agents are preferred if an infection is diagnosed.  
 
6.3.3 Management of diarrhea  
Appearance of grade 1-2 diarrhea attributed to study drug toxicity may be treated with 
loperamide, initiated at the earliest onset (for example 4 mg orally followed by 2 mg orally 
every 2 hours until resolution of diarrhea). 
 
6.3.4 Management of hyperlipidemia and hyperglycemia 
 
Adverse Drug Reaction 
Severity 
Everolimus Dose Adjustment and Management 
Recommendations 
Metabolic events 
(e.g. 
hyperglycemia, 
dyslipidemia) 
Grade 1 
No dose adjustment required. 
Initiate appropriate medical therapy and monitor. 
 
Grade 2 
No dose adjustment required. 
Manage with appropriate medical therapy and monitor. 
 
Grade 3 
Temporary dose interruption. 
Re-initiate study drug at lower dose. 
Manage with appropriate medical therapy and monitor. 
 
Grade 4 
Discontinue study drug and treat with appropriate 
medical therapy. 
 
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary 
habits of the patient. Grade 2 or higher hypercholesterolemia (> 300 mg/dL or 7.75 
mmol/L) or Grade 2 hypertriglyceridemia (>2.5 x ULN) should be treated with a 3-


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hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitor (e.g., atorvastatin, pravastatin, 
fluvastatin) or appropriate triglyceride-lowering medication, in addition to diet.  
 
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is 
associated with an increased risk of a rare but serious skeletal muscle toxicity manifested 
by rhabdomyolysis, markedly elevated creatine kinase (CPK) levels and myoglobinuria, 
acute renal failure and sometimes death.  
 
Participants should be monitored clinically and through serum biochemistry for the 
development of rhabdomyolysis and other adverse events as required in the product 
label/data sheets for HMG-CoA reductase inhibitors. The risk versus benefit of using this 
therapy should be determined for individual participants based on their risk of 
cardiovascular complications of hyperlipidemia. 
 
Dyslipidemia (including hypercholesterolemia and hypertriglyceridemia) has been reported 
in patients taking everolimus.  Monitoring of blood cholesterol and triglycerides prior to 
the start of everolimus therapy and periodically thereafter as well as management with 
appropriate medical therapy is recommended. 
 
 
Hyperglycemia has been observed in participants receiving everolimus therapy. 
Monitoring of fasting serum glucose is recommended prior to the start of Everolimus and 
periodically thereafter. More frequent monitoring is recommended when everolimus is co-
administered with other drugs that may induce hyperglycemia. Optimal glucose control 
should be achieved before starting a participant on everolimus and glucose should be 
monitored during everolimus therapy.  
 
6.3.5 Management of non-infectious pneumonitis  
 
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-
infectious pneumonitis (including interstitial lung disease) have also been described in 
patients taking Everolimus. Some of these have been severe and on rare occasions, a fatal 
outcome was observed. 
 A diagnosis of non-infectious pneumonitis should be considered in patients presenting 
with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, 
cough or dyspnea, and in whom infectious, neoplastic and other non-medicinal causes 
have been excluded by means of appropriate investigations. Patients should be advised 
to report promptly any new or worsening respiratory symptoms. 
 
If non-infectious pneumonitis develops, the guidelines in the Table below should be 
followed. Consultation with a pulmonologist is recommended for any case of pneumonitis 
that develops during the study. 
 


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Table 7: Management of non-infectious pneumonitis 
Worst grade 
pneumonitis 
Required investigations 
Management 
Everolimus dose 
adjustment 
Grade 1 
(Asymptomatic, 
radiographic 
findings only) 
CT scans with lung 
windows. Repeat at least 
every 3 cycles until return 
to within normal limits. 
No specific therapy is 
required. 
Administer 100% of 
everolimus dose. Initiate 
appropriate monitoring. 
Grade 2 
(Symptomatic, not 
interfering with 
Activities of Daily 
Living) 
CT scan with lung 
windows. Consider 
pulmonary function testing 
including: spirometry, 
DLCO and room air 02 
saturation at rest. Consider 
bronchoscopy*. Repeat 
each subsequent cycle until 
return to ≤ grade 1.  Return 
to initial monitoring 
frequency if no recurrence. 
Symptomatic only. 
Consider corticosteroids 
and/or other supportive 
therapy if symptoms are 
troublesome. 
Rule out infection and 
consider interruption of 
Everolimus until recovery 
to Grade ≤ 1. Re-initiate 
Everolimus at one dose 
level lower. Participants 
will be withdrawn from 
study if they fail to recover 
to ≤ Grade 1 within 4 
weeks. Everolimus dose 
cannot be escalated. 
Grade 3 
(Symptomatic, 
Interfering with 
Activities of Daily 
Living. 
O2 indicated 
CT scan with lung 
windows and pulmonary 
function testing including: 
spirometry, DLCO and 
room air 02 saturation at 
rest. Repeat each 
subsequent cycle until 
return to ≤ grade 1. Return 
to initial monitoring 
frequency if no recurrence. 
Bronchoscopy is 
recommended*. 
Prescribe corticosteroids if 
infectious etiology is ruled 
out. Taper as medically 
indicated. 
Rule out infection and hold 
treatment until recovery to 
Grade ≤ 1. Consider re-
initiating Everolimus at 
one dose level lower 
(approximately 50% lower 
than the dose previously 
administered depending on 
individual clinical 
circumstances). 
Discontinue Everolimus if 
failure to recover within ≤ 
4 weeks. If toxicity recurs at 
Grade 3, consider 
discontinuation 
Grade 4 
(Life-threatening, 
ventlatory support 
indicated) 
CT scan with lung 
windows and required 
pulmonary function 
testing, if possible, 
including: spirometry, 
DLCO and room air O2 
saturation at rest. Repeat 
each subsequent cycle until 
return to ≤ grade 1. Return 
to initial monitoring 
frequency if no recurrence. 
Bronchoscopy with biopsy 
and/or BAL is 
recommended if possible*. 
Consider corticosteroids if 
infectious etiology is ruled 
out. Taper as medically 
indicated. 
 
Rule out infection and 
discontinue treatment. 
*If bronchoscopy is performed, a biopsy and/or  bronchiolar lavage (BAL) should be performed. 
 


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6.3.6 Management of Hepatitis reactivation/ flare 
Reactivation of Hepatitis B (HBV) has been observed in patients with cancer receiving 
chemotherapy (Yeo 2004). Sporadic cases of Hepatitis B reactivation have also been seen 
in this setting with Everolimus. Use of antivirals during anti-cancer therapy has been 
shown to reduce the risk of Hepatitis B virus reactivation and associated morbidity and 
mortality (Loomba 2008). A detailed assessment of Hepatitis B/C medical history and risk 
factors must be done for all patients at screening, with testing performed prior to the first 
dose of everolimus.  
 
6.3.6.1 Monitoring and prophylactic treatment for hepatitis B reactivation 
 
Details of monitoring and prophylactic therapy according to the screening results of viral 
load and serologic markers testing. 
 
Table 8: Action to be taken based on screening hepatitis B results 
Test 
Result 
Result 
Result 
Result 
Result 
HBV-DNA 
+ 
+ or - 
- 
- 
- 
HBsAg 
+ or - 
+ 
- 
- 
- 
HBs Ab 
+ or - 
+ or - 
+ 
and no prior HBV 
vaccination 
+ or - 
- 
or + with prior 
HBV 
vaccination 
HBc Ab 
+ or - 
+ or - 
+ or - 
+ 
- 
Recommendation 
Prophylaxis treatment should be 
started 1-2 weeks prior to first dose 
of  study drug 
Monitor HBV-DNA approximately 
every 4-8 weeks 
 
No prophylaxis 
Monitor 
HBV-DNA 
approximately every 3-4 weeks 
 
No 
specific 
action 
 
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of study 
drug.    For HBV reactivation definition and management guidelines, see Table 9. 
 


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Table 9:  Guidelines for management of hepatitis B reactivation 
HBV reactivation  (with or without clinical signs and symptoms)* 
For 
participants 
with 
baseline results:  
Positive HBV-DNA 
OR 
positive HBsAg 
-------------------------------------- 
reactivation is defined as:   
[Increase of 1 log in HBV-
DNA 
relative 
to 
baseline 
HBV-DNA value OR new 
appearance 
of 
measurable 
HBV-DNA] 
 
Treat: Start a second antiviral medication 
AND 
Interrupt study drug administration until resolution:  
• 
 ≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days study drug should be re-
started at one dose lower, if available.  (see Table 3 & 4 – Study 
drug dose reductions) If the participant is already receiving the 
lowest dose of study drug according to the protocol, the participant 
should restart at the same dose after resolution. Both antiviral 
therapies should continue at least 4 weeks after last dose of study 
drug.  
If resolution occurs > 28 days Participants should discontinue 
study drug but continue both antiviral therapies at least 4 weeks 
after last dose of study drug. 
For 
participants 
with 
baseline 
results:  
Negative 
HBV-DNA 
and 
HBsAg  
AND  
[Positive HBs Ab (with no 
prior history of vaccination 
against HBV), OR positive 
HBc Ab]  
------------------------------------- 
reactivation is defined as: 
New appearance of measurable 
HBV-DNA 
Treat : Start first antiviral medication  
AND 
Interrupt study drug administration until resolution:  
 
  ≤ undetectable (negative) HBV-DNA levels 
If resolution occurs within ≤ 28 days study drug should be re-
started at one dose lower, if available. (see Table 3 & 4  – Study 
drug dose reductions) If the participant is already receiving the 
lowest dose of study drug according to the protocol, the participant 
should restart at the same dose after resolution. Antiviral therapy 
should continue at least 4 weeks after last dose of study drug.  
If resolution occurs > 28 days Participants should discontinue 
study drug but continue antiviral therapy at least 4 weeks after last 
dose of study drug. 
* All reactivations of HBV are to be recorded as grade 3 (CTCAE v 4.0 Metabolic 
Laboratory/Other: Viral Re-activation), unless considered life threatening by the investigator; in 
which case they should be recorded as grade 4 (CTCAE v 4.0 Metabolic Laboratory/Other: Viral 
Re-activation). Date of viral reactivation is the date on which the rise or reappearance of HBV-
DNA was recorded. 
 
6.3.6.2 Monitoring for hepatitis C flare 
 
The following two categories of participants should be monitored every 4–8 weeks for 
HCV reactivation: 
 
 Participants with detectable HCV RNA-PCR test at screening. 
 Participants known to have a history of HCV infection, despite a negative viral load 
test at screening (including those that were treated and are considered ‘cured’) 
 
For definitions of HCV flare and actions to be taken in the event of a flare, please refer to 
Table 10. 


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Table 10: Guidelines for management of hepatitis C flare* 
Baseline results 
HCV flare definition* 
HCV flare management 
Detectable HCV-RNA 
 
> 2 log10 IU/mL increase in HCV-RNA 
AND 
ALT elevation > 5 x ULN or 3 x baseline 
level, whichever is higher. 
Discontinue Everolimus 
Knowledge of past hepatitis C 
infection 
with 
no 
detectable 
HCV-RNA 
New appearance of detectable HCV-RNA 
AND 
ALT elevation > 5 x ULN or 3 x baseline 
level, whichever is higher. 
Discontinue Everolimus 
* All flares of HCV are to be recorded as grade 3 (e.g. CTCAE Version 4.0 – Metabolic/Laboratory- Other: Viral 
Flare), unless considered life threatening by the investigator; in which case they should be recorded as grade 4. 
Date of viral flare is the date on which both the clinical criteria described above were met. (e.g., for a patient 
whose HCV-RNA increased by 2 logs on 01 JAN 2011 and whose ALT reached > 5 x ULN on 22 JAN 2011, the 
date of viral flare is 22 JAN 2011). 
 
6.3.7 Management of anemia 
 
Investigator should manage anemia as medically indicated per institutional guidelines. 
 
 
 
 


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7 
STUDY CALENDAR & EVALUATIONS 
 
Study Day 
Pre-study 
Cycles 
(1 cycle = 28 days) 
End of 
treatment 
visit 
Follow 
up12 
-30 days 
-7 days 
Day 
15 
Day 
8 
Day 
15 
30 days    
(± 7) after 
last 
treatment 
 
REQUIRED ASSESSMENTS 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
Physical examination 
X 
 
X 
 
 
X 
 
Vital signs, weight 
X 
 
X 
 
 
X 
 
Karnofsky performance status 
X 
 
X 
 
 
X 
 
Charlson comorbidty score 
X 
 
 
 
 
 
 
Calculated Creatinine Clearance 
(Cokcroft-Gault) 
X 
X 
X 
 
 
X 
 
PTT and INR 
 
X 
 
 
 
 
 
Blood Chemistries1 
 
X 
X 
 
 
X 
 
Cohort 2: Creatinine 
 
 
 
X 
X 
 
 
Cohort 1: WBC, Hgb, Plts 
 
X 
X 
 
 
X 
 
Cohort 2: WBC, Hgb, Plts 
 
X 
X 
X 
X 
X 
 
Fasting serum glucose 
 
X 
 
 
 
 
 
Lipid profile (fasting) 
 
X 
X2 
 
 
X 
 
Hepatitis B and C testing 
X3 
 
 
 
 
 
 
Urine pregnancy 
 
X 
 
 
 
 
 
Adverse event and concomitant 
medication assessment 
X 
 
X 
 
 
X 
 
DISEASE ASSESSMENT 
 
 
 
 
 
 
 
CT chest , abdomen, pelvis 
X 
 
X4 
 
 
 
X 
Bone scan 
X5 
 
X5 
 
 
 
 
CT scan or Brain MRI 
X6 
 
 
 
 
 
 
TREATMENT 
 
 
 
 
 
 
 
Everolimus7 
 
 
X 
X 
X 
 
 
Cohort 2 only: Paclitaxel 
 
 
X 
X 
X 
 
 
CORRELATIVE STUDIES 
 
 
 
 
 
 
 
Archived tumor block 
submission8  
 
 
X 
 
 
 
 
 
Tumor slide submission9 
 
 
X 
 
 
 
 
Optional whole blood10 
 
 
X 
 
 
 
 
Optional plasma and serum 11 
 
 
X 
 
 
X 
 
FOLLOW-UP 
 
 
 
 
 
 
 
Disease progression and survival 
 
 
 
 
 
 
X 
 
See Next Page for Study Calendar & Evaluations Footnotes. 


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Study Calendar & Evaluations Footnotes: 
1. Comprehensive metabolic panel (sodium, potassium, BUN, creatinine, AST, ALT, Alk.phos, total bilirubin, magnesium, calcium, and phosphorus) on day 1 
of each cycle.  
2. A lipid panel should be checked every other month after baseline. 
3. Please refer to section 6.3.6 for testing parameters. 
4. Participants will undergo repeat cross-sectional imaging (CT scan of the chest, abdomen, and pelvis) after every 2 cycles until disease progression. 
5. Bone scan should be done at baseline only if clinically indicated (elevated alkaline phosphatase, bone pain), and repeated every 2 cycles if clinically indicated  
6. Participants with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis. 
7. Participants will receive Everolimus 10 mg PO daily continuously (in the absence of a dose delay or dose reduction for toxicity).  
8. Submission of an archived paraffin embedded tumor block for COXEN analysis.  If the previous biopsy is not available, a discussion needs to take place with 
the Sponsor Investigator ,participants will not need to undergo a new biopsy. See SPM for collection and shipping instructions.  
9. Submission of unstained tumor slides for Immunohistochemical staining and for banking for future use from the participant‘s previous biopsy are requested. If 
the previous biopsy is not available, a discussion needs to take place with the Sponsor Investigator, participants will not need to undergo a new biopsy.  See 
SPM for collection and shipping instructions.   
10. Optional whole blood for banking for future use is requested at Cycle 1 Day 1, pretreatment. See SPM for collection and shipping instructions.   
11. Optional serum and plasma are requested at Cycle 1 Day 1 (pretreatment), Cycle 2 Day1 (pretreatment) and at time of progression. See SPM for collection, 
processing and shipping instructions. 
12. All participants who receive study drug will be followed for disease progression and survival every three months for 2 years from registration for protocol 
therapy, every 6 months for years 3 - 5, and annually thereafter. For survival outcomes, telephone communication is acceptable after participants have been 
followed and treatment related toxicities have resolved or returned to baseline and/or participants have initiated a subsequent therapy. 
 


 
 
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7.1 
Baseline/Screening 
  
7.1.1 Within 30 days prior to registration for protocol therapy: 
 
 
Complete medical history  
 
Complete physical examination (including vital signs, height, body weight) 
 
Karnofsky Performance Status   
 
Charlson comorbidity score (see Appendix A) 
 
Calculated creatinine clearance (Cockroft-Gault equation) 
 
Adverse event and concomitant medication assessment 
 
CT scan or brain MRI to exclude brain metastasis, only in participants with 
neurological symptoms. 
 
Radiological assessment of tumors with a CT scan of the chest, abdomen, and pelvis 
 
Bone scan, if clinically indicated (elevated alkaline phosphatase, bone pain) 
 
Hepatitis B testing - 
The following three categories of participants should be tested for hepatitis B viral 
load and serologic markers, that is, HBV-DNA, HBsAg, HBs Ab, and HBc Ab:   
1. All participants who currently live in (or have lived in) Asia, Africa, Central and 
South America, Eastern Europe, Spain, Portugal, and Greece.  
[http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-2/hepatitis-b.aspx#849] 
2. Participants with any of the following risk factors:  
o known or suspected past hepatitis B infection,  
o blood transfusion(s) prior to 1990,  
o current or prior IV drug users,  
o current or prior dialysis,  
o household contact with hepatitis B infected participant(s),  
o current or prior high-risk sexual activity,  
o body piercing or tattoos,  
o mother known to have hepatitis B 
o history suggestive of hepatitis B infection, e.g., dark urine, jaundice, right 
upper quadrant pain. 
3.  Additional participants at the discretion of the investigator  
NOTE: The management guidelines, in Section 6.3.6.1, are provided according 
to the results of the baseline assessment of viral load and serological markers for 
hepatitis B. 
 Hepatitis C testing - 
Participants with any of the following risk factors for hepatitis C should be tested using 
quantitative RNA-PCR 
o known or suspected past hepatitis C infection (including participants with past 
interferon ‘curative’ treatment),  
o blood transfusions prior to 1990,  
o current or prior IV drug users,  
o current or prior dialysis,  
o Immediate household contact of hepatitis C infected participant(s),  


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o current or prior high-risk sexual activity,  
o body piercing or tattoos,  
o At the discretion of the investigator, additional participants may also be tested 
for hepatitis C.   
NOTE: The management guidelines, in Section 6.3.6.2, are provided according 
to the results of the baseline assessment of hepatitis C viral load. 
 
7.1.2 Within 7 days of registration for protocol therapy: 
 
 Complete blood count (CBC) with differential and platelet count 
 Comprehensive metabolic panel (sodium, potassium, BUN, creatinine, AST, ALT, 
Alk.phos, total bilirubin, magnesium, calcium, and phosphorus) 
 Lipid profile (fasting)   
 Calculated creatinine clearance (Cockroft-Gault equation) 
 PTT and INR 
 Fasting serum glucose 
 Urine pregnancy test for women of childbearing potential 
 
7.1.3 Pregnancy and assessment of fertility: 
 
Women of childbearing potential (WOCBP), defined as all women physiologically capable 
of becoming pregnant), and males of childbearing potential and their sexual partner(s) who 
are WOCBP must use highly effective contraception during the study and for 8 weeks after 
stopping treatment. Highly effective contraception is defined as either: 
 Total abstinence: When this is in line with the preferred and usual lifestyle of the 
subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception] 
 Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) 
or tubal ligation at least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment 
 Male partner sterilization (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). [For female subjects on the study, the vasectomised 
male partner should be the sole partner for that subject]. 
 Use of a combination of any two of the following (a+b or a+c or b+c): 
o Use of oral, injected, implanted or other hormonal methods of contraception 
o Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
o Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/vaginal 
suppository 
 
In case of use of oral contraception, women should have been stable on the oral agent 
before taking study treatment. 
 
Sexually active males must use a condom during intercourse while taking the drug and for 
8 weeks after stopping treatment and should not father a child in this period. 


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A condom is required to be used also by vasectomised men in order to prevent delivery of 
the drug via seminal fluid. 
 
Female partners of male patients must also be advised to use one of the following 
contraception methods: Use of (1) oral, injected, implanted or other hormonal methods of 
contraception, or (2) intrauterine device (IUD) or intrauterine system (IUS), or (3) prior 
male/female sterilization. 
 
7.2 
On Treatment 
 
7.2.1 Day 1 of each cycle (within 3 days prior): 
NOTE: Cycle 1 Day 1 testing need not be repeated if completed within 7 days of starting 
protocol therapy. 
 
 Physical examination, including vital signs and body weight 
 Karnofsky Performance Status  
 CBC with differential and platelet count  
 Comprehensive metabolic panel (sodium, potassium, BUN, creatinine, AST, ALT, 
Alk.phos, total bilirubin, magnesium, calcium, and phosphorus) 
 Calculated creatinine clearance (Cockroft-Gault equation). 
 Lipid profile (fasting)  
 Adverse event and concomitant medication assessment 
 Everolimus administration – cohort 1 
 Everolimus and Paclitaxel administration – cohort 2. CBC and creatinine will be 
performed prior to each dose of paclitaxel.  
 
7.2.2 Correlative sample submissions:  
 
 Submission of an archived paraffin embedded tumor block for COXEN analysis.  If the 
previous biopsy is not available, a discussion needs to take place with the Sponsor  
Investigator, participants will not need to undergo a new biopsy. See SPM for 
collection and shipping instructions.  
 Submission of unstained tumor slides for Immunohistochemical staining and for 
banking for future use from the participant‘s previous biopsy are requested. If the 
previous biopsy is not available, a discussion needs to take place with the Sponsor 
Investigator, participants will not need to undergo a new biopsy. See SPM for 
collection and shipping instructions.   
 Optional whole blood for banking for future use is requested at Cycle 1 Day 1, 
pretreatment. See SPM for collection and shipping instructions.   
 Optional serum and plasma are requested at Cycle 1 Day 1 (pretreatment), Cycle 2 
Day1 (pretreatment) and at time of progression. See SPM for collection, processing 
and shipping instructions. 
 


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7.2.3 Radiological Assessments: 
 
Participants will undergo repeat cross-sectional imaging (CT scan of the chest, abdomen, 
and pelvis) after every 2 cycles (eg, after cycle 2, after cycle 4) until disease progression. 
Bone scans will be repeated at these intervals if clinically indicated. 
 
7.3 
Treatment Discontinuation 
 
A participant will be discontinued from the treatment under the following circumstances: 
 
 If there is evidence of progressive disease by RECIST criteria.  
 If the attending physician thinks a change of therapy would be in the best interest of the 
participant. 
 If the participant requests discontinuation. 
 If the drug(s) exhibit(s) unacceptable adverse event. 
 If a participant becomes pregnant. 
 Treatment interruption for greater than 4 weeks due to treatment related adverse event 
or any other reasons.  
 Participants can stop participating at any time. However, if they decide to stop 
participating in the study, participants will continue to be followed for disease 
progression and survival as indicated in the schedule of events table (if haven’t 
withdrawn consent).  
 
7.4 
End of Treatment Evaluations: 30 days (±7 days) post last therapy 
 
This is a single assessment that will be performed when participant goes off treatment 
because of 1) progressive disease or 2) toxicity, or 3) in cases of physician decision or 
where 4) participant withdraws consent. Participants who withdraw consent should be 
encouraged to have the end of treatment evaluations done. 
 
All participants, including those who discontinue protocol therapy early, should be 
evaluated approximately 30 days after their last dose according to the end of treatment 
evaluations.  Every effort should be made to complete these assessments as close to 30 days 
after the last dose as possible.   
 
The following evaluations will be performed following the last treatment: 
 
 Physical examination, including vital signs and body weight 
 Karnofsky Performance Status  
 CBC with differential and platelet count 
 Comprehensive metabolic panel (sodium, potassium, BUN, creatinine, AST, ALT, 
Alk.phos, total bilitubin, magnesium, calcium, and phosphorus) prior to dosing on day 
1 of each cycle. 
 Lipid profile (fasting)  
 Calculated creatinine clearance (Cockroft-Gault equation) 


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 Adverse event and concomitant medication assessment 
 Radiological assessments of tumors with a CT scan of the chest, abdomen, and pelvis, 
if not done within the last 6 weeks. 
 Bone scan, if clinically indicated, and not done within the last 6 weeks. 
 
7.5 
Follow-Up 
 
All participants who receive study drug will be followed for disease progression and 
survival every 3 months for 2 years from registration for protocol therapy, every 6 months 
for years 3 - 5, and annually thereafter. For survival outcomes, telephone communication is 
acceptable after participants have been followed and treatment related toxicities have 
resolved or returned to baseline and/or participants have initiated a subsequent therapy. 
 
8 
CRITERIA FOR DISEASE EVALUATION 
 
8.1 
Definitions Associated with Response Evaluation Criteria in Solid Tumors (RECIST)  
 
8.1.1 Measurable disease - the presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology.  
 
8.1.2 Measurable lesions - lesions that can be accurately measured in at least one dimension with 
longest diameter (LD) >20 mm using conventional techniques or >10 mm with spiral CT 
scan. 
 
8.1.3 Non-measurable lesions - all other lesions, including small lesions (longest diameter <20 
mm with conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, cystic lesions, and also abdominal masses that are not 
confirmed and followed by imaging techniques. 
 
8.1.4 Baseline documentation of “Target” and “Non-Target” lesions - all measurable lesions up 
to a maximum of five lesions per organ and 10 lesions in total, representative of all 
involved organs should be identified as target lesions and recorded and measured at 
baseline. Target lesions should be selected on the basis of their LD. The baseline sum LD 
will be used as reference by which to characterize the objective tumor.  All other lesions 
(or sites of disease) should be identified as non-target lesions and should also be recorded 
at baseline. Measurements of these lesions are not required, but the presence or absence of 
each should be noted throughout follow-up.  
 
8.2 
Response Criteria for Target Lesions 
 
 
Table 11:  
Response 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions 
Partial Response (PR) 
At least a 30% decrease in the sum of the LD of target 


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lesions, taking as reference the baseline sum LD 
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 
Progressive Disease (PD) 
At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded 
since the treatment started or the appearance of one or more 
new lesions 
 
8.3 
Response Criteria for Non-Target Lesions 
 
Table 12:  
Response 
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(1) 
                                     
  
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 later on by the review panel (or the Sponsor Investigator). 
 
8.4 
Evaluation of best overall response 
 
The objective response rate is the proportion of all participants with confirmed PR or CR 
according to RECIST, from the start of treatment until disease progression/recurrence 
(taking as reference for progressive disease the smallest measurements recorded since the 
start of treatment). 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). In general, the participant's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
 
Table 13: Evaluation of best overall response 
Target Lesions 
Non-Target lesion 
New Lesion 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete Response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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Participants 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 Definitions Associated with Response Evaluation Criteria in Solid Tumors 
(RECIST) 
 
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) to 
confirm the complete response status. 
 
8.5 
Definitions for Response Evaluation 
 
8.5.1 First Documentation of Response - The time between initiation of therapy and first 
documentation of PR or CR. 
 
8.5.2 Confirmation of Response - To be assigned a status of complete or partial response, 
changes in tumor measurements must be confirmed by repeat assessments performed no 
less than four weeks after the criteria for response are first met. 
 
8.6 
Endpoint Definitions 
 
8.6.1 Progression Free Survival (PFS) - The length of time during and after treatment in, which a 
participant is living with a disease that does not get worse. It is the time between the 
initiation of therapy and documented date of progression or death. 
   
8.6.2 Clinical Benefit rate - It is the percentage of participants with documentation of complete 
response, partial response or stable disease after initiation of treatment. 
 
8.7 
Methods of Measurement 
 
Imaging based evaluation is preferred to evaluation by clinical examination.  The same 
imaging modality must be used throughout the study to measure disease. 
 
8.7.1 CT and MRI 
 
CT and MRI are the best currently available and most reproducible methods for measuring 
target lesions.  Conventional CT and MRI should be performed with contiguous cuts of 
10mm or less in slice thickness.  Spiral CT should be performed by use of a 5mm 
contiguous reconstruction algorithm.  This specification applies to tumors of the chest, 
abdomen, and pelvis, while head and neck tumors and those of the extremities require 
specific procedures. 
 
8.7.2 Chest X-Ray 
 


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Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by an aerated lung (CT is preferable).   
 
8.7.3 Clinical Examination 
 
Clinically detected lesions will only be considered measurable when they are superficial 
(e.g. skin nodules and palpable lymph nodes).  For skin lesions, documentation by color 
photography, including a ruler to estimate size of the lesion, is recommended.  
Photographs should be retained at the institution. 
 
8.7.4 Cytology and Histology 
 
Cytologic and histologic techniques can be used to differentiate between complete and 
partial responses in rare cases (e.g. after treatment to differentiate residual benign lesions 
and residual malignant lesions in germ cell tumors).  Cytologic confirmation of the 
neoplastic nature of any effusion that appears or worsens during treatment is required when 
the measurable tumor has met response or stable disease criteria. 
 
 
9 
BIOLOGICAL CORRELATIVES 
 
Please refer to the Study Procedures Manual (SMP) for collection, processing and shipping 
of correlative samples. 
 
mTOR pathway markers by IHC 
 
mTOR pathway markers, including pS-6 and p-4E BP1, are over expressed in the majority 
of participants with invasive urothelial carcinomas 8. Archived tumor specimens will be 
evaluated for PTEN, p-S6, p-4E BP1 by IHC and results will be correlated with clinical 
outcomes.  
 
Fifteen (15) unstained positively charged slides will be collected from the participant’s 
previous biopsy to bank for future use. The participant will not need to undergo a new 
biopsy if the previous biopsy is not available. See SPM for collection and shipping 
instructions.  
 
CoExpression Extrapolation (COXEN) 
 
In recent years, the expanding use of gene array technologies has offered promise for a 
personalized therapeutic approach.  For urothelial carcinoma, the coexpression 
extrapolation (COXEN) algorithm is an example of the power of gene arrays to predict 
optimal drug therapy for an individual participant17.  Through sophisticated informatics 
and biostatistical methodologies, COXEN leverages the existing public National Cancer 
Institute (NCI) Developmental Therapeutics Program drug sensitivity NCI-60 cell line data 
with Affymetrix® gene expression profiles and clinicopathologic human data from 


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participants with tumors not contained in the NCI-60 cell lines (i.e urothelial carcinoma) to 
produce a COXEN score predictive of response to existing drugs.  
 
Formalin-fixed paraffin embedded bladder cancer specimens will be sent to the laboratory 
of Dr. Dan Theodorescu for mRNA profiling (see SPM) and data analysis for generation of 
a COXEN score for everolimus and paclitaxel sensitivity. The COXEN score will be 
generated as previously described 17.   
 
Blood biomarkers 
 
Optional blood banking for future blood biomarker studies: whole blood is requested at 
baseline; serum and plasma are requested at baseline, Cycle 2 Day1 and at progression. See 
SPM for collection, processing and shipping instructions.  
 
10 CTM INFORMATION & ADVERSE EVENTS MANAGEMENT 
 
 
10.1 
Drug Name: Everolimus (RAD-001) 
 
10.1.1 Classification - Mammalian target of rapamycin (mTOR) inhibitor 
 
10.1.2 Action - Everolimus has antiproliferative and antiangiogenic properties. Reduces protein 
synthesis and cell proliferation by binding to the FK binding protein-12 (FKBP-12), an 
intracellular protein, to form a complex that inhibits activation of mTOR (mammalian 
target of rapamycin) serine-threonine kinase activity. Also reduces angiogenesis by 
inhibiting vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF-1) 
expression. 
 
10.1.3 Availability - Study drug will be provided by Novartis via Hoosier Oncology Group. 
 
10.1.4 Storage -  Store everolimus tablets at 25° C (77°F); excursions permitted between 15°–
30°C (59°–86°F). Store in the original container, protect from light and moisture. 
 
 
10.1.5 Administration - Everolimus will be taken at a dose of 10 mg, once daily at the same time 
every day, either with or without food. Everolimus tablets should be swallowed whole with 
a glass of water. The tablets should not be chewed or crushed. For patients unable to 
swallow tablets, the tablet(s) should be dispersed completely in a glass of water 
(containing approximately 30 mL) by gently stirring until the tablet(s) is fully disintegrated 
(approximately 7 minutes), immediately prior to drinking. The glass should be rinsed with 
the same volume of water and the rinse completely swallowed to ensure the entire dose is 
administered. If vomiting occurs, no attempt should be made to replace the vomited dose. 
Patients should be instructed that if they miss a dose on one day, they must not take any 
extra dose the next day, but instead to immediately contact the study center as soon as 
possible to ask for advice. 
 
10.1.6   Side Effects - 
 


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Very Common: ≥ 10% 
 
 
 Infections 
 Thrombocytopenia 
 Neutropenia 
 Anemia 
 Decreased appetite  
 Hyperglycemia 
 Hypercholesterolemia 
 Dysgeusia 
 Headaches 
 Pneumonitis 
 Epistaxis 
 Cough 
 Dyspnea 
 Nausea and vomiting 
 Diarrhea 
 Mouth sores 
 Rash and pruritis 
 Decreased weight 
 Fatigue 
 Asthenia 
 Peripheral edema 
 
Common: 1% to 9% 
 
 Leukopenia, neutropenia, lymphopenia 
 Abdominal pain  
 Hypertriglyceridemia 
 Hyperlipidemia 
 Hypophosphatemia 
 Hypokalemia 
 Diabetes mellitus 
 Difficulty swallowing 
 Hand-foot syndrome, a condition of redness and painful blisters can occur on hands 
and feet. 
 Skin or nail changes (acne, redness, dryness or irritation) 
 Increased blood pressure 
 Hemorrhage 
 Fever 
 Arthralagia 
 Inflammation of the lining of the digestive system and other mucous membranes 
 A participant with hepatitis B or hepatitis C who takes everolimus could be susceptible 
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 Dehydration 
 Insomnia  
 Dry mouth 
 Oral pain 
 Renal failure 
 Dyspepsia 
 Alanine aminotransferase increased, aspartate aminotransferase increased, blood 
creatinine increased 
 
Uncommon to Rare: ˂ 1%  
 Loss of taste sensation 
 Secondary amenorrhea (delayed menstruation), menstrual irregularities 
 Cardiac failure 
 Deep vein thrombosis  
 Hemoptysis 
 Acute renal failure 
 Proteinuria 
 Increased daytime urination 
 Pulmonary embolism  
 Pancytopenia, pure red cell aplasia 
 Non-cardiac chest pain 
 Impaired wound healing 
 Respiratory failure  
 Hypersensitivity - anaphylaxis, dyspnea, flushing, chest pain 
NOTE: Participants should not receive live vaccines and have close contact with people 
who have received live vaccines within 7 days of starting everolimus (Afinitor®) and while 
on this study without consultation with the study doctor. Examples of live vaccines include 
intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella 
(Chicken Pox), and typhoid vaccines. 
 
10.2 
Drug Name: Paclitaxel 
 
10.2.1 Classification - Taxane   
 
 
10.2.2 Action - Paclitaxel is a novel antimicrotubule agent that promotes the assembly of 
microtubules from tubulin dimers and stabilizes microtubules by preventing 
depolymerization. This stability results in the inhibition of the normal dynamic 
reorganization of the microtubule network that is essential for vital interphase and mitotic 
cellular functions. In addition, paclitaxel induces abnormal arrays or “bundles” of 
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10.2.3 Availability - Paclitaxel is commercially available and will not be provided by Hoosier 
Oncology Group. 
 
 
10.2.4 Storage - Unopened vials of TAXOL (paclitaxel) Injection are stable until the date 
indicated on the package when stored between 20°–25° C (68°–77° F), in the original 
package. Neither freezing nor refrigeration adversely affects the stability of the product. 
Upon refrigeration, components in the reaching room temperature with quality under these 
circumstances. precipitate is noted, the vial should recommended are stable at ambient 
conditions for up to 27 hours. 
 
 
10.2.5 Administration - Paclitaxel will be administered intravenously over 1 hour. 
 
10.2.6 Side Effects -  
 
Common: > 10%  
 Cardiovascular: Flushing (28%), ECG abnormal (14% to 23%), edema (21%), 
hypotension (4% to 12%) 
 Dermatologic: Alopecia (87%), rash (12%) 
 Gastrointestinal: Nausea/vomiting (52%), diarrhea (38%), mucositis (17% to 35%; 
grades 3/4: up to 3%), stomatitis (15%; most common at doses >390 mg/m2), 
abdominal pain (with intraperitoneal paclitaxel) 
 Hematologic: Neutropenia (78% to 98%; grade 4: 14% to 75%; onset 8-10 days, 
median nadir 11 days, recovery 15-21 days), leukopenia (90%; grade 4: 17%), anemia 
(47% to 90%; grades 3/4: 2% to 16%), thrombocytopenia (4% to 20%; grades 3/4: 1% 
to 7%), bleeding (14%) 
 Hepatic: Alkaline phosphatase increased (22%), AST increased (19%) 
 Local: Injection site reaction (erythema, tenderness, skin discoloration, swelling: 13%) 
 Neuromuscular & skeletal: Peripheral neuropathy (42% to 70%; grades 3/4: up to 7%), 
arthralgia/myalgia (60%), weakness (17%) 
 Renal: Creatinine increased (observed in KS participants only: 18% to 34%; severe: 
5% to 7%) 
 Miscellaneous: Hypersensitivity reaction (31% to 45%; grades 3/4: up to 2%), 
infection (15% to 30%) 
 
Less Common: 1% - 10%  
 Cardiovascular: Bradycardia (3%), tachycardia (2%), hypertension (1%), rhythm 
abnormalities (1%), syncope (1%), venous thrombosis (1%) 
 Dermatologic: Nail changes (2%) 
 Hematologic: Febrile neutropenia (2%) 
 Hepatic: Bilirubin increased (7%) 
 Respiratory: Dyspnea (2%) 
 
Rare: < 1%  
(Limited to important or life-threatening): Anaphylaxis, ataxia, atrial fibrillation, AV block, 
back pain, cardiac conduction abnormalities, cellulitis, CHF, chills, conjunctivitis, dehydration, 


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enterocolitis, extravasation recall, hepatic encephalopathy, hepatic necrosis, induration, intestinal 
obstruction, intestinal perforation, interstitial pneumonia, ischemic colitis, lacrimation increased, 
maculopapular rash, malaise, MI, necrotic changes and ulceration following extravasation, 
neuroencephalopathy, neutropenic enterocolitis, ototoxicity (tinnitus and hearing loss), 
pancreatitis, paralytic ileus, phlebitis, pruritus, pulmonary embolism, pulmonary fibrosis, radiation 
recall, radiation pneumonitis, pruritus, renal insufficiency, seizure, skin exfoliation, skin fibrosis, 
skin necrosis, Stevens-Johnson syndrome, supraventricular tachycardia, toxic epidermal 
necrolysis, ventricular tachycardia (asymptomatic), visual disturbances (scintillating scotomata) 
 
 
11 ADVERSE EVENTS 
 
11.1 Definitions of Adverse Events 
 
11.1.1 Adverse Event (AE) - Any untoward medical occurrence in a participant or clinical trial 
subject administered an investigational product and which does not necessarily have a 
causal relationship with the treatment.  An adverse event (AE) can, therefore, be any 
unfavorable and unintended sign (including an abnormal finding), symptom, or disease 
temporally associated with the use of an investigational product, whether or not related to 
the investigational product. 
 
11.1.2 Serious Adverse Event (SAE) - A serious adverse event is any untoward medical 
occurrence resulting in one or more of the following: 
 
 Results in death 
 Is life-threatening (defined as an event in which the participant was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe) 
 Requires inpatient hospitalization or prolongation of existing hospitalization,  
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but,  based upon 
appropriate medical and scientific judgment, may jeopardize the participant or may 
require intervention (e.g., medical, surgical) to prevent one of the other serious 
outcomes listed in the definition above).  Examples of such events include, but are not 
limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions not resulting in hospitalization; or the 
development of drug dependency or drug abuse. 
 
Events NOT considered to be SAEs are hospitalization for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures  
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
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definitions of a SAE given above and not resulting in hospital admission 
 respite care in the absence of any deterioration in the patient’s general condition 
 hospital admission solely for administration of study drug or chemotherapy 
 
11.1.3 Unexpected Adverse Event - An adverse event not mentioned in the Investigator's 
Brochure or package insert or the specificity or severity of which is not consistent with the 
Investigator's Brochure or package insert. 
 
11.2 Adverse Event (AE) Assessment and Reporting  
 
Adverse events (AEs) will be recorded from the time of consent and for at least 30 days   
after treatment discontinuation, regardless of whether or not the event(s) are considered 
related to trial medications.  AEs that begin or worsen after consent should be recorded in 
the AE eCRF. Conditions that were already present at that time of consent should be 
recorded in the medical history. AEs (including lab abnormalities that constitute AEs) 
should be described using a diagnosis whenever possible, rather than individual underlying 
signs and symptoms. When a clear diagnosis cannot be identified, each sign or symptom 
should be reported as a separate AE.  
 
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4. If CTCAE grading does not exist for an AE, the severity of mild, 
moderate, severe, and life-threatening, corresponding to Grades 1-4, will be used.  
 
The occurrence of AEs should be sought by non-directive questioning of the patient at each 
visit during the study. AEs also may be detected when they are volunteered by the patient 
during or between visits or through physical exam, lab test, or other assessments. As far as 
possible, each AE should be evaluated to determine: 
 The severity grade (CTCAE Grade 1-4) 
 Its duration (Start and end dates or if continuing at the safety follow-up visit) 
 Its relationship to the study treatment (Reasonable possibility that AE is related: see 
Table 14 below) 
 Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, hospitalized, unknown, not 
applicable) 
 Whether medication or therapy was given (no concomitant mediation/non-drug 
therapy, concomitant medication/non-drug therapy) 
 Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown) 
 Whether it is serious, where a SAE is defined as in the section above. 
 
All AEs 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 AE 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 


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interventions required to treat it, and the outcome. All AEs considered related to trial 
medication will be followed until resolution, return to baseline, or deemed clinically 
insignificant, even if this occurs post-trial. 
 
Information about common side effects already known about the investigational drug can 
be found in the Investigators’ Brochure. This information should be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
 
 
11.3 Serious Adverse Event (SAE) Reporting 
 
11.3.1 Study Center (Site) Requirements for Reporting SAEs  
 
Investigators and other site personnel must report any SAEs occurring during the course of 
the study within 1 business day of discovery of the event.  This includes events both 
related and unrelated to the investigational product.   
 
The definition of "related" being that there is a reasonable possibility the drug caused the 
adverse experience. 
 
Table 14: The relationship of the adverse event to the study drug 
Unrelated 
The Adverse Event is clearly not related to the investigational agent(s) 
Unlikely 
The Adverse Event is doubtfully related to the investigational agent(s) 
Possible 
The Adverse Event  may be related to the investigational agent(s) 
Probable 
The Adverse Event is likely related to the investigational agent(s) 
Definite 
The Adverse Event is clearly related to the investigational agent(s) 
 
The completed SAE Report Form (see SPM) must be faxed to Hoosier Oncology 
Group within 1 business day of discovery of the event.   The investigator is responsible 
for informing the IRB and/or the Regulatory Authority of the SAE as per local 
requirements. 
 
The original copy of the SAE Report and the fax confirmation sheet must be kept within 
the Trial Master File at the study site. 
Follow-up information will be faxed to Hoosier Oncology Group, using a new SAE Report 
Form stating that this is a follow-up to the previously reported SAE and giving the date of 
the original report. Each re-occurrence, complication, or progression of the original event 
should be reported as a follow-up to that event regardless of when it occurs. The follow-up 
information should describe whether the event has resolved or continues, if and how it was 
treated, whether the blind was broken or not (if applicable), and whether the participant 
continued or withdrew from study participation. 
 
11.3.2 Death and Immediately Life-Threatening Events  
 


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Any death and immediately life-threatening event from any cause while a participant is 
receiving trial treatment on this protocol or up to 30 days after the last dose of trial 
treatment, or any death and immediately life-threatening event occurring more than 30 
days after trial treatment has ended but which is felt to be treatment related must be 
reported within one business day of discovery of the event.  All deaths must be reported 
primarily for the purposes of SAE reporting; however, deaths due unequivocally to 
progression are not SAEs.   
 
Your local IRB should be notified and their reporting procedure followed.  The completed 
SAE Reporting Form should be faxed to Hoosier Oncology Group within 1 business day 
of discovery of the event. 
 
11.3.3 HOG Requirements for Reporting SAEs to FDA and Novartis 
 
The Sponsor Investigator has the obligation to report all serious adverse events to the FDA, 
IRB, and Novartis Pharmaceuticals Drug Safety and Epidemiology (DS&E) Department. 
 
Hoosier Oncology Group has been designated to manage the SAE reporting requirements 
for the FDA and Novartis on behalf of Matthew D Galsky, MD, Sponsor Investigator, and 
will be responsible for all communication with the FDA and Novartis. 
 
All events reported to the FDA are to be filed utilizing the Form FDA 3500A (MedWatch 
Form) per federal guidelines. 
 
To ensure participant safety, every SAE, regardless of suspected causality, occurring; 
 after the participant has provided informed consent and at least 30 days after the 
participant has stopped study treatment/participation 
 after protocol-specified procedures begin (e.g., placebo run-in, washout period, 
double-blind treatment, etc.) and 30 days after the participant has stopped study 
treatment 
 after the start of any period in which the study protocol interferes with the standard 
medical treatment given to a participant (e.g., treatment withdrawal during washout 
period, change in treatment to a fixed dose of concomitant medication) and until 30 
days after the participant has stopped study treatment 
 
All SAEs must be reported to Novartis Pharmaceuticals DS&E Dept. (fax: 877-778-9739) 
within 1 business day of Hoosier Oncology Group learning of its occurrence. This 
includes serious, related, labeled (expected) and serious, related, unlabeled (unexpected) 
adverse experiences. All deaths during treatment or within 30 days following completion 
of active protocol therapy must be reported within 5 business days. 
 
Any SAEs experienced after this 30 days period should only be reported to Novartis 
DS&E Dept. if the investigator suspects a causal relationship to the study drug. Recurrent 
episodes, complications, or progression of the initial SAE must be reported as follow-up to 
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information. An SAE occurring at a different time interval or otherwise considered 
completely unrelated to a previously reported one should be reported separately as a new 
event. The end date of the first event must be provided. The original copy of the SAE 
Report and the fax confirmation sheet must be kept within the Trial Master File at the 
study site. 
 
Follow-up information is sent to the same fax number as the original SAE Report Form 
was sent, using a new fax cover sheet, stating that this a follow-up to the previously 
reported SAE, and giving the date of the original report. Each re-occurrence, complication, 
or progression of the original event should be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event 
has resolved or continues, if and how it was treated, whether the blind was broken or not 
(if applicable), and whether the patient continued or withdrew from study participation. 
 
The investigator must assess and record the relationship of each SAE to each specific study 
drug (if there is more than one study drug), complete the SAE Report Form in English, and 
send the completed, signed form by fax to Hoosier Oncology Group  within 1 business 
day of discovery of the event. Hoosier Oncology Group will forward the corresponding 
SAE Report Form to Novartis DS&E Dept. within 1 business day of receipt of the SAE 
Reporting Form. 
 
If the SAE is not previously documented in the Everolimus Investigator’s Brochure or 
Package Insert (new occurrence) and is thought to be related to the Novartis study drug, a 
DS&E associate may urgently require further information from the investigator for Health 
Authority reporting. Novartis may need to issue an Investigator Notification (IN), to 
inform all investigators involved in any study with the same drug that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected 
and reported to the competent authorities and relevant ethics committees in accordance 
with Directive 2001/20/EC or as per national regulatory requirements in participating 
countries. 
 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the comparator drug company by the investigator. 
 
11.4 IND Safety Reports Unrelated to This Trial 
 
IND safety reports not occurring on this trial but involving the study intervention (outside 
SAEs) received from outside sources will be reviewed by the Sponsor Investigator and will 
be forwarded to participating sites for submission to their Institutional Review Boards per 
their guidelines.   
 
11.5 Pregnancies 
 
Any pregnancy that occurs during study participation should be reported. To ensure 
participant safety each pregnancy must also be reported to Novartis DS&E Dept. within 1 
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determine outcome, including spontaneous or voluntary termination, details of the birth, 
and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. The newborn will be followed for at least 12 months. 
 
12 STATISTICAL CONSIDERATIONS 
 
This study will involve two parallel cohorts. The study is not designed for statistical 
comparisons of the cohorts. Each cohort will employ a separate Simon’s 2-stage MinMax 
design.  
 
For cohort 1 (single agent everolimus), the sample size is based on the assumption that a 
clinical benefit rate of ≤ 10% is not worthy of further evaluation while a clinical benefit 
rate of ≥ 30% warrants additional testing. In the first stage, more than 1 participant with an 
objective response or stable disease (at 4 months) out of 15 evaluable participants is 
needed.  In the second stage, an additional 10 evaluable participants  will be required and 
more than 5 participants with an objective response or stable disease (at 4 months) are 
needed to consider the treatment successful with alpha = 0.05 and 80% power. The 
probability of early termination is 55% when the clinical benefit rate is ≤ 10%.  
 
For cohort 2 (single agent everolimus plus paclitaxel), the sample size is based on the 
assumption that a clinical benefit rate of ≤ 25% is not worthy of further evaluation while a 
clinical benefit rate of ≥ 45% warrants additional testing. In the first stage, more than 4 
participants with an objective response or stable disease (at 4 months) out of 17 evaluable 
participants are needed.  In the second stage, an additional 19 evaluable participants (for a 
total of 36 evaluable participants) will be required and more than 13 participants with an 
objective response or stable disease (at 4 months) are needed to consider the treatment 
successful with alpha = 0.05 and 80% power. The probability of early termination is 57% 
when the clinical benefit rate is ≤ 25%.  
 
For both cohorts, the primary endpoint is clinical benefit rate which includes response 
(defined as partial and complete response) and stable disease (at 4 months). It will be 
reported with 95% confidence intervals (CI).   
 
Survival which is part of the secondary endpoints will be calculated from the date of 
initiation of treatment to the death or last date of contact.   Survival at 1 year will be 
estimated from a Kaplan-Meier analysis.  Progression-free survival will be calculated from 
the date of initiation of therapy until progressive disease or death due to any cause.  If the 
participant did not progress nor die, the participant will be censored on the date of the last 
disease assessment performed. Progression-free survival will be analyzed using the method 
of Kaplan and Meier. Toxicities will be graded according to the NCI Common Toxicity 
Criteria (version 4.0). Participants enrolled in this study will be carefully monitored during 
the entire treatment phase and will be followed as is appropriate, with safety evaluations. 
All participants receiving at least 1 dose of the study regimen will be included in the safety 
analysis. Incidence and type of grades 3 and 4 adverse events, including serious adverse 
events, will be tabulated and summarized using descriptive statistics.  
 


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The participant is evaluable for efficacy if the participant receives at least one dose of 
treatment and at least one post-baseline disease evaluation. 
 
Dosage adjustments or interruptions will be based on treatment-related toxicity.  Early 
discontinuation of treatment (<2 cycles) secondary to toxicity will be considered a 
treatment failure.   
 
Assume 10% of the cohorts are nonevaluable or dropout, we plan to accrue 68 (28+40) 
participants. Accrual rate of 2-4 participants per month is anticipated, and thus the trial 
accrual time will be approximately 17-34 months. 
 
Potential biomarkers (mTOR pathway markers, including pS-6 and p-4E BP1 in archival 
tissue using immunohistochemistry) will be assessed by repeating the analysis of each 
clinical outcome with the level of each individual marker included as factor or covariate as 
appropriate.  Markers with a continuous, rather than a discrete, measurement will also be 
evaluated as a discrete factor by dividing participants into low and high expression classes 
at the point of the distribution that maximizes the association between the marker and each 
clinical outcome.  Significance of this association will be evaluated using a test for 
maximal chi-square values. For binary outcomes, chi-square test will be used while for 
time-to-event outcomes, log-rank test will be used. 
 
Archival tissue samples will be submitted to a CLIA-certified lab for transcriptional 
profiling. The Co-Expression Extrapolation algorithm will be utilized to generate scores 
for sensitivity to paclitaxel and/or everolimus. The scores will be correlated with clinical 
outcomes. The correlation will be explored using Kendall’s tau statistic. 
Baseline comorbidity scores will be calculated using the Charlson index and correlated 
with adverse events and clinical outcomes, which also be quantified using Kendall’s tau 
statistic 
 
 
13 TRIAL MANAGEMENT 
 
13.1 Quality Controls and Quality Assurance 
 
13.1.1 Study Monitoring 
 
Monitoring visits to the trial sites will be made periodically during the trial, to ensure all 
aspects of the protocol are followed.  Source documents will be reviewed for verification 
of agreement with data as submitted via the data collection system.  The 
investigator/institution guarantee access to source documents by HOG or its designee and 
appropriate regulatory agencies. 
 
The trial site may also be subject to quality assurance audit by Novartis or its designee as 
well as inspection by appropriate regulatory agencies. 
 


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It is important for the investigator and their relevant personnel to be available during the 
monitoring visits and possible audits and for sufficient time to be devoted to the process. 
 
13.1.2 Data and Safety Monitoring Plan 
 
HOG data safety monitoring activities include: 
 
 Review of clinical trial conducted for progress and safety 
 Review of all adverse events requiring expedited reporting as defined in the protocol 
 Review of reports generated by data quality control review process  
 Notification of the Sponsor Investigator of recommended action 
 Notification of sites coordinated by the HOG of adverse events requiring expedited 
reporting and subsequent committee recommendations for study modifications 
 
13.1.3 Data/Safety Monitoring and Reporting Guidelines 
 
The HOG will compile data summary reports for this trial and submit these reports 
monthly to the Sponsor Investigator.  The HOG will submit data summary reports a 
minimum of twice a year to a Data Safety Monitoring Committee (DSMC) for review.  
 
13.2 Data Handling and Record Keeping 
 
13.2.1 Case Report Forms 
 
An electronic case report form (eCRF) is required and must be completed for each 
included participant.  The completed dataset is the sole property of HOG and should not be 
made available in any form to third parties, except for authorized representatives of 
appropriate Health/Regulatory Authorities, without written permission from HOG. 
 
13.2.2 Record Retention 
 
To enable evaluations and/or audits from Health Authorities/HOG, the investigator agrees 
to keep records, including the identity of all participating participants (sufficient 
information to link records; e.g., hospital records), all original signed informed consent 
forms, copies of all eCRF’s, and detailed records of drug disposition.  To comply with 
international regulations, the records should be retained by the investigator in compliance 
with regulations. 
 
During data entry, range and missing data checks will be performed on-line.  The checks to 
be performed will be documented in the Data Monitoring Plan for the study.  A summary 
report (QC Report) of these checks together with any queries resulting from manual review 
of the eCRF’s will be generated for each site and transmitted to the site and the site 
monitor.  Corrections will be made by the study site personnel.  This will be done on an 
ongoing basis. 
 


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13.3 Changes to the Protocol 
 
Any change or addition (excluding administrative) to this protocol requires a written 
protocol amendment.  All protocol amendments must be reviewed by the Sponsor 
Investigator, Hoosier Oncology Group, and Novartis before implementation. 
 
If it is necessary for the study protocol to be amended, the amendment or a new version of 
the study protocol (amended protocol) will be generated by Hoosier Oncology Group. 
Amendments significantly affecting the safety of subjects, the scope of the investigation or 
the scientific quality of the study require additional approval by the IRB at each study site.   
Local requirements must be followed. A copy of the written approval of the IRB must be 
provided to Novartis. Examples of amendments requiring such approval are: 
a) Increases in drug dose or duration of exposure to subjects, 
b) Significant changes in the study design (e.g. addition or deletion of a control group) 
c) Increases in the number of invasive procedures, 
d) Addition or deletions of a test procedure required for monitoring of safety. 
 
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator or by Novartis in the interests of preserving the safety of all 
patients included in the trial.  If an immediate change to the protocol is felt to be necessary 
by the investigator and is implemented for safety reasons Novartis must be notified and the 
IRB at the center must be informed immediately.   Amendments affecting only 
administrative aspects of the study do not require formal protocol amendments or IRB 
approval but the IRB must be kept informed of such administrative changes. Examples of 
administrative changes not requiring formal protocol amendments and IRB approval 
include: 
a) changes in the staff used to monitor trials      
b) minor changes in the packaging or labeling of study drug. 
 
If a protocol amendment requires a change to the written Informed Consent Form, then the 
IRB must be notified.  Approval of the revised written Informed Consent Form by the IRB 
is required before the revised form is used.  
 
The principal investigator is responsible for the distribution of these documents to his or her 
IRB, and to the staff at his or her center.  The distribution of these documents to the 
regulatory authority will be handled according to local practice. 
 
Novartis’ willingness to supply study drug is predicated upon the review of the protocol.  
Hoosier Oncology Group agrees to provide written notice to Novartis of any modifications 
to the protocol or informed consent. 
 
13.4 Ethics 
 
13.4.1 Ethics Review 
 


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The final study protocol, including the final version of the written Informed Consent Form, 
must be approved or given a favorable opinion in writing by an IRB.  The investigator 
must submit written approval to the HOG office before he or she can enroll any participant 
into the study.   
 
The principal investigator is responsible for informing the IRB of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB must approve all 
advertising used to recruit participants for the study.  The protocol must be re-approved by 
the IRB annually, as local regulations require.  
 
Progress reports and notifications of serious unexpected adverse drug reactions will be 
provided to the IRB according to local regulations and guidelines. 
 
The investigator is also responsible for providing the IRB with reports of any serious 
adverse drug reactions from any other study conducted with the investigational product.  
Novartis will provide this information to the Sponsor Investigator.  These reports will be 
reviewed by the Sponsor Investigator and those considered unexpected and possibly 
related to protocol therapy plus all deaths within 30 days of discontinuing treatment will be 
forwarded to participating sites for submission to their Institutional Review Boards per 
their guidelines.  All other events will be held and submitted to the sites for continuing 
review. 
 
13.4.2 Ethical Conduct of the Study 
 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki, which are consistent with ICH/Good Clinical Practice, and 
applicable regulatory requirements. 
 
13.4.3 Written Informed Consent 
 
The investigator will ensure the participant is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Participants 
must also be notified they are free to discontinue from the study at any time.  The 
participant should be given the opportunity to ask questions and allowed time to consider 
the information provided. 
 
The participant’s signed and dated informed consent must be obtained before conducting 
any procedure specifically for the study.  The investigator must store the original, signed 
written Informed Consent Form.  A copy of the signed written Informed Consent Form 
must be given to the participant. 
 
14 REFERENCES 
 
 
1. 
Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin 2004;54:8-
29. 


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2. 
von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus 
methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: 
results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 
2000;18:3068-77. 
3. 
Dash A, Galsky MD, Vickers AJ, et al. Impact of renal impairment on eligibility for 
adjuvant cisplatin-based chemotherapy in participants with urothelial carcinoma of the bladder. 
Cancer 2006;107:506-13. 
4. 
De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing 
gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in participants with advanced 
urothelial cancer "unfit" for cisplatin-based chemotherapy: phase II--results of EORTC study 
30986. J Clin Oncol 2009;27:5634-9. 
5. 
Bellmunt J, Maroto P, Mellado B, et al. Phase II study of sunitinib as first line treatment in 
participants with advanced urothelial cancer ineligible for cisplatin-based chemotherapy. ASCO 
Genitourinary Oncology Symposium 2008:Abstract 291. 
6. 
Saal LH, Johansson P, Holm K, et al. Poor prognosis in carcinoma is associated with a 
gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proceedings of 
the National Academy of Sciences of the United States of America 2007;104:7564-9. 
7. 
Wu X, Obata T, Khan Q, Highshaw RA, De Vere White R, Sweeney C. The 
phosphatidylinositol-3 kinase pathway regulates bladder cancer cell invasion. BJU international 
2004;93:143-50. 
8. 
Milowsky MI, Tickoo S, Gallagher DJ, Bajorin D, Reuter V. HIF and mTOR pathways in 
invasive urothelial carcinoma: A study with potential therapeutic implications. ASCO 
Genitourinary Oncology Symposium 2008:Abstract 292. 
9. 
Puzio-Kuter AM, Castillo-Martin M, Kinkade CW, et al. Inactivation of p53 and Pten 
promotes invasive bladder cancer. Genes & development 2009;23:675-80. 
10. 
Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell 
carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449-
56. 
11. 
Galsky MD. The role of taxanes in the management of bladder cancer. The oncologist 
2005;10:792-8. 
12. 
Dreicer R, Gustin DM, See WA, Williams RD. Paclitaxel in advanced urothelial 
carcinoma: its role in participants with renal insufficiency and as salvage therapy. The Journal of 
urology 1996;156:1606-8. 
13. 
Faried LS, Faried A, Kanuma T, et al. Inhibition of the mammalian target of rapamycin 
(mTOR) by rapamycin increases chemosensitivity of CaSki cells to paclitaxel. Eur J Cancer 
2006;42:934-47. 


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14. 
Hu L, Hofmann J, Lu Y, Mills GB, Jaffe RB. Inhibition of phosphatidylinositol 3'-kinase 
increases efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Cancer research 
2002;62:1087-92. 
15. 
Campone M, Levy V, Bourbouloux E, et al. Safety and pharmacokinetics of paclitaxel and 
the oral mTOR inhibitor everolimus in advanced solid tumours. British journal of cancer 
2009;100:315-21. 
16. 
O'Regan R, Andre F, Campone M. RAD001 (everolimus) in combination with weekly 
paclitaxel and trastuzumab in participants with HER-2-overexpressing metastatic breast 
cancer with prior resistance to trastuzumab: a multicenter phase I clinical trial. Cancer research 
2009;69:3119. 
17. 
Lee JK, Havaleshko DM, Cho H, et al. A strategy for predicting the chemosensitivity of 
human cancers and its application to drug discovery. Proceedings of the National Academy of 
Sciences of the United States of America 2007;104:13086-91. 


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15 APPENDIX A 
 
Charlson Comorbidity Index 
 
Comorbidity 
Relative Weight Assignment 
Metastatic solid tumor 
6 
AIDS 
6 
Moderate to severe liver disease 
3 
Hemiplegia 
2 
Moderate to severe renal failure 
2 
Diabetes with end organ damage 
2 
Neoplasia 
2 
Leukemia/lymphoma 
2 
Myocardial infarct 
1 
Congestive heart failure 
1 
Peripheral vascular disease 
1 
Cerebrovascular disease 
1 
Dementia 
1 
Chronic obstructive pulmonary disease 
1 
Connective tissue disease 
1 
Peptic ulcer disease 
1 
Mild liver disease 
1 
Diabetes 
1 
From Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987). A new method of classifying prognostic comorbidity 
in longitudinal studies: development and validation. J Chron Dis, 40(5): 373-383 
 
Instructions: 
 
The total score is obtained by adding the relative weight of each co-morbidity.