Conditions: Hepatocellular Carcinoma
Keywords: Advanced HCC Temsirolimus TORISEL Sorafenib
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 29
Healthy volunteers: no

Brief summary:
This Phase II trial is being developed following the completion of a Phase I study of the combination of temsirolimus and sorafenib in 25 first-line therapy patients with advanced hepatocellular carcinoma (December 2009 through April 2012). The maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the combination of temsirolimus is 10 mg IV weekly plus sorafenib 200 mg (oral, twice daily).

Detailed description:
The hypothesis of this single-arm phase II study is that the combination of temsirolimus and sorafenib will achieve a clinically-meaningful median time to progression (TTP) of at least 6 months, with null hypothesis of less than or equal to 3 months, in first-line systemic therapy for patients with advanced Hepatocellular carcinoma (HCC). A randomized trial would be required to formally compare the efficacy of this combination to sorafenib alone and will be indicated if this phase II study achieves a median TTP of at least 6 months. An interim safety analysis will employ stopping rules after 30% of planned patients have been treated with at least one dose of protocol therapy to ensure the combination does not confer excessive toxicity.

A key aspect of this study will be the requirement of histologic confirmation along with adequate archival tissue for correlative tissue analyses to explore new biomarkers of response to mammalian target of rapamycin (mTOR) inhibition. Circulating biomarker data including enumeration of circulating tumor cells (CTC) and measurement of the tumor marker Alpha-fetoprotein (AFP) will be performed at specific time points to evaluate for predictive value. Specimen banking of tissue, serum, and peripheral blood mononuclear cells will be undertaken to enable future novel biomarker studies. Modified RECIST will be performed in addition to standard RECIST 1.1 to explore for improved imaging predictors of response.

Arms:
arm 1: Combination temsirolimus plus sorafenib

Interventions: intervention 1: Temsirolimus intervention 2: Sorafenib:
Intervention descriptions: intervention 1: 10 mg weekly will be administered intravenously over 30 to 60 minutes using an infusion pump starting on Cycle 1, Day 1 of study enrollment. intervention 2: 200 mg tablet twice daily starting on Cycle 1, Day 1 of study enrollment after completion of temsirolimus infusion.

Protocol document:
Prot_SAP_000.pdf: 
Proprietary and Confidential 
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by 
Federal and State laws.  Persons to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed. 
Phase II Trial of the Combination of Temsirolimus and Sorafenib in 
Advanced Hepatocellular Carcinoma 
Protocol Number:  124511 
Study Drug:  Temsirolimus (TORISEL®) 
Version Number:  5.0 
Version Date:  November 17, 2014 
IND Number:  IND Exempt (IND 115966) 
NCT Number: NCT01687673 
Principal Investigator (Sponsor-Investigator) 
Robin K. Kelley, MD 
University of California San Francisco 
katie.kelley@ucsf.edu 
Co-Investigators 
Chloe E. Atreya, MD PhD 
Emily K. Bergsland, MD 
Eric Collisson, MD 
John D. Gordan, MD PhD 
Andrew H. Ko, MD 
W. Michael Korn, MD PhD
Katherine Van Loon, MD
Alan Paul Venook, MD
Thomas Eaton Weber, NP
Statistician 
Jimmy Hwang, PhD 
Lead Clinical Research Coordinators/Sub-site contacts 
Ryan McWhirter, Blake Rosenthal 
UCSF Comprehensive Cancer Center, 
Revision History 
Version 5.0 
Version 4.0 
Version 3.0 
Version 2.0 
11/17/2014 
10/04/2014 
10/15/2012 
08/01/2012 
Version 1.0 
06/25/2012 
Initial Protocol 05/29/2012 
NCT#  01687673


 
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Protocol Signature Page 
Protocol No.: 124511 
Version Date: November 17, 2014 
1. I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Committee on Human Research (CHR), and Data Safety Monitoring Committee 
(DSMC).  
2. I will conduct the study in accordance with applicable CHR requirements, Federal 
regulations, and state and local laws to maintain the protection of the rights and welfare of 
study participants.  
3. I certify that I, and the study staff, have received the requisite training to conduct this 
research protocol.  
4. I have read and understand the information in the Investigators’ Brochure (or Manufacturer’s 
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in 
accordance with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the 
Statement of Investigator (Form FDA 1572), and with local regulatory requirements. In 
accordance with the FDA Modernization Act, I will ensure the registration of the trial on the 
www.clinicaltrials.gov website.  
5. I agree to maintain adequate and accurate records in accordance with CHR policies, 
Federal, state and local laws and regulations. 
UCSF Principal Investigator/Study Chair 
Printed Name 
Signature 
Date 
 
Participating Sites 
Robert H. Lurie Comprehensive Cancer Center 
Northwestern University       
         
 
Principal Investigator 
Site 
Printed Name 
Signature 
Date 
 


 
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Abstract 
Title 
Phase II Trial of the Combination of Temsirolimus and Sorafenib in Advanced 
Hepatocellular Carcinoma 
Patient 
population 
Histologically-confirmed, advanced, treatment-naïve HCC with Child-Pugh A 
or B7 liver dysfunction 
Rationale for 
Study 
To determine efficacy of and explore biomarkers for response to combination 
of temsirolimus plus sorafenib in advanced HCC 
Primary 
Objective 
To determine the median time to progression (TTP) in patients with advanced 
HCC treated with combination of temsirolimus plus sorafenib 
Secondary 
Objectives 
1. To determine response rate (RR) using RECIST 1.1  
2. To measure median progression-free survival (PFS) 
3. To measure median overall survival (OS)  
4. To measure time to treatment failure (TTF) 
5. To measure change in AFP tumor marker and examine for association 
between change in AFP and TTP and best response 
6. To characterize toxicity and tolerability of the combination of temsirolimus
plus sorafenib 
7. To describe TTP, PFS, OS, response rate, AFP response, and toxicity 
and tolerability in subsets defined by HBV, HCV, Asian, and non-Asian 
status 
Study Design 
Single-arm, one-stage, open-label phase II trial to evaluate the efficacy of the 
combination of temsirolimus plus sorafenib in first line therapy for patients 
with histologically-confirmed advanced HCC. 
Number of 
patients 
Target sample size is 25 patients, expected maximum enrollment is 28 
patients. 
Duration of 
Therapy 
Individual patient treatment will continue indefinitely from the time of 
enrollment, until unacceptable toxicity, unmanageable toxicity despite optimal 
supportive care and dose modifications, clinical disease progression or 
progression per RECIST 1.1, withdrawal of consent by the patient, or the 
decision to discontinue treatment by the treating physician due to changes in 
the patient’s condition or other factors which may influence safety or 
compliance. 
Duration of 
Follow up 
After treatment discontinuation, follow up for overall survival monitoring will be
performed for up to 5 years or until death, whichever comes first.   
Duration of 
study 
The study will reach completion approximately 24 months from the time the 
study opens to accrual. The study will end 5 years after the final patient 
discontinues treatment or after all patients are deceased, whichever comes 
first. 


 
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Abstract 
Study Drugs 
Temsirolimus:  10 mg weekly will be administered intravenously over 30 to 60 
minutes using an infusion pump starting on Cycle 1, Day 1 of study 
enrollment.  
Sorafenib:  200 mg tablet twice daily starting on Cycle 1, Day 1 of study 
enrollment after completion of temsirolimus infusion.   
Safety 
Assessments 
Analyses will be performed for all patients having received at least one dose 
of study drug.  The study will use the NCI (CTCAE) Version 4.0. 
Efficacy 
Assessments 
Primary Endpoint 
Median TTP will be calculated in months from date of first dose of protocol 
therapy to date of removal from study for progression; Kaplan-Meier methods 
will be used to summarize the primary endpoint (median TTP). 
Secondary Endpoints 
Response rate (RR) will be measured by RECIST version 1.1; measurements 
will be presented descriptively for the study cohort. 
Median PFS will be calculated in months from date of first dose of protocol 
therapy to date of documented disease progression or death from any cause. 
Kaplan-Meier methods will be used to summarize time-to-event outcomes 
including the primary endpoint (median TTP) and secondary endpoints (PFS, 
TTF, OS). 
Median OS for all enrolled patients who receive at least one dose of protocol 
therapy will be calculated from date of first dose of protocol therapy until date 
of death, using chart review and/or follow up phone calls to determine date of 
death in patients after removal from study. 
TTF will be measured from date of first dose of protocol therapy to date of 
study discontinuation for progression, death, or toxicity. 
In patients with baseline AFP ≥ 20 ng/mL, AFP response will be measured by 
the percent change from baseline value to the value at the time of best AFP 
response.  The change in AFP will also be examined for association with 
absolute TTP and best response. 


 
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Abstract 
Efficacy 
Assessments 
(continued) 
Exploratory Endpoints 
CTC will be enumerated in peripheral blood at baseline and after 1 and 2 
cycles of therapy to evaluate for any relationship between baseline levels and 
change in levels with median TTP and/or OS; baseline level of CTC will be 
compared to proportion with TTP at 6 months to determine if there is an 
association using Fisher’s Exact tests.  Change in CTC levels (increase or 
decrease) after 1 and 2 cycles will be compared to TTP to determine if there 
is an association using Fisher’s Exact tests.    
In all patients with active or chronic HBV infection, changes in HBV DNA 
quantitative by PCR will be characterized using descriptive statistics to 
calculate the proportion of patients with an increase or reactivation in viral 
load while on protocol therapy. 
Unique 
Aspects of this 
Study 
This Phase II trial is being developed following completion of a Phase I study 
of the combination of temsirolimus and sorafenib in 25 first-line therapy 
patients with advanced hepatocellular carcinoma (December 2009 through 
April 2012). The MTD and recommended phase II dose (RP2D) of the 
combination was temsirolimus 10 mg IV weekly plus sorafenib 200 mg PO 
BID. 
 


 
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List of Abbreviations 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical (Classification System) 
AUC 
area under the curve 
BUN 
blood urea nitrogen 
CBC 
complete blood cell (count) 
CHR 
Committee on Human Research (UCSF IRB) 
CR 
complete response 
CRC 
Clinical Research Coordinator 
CRF 
case report form 
CSF 
cerebral spinal fluid 
CT 
computerized tomography 
CTCEA 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTMS 
Clinical Trial Management System 
DFS 
disease-free survival 
DLT 
dose limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECOG 
Eastern Cooperative Oncology Group 
FCBP 
female of childbearing potential 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBeAg 
Hepatitis B “e” antigen 
HBV 
Hepatitis B virus 
HCC 
Hepatocellular carcinoma 
HCT 
Hematocrit 
HCV 
Hepatitis C virus 
HDFCCC Helen Diller Family Comprehensive Cancer Center 
HGB 
Hemoglobin 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonization 


 
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List of Abbreviations 
IND 
investigational new drug application 
IP 
investigational product 
IRB 
Institutional Review Board 
iwCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IV 
Intravenous 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin’s lymphoma 
ORR 
overall response rate 
PD 
disease progression 
PK 
Pharmacokinetics 
PO 
Per os (by mouth, orally) 
PR 
partial response 
PRC 
Protocol Review Committee (UCSF) 
QOL 
Quality of Life 
RBC 
red blood cell (count) 
SD 
stable disease 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
ULN 
upper limit of normal 
WBC 
white blood cell (count) 
 


 
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Table of Contents 
Protocol Signature Page .................................................................................................................. 2 
Abstract  ........................................................................................................................................ 3 
List of Abbreviations ...................................................................................................................... 6 
Table of Contents ............................................................................................................................ 8 
1. 
Introduction .................................................................................................................. 12 
1.1 
Background on Indication ............................................................................................ 12 
1.2 
Background on the Compounds ................................................................................... 12 
1.2.1 
Sorafenib ................................................................................................................ 12 
1.2.2 
Combination of Sorafenib plus mTOR Inhibition .................................................. 17 
1.2.3 
Temsirolimus .......................................................................................................... 19 
1.3 
Rationale for the Proposed Study ................................................................................. 21 
1.4 
Correlative Studies ....................................................................................................... 22 
1.4.1 
Measurement of AFP as HCC Tumor Marker ....................................................... 22 
1.4.2 
Enumeration of Circulating Tumor Cells in HCC .................................................. 23 
1.4.3 
Markers of mTOR Pathway Activation .................................................................. 23 
1.4.4 
Reactivation of Viral Hepatitis B Infection ............................................................ 23 
1.4.5 
Cause of Underlying Liver disease ........................................................................ 24 
1.4.6 
Specimen Banking .................................................................................................. 24 
2. 
Objectives of the Study ................................................................................................ 24 
2.1 
Primary ......................................................................................................................... 24 
2.2 
Secondary ..................................................................................................................... 24 
2.3 
Exploratory Objectives and Other Assessments .......................................................... 25 
2.4 
Endpoints ...................................................................................................................... 25 
2.4.1 
Primary Endpoint ................................................................................................... 25 
2.4.2 
Secondary Endpoints .............................................................................................. 25 
2.4.3 
Exploratory Endpoints ............................................................................................ 26 
3. 
Study Design ................................................................................................................ 26 
3.1 
Characteristics .............................................................................................................. 26 
3.2 
Number of Subjects ...................................................................................................... 26 
3.3 
Eligibility Criteria ......................................................................................................... 26 
3.3.1 
Inclusion Criteria .................................................................................................... 27 
3.3.2 
Exclusion Criteria ................................................................................................... 28 


 
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Table of Contents 
3.4 
Duration of Therapy ..................................................................................................... 30 
3.5 
Duration of Follow Up ................................................................................................. 30 
3.6 
Randomization Procedures ........................................................................................... 30 
3.7 
Study Timeline ............................................................................................................. 30 
3.7.1 
Primary Completion ............................................................................................... 30 
3.7.2 
Study Completion ................................................................................................... 30 
4. 
Study Drugs .................................................................................................................. 31 
4.1 
Description, Supply and Storage of Investigational Drugs .......................................... 31 
4.1.1 
Temsirolimus (TORISEL®) .................................................................................... 31 
4.1.2 
Sorafenib (NEXAVAR®) ....................................................................................... 38 
4.2 
Drug Accountability ..................................................................................................... 40 
4.3 
Drug Ordering .............................................................................................................. 40 
4.4 
Packaging and Labeling of Study Drugs ...................................................................... 41 
5. 
Treatment Plan ............................................................................................................. 41 
5.1 
Dosage and Administration .......................................................................................... 41 
5.2 
Dose Modifications and Dosing Delays ....................................................................... 42 
5.2.1 
Temsirolimus Dose Modifications ......................................................................... 42 
5.2.2 
Sorafenib Dose Modifications ................................................................................ 42 
5.2.3 
Dose Modification Protocol ................................................................................... 42 
5.2.4 
Unacceptable Toxicities ......................................................................................... 49 
5.3 
Management of Toxicities ............................................................................................ 49 
5.3.1 
Supportive Care Guidelines .................................................................................... 50 
6. 
Study Procedures and Observations ............................................................................. 52 
6.1 
Schedule of Procedures and Observations ................................................................... 52 
6.1.1 
Pretreatment Period ................................................................................................ 52 
6.1.2 
Treatment Period .................................................................................................... 53 
6.1.3 
6.1.2.3 Study Procedures Day 8, 15, and 22 of All Cycles after Cycle 1 (within 7 
days) ....................................................................................................................... 55 
6.1.4 
End-of-Treatment Study Procedures (within 60 days) ........................................... 55 
6.1.5 
Post-Treatment/Follow Up Visits ........................................................................... 56 
6.1.6 
Long Term/Survival Follow-up Procedures ........................................................... 56 
6.2 
Usage of Concurrent/Concomitant Medications .......................................................... 60 
6.3 
Reasons to Withdraw a Subject .................................................................................... 60 


 
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Table of Contents 
6.4 
Stopping Rules ............................................................................................................. 60 
6.5 
Medical Guidelines for the Treatment of an Overdose ................................................ 61 
6.6 
Dietary Restrictions ...................................................................................................... 62 
6.7 
Prohibited Medications ................................................................................................. 62 
6.7.1 
Temsirolimus .......................................................................................................... 62 
6.7.2 
Sorafenib ................................................................................................................ 63 
7. 
Reporting and Documentation of Results .................................................................... 63 
7.1 
Evaluation of Efficacy (or Activity) ............................................................................. 63 
7.1.1 
Measurement of Response and Progression ........................................................... 63 
7.1.2 
Time to Event Endpoints ........................................................................................ 67 
7.2 
Evaluation of Safety ..................................................................................................... 67 
7.3 
Evaluation of Exploratory Endpoints ........................................................................... 67 
7.3.1 
Circulating Tumor Cell Measurements .................................................................. 68 
7.3.2 
Markers of mTOR Pathway Activation .................................................................. 68 
7.3.3 
Blood Specimen Banking ....................................................................................... 68 
7.3.4 
Tumor Specimen Banking ...................................................................................... 69 
8. 
Reporting and Documentation of Adverse Events ....................................................... 69 
8.1 
Definitions of Adverse Events ..................................................................................... 69 
8.1.1 
Adverse Event ........................................................................................................ 69 
8.1.2 
Adverse reaction ..................................................................................................... 69 
8.2 
Recording of an Adverse Event .................................................................................... 70 
8.3 
Follow-up of Adverse Events ....................................................................................... 71 
8.4 
Adverse Events Monitoring .......................................................................................... 71 
8.5 
Expedited Reporting ..................................................................................................... 72 
8.6 
Adverse Event Reporting to Funding Organization and  Research Grant Provider ..... 72 
9. 
Statistical Considerations and Evaluation of Results ................................................... 73 
9.1 
Study Endpoints ........................................................................................................... 73 
9.1.1 
Study Design .......................................................................................................... 73 
9.1.2 
Primary Endpoint ................................................................................................... 73 
9.1.3 
Secondary Endpoints .............................................................................................. 73 
9.1.4 
Exploratory Endpoints ............................................................................................ 74 
9.2 
Determination of Sample Size and Accrual Rate ......................................................... 74 
9.2.1 
Sample Size and Power Estimate ........................................................................... 74 


 
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Table of Contents 
9.2.2 
Accrual estimates ................................................................................................... 75 
9.3 
Interim Analyses and Stopping Rules .......................................................................... 75 
9.4 
Analyses Plans .............................................................................................................. 76 
9.4.1 
Analysis Population ................................................................................................ 76 
9.4.2 
Analysis of Primary Endpoints............................................................................... 76 
9.4.3 
Analysis of Secondary Endpoints........................................................................... 76 
9.4.4 
Exploratory Analyses/Assessments ........................................................................ 77 
9.5 
Evaluation of Safety ..................................................................................................... 78 
10. 
Study Management ....................................................................................................... 78 
10.1 
Pre-study Documentation ............................................................................................. 78 
10.2 
Institutional Review Board Approval ........................................................................... 78 
10.3 
Informed Consent ......................................................................................................... 78 
10.4 
Changes in the Protocol ................................................................................................ 78 
10.5 
Handling and Documentation of Clinical Supplies ...................................................... 79 
10.6 
Case Report Forms (CRFs) .......................................................................................... 79 
10.7 
Oversight and Monitoring Plan .................................................................................... 79 
10.8 
Multicenter communication ......................................................................................... 80 
10.9 
Record Keeping and Record Retention ........................................................................ 80 
10.10 Coordinating Center Documentation of Distribution ................................................... 80 
10.11 Regulatory Documentation ........................................................................................... 81 
11. 
References .................................................................................................................... 81 
Appendix 1 ....................................................................................... ECOG Performance Status Criteria
 ...................................................................................................................................... 90 
Appendix 2 ............................................................................................................................ Staging Tools
 ...................................................................................................................................... 90 
Appendix 3 ...... Data and Safety Monitoring Plan for Multicenter Institutional Study (Phase 2 or 3 
Institutional Study) ....................................................................................................... 94 
Appendix 4 ........................................................ Substrates, Inhibitors, and Inducers of CYP3A4 *,**
 ...................................................................................................................................... 97 
Appendix 5 .......................................................... Substrates of CYP2B6, CYP2C8, and CYP2C9*,**
 .................................................................................................................................... 100 
Appendix 6 Substrates of UGT1A1 and UGT1A9* ................................................................... 101 
Appendix 7 Substrates, Inhibitors, and Inducers of P-glycoprotein (P-gp)* .............................. 102 
Appendix 8 .............................................................................................. List of Phosphorus-Rich Foods


 
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1. Introduction 
1.1 
Background on Indication 
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide with an 
incidence of over 600,000 new cases and almost as many deaths annually. (Parkin, Bray et al. 
2005)  Advanced stages of disease at diagnosis often preclude curative treatments, and the 
overall prognosis of patients diagnosed with advanced HCC remains dismal with median 
survival of approximately 8 months.(Llovet, Burroughs et al. 2003; El-Serag 2007; Llovet, Ricci 
et al. 2008)   Historically, systemic therapies for advanced HCC have not been associated with 
a survival benefit, largely due to compromised hepatic function from underlying liver disease as 
well as intrinsic tumor chemoresistance.(Chenivesse, Franco et al. 1993; Soini, Virkajarvi et al. 
1996; Jiang, Lu et al. 1997; Yeo, Mok et al. 2005; Lopez, Villanueva et al. 2006)  In 2008, 
publication of the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol 
(SHARP) phase III trial demonstrated a significant improvement in overall survival (OS) in 
patients with advanced HCC treated with the biologic agent, sorafenib.(Llovet, Ricci et al. 2008) 
The SHARP trial will be discussed in detail below.  Despite improvements in outcome with 
sorafenib, however, the median OS for patients with advanced HCC remains less than a 
year.(Llovet, Ricci et al. 2008)  Multiple recent randomized phase 3 trials of other anti-
angiogenic multikinase inhibitors in HCC, including a first-line trial of sunitinib versus sorafenib 
and a second-line trial of brivanib versus placebo, have failed to show benefit, underscoring the 
challenges of toxicity, comorbidity, and chemoresistance in this notoriously treatment-refractory 
disease.(Cheng 2011; Llovet 2012) New active drugs and combinations are urgently needed. 
1.2 
Background on the Compounds 
1.2.1 
Sorafenib 
Sorafenib is a small molecule bi-aryl urea with multikinase inhibitor activity.  A primary target is 
the serine-threonine kinase, Raf-1, as well as mutant RET, mutant FLT-3, and wild-type and 
mutant c-KIT.(Bayer 2011)  Sorafenib also has antiangiogenic activity, inhibiting receptor 
tyrosine kinases including vascular endothelial growth factor (VEGF) receptors 2 and 3 and the 
platelet derived growth factor receptor-β (PDGFRβ).(Wilhelm, Carter et al. 2004; Liu, Cao et al. 
2006; Chang, Adnane et al. 2007)  Preclinical studies in HCC show that Raf-1 kinase signaling 
along with prolific tumor angiogenesis are common features, providing a molecular rationale for 
the efficacy of this agent.(Huynh, Nguyen et al. 2003; Semela and Dufour 2004; Calvisi, Ladu et 
al. 2006; Liu, Cao et al. 2006; Villanueva, Newell et al. 2007)  In preclinical models of HCC 
including athyrmic mouse xenografts, sorafenib treatment produces both anti-tumor and anti-
angiogenic effects.(Bayer 2011)   
The metabolism of sorafenib is predominantly hepatic via oxidation by CYP3A4 and 
glucuronidation by UGT1A9.(Bayer 2011)  Sorafenib is a moderate to strong inhibitor of 
CYP2C8, 2B6, 2C9, 2C19, 2D6, and 3A4 as well as UGT1A1 and 1A9.  In cultured hepatocytes, 
sorafenib does not induce CYP1A2 or 3A4.  Excretion is predominantly through biliary/fecal 
route.  Bioavailability is moderate to high in animal models.  Terminal half-life from plasma is 4 
hours in dogs, 9 hours in rats, and 6 hours in mice.  There is high plasma protein binding of 
99.5%.  The sorafenib metabolites M2 and M5 also potently inhibit VEGFR2, PDGFRβ, and 


 
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FLT-3, though in xenograft models, M2 has lower efficacy than the parent compound.  In 
preclinical models, sorafenib can be safely combined with multiple conventional cytotoxic agents 
including gemcitabine and cisplatin. 
In human studies, there was evidence of accumulation up to 7-fold upon multiple dosing without 
further increase after 7 days of multiple dosing.  The mean terminal elimination half-life in 
humans is 25 to 48 hours.  It should be administered fasting or with a low- or moderate-fat meal, 
as high-fat meals decrease bioavailability.  In humans, 19% of dose is excreted in urine and 
77% in feces.  M2 is the principle plasma metabolite.  There is high inter-patient PK variability 
not explained by gender, age, weight, or hepatic function.  Prior phase I studies of sorafenib 
have shown significant interpatient pharmacokinetic (PK) variability without clear relationship to 
toxicity.(Strumberg, Richly et al. 2005; Strumberg, Clark et al. 2007)  The exposure values and 
PK are similar in patients with Child-Pugh A and B hepatic dysfunction.  In a phase I study 
studying sorafenib in patients with organ dysfunction, there was no clear effect of renal or 
hepatic dysfunction on sorafenib clearance by PK measures, though toxicity was 
increased.(Miller, Murry et al. 2009)  No dose adjustment is required for patients with mild to 
severe renal impairment not requiring dialysis. The mean AUC of sorafenib was 30% lower in 
Asians than Caucasians but does not appear to correlate with toxicity or efficacy.  There was 
minimal impact on cardiovascular parameters in humans though there is a small to minimal 
mean prolongation of QT/QTc interval.  Human metabolism is predominantly hepatic through 
CYP3A4-mediated oxidation and UGT1A9-mediated glucuronidation.  It may be co-administered 
with CYP3A4 substrates and inhibitors without expected increase in exposure, though inducers 
such as rifampin may reduce sorafenib AUC.  Alteration of GI flora by antibiotics may also 
reduce exposure.  Other agents and classes with potential for drug interactions with sorafenib 
are reviewed in Section 6.7 and Appendices 6-9 Prohibited Medications.   
Additional information on sorafenib is provided in Section 4 Study Drugs as well as in the 
Investigator’s Brochure. (Bayer 2011) 
1.2.1.1 
Phase I and II Clinical Studies of Sorafenib in HCC 
In the phase I setting, sorafenib demonstrated an acceptable safety profile at a dose of 400 mg 
orally twice daily in patients with advanced solid tumors; there was a partial response in a 
patient with HCC.(Strumberg, Richly et al. 2005)  A multicenter phase II trial of sorafenib in 
advanced HCC was published by Abou-Alfa et al in 2006.(Abou-Alfa, Schwartz et al. 2006)  In 
this study, 137 patients with unresectable HCC were treated with sorafenib 400 mg twice daily.  
Almost half of patients (48%) were positive for hepatitis C virus (HCV) infection, while 17% had 
hepatitis B virus (HBV).  The majority demonstrated preserved liver function, with a score of 
Child-Pugh class A in 72% and Child-Pugh class B in 28%.  There were no significant 
differences in sorafenib pharmacokinetic parameters between Child-Pugh class A and B 
patients.  Overall, the toxicity profile of sorafenib was acceptable, with the most common Grade 
3 or 4 toxicities being fatigue, diarrhea, and hand-foot skin reaction in 9.5%, 8.0%, and 5.1% of 
patients, respectively.  There were no patients with a complete response (CR), 11 (8%) with 
partial and minor responses, and 46 (33.6%) with stable disease for at least 16 weeks.  Many 
tumors seemed to have necrosis, however, including some with apparent size increase by 
conventional imaging.  Survival parameters were comparable to those of the best published 
combinations of systemic chemotherapy in advanced HCC.(Yeo, Mok et al. 2005; Abou-Alfa, 
Schwartz et al. 2006; Lopez, Villanueva et al. 2006)  Despite no significant difference in 
pharmacokinetic profiles based upon liver function, subgroup analysis of the 28% of patients 
with Child-Pugh class B cirrhosis in this phase II study showed higher rates of 
hyperbilirubinemia and encephalopathy developing on study by comparison with patients with 
Child-Pugh class A.(Abou-Alfa, Amadori et al. 2011) Patients with Child-Pugh class B liver 
function also demonstrated a shorter median OS of 3.2 months by comparison to 9.5 months for 
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1.2.1.2 
Phase III Clinical Studies of Sorafenib in HCC 
Following upon this phase II study of sorafenib in HCC, the phase III multicenter SHARP trial 
enrolled 602 patients with advanced HCC and preserved liver function from 121 sites in Europe, 
North America, South America, and Australasia.  The patient population was comprised of 
approximately 30% with HCV infection, 20% with HBV infection, and 25% with alcoholic liver 
disease.  Nearly all patients had Child-Pugh class A cirrhosis, with Eastern Cooperative 
Oncology Group performance status score of 0 or 1.  Patients were randomly assigned to 
receive sorafenib at a starting dose of 400 mg twice daily versus placebo. The primary end 
points were overall survival (OS) and time to symptomatic progression, and patients could 
remain on treatment until they experienced disease progression both radiographically and 
symptomatically.  At the second planned interim analysis, OS was significantly longer in the 
sorafenib group compared with placebo, with OS of 10.7 months versus 7.9 months, 
respectively, and hazard ratio (HR) for sorafenib of 0.69 (P < 0.001).  There was no difference in 
time to symptomatic progression, though median time to radiographic progression (TTP) was 
significantly longer in the sorafenib group (5.5 vs 2.8 months, p < 0.001).  Seven partial 
responses by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in the 
sorafenib-treated arm (2%).  Disease control rate (DCR) (a composite of complete response, 
partial response, and stable disease) was significantly higher in the sorafenib group (43% v 
32%; p < 0.002).   
Subgroup analysis from SHARP suggested that patients with HCV have similar safety profile 
and clinical benefit as the entire study population, with a trend towards greater survival benefit 
with median OS 14.0 months for patients with HCV by comparison with 10.7 months for the 
overall population.(Bolondi L. 2008)  Patients with alcohol-related HCC and with macroscopic 
vascular invasion and/or extrahepatic spread also demonstrated survival benefit with sorafenib 
and similar toxicity profile as the overall study population by subgroup analyses from 
SHARP.(Craxi A. 2008; Sherman M 2008)  Subgroup analysis for patients with HBV in the 
SHARP study has not been presented to date.   
Another randomized, placebo-controlled phase III study comparing sorafenib to placebo was 
conducted in 226 Asian patients with unresectable HCC, Child-Pugh class A cirrhosis, and 
greater than 70% with underlying HBV infection.(Cheng, Kang et al. 2009)  Survival was 
significantly prolonged with the use of sorafenib, with median OS 6.5 months in patients treated 
with sorafenib by comparison with 4.2 months for placebo (HR 0.68, p = 0.014). Median TTP 
was 2.8 months in sorafenib group compared to 1.4 months in the placebo group (HR 0.57, p = 
0.0005).  Though sorafenib produced clear benefit, the outcomes in this Asian study were much 
poorer than those of SHARP.  Potential explanations include possible differences in numbers of 
prior therapies, assessment of performance status, exposure to other factors influencing 
hepatocarcinogenesis, or etiology of liver disease between the Asian population and the 
SHARP population.(Kelley and Venook 2008) 
1.2.1.3 
Safety of Sorafenib in HCC 
In the SHARP study, treatment-related adverse events occurred in 80% of patients in the 
sorafenib group by comparison with 52% in the placebo group.  Grade 3 toxicities included 
diarrhea (8%), hand-foot skin reaction (8%), hypertension (2%), and abdominal pain (2%) in the 
treatment group.  Grade 3 or 4 hypophosphatemia (4%) and thrombocytopenia (4%) were also 
more common in patients treated with sorafenib.(Llovet, Ricci et al. 2008)  In the Asian 
randomized, placebo-controlled phase III study, the most common Grade 3 and 4 toxicities were 
hand-foot skin reaction (10.1%), diarrhea (6%), hyperbilirubinemia (3.4%), and fatigue (3.4%) 
with the use of sorafenib.(Cheng, Kang et al. 2009)  As discussed above, subgroup analysis 
from the phase II study of sorafenib in HCC of the 28% of patients with Child-Pugh class B 
cirrhosis showed higher rates of hyperbilirubinemia and encephalopathy developing on study by 
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retrospective single-institution study of 48 patients showed significantly decreased tolerability of 
sorafenib among Asian-American patients compared to non-Asian patients, with only 3% 
tolerating full-dose sorafenib of 400 mg twice daily compared to 40% for non-Asians (P < 
0.01).(Barrera 2009)  Safety data for sorafenib are reviewed in greater detail below in Section 
4.1.2 as well as in the FDA Prescribing Information.(Bayer 2011) 
1.2.1.4 
Mammalian Target of Rapamycin (mTOR) Inhibition in Malignancy 
Another signaling pathway involved in hepatocarcinogenesis is the phosphatase and tensin 
homolog (PTEN)/phosphatidylinositol-3’kinase (PI-3’K)/AKT pathway which activates the 
mammalian target of rapamycin (mTOR) kinase, in turn triggering multiple downstream cell 
growth, survival, and angiogenesis signals.(Dancey 2006; Hopfner, Schuppan et al. 2008; 
Llovet and Bruix 2008)  Dysregulated phosphorylation and activation of mTOR signaling may 
occur due to loss of function of the PTEN tumor suppressor gene, constitutive activation of PI-
3’K, or activation of AKT by aberrant upstream growth factor receptor signaling.(Llovet and Bruix 
2008)   Activated mTOR forms complexes with other proteins, including regulatory associated 
protein of mTOR (Raptor) and Rictor.(Dancey 2006)  The mTOR-Raptor complex in turn 
phosphorylates protein 70 S6 kinase (p70S6K) as well as eukaryotic initiation factor 4E (eIF-4E) 
binding protein-1 (4E-BP1).  P70S6K and 4E-BP1 regulate translation of a host of proteins, 
including several proteins involved in cell proliferation.  Signaling through mTOR also stimulates 
angiogenesis.(Dancey 2006; Semela, Piguet et al. 2007; Hopfner, Schuppan et al. 2008; 
Villanueva, Chiang et al. 2008)  Activation of mTOR may induce endothelial cell proliferation as 
well as increase levels of hypoxia inducible factor (HIF)-1α and HIF-2α, potentially via p70S6K-
mediated translation versus decreased oxygen-dependent degradation.(Zhong, Chiles et al. 
2000; Hudson, Liu et al. 2002; Thomas, Tran et al. 2006)  HIFs induce angiogenesis in 
response to cellular hypoxia by transcriptional activation of target genes including VEGF.(Kaelin 
2005; Del Bufalo, Ciuffreda et al. 2006; Thomas, Tran et al. 2006) 
The mTOR inhibitor, sirolimus, is a macrocyclic lactone rapamycin produced by the soil 
bacterium, Streptomyces hygroscopicus.  Sirolimus demonstrates fungicidal, 
immunosuppressive, and antiproliferative properties and is widely used as an 
immunosuppressant in transplant patients to prevent allograft rejection.(Douros and Suffness 
1981; Dancey 2006)  Temsirolimus, everolimus, and deforolimus are derivatives of sirolimus 
with similar antiproliferative properties in vitro.(Dancey 2006)  Inhibitors of mTOR are also under 
investigation as anti-cancer agents in multiple human malignancies, and two mTOR inhibitors 
have been labeled by the U.S. FDA for use as anti-cancer agents: Everolimus is indicated in the 
treatment of metastatic pancreatic neuroendocrine tumors and advanced RCC, and 
temsirolimus is indicated for the treatment of advanced RCC. 
1.2.1.5 
Non-Clinical Studies of mTOR Pathway Inhibition in HCC 
In vitro, mTOR activation appears exert an oncogenic effect on hepatocellular cell lines.  In the 
non-hepatoma hepatocellular cell line HepaRG, a constitutively active mTOR mutation confers a 
premalignant phenotype, though mutations in mTOR, PTEN, and PIK3CA are rare in studies of 
clinical specimens.(Parent, Kolippakkam et al. 2007; Villanueva, Chiang et al. 2008)  A 
significant proportion of resected HCC tumor specimens feature activation of the mTOR 
pathway, as measured by phosphorylation of one or multiple members of the mTOR cascade 
including mTOR itself, AKT, IGF-1R, 4EBP-1, p-RPS6, and p70S6K, or by increased levels of 
total p70S6K expression.(Sahin, Kannangai et al. 2004; Sieghart, Fuereder et al. 2007; Schmitz, 
Wohlschlaeger et al. 2008; Villanueva, Chiang et al. 2008; Baba, Wohlschlaeger et al. 2009)  In 
a study of 166 liver explants with HCC from orthotopic liver transplant recipients, 
phosphorylated mTOR (p-mTOR) was identified by immunohistochemistry in 41% of tumors; p-
mTOR was not identified in adjacent non-tumor cirrhotic tissue.(Sieghart, Fuereder et al. 2007)  
Phosphorylated p70S6K was present in 49% of HCC tumors in this study, and phosphorylated 
4EBP-1 was present in 39%.  There was no apparent correlation, however, between mTOR 


 
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activation and disease-free or overall survival.  In another study of 101 resected hepatoma 
specimens, phosphorylated AKT (p-AKT) measured by immunohistochemistry was present with 
moderate levels in 50.5% and strong levels in 31.4%, by comparison with no staining in normal 
hepatocellular tissue.(Schmitz, Wohlschlaeger et al. 2008)  Tumors with moderate and strong p-
AKT expression were associated with a trend toward reduced tumor-specific overall survival (P 
= 0.059) in this study.   Two other large studies of HCC resection specimens detected elevated 
levels of phosphorylated p70S6K in 24.5% and p-RPS6 in 47.7% of tumors, respectively, using 
immunohistochemistry; the presence of phosphorylated p70S6K or p-RPS6 was associated with 
poor clinical outcomes in both studies.(Villanueva, Chiang et al. 2008; Baba, Wohlschlaeger et 
al. 2009)  Phosphorylated AKT, mTOR, and p70S6K have also been detected in HCC-
associated sinusoidal endothelial cells by comparison to non-malignant liver tissues.(Li, Tan et 
al. 2008) 
In multiple HCC cell lines, the mTOR inhibitors everolimus and sirolimus have been shown to 
inhibit proliferation, induce cell cycle arrest, and reduce viability.(Villanueva, Chiang et al. 2008; 
Wang, Zhou et al. 2008)  Treatment with sirolimus has also been shown to reduce VEGF and 
HIF-1α mRNA expression in vitro.(Wang, Zhou et al. 2008)  Similarly, temsirolimus 
demonstrates an anti-angiogenic effect in endothelial cells as measured by tube formation 
assays and aortic ring assays.(Semela, Piguet et al. 2007)  Xenograft models suggest that 
mTOR inhibition impairs HCC tumor growth, delays metastatic progression, and prolongs 
survival.(Semela, Piguet et al. 2007; Huynh, Chow et al. 2008; Villanueva, Chiang et al. 2008; 
Wang, Zhou et al. 2008)  In athymic nude mice injected with Huh-7 HCC cells, treatment with 
everolimus was associated with a delay in tumor growth as well as decrease in tumor 
proliferation index as measured by Ki-67 staining by comparison to control mice.(Villanueva, 
Chiang et al. 2008)  In another nude mouse model of the LCI-D20 metastatic HCC cell line, 
administration of sirolimus impaired tumor growth and metastases.(Wang, Zhou et al. 2008)  
Tumor microvessel density and circulating levels of VEGF were reduced, suggesting an anti-
angiogenic effect.  A study in severe combined immunodeficiency (SCID) mice implanted with 
HCC xenograft tumors demonstrated dose-dependent growth inhibition and decreased tumor 
proliferative indices; VEGF levels and tumor microvessel density also declined with 
treatment.(Huynh, Chow et al. 2008) In syngeneic rats implanted with hepatoma cells, treatment 
with sirolimus also reduced tumor growth and metastases and was associated with reduced 
tumor microvessel density, again suggesting an anti-angiogenic effect of sirolimus.(Semela, 
Piguet et al. 2007)  Pharmacodynamic studies showed decreased phosphorylation of 4E-BP1 in 
the treated rats.      
1.2.1.6 
Clinical Studies of mTOR Pathway Inhibition in HCC 
A single-arm phase II trial of sirolimus 20 mg/week in 25 treatment-naïve patients with advanced 
HCC and Child-Pugh A (N = 17) or B (N = 8) cirrhosis demonstrated an objective response rate 
of 8%, with 1 patient achieving a complete radiographic response, 1 with a partial response, 8 
with stable disease, and 13 with progressive disease at best response; 2 patients had grade 5 
toxicity and were unevaluable.(Decaens, Luciani et al. 2012)  The median overall survival was 
25.4 weeks and median time to radiographic progression was 15.3 weeks.   In another small, 
single-arm, pilot study of 21 patients with HCC and 9 with cholangiocarcinoma in Sweden, 
treatment with sirolimus to trough levels between 4 and 15 μg/mL resulted in partial response in 
1 patient and stable disease in 5 patients with HCC, and stable disease in 3 patients with 
cholangiocarcinoma.(Rizell, Andersson et al. 2008)    A phase I/II trial of everolimus in 28 
patients with advanced HCC and 0 to 2 prior systemic treatment regimens showed acceptable 
tolerability with median PFS of 3.8 months and overall survival of 8.4 months, with PFS of 
28.6% at 24 weeks.(Zhu, Abrams et al. 2011)  A randomized phase III trial of everolimus versus 
placebo in advanced HCC patients after failure of sorafenib is ongoing (NCT01035229). 


 
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There is emerging evidence that mTOR inhibition confers an anti-tumor effect as well as 
immunosuppression after orthotopic liver transplantation for HCC.  A case report has been 
published of a liver transplant patient with biopsy-proven recurrent HCC and pulmonary 
metastases in whom, upon switching immunosuppressive regimen to include the mTOR 
inhibitor sirolimus, the pulmonary metastases demonstrated a complete radiographic response. 
(Elsharkawi, Staib et al. 2005)  Small studies of liver transplant patients with recurrent HCC after 
transplant have also suggested a possible antitumor effect when immunosuppression was 
switched to sirolimus-based immunosuppression.(Kornberg, Kupper et al. 2008; Zhou, Wang et 
al. 2008)  In retrospective analysis of 73 consecutive liver transplant patients at a single center 
in China, use of sirolimus by comparison with FK506-based immunosuppression was 
associated with significantly longer overall survival (P = 0.011) and a non-significant trend 
toward prolonged disease-free survival (P = 0.234).(Zhou, Wang et al. 2008)  A meta-analysis 
of 2950 patients treated with liver transplantation for HCC showed that patients treated with 
sirolimus-based immunosuppression had lower recurrence risk than those treated with 
sirolimus-free regimens, with odds ratio of 0.42 (95% confidence interval of 0.21-0.83).(Liang, 
Wang et al. 2012)   
1.2.2 
Combination of Sorafenib plus mTOR Inhibition 
Combination of molecularly targeted therapies offers the theoretical potential for additive or 
synergistic inhibition of shared targets as well as targets in parallel pathways which may provide 
escape mechanisms from single-pathway inhibition.  In the case of mTOR inhibitors and 
Ras/MAPK pathway inhibition, the combination could be addititve or synergistic by blocking a 
pathway parallel to and/or upstream of mTOR kinase, augmenting anti-angiogenic effects, or 
blocking the increase in VEGF which has been reported with VEGFR tyrosine kinase 
inhibition.(Dancey 2006; Deprimo, Bello et al. 2007; Llovet and Bruix 2008; Zhu, Sahani et al. 
2009; Martin, Edeline et al. 2012)   
1.2.2.1 
Preclinical Studies of the Combination of mTOR Inhibition plus  
Sorafenib in HCC 
Xenograft models of HCC have demonstrated additive effects and possible synergy when an 
mTOR inhibitor is combined with sorafenib or another anti-angiogenic multikinase 
inhibitor.(Jasinghe, Xie et al. 2008; Wang, Zhou et al. 2008; Huynh, Ngo et al. 2009)  In nude 
mice orthotopically implanted with highly metastatic human HCC tumor cells (LCI-D20), 
treatment with sirolimus inhibited primary tumor growth as well as lung metastases.(Wang, Zhou 
et al. 2008)  The addition of sorafenib to sirolimus significantly increased anti-tumor effect and 
augmented suppression of angiogenesis as measured by decreased microvessel density and 
circulating VEGF levels by comparison with either agent alone.   In another study, Huh7 and 
SK-HEP-1 HCC cells were implanted subcutaneously into SCID mice.(Jasinghe, Xie et al. 2008)  
Treatment with sirolimus inhibited tumor growth; addition of the multikinase inhibitor ABT-869 
produced significantly greater reduction in tumor growth by comparison with controls or with 
either agent administered alone.   A xenograft model of SCID mice implanted with the human 
HCC cell line 10-0505 and treated with sirolimus, sorafenib, or the combination of both drugs 
showed that combination therapy induced significant tumor regression as well as growth 
inhibition by comparison with either drug alone.(Huynh, Ngo et al. 2009)  Furthermore, 
combination therapy with both sorafenib and sirolimus also blocked the upregulation of cyclin B1 
and Cdk-2, phosphorylation of c-met, and phosphorylation of mTOR targets that were induced 
by single agent therapy.  VEGFR-2 phopshorylation was likewise inhibited while apoptosis was 
increased. In rats implanted with Morris Hepatoma cells, treatment with the combination of 
everolimus plus sorafenib achieved greater tumor reduction than everolimus alone or sequential 
sorafenib then everolimus, and survival was longest in the combination group (P <0.05). 
(Piguet, Saar et al. 2011) 


 
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1.2.2.2 
Clinical Studies of Combination mTOR Inhibition plus Sorafenib 
Preliminary results from a phase I clinical trial of the combination of temsirolimus and sorafenib 
in 24 patients with advanced solid tumors identified partial responses in one patient with non-
Hodgkin’s lymphoma and two patients with thyroid cancer (one papillary, one medullary); 
prolonged stable disease was observed in a patient with RCC.(Patnaik A 2007)  There were no 
patients with HCC or documented liver dysfunction in this trial.  Starting dosages were 
temsirolimus 15 mg intravenously weekly plus sorafenib 200 mg twice daily, with escalation to 
maximum dosages of 25 mg intravenously weekly and 400 mg twice daily, respectively for each 
drug.  Interim results presented at ASCO in 2007 suggested that an intermediate dosage of 
sorafenib 200 mg twice daily with temsirolimus 25 mg intravenously weekly was tolerable.  
Significant mucocutaneous toxicity as well as thrombocytopenia were observed with full 
dosages of both agents.  This study has not been published as of April 2012.  A phase I study of 
sorafenib plus temsirolimus in 25 patients with metastatic melanoma showed significant toxicity 
at higher dose levels, with maximum tolerated dose established as sorafenib 400 mg in the 
morning and 200 mg every evening plus temsirolimus 25 mg intravenously weekly.(Davies, Fox 
et al. 2012)  Best response was stable disease in 10 patients, and median PFS was 2.1 months. 
Dose-limiting toxicities were thrombocytopenia, hand-foot syndrome, transaminase elevation, 
and hypertriglyceridemia.  Matching pre-treatment and day 15 tumor biopsies in a subset of 4 
patients on this study showed decrease in phospho-S6 but minimal change in phospho-ERK 
levels.  In a phase I drug interaction study evaluating the combination of sirolimus and sorafenib 
in 34 patients with refractory solid tumors, best response was stable disease in 9 
patients.(Gangadhar, Cohen et al. 2011)  The treatment regimen was sirolimus 3 mg orally once 
daily (N = 20) or 2 mg twice daily (N = 14) in combination with sorafenib 400 mg twice daily.  
The toxicity profiles were similar to those expected for each drug alone. NCI CTCAE v3.0 grade 
3 or higher toxicities occurring in at least 10% of patients in either or both treatment arms were 
(according to highest incidence): diarrhea in 25%, hypophosphatemia in 50%, anemia in 14%, 
rash in 21%, pain in 10%, hand-foot syndrome in 21%; one patient died of infection while 
another died of arrhythmia. There was no clinically-significant difference in Cmax for each drug 
individually or in combination.  A phase I study of the combination of everolimus plus sorafenib 
in 20 patients with metastatic clear cell RCC identified maximum tolerated dosages of 
everolimus 5 mg daily plus sorafenib 200 mg twice daily.(Harzstark, Small et al. 2011).  Five 
patients (25%) achieved a partial response.  Grade 2 rash was observed in 55% and grade 3 
rash in 10%, grade 2 or 3 hypophosphatemia in 65%, grade 2 or 3 diarrhea in 35%, grade 2 
hypothyroidism in 20%, and grade 2 hypertension and hand-foot syndrome in 30% each.  There 
was no evidence of interaction between everolimus and sorafenib on pharmacokinetic analyses 
in this study. 
There are limited clinical data of the combination of sorafenib plus mTOR inhibition in HCC or 
patients with liver dysfunction.  The metabolism of both sorafenib and temsirolimus is 
predominantly hepatic by the cytochrome P450 (CYP) 3A4 system, raising concern for drug 
interactions and increased toxicity with this combination, particularly in patients with underlying 
hepatic dysfunction. In a case report of a patient with recurrent HCC post liver transplantation 
who had demonstrated progression on sorafenib, the transition of immunosuppression to 
sirolimus and continuation of sorafenib resulted in partial response.(Wang, Speeg et al. 2010)  
In a series of 31 patients with HCC recurrence post liver transplantation, the transition of 
immunosuppression to include mTOR inhibition (everolimus or sirolimus) along with initiation of 
sorafenib was associated with acceptable toxicity, 1/26 (3.8%) patients with partial response, 
and stable disease as best response in 50%, with median overall survival of 19.3 months in this 
highly selected group of patients.(Gomez-Martin, Bustamante et al. 2012)   In this study, 
everolimus, sirolimus, and sorafenib were dosed according to standard practice and investigator 
discretion.   The most common (occurring in at least 2 patients) grade ≥ 3 toxicities were 
asthenia (16.1%), diarrhea (12.9%), hypertension (9.7%), gastrointestinal bleeding (6.5%), and 
hyperglycemia (6.5%).  A phase I study of the combination of everolimus plus sorafenib in 30 


 
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patients with advanced HCC and Child-Pugh class A liver disease was presented by Finn et al 
at the American Society of Clinical Oncology Annual Meeting in 2011.(Finn 2011)  In this study, 
sorafenib was dosed at 400 mg orally twice daily, with dose escalation of everolimus starting at 
2.5 mg daily.  Seventy-three percent of patients were Asian, and 63% had chronic active 
hepatitis B virus infection.  The maximum tolerated dose (MTD) of everolimus in this 
combination was 2.5 mg daily.  Dose-limiting toxicity in the 2.5 mg cohort was grade 3 
transaminase elevation.  In the 5 mg everolimus cohort, grade 3 or 4 thrombocytopenia 
occurred in 5 patients, and 1 patient had grade 3 or 4 hyperbilirubinemia.  Everolimus 
pharmacokinetics were reported to be dose proportional and comparable to monotherapy in 
non-HCC patients.  Best response was stable disease in 10 (62.5%) and 5 (35.7%) of patients 
and median time to progression was 3.5 and 3.6 months in the 2.5 and 5 mg everolimus 
cohorts, respectively. 
1.2.3 
Temsirolimus 
Temsirolimus is a soluble ester analogue of sirolimus which specifically inhibits mTOR protein 
kinase with resulting inhibition of downstream mTOR-dependent protein translation induced by 
growth factor stimulation.(Dudkin, Dilling et al. 2001; Pfizer 2011)   The antiproliferative effects 
of temsirolimus are similar to other rapalogues.(Dancey 2006)  In human HCC cells, both 
rapamycin and temsirolimus induce growth arrest in G1 and decreased proliferation, along with 
reduction in phosphorylation of mTOR and p70S6K in cellular lines, and growth inhibition was in 
HCC PLC/PRF/5 cell xenografts in nude mice.(Hui, Tung et al. 2010)  In a study of 5 cell lines 
including Huh7 and HepB3, temsirolimus treatment suppressed HCC cell proliferation in a dose-
dependent manner, with synergistic inhibition achieved by addition of the microtubule inhibitor, 
vinblastine.(Zhou, Lui et al. 2012)   
The metabolism of temsirolimus is predominantly hepatic via O-demethylation, hydroxylation, 
macrocyclic-ring opening, and ester hydrolysis to its principal metabolite, sirolimus. (Pfizer 
2011) Temsirolimus is moderately bound (85% to 87%) to plasma proteins and has a large 
volume of distribution.  There is extensive metabolism via esterase-mediated hydrolysis to the 
principal active metabolite, sirolimus, and to their isomers and seco-temsirolimus (M4).  There 
are significant species-related differences in sirolimus:temsirolimus ratios thought to be due to 
differences in hydrolytic activity and erythrocyte concentration of FKBP-12; in humans, the 
sirolimus:temsirolimus ratio is 12.3.  The terminal half-lives of temsirolimus and sirolimus were 
17.3 hours and 54.6 hours, respectively.  There was little accumulation on multiple dosing.  
Excretion is principally through the feces with only minor amounts (<10%) excreted in the urine. 
Clearance of the mTOR inhibitor everolimus in patients with hepatic dysfunction is markedly 
reduced, leading to the recommendation that everolimus dosage should be reduced in the 
setting of impaired hepatic function.(Dancey 2006)  A pharmacokinetic and pharmacodynamic 
study of temsirolimus in patients with advanced malignancies and varying degrees of liver 
dysfunction showed no significant difference in temsirolimus exposure in patients with mild to 
moderate liver dysfunction; in patients with Child-Pugh score of C, however, exposure to 
temsirolimus and its metabolite was increased.(Pfizer 2011)  This study was conducted by the 
National Cancer Institute (NCI) Organ Dysfunction Working Group (ODWG) and was presented 
at the American Society of Clinical Oncology Annual Meeting in 2011.(Sarantopoulos 2011)  
The authors demonstrated decreased clearance, prolonged half-life, and increased AUC in 
patients with greater degrees of hepatic dysfunction. According to Prescribing Information, a 
reduction in temsirolimus starting dose to 15 mg weekly is recommended in patients with mild to 
moderate liver dysfunction as defined by bilirubin > 1 to 1.5 times ULN and/or AST > ULN but 
bilirubin within normal limits, and temsirolimus is contraindicated in patients with total bilirubin 
greater than 1.5 times the upper limit of normal.(Wyeth 2011)   
Strong inducers of CYP3A4/5 may decrease exposure to temsirolimus and sirolimus and should 
be avoided.  Strong inhibitors of CYP3A4 may increase exposures and should be avoided.  


 
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Moderate CYP3A4 inhibitors should be used with caution or substituted with an alternate agent.  
Other agents and classes with potential for drug interactions with temsirolimus are reviewed in 
Section 6.7 and Appendices 6-9 Prohibited Medications.   
Temsirolimus has been approved by the FDA for treatment of advanced renal cell carcinoma 
(RCC) and demonstrated a survival benefit as monotherapy by comparison with interferon alpha 
in a multicenter phase III trial.(Hudes, Carducci et al. 2007; Pfizer 2011) In that trial, 626 
patients with previously untreated, poor prognosis, metastatic RCC were randomized to receive 
temsirolimus 25 mg intravenously weekly, 3 million units of interferon alpha subcutaneously 
three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million 
units of interferon alpha three times weekly.(Hudes, Carducci et al. 2007)  The primary 
endpoint, overall survival, was 10.9 months in the temsirolimus group, by comparison with 7.3 
months with interferon alpha and 8.4 months with combination therapy; both overall survival and 
progression free survival (PFS) were significantly prolonged in the temsirolimus group by 
comparison with interferon alpha alone (P = 0.008 and P < 0.001, respectively). 
In a phase III trial of temsirolimus in comparison with interferon alpha or combination therapy in 
advanced RCC, Grade 3 or 4 adverse events occurred in 68.8% of patients enrolled to the 
temsirolimus arm treated with 25 mg intravenously weekly.(Hudes, Carducci et al. 2007; Pfizer 
2011)  Adverse events (with incidence at least 5%) which were significantly more common in 
the temsirolimus arm versus the interferon arm were: rash (37.0% vs 5.5%), pain (27.9% vs 
15.0%), hyperlipemia (27.4% vs 11.0%), hypercholesterolemia (24.5% vs 4.5%), stomatitis 
(19.7% vs 3.5%), pharyngitis (12.0% vs 1.5%), acne (10.1% vs 1.0%), hypokalemia (9.6% vs 
3.5%), edema (9.1% vs 4.0%), rhinitis (9.6% vs 2.0%), allergic reactions (8.7% vs 0.5%), 
infection (6.7% vs 0.5%), face edema (6.7% vs 0.5%), and pruritic rash (5.3% vs 0.5%).(Pfizer 
2011)  Safety data for temsirolimus are reviewed in greater detail below in Section 1.2.3 as well 
as in the Investigator’s Brochure.(Pfizer 2011) 
Additional information on temsirolimus is provided in Section 4 Study Drugs as well as in the 
Investigator’s Brochure.(Pfizer 2011) 
1.2.3.1 
Phase 1 Trial of Temsirolimus plus Sorafenib in HCC 
Investigators at the UCSF Helen Diller Family Comprehensive Cancer Center in partnership 
with the Robert H. Lurie Comprehensive Cancer Center of Northwestern University completed 
enrollment to a phase I clinical trial of the combination of temsirolimus and sorafenib in 25 first-
line therapy for patients with advanced hepatocellular carcinoma from December 2009 and April 
2012.(Kelley 2012)  This study was funded by a competitive grant from the National 
Comprehensive Cancer Network (NCCN).  Four patients remain on study as of April 2012.  The 
MTD and recommended phase II dose (RP2D) of the combination was temsirolimus 10 mg IV 
weekly plus sorafenib 200 mg PO BID.  The most common treatment-related grade 3 or higher 
toxicities by NCI CTCAE v3.0 were: Hypophosphatemia in 52%, thrombocytopenia in 24%, 
transaminitis in 19%, and diarrhea, fatigue, and hand-foot syndrome in 10% each.  Possibly-
related serious adverse events included grade 4 tumor rupture, grade 4 urosepsis, grade 3 
dental infection with grade 2 neutropenia, grade 3 cellulitis with normal neutrophil count, and 
grade 2 pneumonia (1 event each).  Confirmed partial responses were documented in 2 of 21 
(10%) patients, with best response of stable disease in 11 of 21 (52%).  One patient has 
remained on study with confirmed partial response for over 22 months as of April 2012.  Among 
the 16 of 21 (76%) with elevated alpha-fetoprotein (AFP) tumor marker ≥ 20 ng/mL at baseline, 
8 of 16 (50%) had ≥ 50% decline at the time of best AFP response.     
1.2.3.2 
Pharmacokinetics of Temsirolimus plus Sorafenib in Combination 
In the phase I study of temsirolimus and sorafenib discussed above, preliminary results 
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(sirolimus), at steady state, though there were no other drug-drug interactions 
observed.(Patnaik A 2007)  Sorafenib exposure was similar at dosages of both 200 mg and 400 
mg twice daily in this study.  The phase I drug interaction study evaluating the combination of 
sirolimus and sorafenib discussed above showed no significant interactions 
observed.(Gangadhar, Cohen et al. 2011)  Likewise, the available data suggests no clinically 
relevant, measurable pharmacokinetic interaction between everolimus and sorafenib in two 
phase I studies of this combination in RCC (both drugs) and HCC (everolimus only).(Finn 2011; 
Harzstark, Small et al. 2011) Pharmacokinetic analyses for temsirolimus and its primary 
metabolite, sirolimus, from the UCSF-Northwestern phase I trial of temsirolimus plus sorafenib 
in HCC showed  peak drug concentration (Cmax) for temsirolimus was similar before and after 
addition of sorafenib, while that of sirolimus was nonsignificantly increased. (Kelley 2012)  
Clearance of temsirolimus was more rapid after addition of sorafenib (5.86 L/h vs 4.37 L/h, 
statistical t-test, p < 0.05), with a nonsignificant decrease in temsirolimus half-life.  The AUC inf 
for temsirolimus was significantly lower (statistical t-test, p < 0.05) after addition of sorafenib, 
while there was a nonsignificant trend towards increase in Cmax and AUC inf for sirolimus.  
There was significant interpatient variability for sirolimus across timepoints.  Compared to 
healthy volunteers and cancer patients without liver dysfunction who were treated with 25 mg 
dose of temsirolimus, the Cmax for both temsirolimus and sirolimus was lower in this study 
which utilized a 10 mg dose.(Sarantopoulos 2011)  The AUC of single-agent temsirolimus prior 
to addition of sorafenib in this cohort appeared similar to the non-HCC subjects treated at the 25 
mg dose, and clearance was slower.  
1.3 
Rationale for the Proposed Study 
Despite its prominence as the third most common cause of cancer death world-wide, HCC lags 
far behind all other malignancies with only one systemic therapy (sorafenib) with proven benefit 
in advanced disease.  New treatments and combinations are urgently needed in this grim 
disease.  Based upon the emerging evidence for anti-tumor activity of mTOR inhibitors in HCC, 
the molecular rationale for combination of mTOR inhibition with sorafenib, and the provocative 
data from the UCSF-Northwestern phase I trial as reported above, a phase II study is warranted 
to better define the efficacy of this regimen.  This protocol describes a single-arm phase II study 
with overall goal to confirm the signal of efficacy observed in the phase I dose-finding setting, to 
establish the tolerability of the regimen in a larger cohort, and to further explore potential 
biomarkers of response.  The single-arm, one-stage design will expeditiously determine whether 
there is an adequate signal of efficacy and adequate tolerability to warrant a much larger and 
significantly more costly randomized study design with single-agent sorafenib as a control arm, 
noting the recent negative outcomes of multiple large randomized trials in HCC (including the 
second-line BRISK-PS trial of brivanib versus placebo as well as the first-line trial of sunitinib 
versus sorafenib), whose negative results have been attributed in part to insufficient phase II 
data, intolerability, and lack of robust markers of response.(BusinessWire 2011; Cheng 2011) 
The hypothesis of this single-arm phase II study is that the combination of temsirolimus and 
sorafenib will achieve a clinically-meaningful median time to progression (TTP) of at least 6 
months, with null hypothesis of less than or equal to 3 months, in first-line systemic therapy for 
patients with advanced HCC.  A randomized trial would be required to formally compare the 
efficacy of this combination to sorafenib alone and will be indicated if this phase II study 
achieves a median TTP of at least 6 months.  An interim safety analysis will employ stopping 
rules after 30% of planned patients have been treated with at least one dose of protocol therapy 
to ensure the combination does not confer excessive toxicity.   
A key aspect of this study will be the requirement of histologic confirmation along with adequate 
archival tissue for correlative tissue analyses to explore new biomarkers of response to mTOR 
inhibition.  Circulating biomarker data including enumeration of circulating tumor cells (CTC) and 
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predictive value.  Specimen banking of tissue, serum, and peripheral blood mononuclear cells 
will be undertaken to enable future novel biomarker studies.   
1.4 
Correlative Studies 
This trial will include correlative studies to evaluate for potential surrogate markers of prognosis 
and response to therapy in HCC.  In the advanced setting, such markers promise to spare 
patients the toxicity, opportunity loss, and financial expense of futile therapy. As new treatments 
become available, predictive markers may also guide changes in therapy, as well as instruct 
clinical trial design and facilitate the identification of new, efficacious therapies.  Identification of 
predictive and prognostic surrogate markers may someday determine which patients will benefit 
from a course of adjuvant therapy after definitive resection of an early stage hepatoma, or those 
patients with HCC who would benefit from a strategy of maintenance therapy while awaiting 
transplant.  
A practical limitation in prognostic and predictive assessments in HCC, however, is the paucity 
of tissue specimens in patients with advanced disease.  Updated guidelines of the NCCN do not 
require biopsy in patients with classic radiographic enhancement (arterial hyperenhancement, 
venous washout.(NCCN 2012)  These recommendations are in concordance with the American 
Association for the Study of Liver Diseases (AASLD) practice guidelines for radiographic 
diagnosis of hepatocellular carcinoma and have been validated retrospectively.(Compagnon, 
Grandadam et al. 2008; Bruix and Sherman 2011) Percutaneous liver biopsies often yield 
limited quantities of material for testing, introduce risk for significant bleeding in the setting of 
cirrhosis and liver dysfunction, and are at high risk for sampling error, particularly in patients 
with smaller tumors or with history of prior liver-directed therapies such as chemoembolization 
which result in necrosis.  Furthermore, as with most malignancies, serial tumor tissue sampling 
to assess for pharmacodynamic effect or predictive factors of treatment response is not feasible.  
For all of these reasons, studies of tissue-based prognostication in HCC have been largely 
limited to hepatoma resection or explant specimens, which may differ biologically from 
advanced HCC.  Non-invasive surrogate markers, therefore, are of particular importance in 
HCC. 
1.4.1 
Measurement of AFP as HCC Tumor Marker 
Peripheral blood measurements also offer the noninvasive potential to test surrogate markers.  
The most commonly measured blood tumor marker of HCC is alpha-fetoprotein (AFP), a 
glycoprotein highly expressed during hepatocyte development.(Pang, Joh et al. 2008)  AFP is 
secreted by approximately 70% of HCC and is diagnostic as well as prognostic.(Bruix and 
Sherman 2005; Pang, Joh et al. 2008; 2012)  Elevated baseline AFP levels have been shown to 
correlate with worse prognosis after hepatic resection as well as after local therapies such as 
chemoembolization.(O'Suilleabhain, Poon et al. 2003; Yeh, Lee et al. 2003; Masuda T 2007)  
AFP level may also have predictive value; a recent study of patients enrolled in a phase III 
randomized trial comparing two palliative cytotoxic chemotherapy regimens showed that 
patients with AFP decline by at least 20% (designated as AFP responders) demonstrated 
markedly improved survival by comparison with AFP non-responders, with overall survival 13.5 
versus 5.6 months, respectively (p < 0.0001).(Chan, Mo et al. 2009)  AFP changes are also 
associated with response to sorafenib and may be an early surrogate marker of 
response.(Kuzuya, Asahina et al. 2011; Yau, Yao et al. 2011; Personeni, Bozzarelli et al. 2012)  
AFP response data were not presented in SHARP; it is notable, however, that there appeared to 
be a higher median baseline AFP in the placebo patients.(Llovet, Ricci et al. 2008)  With the 
establishment of sorafenib as an effective treatment in HCC, change in AFP levels on treatment 
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1.4.2 
Enumeration of Circulating Tumor Cells in HCC 
Circulating tumor cells (CTC) will also be enumerated in patients in this study.  In the majority of 
carcinomas, tumor cells have been detected in peripheral blood from patients by using the 
CellSearch System (Veridex LLC).(Allard, Matera et al. 2004)  In breast and colon cancer, CTC 
levels convey prognostic information, correlating with PFS and overall survival; changes in CTC 
levels on treatment may also predict response to chemotherapy.(Cristofanilli, Budd et al. 2004; 
Cohen, Punt et al. 2008; Dawood, Broglio et al. 2008)  In a study of 20 patients with locally 
advanced or metastatic hepatocellular carcinoma, CTC were detected using the CellSearch 
system in 9 patients (45%).(Zee BC 2007)  Preliminary results from a pilot study at UCSF of 20 
patients with metastatic HCC show approximately 30% to have ≥ 3 CTC/7.5mL and 47% to 
have ≥ 1 CTC/7.5 mL detected, while none of 10 control patients with non-malignant liver 
disease had detectable CTC (R. Kelley, unpublished results).  A novel slide-based circulating 
epithelial cell assay (CEpiC) has also shown the ability to detect circulating tumor cells in 
patients with epithelial tumors including HCC (personal communication, P. Kuhn, The Scripps 
Research Institute).(Cho, Wendel et al. 2012; Wendel, Bazhenova et al. 2012)  Among 5 
patients treated in the PK expansion cohort of the UCSF-Northwestern phase I trial of 
temsirolimus plus sorafenib in advanced HCC, all 5 had detectable circulating epithelial cells by 
the slide-based CEpiC assay (K. Kelley, unpublished data).  Portal vein tumor invasion is a 
negative prognostic factor in HCC, and multiple studies have shown that tumor invasion or 
tumor thrombosis of the portal vein is a reliable predictor of shorter survival.(Tanaka, Tobe et al. 
1989; Giannelli, Pierri et al. 2002)  This suggests that tumor cells within the vasculature (such 
as are measured by CTC testing) may also be prognostic.  Along with the preliminary data 
showing detectability of CTC in HCC patients treated on the phase I trial of this treatment 
regimen, these data provide the rationale to further explore CTC levels as a potential biomarker 
in the current phase II study. 
1.4.3 
Markers of mTOR Pathway Activation 
Predictive biomarkers are essential to understand the efficacy of mTOR inhibition in HCC. 
Activation of the mTOR pathway (e.g. underexpression or loss of PTEN and/or LKB1, and/or 
overexpression of pAKT and/or pS6RP) is detectable by tumor immunohistochemistry (IHC) in 
approximately 50% of human HCCs and appears to be related to in vitro sensitivity to TORC1 
inhibition in HCC cell lines.1-3 Across tumor types, there are no clinically-validated markers of 
response to mTOR inhibitors.4 In a phase I/II study of everolimus in 28 patients with HCC, 3 of 
11 patients with available baseline tumor specimens demonstrated activation of the mTOR 
pathway by IHC for pAkt (S473), pmTOR, and/or pS6RP (S235/236); the only patient with a PR 
in the study had moderate or high levels of each marker.5 A prolonged partial response to 
everolimus in an HCC patient with high tumor pS6RP expression has been described.6  LKB1 is 
a tumor suppressor which when deficient or deleted is associated with mTOR pathway 
activation, a metastatic phenotype and poor outcomes.7  Preclinical models of LKB1-deficient 
tumors suggest sensitivity to mTOR inhibition.7  A correlative objective will be to examine 
whether tumor mTOR pathway activation as measured by selected IHC markers and by tumor 
next-generation DNA sequencing of a targeted panel including mTOR pathway genes is related 
to clinical outcomes of TORC1 inhibition.  
1.4.4 
Reactivation of Viral Hepatitis B Infection 
Given the potential immunosuppressive effect of mTOR inhibition, monitoring for viral hepatitis 
reactivation or exacerbation will be undertaken in patients with chronic active  HBV or HBV 
carriers undergoing experimental therapy with temsirolimus plus sorafenib. 


 
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1.4.5 
Cause of Underlying Liver disease 
As discussed in the previous sections, disparate outcomes are obtained with the use of 
sorafenib for HCC in a Western patient population with greater proportion having underlying 
HCV infection, by comparison to an Asian patient population with greater proportion having 
underlying HBV infection.(Cheng A. 2008; Kelley and Venook 2008; Llovet, Ricci et al. 2008)   
For this reason, subgroup analyses to compare TTP, PFS, OS, response rate, AFP response, 
and toxicity and tolerability based upon cause of underlying liver disease as well as Asian 
versus non-Asian ethnicity will be performed as exploratory endpoints. 
1.4.6 
Specimen Banking 
Studies in archival hepatoma tissue have suggested the prognostic value of a host of molecular 
features of HCC.  These include overexpression of angiogenic factors, activation of the 
Ras/Raf/ERK/MEK pathway, and aberrant mTOR pathway signaling.(Kim RD 2008; Li, Tan et 
al. 2008; Schmitz, Wohlschlaeger et al. 2008; Villanueva, Chiang et al. 2008; Baba, 
Wohlschlaeger et al. 2009)  In resected hepatoma tissue specimens, activation of components 
of the mTOR pathway including AKT and p70S6K correlate with a more invasive phenotype and 
poorer prognosis.(Li, Tan et al. 2008; Schmitz, Wohlschlaeger et al. 2008; Villanueva, Chiang et 
al. 2008)  Down-regulation of the tumor-suppressor PTEN which regulates mTOR activation 
may also confer poorer prognosis.(Villanueva, Chiang et al. 2008)  The success of sorafenib in 
HCC raises the question of whether tissue markers of Ras/Raf/ERK/MEK pathway activation 
may also predict response to this agent.  In the phase II study of sorafenib in HCC, higher 
pretreatment tumor phosphorylated ERK (pERK) levels within the nucleus, as measured by 
immunohistochemistry (IHC) in 33 patients, appeared to correlate with longer time to 
progression, though this association was not observed among the 110 patients with tissue 
pERK IHC testing from the SHARP trial.(Abou-Alfa, Schwartz et al. 2006; Llovet 2012) In 
another study of liver resection or explant specimens, increased levels of cytoplasmic pERK by 
IHC appeared to correlate with poorer prognosis and were associated with HCV infection, 
though this study did not involve patients treated with sorafenib.(Schmitz, Wohlschlaeger et al. 
2008)  Preclinical studies suggest that loss of PTEN activity and increased levels of activated 
AKT may confer sensitivity to mTOR inhibitors in vitro.(Neshat, Mellinghoff et al. 2001; 
Podsypanina, Lee et al. 2001)  The degree and duration of p70S6K inhibition in PBMCs may 
also correlate with response to mTOR inhibitors.(Peralba, DeGraffenried et al. 2003; Boulay, 
Zumstein-Mecker et al. 2004) 
Although we do not expect to have adequate numbers or quantities of tissue specimens to 
perform molecular testing in the context of this trial, we do plan to bank optional patient blood 
specimens (including serum, PBMC, whole blood, and plasma) specimens as well as fixed left-
over tissue specimens when available from all enrolled patients in this trial for possible future 
molecular, pharmacogenomic, and/or proteomic testing.  Such testing would be indicated if 
there is a subset of patients with sustained radiographic response and/or prolonged disease 
control to suggest the existence of underlying predictive biomarkers. 
2. Objectives of the Study 
2.1 
Primary 
 
To determine the median time to progression (TTP) in patients with advanced HCC treated 
with combination of temsirolimus plus sorafenib 
2.2 
Secondary 
 
To determine response rate (RR) using RECIST 1.1  
 
To measure median progression-free survival (PFS) 


 
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 
To measure median overall survival (OS)  
 
To measure time to treatment failure (TTF) 
 
To measure change in AFP tumor marker and examine for association between change in 
AFP and TTP and best response 
 
To characterize toxicity and tolerability of the combination of temsirolimus plus sorafenib, 
including describing frequency of dose reductions, delays, and discontinuation for toxicity  
2.3 
Exploratory Objectives and Other Assessments 
 
TTP, RR, PFS, OS, TTF, AFP response, and toxicity and tolerability will be described in 
subsets defined by HBV, HCV, Asian, and non-Asian status. 
 
To enumerate CTC at baseline and after 1 and 2 cycles of therapy to evaluate for any 
relationship between baseline levels and change in levels with median TTP and/or OS 
 
To characterize baseline mTOR pathway activation by immunohistochemistry (IHC) for 
selected markers such as pS6RP, pAKT, PTEN, and LKB1, and by tumor next-generation 
DNA sequencing of targeted genes including mTOR pathway in archival tumor specimens 
from HCC patients treated with temsirolimus plus sorafenib. 
 
To examine the relationship between baseline mTOR pathway activation by IHC and by 
sequencing and clinical outcomes on treatment with temsirolimus plus sorafenib. 
 
In patients with chronic active HBV infection or exposure, to monitor hepatitis viral load 
during and after therapy with an mTOR inhibitor 
 
To bank peripheral blood specimens and left-over archival pathology or cytology specimens 
for future research 
2.4 
Endpoints 
2.4.1 
Primary Endpoint 
 
Median TTP will be calculated in months from date of first dose of protocol therapy to date of 
removal from study for progression. For patients removed from study for other reasons than 
progression (such as toxicity, withdrawal of consent, death without documented progression, 
or other reasons without clinical or radiographic evidence of tumor progression), TTP will be 
censored at the date last known to be progression-free.   
2.4.2 
Secondary Endpoints 
 
Response rate (RR) will be measured by RECIST version 1.1.   
 
Median PFS will be calculated in months from date of first dose of protocol therapy to date 
of documented disease progression or death from any cause.  For patients removed from 
study for other reasons than progression or death, PFS will be censored at the date last 
known to be progression-free. 
 
Median OS for all enrolled patients who receive at least one dose of protocol therapy will be 
calculated from date of first dose of protocol therapy until date of death, using chart review 
and/or follow up phone calls to determine date of death in patients after removal from study.   
 
TTF will be measured from date of first dose of protocol therapy to date of study 
discontinuation for progression, death, or adverse events (related or unrelated).  For 
patients removed from study for other reasons (such as noncompliance or withdrawal of 
consent), TTF will be censored at the date of study discontinuation.  
 
In patients with baseline AFP ≥ 20 ng/mL, AFP response will be measured by the percent 
change from baseline value to the value at the time of best AFP response.  The proportion 


 
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of ≥ 50% decline from baseline will be measured.  The change in AFP will also be examined 
for association with absolute TTP and best response. 
 
Toxicity will be measured using Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0.  The frequency of dose reduction, treatment delays, and discontinuation for lack 
of tolerability will be quantified. 
2.4.3 
Exploratory Endpoints 
 
TTP, RR, PFS, OS, TTF, AFP response, and toxicity and tolerability will be described in 
subsets defined by HBV, HCV, Asian, and non-Asian status. 
 
CTC will be enumerated in peripheral blood at baseline and after 1 and 2 cycles of therapy 
to evaluate for any relationship between baseline levels and change in levels with median 
TTP and/or OS. 
 
Baseline mTOR pathway activation status as measured by immunohistochemistry (IHC) for 
selected markers such as pS6RP, pAKT, PTEN, and LKB1, and by a targeted next-
generation tumor DNA sequencing panel including mTOR pathway genes in archival tumor 
specimens. 
 
Relationship between baseline mTOR pathway activation by IHC and/or sequencing and 
clinical outcomes including TTP and AFP response. 
 
In patients with chronic active HBV and/or positive HBcAb, hepatitis B viral DNA quantitative 
will be monitored for rates of viremia/reactivation on study. 
 
Optional patient blood specimens (including serum, PBMC, whole blood, and plasma) and 
left-over archival pathology or cytology specimens will be banked in the UCSF Hepatobiliary 
Tissue Bank for future research. 
3. Study Design 
3.1 
Characteristics 
This study is a single-arm, one-stage, open-label phase II trial to evaluate the efficacy of the 
combination of temsirolimus plus sorafenib in first line therapy for patients with histologically-
confirmed advanced HCC. 
3.2 
Number of Subjects 
The target sample size is 25 evaluable patients for the primary endpoint. With the expectation of 
approximately 10% ineligibility rate, the expected maximum enrollment will be 28 patients.  
Eligible patients who receive at least one dose of protocol therapy will not be replaced.  Patients 
will be replaced and removed from study if determined to be ineligible after enrollment (for 
reasons such as  inability to comply/withdrawal of consent or other ineligibility) 
3.3 
Eligibility Criteria 
The study population will be patients with advanced, unresectable HCC with adequate 
performance status and Child-Pugh class A or B with ≤ 7 points liver function who have not 
received prior systemic therapy including no prior sorafenib. 
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria.  In addition, the patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required evaluations and all 
regulatory requirements for informed consent.  The written informed consent must be obtained 
from the patient prior to enrollment.  The following criteria apply to all patients enrolled onto the 
study unless otherwise specified. 


 
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3.3.1 
Inclusion Criteria 
1. Patients must have histologically diagnosed AJCC stage II, III, or IV HCC not eligible for 
curative resection, transplantation, or ablative therapies 
a. Cases with mixed, composite, or combined HCC-cholangiocarcinoma histology are 
eligible with approval from study chair and provided the treating investigator believes 
it is in the best interest of the patient to treat the tumor with therapy targeted towards 
the HCC component of tumor based upon review of pathology and clinical 
characteristics 
2. Radiographically measurable disease by RECIST version 1.1 in at least one site not 
previously treated with chemoembolization, radioembolization, or other local ablative 
procedures (i.e. must have at least one measurable target lesion, either within the liver or in 
a measurable metastatic site); a new area of tumor progression within or adjacent to a 
previously-treated lesion, if clearly measurable by a Radiologist, is acceptable 
3. No prior systemic cytotoxic chemotherapy or targeted therapy (including sorafenib) for HCC  
4. Prior chemoembolization, local ablative therapies, or hepatic resection permitted if 
completed ≥ 4 weeks prior to study enrollment if patient has recovered with ≤ grade 1 
toxicity and if measurable disease (criterion 2) is present 
5. Prior radiation for bone or brain metastases is permitted if patient is now asymptomatic and 
has completed all radiation and steroid therapy (if applicable) for brain or bone metastases  
≥ 2 weeks prior to study enrollment. 
6. Age ≥ 18 years. 
7. Child-Pugh score of A or B with ≤ 7 points and meeting laboratory eligibility for all 
parameters 
8. ECOG performance status of 0 or 1 
9. Life expectancy greater than 3 months 
10. Treatment with appropriate antiviral therapy for patients with active HBV infection is required 
11. Treatment for clinically-significant hyperglycemia, hyperlipidemia, or hypertension that 
develops on study is required 
12. Baseline blood pressure must be adequately controlled with or without antihypertensive 
medications prior to enrollment (systolic ≤ 150 mm Hg, diastolic ≤ 90 mm Hg) 
13. Baseline cholesterol must be < 350 mg/dL and triglycerides < 300 mg/dL (with or without the 
use of antihyperlipidemic medications) 
14. Baseline fasting blood glucose must be ≤ 140 mg/dL and hemoglobin A1c less than 7.5% 
(with or without the use of anti-diabetic medications) 
15. Adequate baseline organ and marrow function as defined below 
Adequate bone marrow function: 
absolute neutrophil count 
≥ 1,000/mcL 
platelets 
≥ 75,000/mcL 


 
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hemoglobin 
≥ 8.5 g/dL 
Adequate hepatic function: 
total bilirubin 
≤ 2 mg/dL or ≤ 1.5 times ULN 
AST(SGOT) & ALT (SGPT) ≤ 5 X ULN 
INR 
≤1. 5 X ULN 
Adequate renal function: 
albumin 
≥ 2.8 g/dL 
creatinine 
≤1. 5 X ULN 
16. Able to tolerate oral therapy. 
17. Ability to understand and willingness to provide informed consent, and the willingness to 
comply with the requirements of the protocol. Informed consent may be obtained with the 
assistance of a medical translator according to institutional policies. 
18. The effects of temsirolimus on the developing human fetus are unknown.  For this reason 
and because sorafenib - also being used in this trial - is known to be teratogenic, women of 
child-bearing potential must have a negative pregnancy test within 14 days of study 
enrollment.  
Also, women of child-bearing potential and men must agree to use two methods adequate 
contraception (hormonal plus barrier or two forms of barrier) or abstinence prior to study 
entry and for the duration of study participation.  Should a woman become pregnant or 
suspect she is pregnant while she or her partner is participating in this study, she needs to 
inform her treating physician immediately.  Men treated or enrolled on this protocol must 
also agree to use adequate contraception prior to the study, or be surgically sterile, for the 
duration of study participation, and for 3 months after completion of study drug 
administration. 
19. Eligibility of patients receiving any medications or substances known to affect or with 
potential to affect the activity or pharmacokinetics of temsirolimus and/or sorafenib will be 
determined following review of the case by the Study Chair.  Efforts should be made to 
switch patients who are taking enzyme-inducing anti-convulsant agents to other 
medications.  A list of medications and substances known or with the potential to interact 
with selected relevant CYP450 isoenzymes, P-glycoprotein pathway, and/or UGT1A1 
glucuronidation is provided in Appendices 6-9. 
3.3.2 
Exclusion Criteria 
1. Biliary tract cancers or fibrolamellar variant tumors are excluded. 
a. Cases with mixed, composite, or combined HCC-cholangiocarcinoma histology are 
eligible with approval from study chair and provided the treating investigator believes it 
is in the best interest of the patient to treat the tumor with therapy targeted towards the 
HCC component of tumor based upon review of pathology and clinical characteristics 
2. Prior systemic or antiangiogenic therapy for HCC (including thalidomide, sorafenib, sunitinib, 
or bevacizumab).  Prior systemic therapy for other diagnoses is permitted if greater than 6 
months have elapsed since last dose, any prior toxicity has recovered to ≤ grade 1 by 
CTCAE v4.0, and treatment was not discontinued for toxicity.   
3. Prior treatment with mTOR inhibitor or other molecularly targeted therapy.\ 


 
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4. Prior systemic cytotoxic therapies for HCC (chemoembolization is permitted if inclusion 
criteria are met). 
5. Treatment with other investigational agents. 
6. Immunosuppressive medications including systemic corticosteroids unless used for adrenal 
replacement, appetite stimulation, acute therapy for asthma or bronchitis exacerbation (≤ 2 
weeks), or antiemesis 
7. Patients with known HIV infection are ineligible due to risk of pharmacokinetic interactions 
between anti-retroviral therapy and the study drugs, as well as potential for significant 
immunosuppression and serious infections with mTOR inhibition. 
8. Patients who have undergone liver transplantation are excluded. 
9. Uncontrolled hypertension (> 150/90 mmHg). 
10. Uncontrolled hyperlipidemia (total cholesterol > 350 or triglycerides > 300).   
11. Symptomatic brain or bone metastases; prior radiation and/or steroid therapy for brain or 
bone metastases (if applicable) must be completed ≥ 2 weeks prior to study enrollment. 
12. History of seizure disorder requiring antiepileptic medication or brain metastases with 
seizures.   
13. Serious non-healing wound, ulcer, bone fracture, or abscess. 
14. Major surgical procedure less than 4 weeks from start of protocol treatment. 
15. Patients requiring chronic anticoagulation with warfarin are excluded. Patients treated with 
low molecular weight heparin or unfractionated heparin are eligible if on a stable dose 
without evidence of clinically significant bleeding for at least 2 weeks prior to enrollment. 
16. Active second malignancy other than non-melanoma skin cancer or cervical carcinoma in 
situ.  (Patients with history of malignancy are not considered to have a “currently active” 
malignancy if they have completed therapy and are now considered by their physician to be 
at less than 30% risk for relapse.) 
17. Uncontrolled intercurrent illness including, but not limited to: Ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac 
arrhythmia, uncontrolled peripheral vascular disease, myocardial infarction within preceding 
12 months, cerebrovascular accident within preceding 12 months, pulmonary disease 
impairing functional status or requiring oxygen, impairment in gastrointestinal function that 
may affect or alter absorption of oral medications (such as malabsorption or history of 
gastrectomy or bowel resection).   
18. Patients will be excluded if there is any history of allergic reaction(s) attributed to 
compounds of similar composition to temsirolimus, sorafenib, their metabolites, or any 
component of their formulation (including excipients and polysorbate 80).  This includes 
hypersensitivity to macrolide antibiotics due to potential for cross-reactivity with 
temsirolimus. 
19. Pregnant or lactating women are excluded from this study because temsirolimus and 
sorafenib are drugs with the potential for teratogenic or abortifacient effects.  Because there 
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of the mother with temsirolimus or sorafenib, breastfeeding should be discontinued if the 
mother is receiving temsirolimus/sorafenib treatment. 
20. Patients who require prohibited medications with potential for serious interactions with 
protocol therapy, and who cannot have therapeutic substitution are excluded.  Patients 
receiving any medications or substances that are inhibitors or inducers of CYP450 
enzyme(s) are ineligible.  Lists of prohibited medications and substances known, or with the 
potential to interact with the specified CYP450 enzyme(s) isoenzymes are provided in 
Appendices 6-9 Prohibited Medications  
21. Psychiatric illness, other significant medical illness, or social situation which, in the 
investigator’s opinion, would limit compliance or ability to comply with study requirements. 
3.4 
Duration of Therapy 
In the absence of treatment delays due to adverse events, individual patient treatment may 
continue indefinitely, or until: 
 
Disease progression by RECIST 1.1 or clinically 
 
Inter-current illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) toxicity, or unmanageable toxicity despite optimal supportive 
care and dose modifications (Section 5 Treatment Plan) 
 
Patients decides to withdraw from the study or is unable to comply with study procedures 
 
General or specific changes in the patients’ condition, or other factors which may influence 
safety or compliance, that render the patient unacceptable for further treatment in the 
judgment of the investigator 
When a patient is discontinued from the study, the reason(s) for discontinuation will be 
documented in study records.   
3.5 
Duration of Follow Up 
After treatment discontinuation, follow up for overall survival monitoring will be performed as 
described in Section 6.1 Schedule of Procedures and Observations for up to 5 years or until 
death, whichever comes first.  The study will end 5 years after the final patient discontinues 
treatment or after all patients are deceased, whichever comes first. 
3.6 
Randomization Procedures 
This study does not involve randomization 
3.7 
Study Timeline 
3.7.1 
Primary Completion 
Based upon the accrual rate to the predecessor phase I trial of this regimen at UCSF and 
Northwestern, the study is expected to complete accrual approximately 24 months from the time 
the study opens to accrual. 
3.7.2 
Study Completion 
The study is expected to reach completion once the final patient has been enrolled and all 
patients have had potential for at least 6 months of follow up or been removed from study.  
Study completion is expected approximately 2.5 years from study opening. 


 
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4. Study Drugs 
4.1 
Description, Supply and Storage of Investigational Drugs 
4.1.1 
Temsirolimus (TORISEL®) 
Please refer to the updated Investigator’s Brochure as well as Package Insert for temsirolimus 
for complete drug information. (Pfizer 2011; Wyeth 2011) 
Temsirolimus is supplied as a kit containing TORISEL® injection vial and a diluents vial.  The 
TORISEL® vial contains temsirolimus at a concentration of 25 mg/mL.  The vial contains an 
overfill of 0.2 mL to ensure the ability to withdraw the recommended dose.  The diluent vial 
includes a deliverable volume of 1.8 mL. This vial contains an overfill in order to ensure that the 
appropriate volume can be withdrawn. 
Classification 
Temsirolimus is a specific inhibitor of the mammalian target of rapamycin (mTOR), an enzyme 
that regulates cell growth and proliferation. 
Mechanism of Action 
Temsirolimus is an inhibitor of mTOR (mammalian target of rapamycin).  Temsirolimus binds to 
an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mTOR 
that controls cell division.  Inhibition of mTOR activity resulted in a G1 growth arrest in treated 
tumor cells.  When mTOR was inhibited, its ability to phosphorylate p70S6k and S6 ribosomal 
protein, which are downstream of mTOR in the PI3 kinase/AKT pathway was blocked.  In in vitro 
studies using renal cell carcinoma cell lines, temsirolimus inhibited the activity of mTOR and 
resulted in reduced levels of the hypoxia-inducible factors HIF-1 and HIF-2 alpha, and the 
vascular endothelial growth factor (VEGF). 
Metabolism 
Cytochrome P450 3A4 is the major isozyme responsible for the formation of five temsirolimus 
metabolites. Sirolimus, an active metabolite of temsirolimus, is the principal metabolite in 
humans following intravenous treatment. The remainder of the metabolites account for less than 
10% of radioactivity in the plasma. In human liver microsomes temsirolimus was an inhibitor of 
CYP2D6 and 3A4. However, there was no effect observed in vivo when temsirolimus was 
administered with desipramine (a CYP2D6 substrate), and no effect is anticipated with 
substrates of CYP3A4 metabolism.   
Elimination is primarily via the feces. After a single IV dose of [14C]-temsirolimus approximately 
82% of total radioactivity was eliminated within 14 days, with 4.6% and 78% of the administered 
radioactivity recovered in the urine and feces, respectively. Following a single 25 mg dose of 
TORISEL® in patients with cancer, temsirolimus mean (CV) systemic clearance was 16.2 (22%) 
L/h. Temsirolimus exhibits a bi-exponential decline in whole blood concentrations and the mean 
half-lives of temsirolimus and sirolimus were 17.3 hr and 54.6 hr. 
Temsirolimus is a substrate of the efflux transporter P-glycoprotein (Pgp) in vitro. If TORISEL® is 
administered with drugs that inhibit Pgp, increased concentrations of temsirolimus are likely, 
and caution should be exercised. In vitro, temsirolimus inhibited human Pgp (IC50 value of 
2μM). If TORISEL® is administered with drugs that are substrates of Pgp, increased 
concentrations of the substrate drug are likely and caution should be exercised. 
No dosage adjustment for temsirolimus is recommended in patients with renal impairment. 
There have been no clinical studies of this agent in patients with impaired renal function, though 
renal impairment is not expected to markedly influence drug exposure. Less than 5% of total 
radioactivity was excreted in the urine following a 25 mg intravenous dose of [14C]-labeled 


 
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temsirolimus in healthy subjects. Temsirolimus has not been studied in patients undergoing 
hemodialysis. 
Temsirolimus is cleared predominantly by the liver. 
Contraindications 
Temsirolimus IV is contraindicated in persons with known hypersensitivity to temsirolimus or any 
component of the formulation. Temsirolimus is contraindicated in patients with bilirubin >1.5 x 
ULN. 
Availability 
Temsirolimus is FDA-approved for the treatment of advanced renal cell carcinoma (RCC).  
Temsirolimus will be supplied for this trial directly by the manufacturer, Pfizer, Inc., from 
commercial supplies.  See Section 4.2 Drug Accountability. 
Storage and handling 
Temsirolimus Concentrate for Injection should be stored refrigerated (2C to 8C) and 
protected from light. When co-packaged with Temsirolimus Concentrate for Injection, Diluent for 
Temsirolimus Concentrate for Injection should be stored refrigerated (2C to 8º C). The active 
product and diluent must be allowed to warm to room temperature for approximately 1 hour 
before dilution. Dilution of Temsirolimus Concentrate for Injection in Diluent for Temsirolimus 
Concentrate for Injection must be followed by further dilution into an infusion bag or bottle of 
0.9% sodium chloride injection. The drug-diluent mixture is stable for up to 24 hours at 
controlled room temperature. 
The final diluted infusion solution (drug-diluent in sodium chloride injection) should be stored in 
a secured, clean environment, at room temperature, and administered within 6 hours from the 
time that the concentrate-diluent mixture is added to the 0.9% sodium chloride injection. 
Admixtures of temsirolimus are stable under ordinary fluorescent room light, but should be 
protected from excessive light, such as sunlight. Temsirolimus Concentrate for Injection, when 
constituted, contains polysorbate 80, which is 
known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl 
chloride (PVC). This should be considered during the preparation and administration of 
Temsirolimus Concentrate for Injection admixture, including storage time elapsed when in direct 
contact with PVC following constitution. It is recommended to use infusion bags and sets 
composed of glass, polyolefin, or polyethylene, to avoid excessive loss of drug and to decrease 
the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction. 
An in-line filter with a pore size of not greater than 5 microns is recommended for administration. 
The following are examples of in-line filters that are compatible with Temsirolimus Concentrate 
for Injection: 
 
IV 6200 Disposable IV Filter 0.2 m, by EPS, Inc. 
 
IV 6120 Disposable IV Filter 1.2 m, by EPS, Inc. 
 
LV 5000 Large Volume 5 m Conical Filter, by B. Braun 
 
Codan 0.2 m monofilter 
 
Baxter Paclitaxel Set with 0.22 m filter 
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Refer to the temsirolimus Package Insert for updated and complete storage and handling 
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Preparation 
During handling and preparation of admixtures, temsirolimus should be protected from 
excessive room light and sunlight. Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration, whenever solution and container 
permit. In order to minimize the patient exposure to the plasticizer DEHP (di-2-ethylhexyl 
phthalate), which may be leached from PVC infusion bags or sets, the final temsirolimus dilution 
for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, 
polyolefin) and administered through polyethylene-lined administration sets.  
Dilution: In preparing the TORISEL® administration solution, follow this two-step dilution process 
in an aseptic manner.  
Step 1: Inject 1.8 mL of DILUENT for TORISEL® into the vial of TORISEL® (temsirolimus) 
injection (25 mg/ml). The TORISEL® (temsirolimus) vial contains an overfill of 0.2 mL (30 mg/1.2 
mL). Due to the intentional overfill in the TORISEL® injection vial, the drug concentration of the 
resulting solution will be 10 mg/mL. A total volume of 3 mL will be obtained including the overfill. 
Mix well by inversion of the vial. Allow sufficient time for air bubbles to subside. This 10 mg/mL 
drug solution/diluent mixture must be further diluted as described in Step 2 below. The solution 
is clear to slightly turbid, colorless to yellow, and free from visual particulates. The 10 mg/mL 
drug solution/diluent mixture is stable for up to 24 hours at controlled room temperature.  
Step 2: Withdraw the required amount of temsirolimus from the 10 mg/mL drug solution/diluent 
mixture prepared in Step 1. Inject rapidly into a 250 mL container (glass, polyolefin, or 
polyethylene) of 0.9% sodium chloride injection. Mix the admixture by inversion of the bag or 
bottle. Avoid excessive shaking as this may cause foaming. 
Administration 
Administration of the final diluted infusion solution should be completed within six hours from the 
time that the concentrate diluent mixture is added to the sodium chloride injection. 
Temsirolimus Concentrate for Injection is infused over a 30-60 minute period (60 minutes for all 
doses during cycle one) once a week. The use of an infusion pump is the preferred method of 
administration to ensure accurate delivery of the drug. It is recommended to use infusion bags 
and sets composed of glass, polyolefin, or polyethylene, to avoid excessive loss of drug and to 
decrease the rate of di-(2-ethylhexyl) phthalate (DEHP) extraction. This should be considered 
during the preparation and administration of Temsirolimus Concentrate for Injection admixture, 
including storage time elapsed when in direct contact with PVC following constitution. An in-line 
filter with a pore size of not greater than 5 microns is recommended for administration. 
Incompatibilities 
Undiluted TORISEL® injection should not be added directly to aqueous infusion solutions. Direct 
addition of TORISEL® injection to aqueous solutions will result in precipitation of drug. Always 
combine TORISEL® injection with DILUENT for TORISEL® before adding to infusion solutions. It 
is recommended that TORISEL® be administered in 0.9% sodium chloride injection after 
combining with diluent. The stability of TORISEL® in other infusion solutions has not been 
evaluated. Addition of other drugs or nutritional agents to admixtures of TORISEL® in sodium 
chloride injection has not been evaluated and should be avoided. Temsirolimus is degraded by 
both acids and bases, and thus combinations of temsirolimus with agents capable of modifying 
solution pH should be avoided. 
Side Effects 
Complete and updated adverse event information is available in the Investigator’s Brochure 
and/or Package Insert for temsirolimus (TORISEL®). (Pfizer 2011; Wyeth 2011) 


 
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The most common adverse reactions (incidence ≥ 30%) are rash, asthenia, mucositis, nausea, 
edema, and anorexia.  The most common laboratory abnormalities (incidence ≥ 30%) are 
anemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, elevated alkaline phosphatase, 
elevated serum creatinine, lymphopenia, hypophosphatemia, thrombocytopenia, elevated AST, 
and leukopenia.  Specific adverse events which may be associated with temsirolimus and/or 
special precautions for its use include but are not limited to: 
Hypersensitivity Reactions 
Hypersensitivity/infusion reactions, including but not limited to flushing, chest pain, dyspnea, 
hypotension, apnea, loss of consciousness, hypersensitivity and anaphylaxis, have been 
associated with the administration of temsirolimus.  These reactions can occur very early in the 
first infusion, but may also occur with subsequent infusions. Patients should be monitored 
throughout the infusion and appropriate supportive care should be available.  Temsirolimus 
infusion should be interrupted in all patients with severe infusion reactions and appropriate 
medical therapy administered. temsirolimus should be used with caution in persons with known 
hypersensitivity to temsirolimus or its metabolites (including sirolimus), polysorbate 80, or to any 
other component (including the excipients) of temsirolimus.  An H1 antihistamine should be 
administered to patients before the start of the intravenous temsirolimus infusion.  Temsirolimus 
should be used with caution in patients with known hypersensitivity to an antihistamine, or 
patients who cannot receive an antihistamine for other medical reasons. If a patient develops a 
hypersensitivity reaction during the temsirolimus infusion, the infusion should be stopped and 
the patient should be observed for at least 30 to 60 minutes (depending on the severity of the 
reaction). At the discretion of the physician, treatment may be resumed with the administration 
of an H1-receptor antagonist (such as diphenhydramine), if not previously administered, and/or 
an H2-receptor antagonist (such as intravenous famotidine 20 mg or intravenous ranitidine 50 
mg) approximately 30 minutes before restarting the temsirolimus infusion. The infusion may 
then be resumed at a slower rate (up to 60 minutes).  A benefit-risk assessment should be done 
prior to the continuation of temsirolimus therapy in patients with severe or life-threatening 
reactions. 
Hyperglycemia/Glucose Intolerance 
The use of temsirolimus is likely to result in increases in serum glucose. In the phase 3 trial, 
89% of patients receiving temsirolimus had at least one elevated serum glucose while on 
treatment, and 26% of patients reported hyperglycemia as an adverse event. This may result in 
the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent 
therapy. Serum glucose should be tested before and during treatment with temsirolimus. 
Patients should be advised to report excessive thirst or any increase in the volume or frequency 
of urination. 
Infections 
The use of temsirolimus may result in immunosuppression. Patients should be carefully 
observed for the occurrence of infections, including opportunistic infections. 
Interstitial Lung Disease 
Cases of interstitial lung disease, some resulting in death, occurred in patients who received 
temsirolimus. Some patients were asymptomatic, or had minimal symptoms, with infiltrates 
detected on computed tomography scan or chest radiograph. Others presented with symptoms 
such as dyspnea, cough, hypoxia, and fever. Some patients required discontinuation of 
temsirolimus and/or treatment with corticosteroids and/or antibiotics, while some patients 
continued treatment without additional intervention. Patients should be advised to report 
promptly any new or worsening respiratory symptoms. It is recommended that patients undergo 
baseline radiographic assessment by lung computed tomography scan or chest radiograph prior 
to the initiation of temsirolimus L therapy. Follow such assessments periodically, even in the 


 
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absence of clinical respiratory symptoms. It is recommended that patients be followed closely 
for occurrence of clinical respiratory symptoms. If clinically significant respiratory symptoms 
develop, consider withholding temsirolimus administration until after recovery of symptoms and 
improvement of radiographic findings related to pneumonitis. Empiric treatment with 
corticosteroids and/or antibiotics may be considered. 
Hyperlipemia 
The use of temsirolimus is likely to result in increases in serum triglycerides and cholesterol. In 
the phase 3 trial, 87% of patients receiving temsirolimus had at least one elevated serum 
cholesterol value and 83% had at least one elevated serum triglyceride value. This may require 
initiation, or increase in the dose, of lipid-lowering agents. Serum cholesterol and triglycerides 
should be tested before and during treatment with temsirolimus. 
Bowel Perforation 
Cases of fatal bowel perforation occurred in patients who received TORISEL®. These patients 
presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute 
abdomen. Patients should be advised to report promptly any new or worsening abdominal pain 
or blood in their stools. 
Renal Failure 
Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to 
disease progression occurred in patients who received temsirolimus. Some of these cases were 
not responsive to dialysis. 
Wound Healing Complications 
Use of temsirolimus has been associated with abnormal wound healing. Therefore, caution 
should be exercised with the use of TORISEL® in the perioperative period. 
Intracerebral Hemorrhage 
Patients with central nervous system tumors (primary CNS tumor or metastases) and/or 
receiving anticoagulation therapy may be at an increased risk of developing intracerebral 
bleeding (including fatal outcomes) while receiving temsirolimus L. 
Thrombocytopenia and Neutropenia 
Grades 3 and 4 thrombocytopenia and neutropenia have been observed in subjects with mantle 
cell lymphoma. 
Local Injection Site Reactions 
There are also postmarketing reports of temsirolimus extravasations resulting in swelling, pain, 
warmth, and erythema. 
Stevens-Johnson Syndrome 
This life-threatening skin rash has been reported in patients who received temsirolimus. 
Rare but Serious Events 
The following adverse reactions have been identified during post approval use of temsirolimus. 
Because these reactions are reported voluntarily from a population of uncertain size, it is not 
always possible to readily estimate their frequency or establish a causal relationship to drug 
exposure. The following adverse reactions have been observed in patients receiving 
temsirolimus: pleural effusion, hemodynamically significant pericardial effusions requiring 
intervention, convulsions, rhabdomyolysis, Stevens-Johnson Syndrome, and complex regional 
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Co-administration with Inducers or Inhibitors of CYP3A Metabolism 
Agents Inducing CYP3A Metabolism:  Strong inducers of CYP3A4/5 such as dexamethasone, 
carbamazepine, phenytoin, phenobarbital, rifampin, rifabutin, and rifampacin may decrease 
exposure of the active metabolite, sirolimus. If alternative treatment cannot be administered, a 
dose adjustment should be considered. St. John’s Wort may decrease temsirolimus plasma 
concentrations unpredictably. Patients receiving temsirolimus should not take St. John’s Wort 
concomitantly. 
Agents Inhibiting CYP3A Metabolism: Strong CYP3A4 inhibitors such as atazanavir, 
clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, 
saquinavir, and telithromycin may increase blood concentrations of the active metabolite 
sirolimus.  If alternative treatments cannot be administered, a dose adjustment should be 
considered. 
Concomitant use of temsirolimus with sunitinib 
The combination of temsirolimus and sunitinib resulted in dose-limiting toxicity.  Dose-limiting 
toxicities (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring 
hospitalization) were observed in two out of three patients treated in the first cohort of a phase 1 
study at doses of temsirolimus 15 mg IV per week and sunitinib 25 mg oral per day (Days 1-28 
followed by a 2-week rest). 
Administration of Vaccinations 
The use of live vaccines and close contact with those who have received live vaccines should 
be avoided during treatment with temsirolimus. Examples of live vaccines are: intranasal 
influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid 
vaccines. 
Use in Pregnancy 
Pregnancy Category D. Temsirolimus administered daily as an oral formulation caused embryo-
fetal and intrauterine toxicities in rats and rabbits at human sub-therapeutic exposures. Embryo-
fetal adverse effects in rats consisted of reduced fetal weight and reduced ossifications, and in 
rabbits included reduced fetal weight, omphalocele, bifurcated sternabrae, notched ribs, and 
incomplete ossifications. In rats, the intrauterine and embryo-fetal adverse effects were 
observed at the oral dose of 2.7 mg/m2/day (approximately 0.04-fold the AUC in cancer patients 
at the human recommended dose). In rabbits, the intrauterine and embryo-fetal adverse effects 
were observed at the oral dose of ≥7.2 mg/m2/day (approximately 0.12-fold the AUC in cancer 
patients at the recommended human dose). Women of childbearing potential should be advised 
to avoid becoming pregnant throughout treatment and for 3 months after TORISEL® therapy has 
stopped. Temsirolimus can cause fetal harm when administered to a pregnant woman. If this 
drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the 
patient should be apprised of the potential hazard to the fetus. Men should be counseled 
regarding the effects of TORISEL® on the fetus and sperm prior to starting treatment. Men with 
partners of childbearing potential should use reliable contraception throughout treatment and 
are recommended to continue this for 3 months after the last dose of TORISEL®. 
Use in Breastfeeding 
It is not known whether temsirolimus is excreted into human milk.  Animal studies suggest 
potential for tumorigenicity for sirolimus (active metabolite of temsirolimus) in animal studies.  
Breastfeeding patients are excluded from this study. 
Use in Elderly Patients 
Based on the results of a phase 3 study, elderly patients may be more likely to experience 
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4.1.2 
Sorafenib (NEXAVAR®) 
Please refer to the Investigator’s Brochure and Package Insert for sorafenib for complete 
information. (Bayer 2011) 
NEXAVAR® is prepared as tablets containing sorafenib tosylate (274 mg) equivalent to 200 mg 
of sorafenib.  NEXAVAR® tablets are round, biconvex, red film-coated tablets, debossed with 
the “Bayer cross” on one side and “200” on the other side. 
Classification 
Sorafenib is a small molecule bi-aryl urea with multikinase inhibitor activity. 
Mechanism of Action 
Sorafenib inhibits receptor tyrosine kinases including VEGFR2, VEGFR3, and PDGFR, 
receptors involved in angiogenesis.  Sorafenib also inhibits the serine-threonine kinase Raf-1 in 
the Ras/Raf/MAPK/MEK pathway which is an important signaling pathway in cellular 
proliferation.  Sorafenib demonstrates anti-tumor activity in hepatocellular carcinoma xenograft 
models, as well as specific anti-angiogenic activity with reduction in microvessel density. 
Metabolism 
In vitro and in vivo data indicate that sorafenib is metabolized primarily by the liver. Systemic 
exposure and safety data were comparable in patients with Child-Pugh A and B hepatic 
impairment. Sorafenib has not been studied in patients with Child-Pugh C hepatic impairment. 
No dosage adjustment is necessary when administering sorafenib to patients with Child-Pugh A 
and B hepatic impairment. Sorafenib has not been studied in patients undergoing renal dialysis. 
However, there is no evidence of increased toxicity in patients with moderate to severe renal 
impairment. 
Contraindications 
Sorafenib is contraindicated in patients with known severe hypersensitivity to sorafenib or any 
other component of NEXAVAR®. 
Availability 
Sorafenib is FDA-approved for the treatment of unresectable HCC and advanced RCC.  Locally-
obtained, commercial supplies of sorafenib will be prescribed for this study. 
Storage and handling 
The tablets are packaged in high-density polyethylene bottles (climate zones I/II) or alu-alu 
blisters (climate zones III/IV).  They should only be stored in the pack provided.  The storage 
temperature for high density polyethylene bottles should not exceed 25° C.  
Refer to the sorafenib Package Insert for complete storage and handling information. 
Side Effects 
Complete and updated adverse event information is available in the Investigational Drug 
Brochure and/or product Package Insert. (Bayer 2011). 
The most common adverse reactions (≥ 20%), which were considered to be related to 
NEXAVAR, are fatigue, weight loss, rash/desquamation, hand-foot skin reaction, alopecia, 
diarrhea, anorexia, nausea, and abdominal pain.  Specific adverse events which may be 
associated with sorafenib and/or special precautions for its use include but are not limited to: 
Dermatologic 


 
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Dermatological AEs (rash and HFSR) represented the most common AEs attributed to 
sorafenib. These events were rarely serious but did frequently lead to a transient dose 
interruption or reduction. Although these events may be troublesome and in some cases 
interfere with activities of daily living, these events were amenable to remedial therapy and were 
generally reversible. Management of dermatologic toxicities may include topical therapies for 
symptomatic relief, temporary treatment interruption and/or dose modification of sorafenib, 
which in severe or persistent cases, might include permanently discontinuing sorafenib. Patients 
with discomfort due to HFSR may be treated with topical emollients, high-potency topical 
steroids, or keratolytic creams (urea/salicylic acid). 
Gastrointestinal 
Gastrointestinal AEs (nausea, diarrhea) were the second most common toxicities associated 
with sorafenib. These events were rarely serious but did frequently lead to dose interruptions or 
reductions. The events were amenable to therapy and were generally considered an acceptable 
risk in this patient population. Patients with poorly tolerated GI or skin toxicities may be 
successfully managed with a brief dose interruption (until symptoms improve/resolve). 
Symptomatic therapies may also be initiated at the physician’s discretion. 
Gastrointestinal perforation has been reported as an uncommon event in patients taking 
sorafe
associated with apparent intra-abdominal tumor. Sorafenib therapy should be discontinued in 
case of such an event. 
Hypertension 
Hypertension was usually mild to moderate, occurred early in the course of treatment, and was 
amenable to management with standard antihypertensive therapy. Blood pressure should be 
checked regularly within the first 2 to 3 weeks of starting sorafenib therapy and then monitored 
and treated, if required, in accordance with standard medical practice. In cases of severe or 
persistent hypertension that persists despite antihypertensive therapy, permanent 
discontinuation of sorafenib should be considered.  
Rare but Serious Events 
Reversible posterior leukoencephalopathy, interstitial lung disease (ILD)-like events and 
Stevens-Johnson Syndrome have been reported as uncommon events in patients taking 
sorafenib.  
Fatigue and Anorexia 
Although fatigue and anorexia may be troublesome and in some cases severe, these events 
would be considered an acceptable risk in this patient population. 
Vascular Events and Bleeding 
The data do not suggest an appreciable risk of thrombosis or ischemic events associated with 
sorafenib, but in a placebo controlled study with a total of 768 patients in the intent-to-treat 
population, there was a slightly increased incidence of Grade 3 and 4 bleeding events in the 
sorafenib group and 1 [
of bleeding in a population of subjects with HCC, which is normally prone to bleeding 
complications. Patients receiving coagulation treatment should be routinely monitored. If any 
bleeding event necessitates medical intervention, it is recommended that permanent 
discontinuation of sorafenib be considered. 
There was no indication of wound healing impairment in patients undergoing surgery while 
taking sorafenib.  There was no influence on wound healing capacity as investigated in a rat 
model. However, temporary interruption of sorafenib is recommended in patients undergoing 


 
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major surgical procedures. Prior to elective procedures, it is recommended that sorafenib be 
interrupted for 5-7 days. There is limited clinical experience regarding the timing of reinitiation of 
sorafenib therapy following major surgical intervention. Therefore, the decision to resume 
sorafenib therapy following a major surgical intervention should be based on clinical judgment 
taking co-morbidities and need for adequate wound healing into consideration.  
Patients with vascular diseases such as wet macular degeneration, vasculitis, or new peptic 
ulcer or other evidence of bleeding may receive the full dose of sorafenib but require close 
monitoring in accordance with established medical practice. 
Cardiac Ischemia; Infarction 
Physicians should also discuss with patients that cardiac ischemia and/or infarction has been 
reported during NEXAVAR® treatment, and that they should immediately report any episodes of 
chest pain or other symptoms of cardiac ischemia and/or infarction. 
Infections 
The data suggest that sorafenib has a mild lymphopenic effect with a small increase in the risk 
of infection. The effect of sorafenib on leukocyte count does not pose a significant safety 
concern. 
Hypophosphatemia 
Hypophosphatemia appears to be associated with sorafenib therapy.  There were no instances 
of severe hypophosphatemia, defined as a serum phosphate value below 1.0 mg/dL, and there 
were no evident clinical manifestations associated with hypophosphatemia. 
Neuropathy 
Sorafenib was infrequently associated with peripheral neuropathy.  The timing of these events 
suggests an inflammatory process rather than a cumulative neurotoxic effect. 
Birth Defects, Fetal Loss, and Breastfeeding 
Physicians should inform female patients that sorafenib may cause birth defects or fetal loss 
and that they should not become pregnant during treatment with sorafenib and for at least 2 
weeks after stopping treatment.  Both male and female patients should be counseled to use 
effective birth control during treatment with sorafenib and for at least 2 weeks after stopping 
treatment.  Female patients should also be advised against breast-feeding while receiving 
sorafenib. 
4.2 
Drug Accountability 
The Investigational Pharmacist will manage drug accountability records for temsirolimus. 
Sorafenib will be procured from commercial supplies and accounted for according to standard of 
care. 
4.3 
Drug Ordering 
Sorafenib will be ordered as a standard of care medication and will be obtained from 
commercial supplies. 
Temsirolimus will be supplied for this trial directly by the manufacturer, Pfizer, Inc., from 
commercial supplies.  Temsirolimus will be shipped directly to the primary study site: UCSF 
Helen Diller Family Comprehensive Cancer Center, and to the study sub-site: Robert H. Lurie 
Comprehensive Cancer Center of Northwestern University.  Both sites will be responsible for 
direct distribution of the drug to the study patients and for drug accountability at each respective 
site. 


 
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To obtain temsirolimus study drug supply or for questions about temsirolimus supply, each site 
will contact Pfizer, Inc. directly: 
 
 
At the conclusion of the study, each institution will promptly contact the individual identified 
above at the research grant provider (Pfizer, Inc.) for instruction regarding whether to return all 
unused temsirolimus and associated diluent at the research grant provider’s expense, or 
whether to dispose properly of temsirolimus and associated diluent at its own expense and 
submit documentation of such destruction.  The determination as to whether the study drug 
shall be returned or destroyed is solely within the research grant provider’s discretion. 
4.4 
Packaging and Labeling of Study Drugs 
Drugs will be packaged and labeled per UCSF institutional standards, adhering to applicable 
local and federal laws. 
5. Treatment Plan 
5.1 
Dosage and Administration 
Treatment will be administered on an outpatient basis. 
Temsirolimus at a dose of 10 mg weekly will be administered intravenously over 60 minutes 
using an infusion pump in the study site infusion center starting on Cycle 1, Day 1 of study 
enrollment.  Infusion will be given through non-DEHP-containing tubing with an in-line 
polyethersulfone filter (≤ 5 microns).  Premedication with diphenhydramine 25-50 mg IV will be 
administered 30 minutes prior to each temsirolimus infusion.  Patients will be monitored by 
infusion center nursing staff every 15 minutes during infusion, with treatment interruption 
required for any evidence of an infusion reaction.  If hypersensitivity symptoms develop, infusion 
will be stopped.  Patients will be treated with additional H1 antagonist as well as an H2 
antagonist (such as famotidine 20 mg or ranitidine 50 mg intravenously) at discretion of treating 
investigator.  If hypersensitivity symptoms are mild (Grade 1 or 2) and resolve over 30-60 
minutes of observation and with administration of additional H1 and H2 blocker, infusion may 
resume with caution at a reduced rate (over approximately 60 minutes), at the discretion of the 
treating investigator.  Additional supportive care measures will be available in each study site 
infusion center in case of severe hypersensitivity reaction.  Temsirolimus dosing will continue 
weekly (± 3 days) until unacceptable toxicity, disease progression, the withdrawal of consent by 
the patient, or the decision to discontinue treatment by the treating physician.  Subsequent 
infusions starting Cycle 2, Day 1 may be given over 30 minutes if no evidence of infusion 
reaction is observed after the first cycle has been completed.   
Patients will be instructed to take sorafenib at starting dose of 200 mg 1 tab twice daily starting 
on Cycle 1, Day 1 of study enrollment after completion of temsirolimus infusion.  Sorafenib will 
be ingested with water on an empty stomach, either 1 hour before or 2 hours after food 
ingestion.  If unable to tolerate sorafenib on an empty stomach, it may be taken with a low fat 
meal.  The tablet will be swallowed whole.  Sorafenib dosing will continue daily or twice daily 
without interruption until unacceptable toxicity, disease progression, the withdrawal of consent 
by the patient, or the decision to discontinue treatment by the treating physician (see Section 
6.3 Reasons to Withdraw a Subject). 


 
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Table 5.1 
Regimen Description 
Study Drug 
Premedication; precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Temsirolimus 
Premedicate with diphenhydramine 
30 minutes prior to temsirolimus 
infusion; monitor every 15 minutes 
during infusion; administer with in-line 
filter 
10 mg 
IV 
Weekly(± 3 
days) 
4 weeks 
(28 days) 
Sorafenib 
Take on empty stomach or with low 
fat meal 
200 mg 
Oral 
BID 
5.2 
Dose Modifications and Dosing Delays 
The following adjustments should be made in the appropriate drug (depending on attribution of 
toxicity) based upon the guidelines below in Section 5.2.3 Dose Modification Protocol.  If either 
study drug is discontinued, a patient will be removed from study.   
5.2.1 
Temsirolimus Dose Modifications 
Patient Temsirolimus Dose Level 
Temsirolimus Dose Modification 
10 mg IV weekly (starting dose) 
↓to 7.5 mg IV weekly 
7.5 mg IV weekly 
↓to 5 mg IV weekly 
5 mg IV weekly 
Discontinue 
 
5.2.2 
Sorafenib Dose Modifications 
Patient Sorafenib Dose Level 
Sorafenib Dose Modification 
200 mg PO BID (starting dose) 
↓ to 200 mg QD 
200 mg PO QD 
↓ to 200 mg PO QOD 
200 mg PO QOD 
Discontinue 
 
5.2.3 
Dose Modification Protocol 
 
Held doses of either drug will be considered as omitted.  (For example, if temsirolimus is held 
on cycle 2, day 8, the next dose of temsirolimus the following week will be considered cycle 2, 
day 15, rather than delaying the cycle and repeating the day 8 dose.) 
 
Laboratory values should be rounded to one significant digit. 
 
For any toxicity (regardless of grade), despite optimal supportive care, that is felt by the 
treating investigator to represent a risk to the patient’s safety, additional dose reduction, 


 
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treatment delay, or treatment discontinuation is permitted at the discretion of the treating 
investigator. 
Toxicity 
Grade 
(NCI CTCAE v4.0) 
Temsirolimus 
Adjustment 
Sorafenib 
Adjustment 
HEMATOLOGIC 
Neutropenia 
Grade 1 
(ANC 1500 to < 2000/mm3) 
No change 
No change 
Grade 2 
(ANC 1000 to < 1500/mm3) 
No change 
No change 
Grade 3 
(ANC 500 to < 1000/mm3) 
Hold both drugs and recheck weekly until ≤ Grade 2, 
then decrease TEM by 1 DL and continue SOR at 
same dose; if recurs, hold both drugs and recheck 
weekly until ≤ Grade 2, then decrease SOR by 1 DL 
and continue TEM at same dose; continue 
alternating dose reductions if toxicity recurs 
Grade 4 
(ANC < 500/mm3) 
Hold both drugs and recheck weekly until ≤ Grade 2, 
then decrease both drugs by 1 DL 
Lymphopenia 
Any Grade 
No dose reductions or delays will be performed for 
lymphopenia 
Thrombocytopenia 
Grade 1 
(PLT 75,000 to < LLN/mm3) 
No change 
No change 
Grade 2 
(PLT 50,000 to < 75,000/mm3) 
No change 
No change 
Grade 3 
(PLT 25,000 to < 50,000/mm3) 
Hold both drugs and recheck weekly until ≤ Grade 2, 
then decrease TEM by 1 DL and continue SOR at 
same dose; if recurs, hold both drugs and recheck 
weekly until ≤ Grade 2, then decrease SOR by 1 DL 
and continue TEM at same dose; continue 
alternating dose reductions if toxicity recurs 
Grade 4 
(PLT < 25,000/mm3) 
Hold both drugs and recheck weekly until ≤ Grade 2, 
then decrease both drugs by 1 DL 
Anemia 
Any Grade 
No dose reductions or delays will be performed for 
anemia; transfusions and/or growth factor support 
may be used at the discretion of the investigator 
GASTROINTESTINAL (EXCLUDING HEPATIC DYSFUNCTION) 
Nausea/vomiting, 
constipation, or 
mucositis 
 
(despite optimal 
supportive care) 
Grade 1 
No change 
No change 
Grade 2 
No change 
No change 
Grade 3 
Hold both drugs until ≤ Grade 2, then decrease TEM 
by 1 DL and continue SOR at same dose; if recurs, 
hold both drugs until ≤ Grade 2, then decrease SOR 
by 1 DL and continue TEM at same dose; continue 
alternating dose reductions if toxicity recurs 
Grade 4 
Hold both drugs until ≤ Grade 2, then decrease both 
drugs by 1 DL 
Diarrhea 
 
(despite optimal 
supportive care) 
Grade 1 
No change 
No change 
Grade 2 
No change 
No change 
Grade 3 
Hold both drugs until ≤ Grade 2, then decrease SOR 
by 1 DL and continue TEM at same dose; if recurs, 
hold both drugs until ≤ Grade 2, then decrease TEM 
by 1 DL and continue SOR at same dose; continue 
alternating dose reductions if toxicity recurs 
Grade 4 
Hold both drugs until ≤ Grade 2, then decrease both 
drugs by 1 DL 


 
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Toxicity 
Grade 
(NCI CTCAE v4.0) 
Temsirolimus 
Adjustment 
Sorafenib 
Adjustment 
HEPATIC DYSFUNCTION 
Hyperbilirubinemia 
 
(substitute direct 
bilirubin values and 
normal ranges for 
patients with Gilbert’s 
Syndrome) 
Grade 1 
(BILT > ULN to 1.5 times ULN) 
No change 
No change 
Grade 2 
(BILT > 1.5 to 3 times ULN) 
Hold both drugs and recheck weekly until ≤ Grade 1, 
then decrease SOR by 1 DL and continue TEM at 
same dose; if recurs, hold both drugs and recheck 
weekly until ≤ Grade 2, then decrease TEM by 1 DL 
and continue SOR at same dose; continue 
alternating dose reductions if toxicity recurs 
Grade 3 
(BILT > 3 to 10 times ULN) 
Hold both drugs and recheck weekly until ≤ Grade 1, 
then decrease both drugs by 1 DL 
Grade 4 
(BILT > 10 times ULN) 
Discontinue protocol therapy 
Transaminase and 
alkaline phosphatase 
elevation 
 (if assessed as 
treatment-related, 
clinically relevant, and 
≥ 2 grades from 
baseline) 
Grade 1 
(> ULN to 2.5 times ULN) 
No change 
No change 
Grade 2 
(> 2.5 to 5 times ULN) 
No change 
No change 
Grade 3 
(> 5 to 20 times ULN) 
Hold both drugs and recheck weekly until ≤ Grade 2, 
then decrease SOR by 1 DL and continue TEM at 
same dose; if recurs, hold both drugs and recheck 
weekly until ≤ Grade 2, then decrease TEM by 1 DL 
and continue SOR at same dose; continue 
alternating dose reductions if toxicity recurs 
Grade 4 
(> 20 times ULN) 
Discontinue protocol therapy 
Ascites 
Grade 1 
(Asymptomatic) 
No change 
No change 
Grade 2 
(Symptomatic, requiring diuretic) 
No change 
New ascites: Hold SOR 
and reevaluate weekly; if 
recovers to ≤ Grade 1, then 
decrease SOR by 1 DL; if 
recurs/worsens, decrease 
TEM by 1 DL; continue 
alternating dose reductions 
if toxicity recurs 
Worsening in baseline 
Grade 1 or 2 ascites: 
Optimize with supportive 
care including diuretic 
regimen as needed; if 
recurs/worsens, decrease 
SOR by 1 DL; if 
recurs/worsens, decrease 
TEM by 1 DL; continue 
alternating dose reductions 
if toxicity recurs 


 
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Toxicity 
Grade 
(NCI CTCAE v4.0) 
Temsirolimus 
Adjustment 
Sorafenib 
Adjustment 
Grade 3 
(Symptomatic, requiring 
paracentesis) 
No change 
New ascites: Hold SOR 
and reevaluate weekly; if 
recovers to ≤ Grade 1, then 
decrease SOR by 1 DL; if 
recurs, decrease TEM by 1 
DL; if recurs/worsens 
despite  dose reductions in 
both drugs plus optimal 
supportive care, remove 
from study 
Worsening in baseline 
Grade 1 or 2 ascites: 
Optimize with diuretic 
regimen and paracentesis 
if needed for symptoms; if 
repeat paracentesis is 
required after ≥ 2 weeks 
despite optimizing 
supportive care and 
diuretics, decrease 
sorafenib by 1 DL; if 
recurs/worsens, decrease 
TEM by 1 DL; if 
recurs/worsens despite  
dose reductions in both 
drugs plus optimal 
supportive care, remove 
from study 
Grade 4 
(Life threatening) 
Discontinue protocol therapy 


 
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Toxicity 
Grade 
(NCI CTCAE v4.0) 
Temsirolimus 
Adjustment 
Sorafenib 
Adjustment 
CARDIOVASCULAR AND VASCULAR 
Hypertension 
Blood Pressure (BP) ≤ 140/90 
No change 
BP >140/90 and ≤ 160/100 
No change in study drugs; optimize anti-hypertensive 
regimen for goal BP ≤ 140/90; see section 6.1 
BP > 160/100 
If pre-treatment BP > 160/100, hold both drugs and 
treat according to Section 6.1; if BP remains > 
160/100 despite optimal medical management, 
hold both drugs until≤ 160/100, then decrease SOR 
by 1 DL; if HTN recurs with BP > 160/100, repeat 
and decrease SOR by 1 DL; if recurs again > 
160/100, discontinue protocol therapy  
Grade 4 
Discontinue protocol therapy 
Hemorrhage 
Grades 1, 2 
(Mild, not requiring transfusion) 
No change 
No change 
Grade 3 
(Requiring transfusion) 
No change 
Hold SOR until ≤ Grade 2, 
HCT stable for ≥ 1 week, 
bleeding resolved, and 
there is no known anatomic 
or pathologic condition that 
significantly increases risk 
of recurrent bleeding, then 
resume at same dose; if 
recurs, discontinue 
protocol therapy 
Grade 4 
(Catastrophic or CNS) 
Discontinue protocol therapy 
Arterial thrombosis, 
including myocardial 
ischemia or infarction, 
cerebrovascular 
accident, or 
mesenteric ischemia 
Any Grade 
Discontinue protocol therapy 
Venous thrombo-
embolism* requiring 
anticoagulation 
(*excluding portal or 
hepatic vessel 
thrombosis or tumor 
thrombus) 
Any Grade 
Discontinue protocol therapy 
RENAL AND METABOLIC 
Elevated creatinine 
 
(despite optimal 
supportive care, i.e. 
hydration if 
dehydrated, and if 
assessed as 
treatment-related, 
clinically relevant, and 
≥ 1 grade from 
baseline) 
Grade 1 
(CRE > ULN to 1.5  times ULN) 
No change 
No change 
Grade 2 
(CRE > 1.5 to 3 times ULN) 
Hold both drugs and recheck weekly until ≤ Grade 1, 
then resume at prior doses; if recurs, hold both drugs 
and recheck weekly until ≤ Grade 1, then decrease 
TEM by 1 DL and continue SOR at same dose; if 
recurs again, hold both drugs and recheck weekly 
until ≤ Grade 1, then decrease SOR by 1 DL and 
continue TEM at same dose; continue alternating 
dose reductions if toxicity recurs 
Grade 3 
(CRE > 3 to 6 times ULN) 
Hold both drugs and recheck weekly until ≤ Grade 1, 
then decrease both drugs by 1 DL 
Grade 4 
(CRE > 6 times ULN) 
Discontinue protocol therapy 
Hypo-phosphatemia 
 
Grade 1 
No change 
No change 
Grade 2 
No change 
No change 


 
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Toxicity 
Grade 
(NCI CTCAE v4.0) 
Temsirolimus 
Adjustment 
Sorafenib 
Adjustment 
(despite optimal 
supportive care, i.e. 
electrolyte repletion) 
Grade 3 
Asymptomatic, first occurrence:  Increase oral 
phosphate repletion regimen up to 3.5 grams per day 
as tolerated, encourage increased intake of 
phosphorus-rich foods, and continue study drug 
treatment.  Recheck in 1 week.  If ≤ Grade 2, 
continue treatment at current study drug dosage with 
the increased phosphate repletion.  If remains ≥ 
Grade 3, hold TEM, continue SOR, and continue 
increased phosphate repletion.  Recheck weekly until 
≤ Grade 2, then restart TEM with dose reduction by 1 
DL and continue SOR at prior dose. 
Asymptomatic, recurrent: If recurs after 1 dose level 
reduction in TEM despite continuing the highest 
tolerable dose of oral phosphate supplementation*, 
hold both drugs, continue repleting phosphate, and 
recheck weekly.  Once recovers to ≤ Grade 2, 
decrease SOR by 1 DL and continue TEM at prior 
dose.  Continue this protocol with alternating drug 
dose reductions if asymptomatic Grade 3 toxicity 
recurs.  
*If asymptomatic Grade 3 hypophosphatemia recurs 
but patients have not been taking the highest 
tolerable dose of oral phosphate 
supplementation, follow the hypophosphatemia 
algorithm above as for the first occurrence of 
asymptomatic grade 3 hypophosphatemia. 
Symptomatic, first occurrence: Increase oral 
phosphate repletion regimen up to 3.5 grams per day 
as tolerated, encourage increased intake of 
phosphorus-rich foods, and hold both TEM and SOR. 
Consider cautious intravenous phosphate 
supplementation at the investigator’s discretion and 
according to standard institutional protocols.  
Recheck weekly until ≤ Grade 2 and asymptomatic, 
then decrease TEM by 1 DL and resume SOR at 
prior dose. 
Symptomatic, recurrent: If recurs after 1 DL reduction 
in TEM and despite continuing the highest tolerable 
dose of oral phosphate supplementation*, hold both 
drugs and continue repleting phosphate.  Consider 
cautious intravenous phosphate supplementation at 
the investigator’s discretion and according to 
standard institutional protocols.  Recheck weekly.  
Once recovers to ≤ Grade 2 and asymptomatic, 
decrease SOR by 1 DL and continue TEM at prior 
dose. Continue this protocol with alternating drug 
dose reductions if toxicity recurs. *If symptomatic 
Grade 3 hypophosphatemia recurs but patients have 
not been taking the highest tolerable dose of oral 
phosphate supplementation, follow the 
hypophosphatemia algorithm above as for the first 
occurrence of symptomatic grade 3 
hypophosphatemia. 
Grade 4 
(< 1.0 mg/dL) 
Follow protocol above for symptomatic Grade 3 
hypophosphatemia. 
Hyperglycemia 
Grade 1 
No change 
No change 


 
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Toxicity 
Grade 
(NCI CTCAE v4.0) 
Temsirolimus 
Adjustment 
Sorafenib 
Adjustment 
 
(despite optimal 
supportive care) 
Grade 2 
No change 
No change 
Grade 3 
Hold TEM and recheck 
weekly until ≤ Grade 2, 
then decrease by 1 DL 
No change 
Grade 4 
Discontinue protocol therapy 
Hyperlipidemia 
 
(despite optimal 
supportive care) 
Grade 1 
No change 
No change 
Grade 2 
No change 
No change 
Grade 3 
Hold TEM and recheck 
weekly until ≤ Grade 2, 
then decrease by 1 DL 
No change 
Grade 4 
Hold TEM and recheck 
weekly until ≤ Grade 2, 
then decrease by 1 DL 
No change 
DERMATOLOGIC 
Hand-foot syndrome 
 
(despite optimal 
supportive care) 
Grade 1 
(Numbness, discomfort, 
dysesthesia/paresthesia, tingling, 
painless swelling, or erythema that 
does not disrupt normal activities) 
No change 
No change 
Grade 2 
(Painful erythema, swelling, or 
discomfort that disrupts normal 
activities) 
No change 
Hold SOR until ≤ Grade 1, 
then resume at prior dose; 
if recurs, hold SOR until  ≤ 
Grade 1, then decrease by 
1 DL 
Grade 3 
(Moist desquamation, ulceration, 
blistering, or severe pain that 
disrupts ADL) 
No change 
Hold SOR until ≤ Grade 1, 
then decrease by 1 DL 
Grade 4 
Discontinue protocol therapy 
Other dermatologic 
toxicity (including 
dermatitis, non-
healing wound, 
pruritis, 
desquamation) 
 
(despite optimal 
supportive care) 
 
Grade 1 
No change 
No change 
Grade 2 
No change 
Hold SOR until ≤ Grade 1, 
then resume at prior dose; 
if recurs, hold SOR until  ≤ 
Grade 1, then decrease by 
1 DL 
Grade 3 
Hold both drugs until ≤ Grade 1, then reduce SOR 
and/or TEM by 1 DL based upon the investigator’s 
attribution of toxicity 
Grade 4 
Discontinue protocol therapy if severe or life-
threatening toxicity, versus apply modification for 
Grade 3 
OTHER 
Other toxicities* 
 
(despite optimal 
supportive care) 
Grade 1 
No change 
No change 
Grade 2 
No change 
No change 
Grade 3 
Hold both drugs until ≤ Grade 1, then reduce SOR 
and/or TEM by 1 DL based upon the investigator’s 
attribution of toxicity 
Grade 4 
Discontinue protocol therapy if severe or life-
threatening toxicity, versus apply modification for 
Grade 3 
*For any toxicity (regardless of grade), despite optimal supportive care, that is felt by the treating investigator to 
represent a risk to the patient’s safety, additional dose reduction, treatment delay, or treatment discontinuation 
is permitted at the discretion of the treating investigator. 


 
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5.2.4 
Unacceptable Toxicities 
Patients must be removed from the study and protocol therapy discontinued for toxicities 
deemed by the treating investigator as unacceptable.  These toxicities include but are not 
limited to: 
 
Thrombotic events, including cerebrovascular accident, myocardial infarction or ischemia, 
gastrointestinal infarction or ischemia, pulmonary embolus, or any thrombotic event requiring 
anticoagulation.  New appearance of hepatic or portal vein thromboses are excluded.  
Patients with superficial thrombophlebitis, superficial venous thrombosis, or portal venous or 
hepatic vessel thrombosis not requiring anticoagulation may remain on therapy at the 
discretion of the treating physician.   
 
Recurrent grade 3 or any grade 4 hemorrhage. 
 
Gastrointestinal perforation requiring medical or surgical therapy. 
 
Wound dehiscence requiring medical or surgical therapy. 
 
Grade 4 hypertension despite optimal medical management. 
 
Grade 4 hypersensitivity reaction to either study drug, or Grade 3 reaction that recurs 
despite optimal supportive care. 
 
Any Grade 3 or 4 toxicity that is deemed serious and/or life-threatening by the treating 
investigator. 
 
Any irreversible (≥ 2 weeks despite optimal supportive care) Grade 3 or 4 toxicity (excluding 
nausea, vomiting, asymptomatic Grade 3 hypophosphatemia or Grade 3 hyponatremia, 
anemia, lymphopenia, or fatigue). 
5.3 
Management of Toxicities 
Each patient receiving at least 1 dose of temsirolimus in combination with at least 1 dose of 
sorafenib will be evaluable for safety.  The safety parameters include all laboratory tests and 
hematological abnormalities, physical findings, and spontaneous reports of adverse events 
reported to the investigator by patients. 
Each patient will be assessed periodically for the development of any toxicity as outlined in 
Table 6.1, Schedule of Study Procedures and Assessments.  Toxicity will be assessed 
according to the NCI CTCAE v4.0.  Dose adjustments, treatment delay, and treatment 
discontinuation will be determined according to the system showing the greatest degree of 
toxicity. Toxicity will be formally assessed at protocol-defined assessment timepoints well as by 
investigator review of weekly laboratory testing and, in the interim, by patient contact with the 
study coordinator and/or treating investigator should new symptoms arise between visits.  
General principles of toxicity management are listed below: 
 
Temsirolimus and sorafenib will be dose-adjusted according to investigator’s attribution of 
toxicity.  In equivocal cases, the decision may be made by treating investigator. 
 
Asymptomatic changes in laboratory values require dose modification only if assessed to be 
treatment-related, clinically relevant, and represent a change of ≥ 2 grades from baseline. 
 
If toxicity occurs, supportive care medications should be applied to ameliorate signs and 
symptoms (including antiemetics for nausea and vomiting, antidiarrheals for diarrhea, 
antipyretics and antihistamines for drug fever, antihypertensives for hypertension, and 
phosphate repletion for hypophosphatemia) before toxicity grade is determined. 


 
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 
A patient will be removed from protocol therapy if either of the two study drugs is 
discontinued.  
 
Temsirolimus will be discontinued if it is not tolerated at a dose of 5 mg IV weekly.   
 
Sorafenib will be discontinued if it is not tolerated at a dose of 200 mg PO every other day. 
 
Once a dose has been reduced for toxicity, it should not be re-escalated. 
 
In obese patients, all dosing is to be determined by the patient’s actual body weight.  
 
If there is more than one indication for dose modification, use the more strict dose 
modification (i.e. modify according to the most severe toxicity). 
 
If treatment with either of the two study drugs is held for treatment-related toxicity for longer 
than 28 days (1 cycle), a patient should be removed from study. 
 
In selected cases where the investigator assesses the patient as having clinical benefit from 
protocol therapy, treatment may be resumed after > 28 day delay along with dose reduction, 
optimal supportive care, and close monitoring at the discretion of the treating investigator 
with the approval of the Study Chair. 
5.3.1 
Supportive Care Guidelines 
Supportive medications to alleviate or mitigate adverse effects of protocol therapy may include 
the following agents at the discretion of the treating investigator and according to institutional 
standards of care.  All medications must be reviewed for potential interaction with study drug 
therapy (see Appendices).  The treating investigator, Investigational Pharmacist, and/or Study 
Chair should be alerted if the patient is prescribed any agent known to affect or with the 
potential to affect selected P450 isoenzymes or other drug metabolism pathways. 
 
Antidiarrheal Agents:  Patients should be instructed to begin loperamide at the earliest signs 
of a poorly formed or loose stool.  Oral loperamide should be prescribed in the following 
manner: 4 mg at first onset of diarrhea then 2 mg every 2 hours until diarrhea-free for at 
least 12 hours up to 16 mg daily. 
 
Antiemetic Agents:  Drugs such as lorazepam, prochlorperazine, or serotonin antagonists 
may be used if clinically indicated. 
 
Antihistamines:  An antihistamine such as diphenhydramine may be used to manage 
dermatitis associated with therapy at the discretion of the treating physician. 
 
Anti-diabetic Agents:  For patients who develop clinically significant hyperglycemia on study 
protocol, anti-diabetic therapy and dietary modification are required.  The oral anti-diabetic 
agents, glyburide or metformin, may be instituted at the discretion of the treating physician, 
assuming no contraindication.  Metformin must be temporarily discontinued for ≥ 48 hours 
before and after iodinated contrast imaging, with confirmation of stable renal function prior to 
resuming this agent after contrast exposure.  Use of glipizide and glimepiride (CYP2C9 
substrates) should be avoided or used with caution due to potential interaction with 
sorafenib.  Insulin may be instituted at the discretion of the treating physician to optimize 
glycemic control.  Management of complications of hyperglycemia should be performed by 
treating physician according to institutional standard practices.  All patients who develop 
clinically significant hyperglycemia on study protocol must receive diabetic teaching and 
education materials.   
 
Antihyperlipidemic Agents: Patients who develop serum cholesterol > 350 mg/dL and/or 
triglycerides > 300 mg/dL while on therapy will require medication (assuming no 
contraindications and with standard precautions as appropriate for the class of agents 
chosen) and/or dietary modifications at the discretion of the treating investigator. Pravastatin 
or rosuvastatin is recommended if LDL and/or total cholesterol are elevated, with or without 


 
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elevated triglycerides, because these agents are not CYP 3A4 substrates.  Atorvastatin may 
also be used with caution.  If tryglycerides alone are elevated, fenofibrate may be 
considered.    
 
Antihypertensive Agents:  Patients who develop blood pressures > 140/90 mm Hg on at 
least 2 occasions should be managed with oral antihypertensives including amlodipine, 
hydrochlorothiazide, or metoprolol by their treating physician. Angiotensin converting 
enzyme (ACE) inhibitors should be used with caution due to increased risk for angioedema 
when used in combination with temsirolimus.  Use of angiotensin receptor blockers (ARB) 
which are CYP2C9 substrates as well as inhibitors should be avoided or used with caution 
due to potential for interaction with sorafenib which is also a CYP2C9 inhibitor.  Blood 
pressure and any relevant laboratory parameters should be rechecked within 7 days of 
starting a new medication.   
 
Diuretics:  Diuretics such as furosemide may be used for the management of periorbital or 
lower extremity edema or ascites at the discretion of the treating physician.  Severe 
episodes of edema, such as congestive heart failure, pleural effusion, ascites, pericardial 
effusion, or pulmonary edema may require additional measures such as percutaneous 
drainage or hospitalization.  
 
Electrolyte Supplementation:  Electrolytes should be repleted according to standard 
institutional protocols.  Specific recommendations for prevention and management of 
hypophosphatemia, a common side effect of temsirolimus, are provided below: 
 
For patients enrolled on study with baseline hypophosphatemia ≥ Grade 2 (< 2.5 mg/dL) 
prior to start of study drug therapy, and for patients who develop hypophosphatemia on 
study drug treatment, phosphate supplementation should be initiated with over-the-
counter phosphate tablets, caplets, or powders.  Recommended starting dosage is 250 
mg to 500 mg elemental phosphate four times daily, assuming no contraindications 
(such as hyperkalemia, severe diarrhea or dehydration, or severe renal insufficiency). 
The dose may be increased up to up to a total dose of 3.5 grams daily, assuming no 
contraindications.  Administer after meals and at bedtime.  Serum phosphate should be 
rechecked within 7 days after starting supplements. 
 
For patients on study drug therapy who have had prior episodes of hypophosphatemia, 
oral phosphate supplementation should be continued until serum phosphorus level is ≥ 
3.0 mg/dL.  Supplementation should be restarted if level < 2.5 mg/dL. 
 
For patients who have discontinued study drug therapy, phosphate supplementation and 
monitoring for purposes of the study may be discontinued once serum phosphate level 
returns to baseline. 
 
Phosphate levels should be rechecked within 7 days after starting supplements, and 
followed at least weekly thereafter while on protocol therapy. 
 
Intravenous therapy may be administered at the treating investigator’s discretion. 
Intravenous repletion should be administered with caution according to standard 
institutional protocols.   
 
All patients enrolled in study should be provided list of phosphorus-rich foods.  Patients 
with serum phosphate levels < 2.5 mg/dL should be encouraged to increase intake of 
these foods if tolerated and no contraindications. 
 
Growth Factors:  Erythropoietin or darbopoietin are permitted at the discretion of the treating 
physician.  Filgrastim and PEG-filgrastim (Neulasta) should not be used in place of protocol-
specified dose reductions or delays for myelosuppression, nor should they be used 
prophylactically because of concern for myelosuppression from a prior cycle of chemotherapy.  
For treatment of febrile neutropenia, the use of colony-stimulating factors should not be 
routinely instituted as an adjunct to appropriate antibiotic therapy.  The use of granulocyte 
colony-stimulating factors may be indicated, however, in subjects who have prognostic factors 


 
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that are predictive of clinical deterioration such as pneumonia, hypotension, multi-organ 
dysfunction, sepsis syndrome, or fungal infection.  Investigators should use discretion in 
initiating colony-stimulating factors in these settings. 
 
Topical Agents:  Topical steroid creams may be used to manage pruritic skin toxicity at the 
discretion of the treating physician.  Non-alcohol-based topical emollients such as Aquaphor 
may be used for hand-foot syndrome or desquamating rashes.  Non-alcohol-based 
moisturizers may be used for dry skin. 
 
Treatment of Infusion Reactions: Subjects who experience study drug-associated temperature 
elevations ≥ 38.5°C or other infusion-related symptoms may be treated symptomatically with 
acetaminophen, diphenhydramine, meperidine, or other medications at the discretion of the 
treating investigator.  See Section 4.1.1 and Package Insert and Investigator’s Brochure for 
temsirolimus for further information on management of infusion reactions.(Pfizer 2011; Wyeth 
2011) 
6. Study Procedures and Observations 
6.1 
Schedule of Procedures and Observations 
The study-specific assessments are detailed in this section and outlined in Table 6.1 Schedule 
of Study Procedures and Assessments. For more details on the study procedures, please refer 
to Study Laboratory and Procedures Manual. 
Screening assessments must be performed within 28 days prior to the first dose of 
investigational product. 
All on-study visit procedures are allowed a window of ± 7 days unless otherwise noted. 
All patients who are consented will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The system is 
password protected and meets HIPAA requirements.  A written, signed, informed consent form 
(ICF) and a Health Insurance Portability and Accountability Act (HIPAA) authorization must be 
obtained before any study-specific assessments are initiated.  A copy of the signed ICF will be 
given to the subject and a copy will be filed in the medical record.  The original will be kept on 
file with the study records.   
6.1.1 
Pretreatment Period 
Patients with hypertension, diabetes mellitus, hyperlipidemia, and/or hepatitis B virus infection 
require optimization of these conditions prior to starting protocol therapy if found eligible upon 
screening. 
6.1.1.1 
Screening Assessments  
The Screening procedures and assessments must be completed within 28 days of the Day 1 
Visit unless otherwise stated.  Any results falling outside of the reference ranges may be 
repeated at the discretion of the investigator. 
 
Complete physical examination, including height and weight measurement 
 
Vital signs, including temperature, blood pressure, heart rate, pain score, and oxygen 
saturation 
 
Complete medical history with annotation to include demographics, past medical history, 
presentation at diagnosis, prior biopsy pathologic results (if any), prior radiologic 
assessments, prior therapies (including surgery, radiation, or local therapies such as 
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 
Documentation of disease status including CT chest (with or without contrast) and contrast-
enhanced CT and/or MRI abdomen/pelvis, preferably multiphasic 
 
ECOG Performance Status – see Appendix 1 
 
Child-Pugh class assessment – see Appendix 2 
 
BCLC and CLIP stage – see Appendix 3 
 
History of prior treatments and any residual toxicity relating to prior treatment  
 
Baseline medications taken within 28 days of Day 1 
 
Obtain archival tumor specimens (prefer at least 1 tumor block and/or at least 10 unstained 
slides plus 1 H&E slide) and pathology report (locally-obtained pathology report is 
acceptable at start of study) to confirm diagnosis of HCC, and for specimen banking of left-
over frozen or fixed tumor specimens from all enrolled patients; patients may start study 
prior to obtaining the archival specimen(s) provided the pathology report has been reviewed 
and filed in study records 
 
Screening laboratory parameters: CBC w/ Diff, complete metabolic panel (electrolytes, BUN, 
creatinine, glucose, calcium, magnesium, phosphorus, total bilirubin, alkaline phosphatase, 
albumin, AST, and ALT), PT/INR, fasting blood glucose, hemoglobin A1c, fasting total 
cholesterol and triglycerides; hepatitis B and C serologies (HBsAb, HBsAg, HBcAb total and 
IgM; HCV Ab) (hepatitis B and C serologies may be performed >28 days from Day 1) 
 
Measurement of hepatitis B viral load (HBV DNA quantitative by PCR) if HBsAg, HBcAb 
total, and/or HBcAb IgM is/are positive (within 28 days of Day 1) 
 
Confirmation of antiviral therapy with an appropriate antiviral agent for HBV is required in 
patients with positive hepatitis B surface antigen, HBcAb IgM, and/or viral load - appropriate 
first line agents include entecavir, tenofovir, and lamivudine (note that lamivudine has higher 
resistance rates) 
 
Patients with a positive HBV viral load, HBcAb IgM, and/or HBsAg should be referred to a 
hepatologist if not already under the care of a hepatologist 
 
Initiate standing phosphate repletion for patients with baseline ≥ Grade 2 hypophosphatemia 
– see Section 5.3.1 Dose Modification and Dosing Delays 
 
Confirmation of adequate blood pressure control with agents compatible with study drugs – 
see Sections 5.3.1 and 6.7 and Appendices 6-9 Prohibited Medications 
 
Serum or urine pregnancy test for women of childbearing potential within 14 days from start 
of study prior to the start of study drug 
6.1.2 
Treatment Period 
6.1.2.1 
Study Procedures – Cycle 1  
Days 1, 8, 15, and 22 (within 7 days) 
 
Complete physical examination, including height and weight measurement 
 
Vital signs, including temperature, blood pressure, heart rate, pain score, and oxygen 
saturation  
 
Evaluation of clinical response or deterioration 
 
Evaluation of adverse events 
 
Concomitant medications 


 
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 
Safety laboratory assessments:  CBC w/ Diff, complete metabolic panel (electrolytes, 
BUN, creatinine, glucose, calcium, magnesium, phosphorus, total bilirubin, direct bilirubin, 
alkaline phosphatase, albumin, AST, and ALT), INR 
 
Serum AFP tumor marker (Day 1 only) 
 
Blood specimen collection for CTC testing (Day 1 only)  
 
Banking of blood specimens for possible future correlative studies (Day 1 and 8 only) (See 
Study Laboratory and Procedures Manual) 


 
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6.1.2.2 
Study Procedures – Day 1 of Cycles 2 and beyond (within 7 days) 
 
Complete physical examination, including height and weight measurement 
 
Vital signs, including temperature, blood pressure, heart rate, pain score, and oxygen 
saturation  
 
Evaluation of clinical response or deterioration 
 
Evaluation of adverse events 
 
Concomitant medications 
 
ECOG Performance Status 
 
Safety laboratory assessments:  CBC w/ Diff, complete metabolic panel (electrolytes, BUN, 
creatinine, glucose, calcium, magnesium, phosphorus, total bilirubin, direct bilirubin, alkaline 
phosphatase, albumin, AST, and ALT), INR 
 
Fasting total cholesterol, triglycerides, and blood glucose (odd cycles only) 
 
Hepatitis B viral DNA quantitative in patients with positive hepatitis B viral load at baseline 
and/or positive HBsAg, HBcAb total, and/or HBcAb IgM (odd cycles only or more frequently 
at investigator’s discretion). 
 
Imaging with CT chest (with or without contrast) plus triphasic CT abdomen and pelvis with 
intravenous contrast or triphasic gadolinium-enhanced MRI abdomen/pelvis to assess sites 
of known tumor using RECIST 1.1 measurements and to monitor for lung toxicity (odd 
cycles only, every 8 weeks ± 7 days, starting Cycle 3, Day 1) 
 
Initial assessment of response or progression will be made based upon standard of care 
Radiology review plus clinical assessment if RECIST 1.1 measurements are not available at 
the time of study visit.  In patients without signs of clinical progression, progression must be 
confirmed by RECIST 1.1 prior to removal from study.  If progression is identified by 
RECIST 1.1 that was not identified by standard of care Radiology review plus clinical 
assessment, a patient will be removed from study at date of next scheduled study visit.  
Efforts will be made to obtain RECIST 1.1 measurements for patients treated at both sites 
within approximately 7 days of start of odd cycles.  
 
Serum AFP tumor marker 
 
Blood specimen collection for CTC testing (Cycles 2 and 3 only) 
 
Banking of blood specimens (Cycles 3 and End-of-Treatment only) 
6.1.3 
6.1.2.3 
Study Procedures Day 8, 15, and 22 of All Cycles after Cycle 1 
(within 7 days) 
 
Weight measurement and vital signs including temperature, blood pressure, heart rate, pain 
score, and oxygen saturation 
 
Safety laboratory assessments:  CBC w/Diff, complete metabolic panel (electrolytes, BUN, 
creatinine, glucose, calcium, magnesium, phosphorus, total bilirubin, direct bilirubin, alkaline 
phosphatase, albumin, AST, and ALT), INR 
6.1.4 
End-of-Treatment Study Procedures (within 60 days) 
End-of-Treatment is defined as the day on which a decision is made by an investigator to 
discontinue a patient’s participation in the study, often due to disease progression or toxicity, or 
by a patient to withdraw consent; this may also be referred to as the last day on study and may 
not necessarily coincide with the last day of protocol therapy, particularly if study drug has been 
held for toxicity. 


 
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 
Complete physical examination, including height and weight measurement 
 
Vital signs, including temperature, blood pressure, heart rate, pain score, and oxygen 
saturation 
 
Update medical history 
 
Evaluation of clinical response or deterioration 
 
Evaluation of adverse events 
 
Concomitant medications 
 
ECOG Performance Status 
 
Child-Pugh class assessment 
 
Safety laboratory assessments:  CBC w/ Diff, complete metabolic panel (electrolytes, BUN, 
creatinine, glucose, calcium, magnesium, phosphorus, total bilirubin, direct bilirubin, alkaline 
phosphatase, albumin, AST, and ALT), INR; serum AFP and HBV DNA quantitative by PCR 
should be measured if not done within 4 weeks 
 
If not done within preceding 8 weeks, imaging with CT chest (with or without contrast) plus 
triphasic CT abdomen and pelvis with intravenous contrast or triphasic gadolinium-
enhanced MRI abdomen/pelvis to assess sites of known tumor using RECIST 1.1 
measurements and to monitor for lung toxicity 
 
Banking of blood specimens if >4 weeks since specimens collected for banking 
6.1.5 
Post-Treatment/Follow Up Visits 
The study termination visit will be the last follow-up assessment visit for patients removed from 
study for disease progression with < grade 2 treatment-related toxicity and stable or 
undetectable hepatitis B load, if applicable.  Such patients will follow up with their primary 
oncologist and hepatologist (if applicable) after removal from study. 
Patients who are experiencing clinically relevant, treatment-related ≥ grade 2 toxicities or other 
adverse events at study termination will be followed periodically at intervals determined by the 
treating investigator until resolution, stabilization, or the assessment of irreversibility of the 
toxicity or toxicities in question, until the patient starts a new treatment, or until death, whichever 
comes first.  For these patients, the study coordinator and treating investigator will confer within 
8 weeks after a patient’s study termination, to determine the resolution, stabilization, 
irreversibility and/or need for further follow-up of ongoing, clinically relevant, treatment-related ≥ 
grade 2 toxicities present at study termination, based upon clinical encounter, telephone follow-
up, and/or medical records. 
Follow up for ongoing treatment-related grade ≥ 2 toxicities at the time of study termination may 
also be performed at an outside physician’s office if deemed in the patient’s best interest, 
provided that the results are faxed as source documents to the treating investigator and site 
clinical research coordinator. (For example, follow up for thrombocytopenia on study drugs may 
be performed at an outside laboratory and faxed to the study site.  Examination to confirm 
resolution of mucositis or hand-foot syndrome off study may be performed by an outside 
physician provided that a copy of the encounter note documenting the physical examination 
findings is filed in the patient’s study chart.  The treating investigator may also confirm resolution 
of symptomatic toxicities, such as hand-foot syndrome or stomatitis, with the patient by 
telephone.) 
6.1.6 
Long Term/Survival Follow-up Procedures 
Patients will be followed every 3-6 months (±3 months) for up to 5 years after study 
discontinuation or until death, whichever comes first. 


 
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The following procedures will be performed at standard-of-care clinic visits with treating 
investigator or by telephone calls from treating investigator or a designated study coordinator (± 
2 months): 
 
Evaluation of clinical response or deterioration. 
 
Overall survival will be measured from time of first dose of protocol therapy to date of death; 
for patients who are lost to follow up, survival will be censored at date last known to be alive. 
 
Evaluation of any residual symptomatic adverse events (if applicable). 
 
Other anti-cancer therapies. 
 


 
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Table 6.1 
Schedule of Study Procedures and Assessments 
Period/Procedure 
Screening 
Cycle 1 
Cycle 2 and future Cycles 
End of 
Treatment 
visit 
Follow 
Up Visit* 
Study Day/Visit Day 
-28 to 1 
1 
8 
15 
22 
1 
8 
15 
22 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Archival Specimen 
Collection 1 
X 
 
 
 
 
 
 
 
 
 
 
AE assessment 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
Concomitant medications 
X 2 
X 
X 
X 
X 
X 
 
 
 
X 
 
Treatment/Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
Temsirolimus17 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Sorafenib 3  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Clinical procedures 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 4 
X 
X 
X 
 
Medical history 
X 
 
 
 
 
 
 
 
 
X  
X 6 
Liver disease assessment 5 
X 
 
 
 
 
 
 
 
 
 
 
Performance Status  
X 
 
 
 
 
X 
 
 
 
X 
 
Laboratory procedures 
 
 
 
 
 
 
 
 
 
 
 
Hematology (CBC w/Diff) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood chemistry 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation 8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AFP 
 
X  
 
 
 
X   
 
 
 
X 
 
HCV, HBV sAb, HBV sAg, 
HBV cAb total & IgM16 
X 
 
 
 
 
 
 
 
 
 
 
Hemoglobin A1c 
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis B viral DNA 
quantitative by PCR 9 
X9 
 
 
 
 
X 9 
 
 
 
X9 
 
Fasting total cholesterol, 
triglycerides, and blood 
glucose10 
X10 
 
 
 
 
X10 
 
 
 
 
 


 
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Table 6.1 
Schedule of Study Procedures and Assessments 
Period/Procedure 
Screening 
Cycle 1 
Cycle 2 and future Cycles 
End of 
Treatment 
visit 
Follow 
Up Visit* 
Study Day/Visit Day 
-28 to 1 
1 
8 
15 
22 
1 
8 
15 
22 
Standing phosphate 
repletion 11 
X11 
X11 
 
 
 
X11 
 
 
 
 
 
CTC 12 
 
X12 
 
 
 
X12 
 
 
 
 
 
Banking blood samples13 
 
X13 
X13 
 
 
X13 
 
 
 
X 13 
 
Pregnancy test (HCG) 
X 
 
 
 
 
 
 
 
 
 
 
Imaging procedures 
 
 
 
 
 
 
 
 
 
 
 
Imaging (CT or MRI) 
X 
 
 
 
 
X 14 
 
 
 
X 15 
 
* Patients will be followed every 3-6 months for up to 5 years after study discontinuation or until death, at standard-of-care clinic visits with treating investigator or by telephone 
calls from treating investigator or a designated study coordinator (± 3 months) 
1 May start study prior to obtaining specimens if pathology report is available  
2 Confirmation of antiviral therapy with an appropriate antiviral agent for HBV is required in patients with positive hepatitis B surface antigen, HBcAb IgM, and/or viral load 
3 Sorafenib will be taken orally twice daily at starting dose with modifications per Section 5.2.3 
4 Weight and vital signs on Days 8, 15, 22 of Cycle 2 and future cycles 
5 Disease assessment including Child-Pugh, BCLC, and CLIP scores 
6 Evaluation of clinical response or deterioration at Follow-Up Visit: overall survival will be measured from time of first dose of therapy to date of death, evaluation of any residual 
symptomatic adverse events (if applicable), other anti-cancer therapies 
7 Complete metabolic panel (electrolytes, BUN, creatinine, glucose, calcium, magnesium, phosphorus, total and direct bilirubin, alkaline phosphatase, albumin, AST, and ALT) 
8 Prothrombin time/ international normalized ratio (PT/INR) 
9 Hepatitis B viral DNA quantitative in patients with positive hepatitis B viral load at baseline (Screening) and/or positive HBsAg, HBcAb total, and/or HBcAb IgM (odd cycles only or 
more frequently at investigator’s discretion), and end of treatment if not measured within 4 weeks prior. 
10 Screening and Day 1 of odd cycles only (Cycle 3, 5, 7, etc.) 
11 Initiate standing phosphate repletion for patients with baseline ≥ Grade 2 hypophosphatemia; adjust dosage as clinically indicated at each visit 
12 CTC on Day 1 of Cycles 1, 2 & 3 only. See Study Laboratory and Procedures Manual for instructions 
13 Banking blood samples on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 3 Day 1, and at End of Treatment (if not done within 4 wks). See Study Laboratory and Procedures Manual 
for instructions 
14 Odd cycles only, every 8 weeks ± 7 days, starting Cycle 3, Day 1 
15 If not done within 8 weeks, imaging with CT chest (with or without contrast) plus triphasic CT abdomen and pelvis with intravenous contrast or triphasic gadolinium-enhanced MRI 
abdomen/pelvis 
16 May use values from >28 days from registration 
17 Temsirolimus infusion may be performed within ± 3 days 


 
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6.2 
Usage of Concurrent/Concomitant Medications 
Concomitant medications are any prescription medications or over-the-counter preparations 
used by the patient within 28 days of initiating study treatment, during study treatment, or until 
28 days following study termination.  The details of all concurrent medications including vitamins 
and alternative therapies will be recorded on the case report forms (CRFs).   All medications 
must be reviewed for potential interaction with study drug therapy.  All concomitant medications 
and blood products, as well as supportive interventions (such as analgesic use, paracentesis, 
etc.) received by patients from screening until the end of study visit will be recorded in CRFs.  
Because there is a potential for interaction between the study drugs temsirolimus and sorafenib 
and other concomitantly administered drugs through hepatic metabolism by the cytochrome 
P450 system (predominantly CYP3A4), P-glycoprotein metabolism, and/or through 
glucuronidation by UGT1A1 and UGT1A9, the case report form must capture the concurrent use 
of all other drugs, over-the-counter medications, or alternative therapies.  The Study Chair 
should be alerted if the patient is taking any agent known to affect or with the potential to affect 
selected P450 isoenzymes or other drug metabolism pathways. 
Use of any inducers and strong inhibitors of CYP3A4 is prohibited while undergoing 
protocol therapy. Use of substrates of CYP3A4, CYP2B6, CYP2C8, and CYP2C9 with a 
narrow therapeutic range or which are assessed as sensitive by FDA guidelines is also 
prohibited.(2009)  Please refer to Appendices B6-9 for definitions and lists of these 
agents.  Patients who have taken medications that are known to be inducers or strong 
inhibitors of CYP3A4 within 28 days before registration will be excluded from study.   
Substrates of CYP3A4, CYP2D6, CYP2C8, and CYP2C9 with a narrow therapeutic range or 
assessed as sensitive by FDA guidelines must not have been taken within 5 half-lives of the 
specific drug in question at the time of start of study.  Medications which are weak to moderate 
inhibitors of CYP3A4 enzymes must be reviewed by the Study Chair or Investigational 
Pharmacist for approval before concomitant use.  Inhibitors or inducers of P-gp, substrates of 
UGT1A1 and UGT1A9, and other substrates of CYP3A4, CYP2B6, CYP2C8, and CYP2C9 
should be avoided or used with caution.  Selected medications and substances known or with 
the potential to interact with or be metabolized by relevant cytochrome P450 isoenzymes 
(CYP3A4, CYP2B6, CYP2C8, CYP2C9), P-glycoprotein pathway, and/or UGT1A1 and UGT1A9 
glucuronidation are provided in Appendices 6-9.  If the investigator is unsure of potential for 
drug-drug interaction, the Investigational Pharmacist will be consulted.  For the most up to date 
table of cytochrome P450-related drug interactions, please refer to the Indiana University drug 
interaction table at the following website: 
http://medicine.iupui.edu/clinpharm/ddis/ClinicalTable.asp 
6.3 
Reasons to Withdraw a Subject 
The Investigator will withdraw a patient whenever continued participation is no longer in the 
patient’s best interests.  Reasons for withdrawing a patient include, but are not limited to, 
disease progression, the occurrence of an adverse event or a concurrent illness, a patient’s 
request to end participation, or simply significant uncertainty on the part of the Investigator that 
continued participation is prudent.  There may also be administrative reasons to terminate 
participation, such as concern about a patient’s compliance with the prescribed treatment 
regimen. 
6.4 
Stopping Rules 
No interim assessment for primary endpoint is planned, but there will be a planned interim 
safety analysis by the UCSF Data and Safety Monitoring Committee after the first 30% of the 
planned study participants (8 patients) have enrolled and completed at least one cycle of 
protocol therapy or been removed for toxicity. Study accrual will not be interrupted for the early 


 
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safety assessment. The proportion of patients with treatment-related adverse events of grade 3 
or higher and/or an unacceptable toxicity event (with exceptions defined below) will be 
summarized with 90% two-sided exact confidence intervals. Each confidence interval will be no 
wider than ±0.17. If the lower confidence bound (LCB) exceeds 0.17, adverse events will be 
evaluated and a decision will be made whether to amend the protocol or close the study.  
 
If the true rate of treatment-related toxicity is 25%, the probability that 3 or more patients will 
have adverse events of grade 3 or greater is 32%. A summary of probabilities for a range of true 
toxicity rates is shown below.  If 3 or more patients among the first 8 experience an eligible 
grade 3 or higher and/or unacceptable toxicity event, a decision will be made whether to amend 
the study or close the study due to toxicity. 
 
True Toxicity Rate 
Probability 3 or more 
of 8 patients 
experience AEs of 
grade 3 or greater 
Probability 2 or more 
of 8 patients 
experience AEs of 
grade 3 or greater 
Probability 1 or more 
of 8 patients 
experience AEs of 
grade 3 or greater 
10% 
3.8% 
18.7% 
57% 
20% 
20.3% 
50.0% 
83% 
25% 
32.0% 
63.3% 
89% 
30% 
44.8% 
74.5% 
94% 
Exceptions of toxicity which will not be included for interim safety analyses are: 
 
Asymptomatic Grade 3 toxicity in laboratory values despite optimal supportive care (such as 
hydration or electrolyte repletion) must be treatment-related, clinically relevant*, and 
represent a change of ≥ 2 grades from baseline.  Grade 3 hypertriglyceridemia is excluded if 
peak serum triglycerides are < 1500 mg/dL and recover to < 300 mg/dL with optimal medical 
management by the start of Cycle 2.  Asymptomatic Grade 3 hypophosphatemia is also 
excluded.   
 
Grade 3 hypertension that resolves to <140/90 within 14 days of adjustment or addition of 
oral blood pressure medication(s) is also excluded.  Hypertension that requires 
hospitalization or intravenous medication for control will be considered unacceptable toxicity. 
 
Grade 3 ascites, encephalopathy, or other toxicities associated with chronic liver disease 
must be ≥ 2 grades greater than baseline to be considered a DLT. 
 
Fatigue is excluded. 
 
Toxicity attributed to hepatocellular carcinoma is excluded. 
*Clinically relevant is defined as toxicity which places the patient at risk for morbidity by the 
judgment of the treating investigator.   
6.5 
Medical Guidelines for the Treatment of an Overdose 
There is no specific treatment for TORISEL® intravenous overdose.  Temsirolimus has been 
administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as 
high as 220 mg/m2.  The risk of several serious adverse events, including thrombosis, bowel 
perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of 
temsirlimus greater than 25 mg.(Pfizer 2011; Wyeth 2011) 


 
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There is no specific treatment for NEXAVAR overdose. The highest dose of sorafenib studied 
clinically is 800 mg twice daily. The adverse reactions observed at this dose were primarily 
diarrhea and dermatologic. No information is available on symptoms of acute overdose in 
animals because of the saturation of absorption in oral acute toxicity studies conducted in 
animals. In cases of suspected overdose, sorafenib should be withheld and supportive care 
instituted.(Bayer 2011) 
6.6 
Dietary Restrictions 
Avoid grapefruit and grapefruit juice (may increase levels or toxicity of sirolimus). 
Avoid supplements containing St. John’s Wort, alfalfa, aloe, bilberry, bitter melon, burdock, 
celery, damiana, echinacea, fenugreek, garcinia, garlic, ginseng (American), gymnema, 
marshmallow, stinging nettle. 
6.7 
Prohibited Medications 
6.7.1 
Temsirolimus  
Temsirolimus is metabolized by CYP3A4 to its active metabolite sirolimus which is a substrate 
of both CYP3A4 and P-glycoprotein.  Temsirolimus also inhibits P-glycoprotein.  Temsirolimus 
has been shown to inhibit CYP2D6 in vitro, but no effect is expected in vivo.  See Appendices  
4-7. 
CYP3A4 inhibitors 
May decrease metabolism of temsirolimus and sirolimus.  Strong inhibitors of CYP3A4 are 
prohibited; other inhibitors should be avoided or used with caution. 
CYP3A4 Inducers 
May increase metabolism of temsirolimus and sirolimus.  All inducers of CYP3A4 are prohibited.  
Sensitive CYP3A4 substrates and those with a narrow therapeutic range as defined by 
FDA are prohibited.  
P-glycoprotein inhibitors 
May increase serum concentration of temsirolimus and sirolimus which are P-glycoprotein 
substrates, or alter distribution.  Should be avoided or used with caution. 
P-glycoprotein inducers 
May decrease serum concentration of temsirolimus and sirolimus which are P-glycoprotein 
substrates, or alter distribution.   Should be avoided or used with caution. 
ACE inhibitors 
Risk of angioedema may be increased by temsirolimus.  May be used with caution. 
Cardiac glycosides 
Temsirolimus may inhibit transport by P-glycoprotein.  Use is prohibited. 
Herbal/Nutriceutical 
Avoid supplements containing St. John’s Wort, alfalfa, aloe, bilberry, bitter melon, burdock, 
celery, damiana, echinacea, fenugreek, garcinia, garlic, ginseng (American), gymnema, 
marshmallow, stinging nettle. 
Vaccines 


 
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Temsirolimus may diminish efficacy of vaccination and/or increase risk of toxicity from live 
vaccines.  Should be avoided during protocol treatment. 
6.7.2 
Sorafenib 
Sorafenib is metabolized by CYP3A4 and UGT1A9 and has been shown to inhibit CYP2B6, 
CYP2C8, and CYP2C9 as well as UGT1A1 and UGT1A9. Though inhibition of CYP2C9 has 
been documented, no effect was observed in an interaction study with warfarin. See 
Appendices 4-7. 
CYP3A4 inhibitors 
May increase serum concentration and toxicity of sorafenib. Strong inhibitors of CYP3A4 are 
prohibited; other CYP3A4 inhibitors should be avoided or used with caution. 
CYP3A4 inducers 
May decrease serum concentration of sorafenib. All inducers of CYP3A4 are prohibited. 
Sensitive CYP3A, CYP2B6, CYP2C8, and CYP2C9 substrates and those with a narrow 
therapeutic range as defined by FDA are prohibited. (2009) 
Other substrates of CYP3A4, CYP2B6, CYP2C8, and CYP2C9 should be avoided or used with 
caution. 
UGT1A1 and UGT1A9 substrates 
Sorafenib inhibits UGT1A1 and UGT1A9 and may increase exposure to these drugs; should be 
avoided or used with caution. 
Doxorubicin 
Sorafenib has been shown to increase levels of doxorubicin in vitro. Use is prohibited. 
Herbal/Nutriceutical 
Avoid echinacea and St. John’s Wort as well as any herbal products which may interact with 
CYP3A4 system. 
A detailed list of agents that should be avoided or used with caution due to risk for interaction 
with temsirolimus and sorafenib are in Appendices 6-9. 
7. Reporting and Documentation of Results 
7.1 
Evaluation of Efficacy (or Activity) 
7.1.1 
Measurement of Response and Progression 
Target and non-target lesions will be defined by RECIST guidelines (version 1.1): (Therasse, 
Arbuck et al. 2000) (Eisenhauer, Therasse et al.)  All enrolled patients will imaging of chest, 
abdomen, and pelvis at baseline and after every 2 cycles (8 weeks ± 7 days) of protocol 
therapy.  RECIST 1.1 measurements will be performed by centralized radiologist at UCSF, 
without knowledge of patients’ clinical responses to protocol therapy, imaging studies during first 
6 months on protocol therapy (including post-cycle 6 imaging), then at each study site by 
qualified investigator and/or radiologist for subsequent studies for patients who remain on 
protocol therapy.  The schedule and methods of radiographic evaluation are described in 
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7.1.1.1 
Definitions 
Evaluable for toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with the study drug.  
The study will use the CTCAE Version 4.0 for reporting adverse events. 
Evaluable for efficacy 
All enrolled patients who have received at least one dose of study drug (unless determined to 
be ineligible and replaced for reasons such as inability to comply or withdrawal of consent) will 
be evaluable for the primary efficacy endpoint according to the definitions stated below.   
7.1.1.2 
 Disease Parameters 
Measurable disease 
Measurable disease is defined as lesions (or tumors) that can be accurately measured in at 
least one dimension (longest diameter to be recorded) with a minimum size of 10mm by CT 
scan (irrespective of scanner type) and MRI (no less than double the slice thickness and a 
minimum of 10mm), 10mm caliper measurement by clinical exam (when superficial), and/or 
20mm by chest X-ray (if clearly defined and surrounded by aerated lung). 
All tumor measurements will be recorded in millimeters or decimal fractions of centimeters.  
Previously irradiated lesions are considered non-measurable except in cases of documented 
progression of the lesion since the completion of radiation therapy. 
Non-measurable disease 
Non-measurable disease is all other lesions (or sites of disease), including small lesions 
(longest diameter < 20 mm with conventional techniques or < 10 mm using spiral CT scan).  
Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by reproducible imaging techniquesare all non-
measurable. 
Target lesions 
All measurable lesions up to a maximum of 5 lesions total (and a maximum of two lesions per 
organ) representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline.  Target lesions will be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically).  A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD.  The baseline sum LD will be used as 
reference by which to characterize the objective tumor response. 
Non-target lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  It is possible to record multiple non-target lesions involving the same organ as a 
single item on the case record form (e.g. “multiple enlarged pelvic lymph nodes” or “multiple 
liver metastases”). Measurements of these lesions are not required, but the presence or 
absence of each will be noted throughout follow-up. 
7.1.1.3 
Methods for Evaluation of Measurable Disease 
All measurements will be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations will be performed as closely as possible to the beginning of treatment and 
never more than 28 days before the beginning of the treatment. 


 
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The same method of assessment and the same technique will be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the antitumor effect of a treatment. 
Conventional CT and MRI 
These techniques should be performed with cuts of 10 mm or less in slice thickness 
contiguously.  Spiral CT should be performed using a 5 mm contiguous reconstruction 
algorithm.  This applies to tumors of the chest, abdomen, and pelvis.  Triphasic imaging of 
abdomen should be obtained when feasible. 
Cytology, Histology.  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
7.1.1.4 
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions, determined by two separate observations conducted not 
less than 4 weeks apart.  Any pathological lymph nodes (whether target or non-target) must 
have reduction in short axis to <10 mm (the sum may not be “0” if there are target nodes).  
There can be no appearance of new lesions. 
Partial Response (PR) 
At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as 
reference the baseline sum LD.  There can be no appearance of new lesions. 
Progressive Disease (PD) 
At least a 20% increase in the sum of the SLD of target lesions, taking as reference the smallest 
sum SLD recorded since the treatment started and minimum 5 mm increase over the nadir, or 
the appearance of one or more new lesions. 
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. 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (< 10 mm short axis). 
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) 


 
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Appearance of one or more new lesions and/or unequivocal progression of existing non-target 
lesions. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
Table 3.1.1.4 Response Criteria 
Target 
Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Response for this Category 
Also Requires 
CR 
CR 
No 
CR 
> 4 weeks confirmation 
CR 
Non-CR/ Non-
PD 
No 
PR 
> 4 weeks confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at least once > 4 weeks 
from baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression 
Duration of Response 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are met for 
CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
 
Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started.  
7.1.1.5 
Centralized Review of Radiology 
Radiographic assessments will be performed by a Radiologist at UCSF without knowledge of 
patients’ clinical responses to protocol therapy for all patients’ imaging studies during the first 6 
months’ on therapy (including imaging after completion of cycle 6).  For patients enrolled on 
study at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 
standard CT or MRI images will be acquired at that study site, stored on a CD as DICOM 
images, and shipped via FEDEX to the designated UCSF study coordinator.  After cycle 6 
imaging, RECIST 1.1 measurements may be performed at the treating site by a qualified 
investigator or radiologist.  See Study Laboratory and Procedures Manual for detailed 
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Initial assessment of response or progression may be made based upon standard of care 
Radiology review plus clinical assessment if RECIST 1.1 measurements are not available at the 
time of study visit.  In patients without signs of clinical progression, progression must be 
confirmed by RECIST 1.1 prior to removal from study.  If progression is identified by RECIST 
1.1 that was not identified by standard of care Radiology review plus clinical assessment, a 
patient will be removed from study at date of next scheduled study visit.  Efforts will be made to 
obtain RECIST 1.1 measurements for patients treated at both sites within approximately 7 days 
of start of odd cycles.  
7.1.2 
Time to Event Endpoints 
Time to Progression (TTP) 
TTP is defined as the duration from date of first dose of protocol therapy to date of removal from 
study for radiographic (per RECIST 1.1) and/or clinical progression including death attributed to 
progression. For patients removed from study for other reasons than progression (such as 
toxicity, withdrawal of consent, death without documented progression, or other reasons without 
clinical or radiographic evidence of tumor progression), TTP will be censored at the date of 
study discontinuation.  
Time to Treatment Failure (TTF) 
TTF will be measured from date of first dose of protocol therapy to date of study discontinuation 
for progression, death, or toxicity.  For patients removed from study for other reasons (such as 
noncompliance or withdrawal of consent), TTF will be censored at the date of study 
discontinuation.  
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from date of first dose of 
protocol therapy to time of documented radiographic and/or clinical disease progression or 
death from any cause. Patients who have not progressed or died are censored at the date last 
known to be progression-free.   
Overall Survival (OS) 
Median OS for all enrolled  patients who receive at least one dose of protocol therapy will be 
calculated from date of first dose of protocol therapy until date of death, using chart review 
and/or follow up phone calls to determine date of death in patients after removal from study.  
The survival of patients still alive after 5 years of follow up post study discontinuation will be 
censored.  Alive patients are censored at the date last known alive.  
7.2 
Evaluation of Safety 
Analyses will be performed for all patients having received at least one dose of study drug.  The 
study will use the CTCAE Version 4.0 for reporting of non-hematologic adverse events and 
hematologic adverse events. 
7.3 
Evaluation of Exploratory Endpoints 
Assessment of CTC enumeration, and patient blood specimen banking) is described below.  
Other exploratory endpoints (specifically, indices of viral hepatitis reactivation, and correlation 
between outcome measures and cause of viral hepatitis) will be measured/performed according 
to standard institutional procedures. 


 
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7.3.1 
Circulating Tumor Cell Measurements 
CTC will be enumerated using a novel slide-based assay (CEpiC) at baseline and on Day 1 of 
Cycles 2 and 3 (up to 7 days before treatment date).  The slide-based circulating epithelial cell 
assay (CEpiC) is a new methodology to identify circulating epithelial cells and credential them 
as tumor cells.  In the assay, each tube of approximately 7.5 mL (0.5 TBS) of anti-coagulated 
peripheral blood is lysed and all mononuclear cells are plated on cell adhesion glass slides.  
After appropriate pre-processing, the monolayer is incubated with a pan-anti-cytokeratin 
antibody and subsequently with a secondary fluorescent antibody.  The samples are also 
stained with the nuclear stain DAPI.  Slides are then analyzed with an automated digital 
microscope and data analyzed and correlated.  The analysis predominantly consists of a 
cytometric and morphologic correlation that identifies intact cells that have a cytoplasmic 
cytokeratin stain consistent with epithelial cells.  Controls include identically processed normal 
donor blood and sub-sampling of the patient blood excluding the primary antibody.  The result of 
the CEpiC assay is the count of positive CEpiCs per milliliter of peripheral blood with associated 
imagery.  CTC testing and analysis will be performed in the laboratory of Peter Kuhn, Ph.D., at 
the Scripps Research Institute, with the assistance of the clinical coordinator, Madelyn 
Luttgen.  CTC testing will be performed without knowledge of the patients' clinical status.   
Please see Study Laboratory and Procedures Manual for instructions regarding the collection, 
shipping, and handling of blood specimens for the CEpiC assay.   
7.3.2 
Markers of mTOR Pathway Activation 
Archival tumor blocks will be accessioned then sectioned into 5 µm slides (3-5 plus H&E) and 
submitted to the UCSF Immunohistochemistry Core to perform IHC for selected mTOR pathway 
activation markers such as pAKT (S473), pS6RP (S235/236), PTEN (rabbit polyclonal antibody 
PN37), and LKB1 (D60C5). Optimization for each antibody will be performed using breast tumor 
samples as positive controls. The Director of the Core, 
, will read and provide 
reports for each case including intensity (0-3+), percentage positivity, distribution (very focal, 
focal, diffuse), and intracellular localization (membranous, cytoplasmic, nuclear) for each  
stain.7-10    
In addition, FFPE sections from consenting patients will be submitted to the UCSF Clinical 
Cancer Genomics Lab (CCGL) for sequencing using hybridization-based target enrichment to 
analyze ~539 cancer-related genes for mutations (including mTOR pathway genes such as 
mTOR, AKT, TSC1/2, PTEN, PIK3CA) and copy number changes; selected genes will be 
analyzed for structural rearrangements (http://cancer.ucsf.edu/CCGL). Paired whole blood 
samples also will be sequenced for germline comparison.  
7.3.3 
Blood Specimen Banking 
Blood samples totaling approximately 15-20 mL (1 to 1.3 TBS) optional patient blood samples 
(including serum, PBMC, whole blood, and plasma) will be obtained from all patients enrolled on 
this study additional potential future biomarker research.  These blood samples will be taken at 
baseline, before temsirolimus dose on Cycle 1 Day 8, after completing 2 cycles of therapy (8 
weeks ± 7 days), and at the end of treatment (if ≥ 4 weeks since last specimen(s) banked).  For 
sample processing, handling, and shipping see Study Laboratory and Procedures Manual.  The 
analyses will be performed by an investigator-approved laboratory. 


 
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7.3.4 
Tumor Specimen Banking 
Fresh specimen or formalin-fixed paraffin-embedded diagnosis tumor tissue and/or 10 to 20 
unstained slides plus H&E slide from a tumor tissue block as well as corresponding pathology 
reports from initial diagnosis and/or subsequent tumor sampling will be retrospectively obtained.  
Specimens will be requisitioned from Pathology Department for banking as soon as possible 
after start of study.  See Specimen Banking Procedures Manual.   
8. Reporting and Documentation of Adverse Events 
8.1 
Definitions of Adverse Events 
8.1.1 
Adverse Event 
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related.  More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, without any judgment about causality.  An adverse event can arise from any use of the 
drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose.  
8.1.2 
Adverse reaction 
An adverse reaction is defined as any adverse event caused by the use of a drug.  Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event. 
8.1.2.1 
Suspected  
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship 
between the drug and the adverse event.  A suspected adverse reaction implies a lesser degree 
of certainty about causality than an adverse reaction. 
8.1.2.2 
Unexpected  
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in 
the investigator brochure or package insert(s), or is not listed at the specificity or severity that 
has been observed, or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the current 
application.  
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or 
as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure.  For example, a certain number of non-acute deaths in a cancer trial 
would be anticipated as an outcome of the underlying disease, but such deaths would generally 
not be listed as a suspected adverse reaction in the investigator brochure. 


 
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Some adverse events are listed in the Investigator Brochure as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not been observed with the drug under investigation.  Such events would be considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class 
effect, the first case of angioedema observed with the drug under investigation should be 
considered unexpected for reporting purposes. 
8.1.2.3 
Serious 
An adverse event or suspected adverse reaction is considered serious if, in the view of either 
the investigator or sponsor, without regard to causality, it results in any of the following 
outcomes:  
 
Death 
 
Life-threatening adverse event 
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
A persistent or significant disability or incapacity  
 
Congenital anomaly/birth defect 
 
Results in cancer 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
8.1.2.4 
Life-threatening 
An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
the sponsor-investigator, its occurrence places the patient or subject at immediate risk of death. 
It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death.  
8.2 
Recording of an Adverse Event 
All grade 3 and above adverse events will be entered into OnCore®, whether or not the event is 
believed to be associated with use of the study drug.  Data about these events and their severity 
will be recorded using the NCI CTCAE v4.0.   
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into OnCore® using the classification 
system listed below:  


 
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Relationship  
Attribution  
Description  
Unrelated to investigational 
drug/intervention 
Unrelated 
The AE is clearly NOT related to the 
intervention  
Unlikely 
The AE is doubtfully related to the intervention  
Related to investigational 
drug/intervention 
Possible 
The AE may be related to the intervention  
Probable 
The AE is likely related to the intervention  
Definite 
The AE is clearly related to the intervention  
 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE.  When specific adverse events are not listed in the CTCAE they will be 
graded by the Investigator as none, mild, moderate or severe according to the following grades 
and definitions: 
Grade 0 
No AE (or within normal limits) 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL) 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL 
Grade 4: Life-threatening consequences; urgent intervention indicated 
Grade 5: Death related to AE 
8.3 
Follow-up of Adverse Events 
All adverse events will be followed with appropriate medical management until resolved.  
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  For selected adverse events for which administration of the 
investigational drug was stopped, a re-challenge of the subject with the investigational drug may 
be conducted if considered both safe and ethical by the Investigator. 
8.4 
Adverse Events Monitoring  
All adverse events, whether or not unexpected, and whether or not considered to be associated 
with the use of the study drug, will be entered into OnCore®, as noted above. 
The Investigator will assess all adverse events and determine reportability requirements to the 
UCSF Data and Safety Monitoring Committee (DSMC) and UCSF’s Institutional Review Board, 
the Committee on Human Research (CHR); and, when the study is conducted under an 
Investigational New Drug Application (IND), to the Food and Drug Administration (FDA) if it 
meets the FDA reporting criteria. 
All adverse events entered into OnCore® will be reviewed by the Helen Diller Family 
Comprehensive Cancer Center Site Committee on a weekly basis.  The Site Committee will 
review and discuss at each weekly meeting the selected toxicity, the toxicity grade, and the 
attribution of relationship of the adverse event to the administration of the study drug(s). 
In addition, all adverse events and suspected adverse reactions considered “serious,” entered 
into OnCore® will be reviewed and monitored by the Data and Safety Monitoring Committee on 
an ongoing basis, discussed at DSMC meetings which take place every six (6) weeks. 


 
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8.5 
Expedited Reporting 
Reporting to the Data and Safety Monitoring Committee 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 
or to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or 
qualified alternate) within 1 business day of knowledge of the event.  The contact may be by 
phone or e-mail. 
Reporting to UCSF Committee on Human Research (Institutional Review Board) 
The Principal Investigator must report events meeting the UCSF CHR definition of 
“Unanticipated Problem” (UP) within 5 business days of his/her awareness of the event.  
 
 
Expedited Reporting to the Food and Drug Administration 
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32).  
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected.  The Sponsor-Investigator needs to ensure that the event meets all 
three definitions:  
 
Suspected adverse reaction (as defined in 8.1.2.1) 
 
Unexpected (as defined in 8.1.2.2) 
 
Serious (as defined in 8.1.2.3) 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report. 
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)).  
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)).  
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)).  
8.6 
Adverse Event Reporting to Funding Organization and  
Research Grant Provider 
In addition to complying with all applicable regulatory reporting laws and regulations, each site 
will report the following information in writing to NCCN and research grant provider (Pfizer) in 
writing within 24 hours of the Investigator’s awareness of occurrence. Principal Investigator 
should report SAEs as soon as they are determined to meet the definition, even if complete 
information is not yet available: 
a) a death, regardless of whether it is considered related to treatment with the Study Drug 


 
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b) a non-fatal SAE that occurs during the reporting period and that is assessed by the Principal 
Investigator as both related to treatment with the Study Drug and unexpected for that 
product  
c) an SAE assessed by the Principal Investigator as related to the Study Drug that occurs after 
the SAE reporting period, 
d) an otherwise reportable event - Exposure During Pregnancy, Exposure During Lactation, 
Occupational Exposure, and Lack Of Effect.  Even though there may not be an associated 
SAE, exposure to the Study Drug during pregnancy, exposure to the Study Drug during 
lactation, and occupational exposure to the Study Drug are reportable, and lack of effect of 
the Study Drug may also be reportable.  
An event should be considered “related” to the Study Drug if a relationship is at least a 
reasonable possibility, and “unexpectedness” should be based upon a single safety 
reference document identified by the Principal Investigator and documented in association 
with the study. 
Follow-up information regarding any of the above 
 
The participating investigator should include his or her assessment of the causal 
relationship between each SAE and the research grant provider’s product. 
 
Reports to NCCN will include the cover page provided (see Appendix J attached hereto), 
and reference Protocol Number NCCN-T12.  Submit to NCCN via fax at 1-215-358-7699 
or via e-mail to ORPReports@nccn.org 
 
Reports to Pfizer, Inc. will include the Reportable Event Fax Cover sheet (see Appendix 
3.1) (use NCCN-T12 as the external reference number).  Submit to the Pfizer U.S. 
Clinical Trial Department 
. 
 
A copy of the report should be sent to the coordinating center CRC  
9. Statistical Considerations and Evaluation of Results 
9.1 
Study Endpoints 
9.1.1 
Study Design 
This study is a single-arm, one-stage, open-label phase II trial to evaluate the efficacy of the 
combination of temsirolimus plus sorafenib in first line therapy for patients with histologically-
confirmed advanced HCC. 
9.1.2 
Primary Endpoint 
Median TTP will be calculated in months from date of first dose of protocol therapy to date of 
removal from study for radiographic (per RECIST 1.1) and/or clinical progression including 
death attributed to progression. For patients removed from study for other reasons than 
progression (such as toxicity, withdrawal of consent, or death from other causes than 
documented radiographic and/or clinical progression), TTP will be censored at the date last 
known to be progression-free.  
9.1.3 
Secondary Endpoints 
1. 
Response rate (RR) will be measured by RECIST version 1.1.   


 
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2. 
Median PFS will be calculated in months from date of first dose of protocol therapy to 
date of study removal for documented radiographic and/or clinical disease progression 
or death from any cause.  For patients removed from study for other reasons than 
progression or death, PFS will be censored at the date last known to be progression-free. 
3. 
Median OS for all enrolled patients who receive at least one dose of protocol therapy will 
be calculated from date of first dose of protocol therapy until date of death, using chart 
review and/or follow up phone calls to determine date of death in patients after removal 
from study.  The survival of patients still alive after 5 years of follow up post study 
discontinuation will be censored.   
4. 
TTF will be measured from date of first dose of protocol therapy to date of removal from 
study for progression, death, or toxicity.  For patients removed from study for other 
reasons (such as noncompliance or withdrawal of consent), TTF will be censored at the 
date of study discontinuation.  
5. 
In patients with baseline AFP ≥ 20 ng/mL, AFP response will be measured by the 
percent change from baseline value to the value at the time of best AFP response.  The 
proportion of ≥ 50% decline from baseline will be measured.  The change in AFP will 
also be examined for association with absolute TTP and best response. 
6. 
Toxicity will be measured using Common Terminology Criteria for Adverse Events 
CTCAE) version 4.0.  The frequency of dose reduction, treatment delays, and 
discontinuation for lack of tolerability will be quantified. 
9.1.4 
Exploratory Endpoints 
1. TTP, RR, PFS, OS, TTF, AFP response, and toxicity and tolerability will be described in 
subsets defined by HBV, HCV, Asian, and non-Asian status. 
2. CTC will be enumerated in peripheral blood at baseline and after 1 and 2 cycles of therapy 
to evaluate for any relationship between baseline levels and change in levels with median 
TTP and/or OS. 
3. Archival tumor specimens will be sectioned for IHC testing of selected mTOR pathway 
markers and next-generation sequencing.  Markers will be dichotomized as high or low 
using published cutpoints to describe incidence of activation in study population and 
explore for relationship to clinical outcomes including TTP and AFP response. 
4. In patients with chronic active HBV and/or positive HBcAb, hepatitis B viral DNA 
quantitative will be monitored for rates of viremia/reactivation on study. 
5. Optional patient blood specimens (including serum, PBMC, whole blood, and plasma) and 
left-over archival pathology specimens will be banked in the UCSF Hepatobiliary Tissue 
Bank (HBTB) for future research. 
9.2 
Determination of Sample Size and Accrual Rate 
9.2.1 
Sample Size and Power Estimate 
The sample size for this phase II study will be 25 patients under the assumption that the time to 
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during the study accrual. A sample size of 25 evaluable patients will have sufficient power to 
detect the difference between the null hypothesis that the median TTP is less than 3 months 
(based on historical controls) and the alternative hypothesis that the median TTP is more than 6 
months. The study will have a 1-sided significance level of 10% and a power of 88% under the 
exact test for comparison of the TTP rates between p0 < 25% versus p1 > 50% at 6 months.  
A median TTP of > 6 months would constitute a meaningful outcome in advanced HCC, based 
upon the benchmarks of first-line TTP of 5.5 months in the SHARP study and 2.8 months in the 
Asia-Pacific study.(Llovet, Ricci et al. 2008; Cheng, Kang et al. 2009)  If median TTP is > 6 
months in this study, a randomized phase II trial to compare the combination therapy to single-
agent sorafenib should be considered.   Such a trial would be much larger and more costly, 
however, and should not be undertaken prior to the current study to confirm that there is 
tolerability and a signal of efficacy to warrant proceeding with the larger trial, noting in particular 
the challenges to accrual in first-line HCC studies historically, as faced by contemporary 
cooperative group studies CALGB 80802 and ECOG 1208. 
Accrual of 25 paired archival tumor and blood specimens also constitutes a meaningful endpoint 
in that it will enable future biomarker studies in subsets of patients with radiographic response, 
AFP response, prolonged stable disease, and primary progression, including potential 
exploratory studies for association with tissue biomarkers of mTOR pathway activation (such as 
pS6 staining).(Villanueva, Chiang et al. 2008) 
9.2.2 
Accrual estimates 
It is estimated that 12 patients will be accrued annually (approximately 1 patient per month) 
combined between UCSF and Northwestern.  This estimate is based upon the accrual to the 
predecessor Phase I study of this combination which enrolled 25 patients with similar eligibility 
criteria between December 2009 and April 2012.  It is expected that the Phase II study will 
accrue faster than the Phase I due to the established infrastructure and momentum from the 
Phase I study, along with no requirement for delays for dose escalation and frequent 
amendments which were associated with the Phase I study.   
9.3 
Interim Analyses and Stopping Rules 
No interim assessment for primary endpoint is planned, but there will be a planned interim 
safety analysis by the UCSF Data and Safety Monitoring Board after the first 30% of the 
planned study participants (8 patients) have enrolled and completed at least one cycle of 
protocol therapy or been removed for toxicity. Study accrual will not be interrupted for the early 
safety assessment. The proportion of patients with treatment-related adverse events of grade 3 
or higher and/or an unacceptable toxicity event (with exceptions defined in Section 6.4) will be 
summarized with 90% two-sided exact confidence intervals. Each confidence interval will be no 
wider than ±0.17. If the lower confidence bound (LCB) exceeds 0.17, adverse events will be 
evaluated and a decision will be made whether to amend the protocol or close the study.  
If the true rate of treatment-related toxicity is 25%, the probability that 3 or more patients will 
have adverse events of grade 3 or greater is 32%. A summary of probabilities for a range of true 
toxicity rates is shown below.  If 3 or more patients among the first 8 experience an eligible 
grade 3 or higher and/or unacceptable toxicity event, a decision will be made whether to amend 
the study or close the study due to toxicity. 
 
True Toxicity Rate 
Probability 3 or more 
of 8 patients 
experience AEs of 
grade 3 or greater 
Probability 2 or more 
of 8 patients 
experience AEs of 
grade 3 or greater 
Probability 1 or more 
of 8 patients 
experience AEs of 
grade 3 or greater 


 
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10% 
3.8% 
18.7% 
57% 
20% 
20.3% 
50.0% 
83% 
25% 
32.0% 
63.3% 
89% 
30% 
44.8% 
74.5% 
94% 
9.4 
Analyses Plans 
Analyses of primary and secondary endpoints as well as exploratory analyses will be conducted 
by 
 the designated biostatistician for 
this protocol. Demographic and other baseline characteristics will be summarized in the 
aggregate manner. For continuous demographic/baseline variables including age, weight, and 
vital signs, results will be summarized and presented as N, mean, standard deviation, median, 
and minimum and maximum values. For categorical variables such as race/ethnicity, the 
number and percentage of subjects will be used. Statistical comparisons of these baseline 
characteristics will be performed using the Wilcoxon rank-sum test for continuous variables and 
Fisher’s exact test for categorical variables. 
9.4.1 
Analysis Population 
The safety population will include all enrolled patients who receive at least one dose of the 
study drug.  All patients will be evaluable for toxicity and safety assessment from the time of 
their first treatment with the study drug. 
The evaluable population for efficacy will include all enrolled patients who have received at 
least one dose of study drug (unless determined to be ineligible and replaced for reasons such 
as inability to comply or withdrawal of consent).  These patients will have their response 
classified according to the definitions stated below.   
9.4.2 
Analysis of Primary Endpoints 
Kaplan-Meier methods will be used to summarize the primary endpoint (median TTP) with 95% 
confidence intervals.  The proportion of patients with TTP equal to or exceeding 6 months will 
also be calculated and reported along with 95% confidence intervals.  
9.4.3 
Analysis of Secondary Endpoints 
Response rates will be summarized and presented with 95% exact binomial confidence 
intervals. The comparison of response rates will use Fisher’s exact test.  
Kaplan-Meier methods will be used to summarize time-to-event outcomes including the primary 
endpoint (median TTP) and secondary endpoints (PFS, TTF, OS).  Proportions of patients with 
TTP, PFS, and TTF equal to or exceeding 6 months will be calculated with 95% confidence 
intervals.  Tumor response by RECIST 1.1 measurements will be presented descriptively for the 
study cohort. 
 
AFP Response:  Baseline levels (high or low) will be compared to absolute TTP to 
determine if there is an association using Fisher’s Exact tests or by Wilcoxon Rank-Sum 
test.  Changes in levels on therapy with temsirolimus and sorafenib will be measured as 
an increase by ≥ 50% from baseline, stable value within 50% of baseline, or decrease by ≥ 
50% from baseline.  The change in level will be used to evaluate the predictive value for 
TTP. Fisher’s Exact tests will be used to test for significance.  Kaplan-Meier methods and 
Log-rank tests will also be used to estimate TTP based on the AFP.   


 
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9.4.4 
Exploratory Analyses/Assessments 
 
CTC levels:  Baseline level of CTC (detectable or undetectable) will be compared to 
proportion with TTP at 6 months to determine if there is an association using Fisher’s 
Exact tests.  Change in CTC levels (increase or decrease) after 1 and 2 cycles will be 
compared to proportion with TTP at 6 months to determine if there is an association using 
Fisher’s Exact tests.   Markers of mTOR pathway activation: Descriptive statistics will 
summarize the IHC parameters of staining intensity, percentage positivity, distribution, and 
intracellular localization for each protein. Due to possible limited specimen quantity, IHC 
outcomes will be dichotomized. Activation will be measured by % positive cells and 
intensity using published IHC cutpoints for high/low: cytoplasmic pAkt > 40% or 2-3+, 
cytoplasmic PTEN intensity < 10% or 0-1+, cytoplasmic pS6RP > 70% or 2-3+, or LKB1 0-
1.7-12 Univariate analysis using Cox’s model will be performed to test whether the 
dichotomized expression of each protein using the published cutpoints is a significant 
predictor of TTP. Results for each test will include the hazard ratio (HR) with 95% 
confidence intervals. The association between each protein and the two binary coding 
schemes for AFP decline (≥ 50% or ≥ 20%) on C2D1 will be tested using Fisher’s exact 
test. Results for each test will be summarized with proportions with pathway activation and 
95% confidence intervals for each AFP subset. Each patient will also be categorized as 
having overall mTOR pathway activation (defined as any combination of high pAKT, high 
pS6RP, low PTEN, and/or low LKB1) or not. This binary variable will also be examined for 
its relationship with TTP, OS, AFP response, and other clinical endpoints using the same 
methods described above. For each test of association with AFP change, based upon 
Fisher’s exact test large differences can be detected (e.g. 10% among 7 patients with 
marker-low, 80% among 8 patients with marker-low) (power=81%, α2=10%). The sample 
size is too small to test for a difference in TTP, OS, or other clinical endpoints according to 
pathway activation status. The expected sample size will be ≥ 25 cases (expect 40 to 45 
cases) with IHC-quality archival tumor, with the expectation that ~75% of cases will be 
evaluable for TTP (n ≥ 18) and 60% evaluable for AFP response on C2D1 (n ≥ 15).  
Genotype findings will be dichotomized as presence or absence of any mTOR pathway 
aberration or combination thereof (e.g. mutations in AKT, mTOR, PTEN, PIK3CA, and/or 
TSC1/2). This binary variable will be examined for its relationship with time to progression, 
overall survival, AFP response, and other clinical endpoints by univariate analysis using 
Cox’s model. Concordance between primary and metastatic specimens on mutational 
profile will be described individually due to small sample size.  Other tumor genotype 
findings and relationship to clinicopathologic covariates will be reported descriptively. 
To optimize sample size and ensure adequate number of evaluable cases, these analyses 
of mTOR pathway IHC and genotype markers will also be performed on cases and 
samples CC#09455 when available, to ensure at least 25 evaluable cases with adequate 
archival tumor for testing.  Although pooling of data and specimens across studies 
introduces potential confounding, it is appropriate for these exploratory analyses as the 
eligibility criteria and protocol therapy were overlapping for CC#09455 and the current 
study.   
 
Hepatitis B viral load: In all patients with active HBV infection, changes in HBV DNA 
quantitative by PCR (conversion from undetectable at baseline to detectable on study or 
an increase by ≥ 50% from baseline versus unchanged from baseline) will be 
characterized using descriptive statistics (mean, median, standard deviation, and 95% 
confidence interval) to calculate the proportion of patients with an increase in viral load 
while on protocol therapy.     
 
Future biomarker research on banked specimens will be reported outside of the main 
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9.5 
Evaluation of Safety 
Analyses will be performed for all patients having received at least one dose of study drug.  The 
study will use the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. 
10. Study Management 
10.1 Pre-study Documentation 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects.   
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements.  
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements. 
10.2 Institutional Review Board Approval 
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF CHR (UCSF Institutional Review Board).  Prior to obtaining CHR 
approval, the protocol must be approved by the Helen Diller Family Comprehensive Cancer 
Center Site Committee and by the Protocol Review Committee (PRC).  The initial protocol and 
all protocol amendments must be approved by the IRB prior to implementation.   
10.3 Informed Consent 
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants 
must sign the CHR-approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  
The original signed copy of the consent document must be retained in the medical record or 
research file.  
10.4 Changes in the Protocol 
Once the protocol has been approved by the UCSF CHR, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the Investigator 
and approved by PRC and the CHR prior to implementation.   
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to CHR approval.  In this circumstance, however, the 
Investigator must then notify the CHR in writing within five (5) working days after 
implementation.  The Study Chair and the UCSF study team will be responsible for updating any 
participating sites. 


 
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10.5 Handling and Documentation of Clinical Supplies 
The UCSF Principal Investigator and each participating site will maintain complete records 
showing the receipt, dispensation, return, or other disposition of all investigational drugs.  The 
date, quantity and batch or code number of the drug, and the identification of patients to whom 
study drug has been dispensed by patient number and initials will be included.  The sponsor-
investigator will maintain written records of any disposition of the study drug. 
The Principal Investigator shall not make the investigational drug available to any individuals 
other than to qualified study patients.  Furthermore, the Principal Investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol. 
10.6 Case Report Forms (CRFs) 
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis.  All study data will be entered into OnCore® via standardized 
CRFs in accordance with the CTMS study calendar, using single data entry with a secure 
access account.  The Clinical Research Coordinator (CRC) will complete the CRFs as soon as 
possible upon completion of the study visit; the Investigator will review and approve the 
completed CRFs.  
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records maintained by 
UCSF personnel.  All source documentation should be kept in separate research folders for 
each patient. 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate.  
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies. 
The Principal Investigator will be responsible for ensuring the accurate capture of study data.  At 
study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked.  Any changes to the data entered into the CRFs  after that time can 
only be made by joint written agreement among the Study Chair, the Trial Statistician, and the 
Protocol Project Manager. 
10.7 Oversight and Monitoring Plan 
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring 
entity for this study.  The UCSF DSMC will monitor the study in accordance with the NCI-
approved Data and Safety Monitoring Plan (DSMP).  The DSMC will routinely review all adverse 
events and suspected adverse reactions considered “serious”.  The DSMC will audit study-
related activities to ensure that the study is conducted in accordance with the protocol, local 
standard operating procedures, FDA regulations, and Good Clinical Practice (GCP).  Significant 
results of the DSMC audit will be communicated to the IRB and the appropriate regulatory 
authorities at the time of continuing review, or in an expedited fashion, as applicable.  See 
Appendix 3, Data and Safety Monitoring Plan for additional information. 


 
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10.8 Multicenter communication 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate, at minimum, monthly conference calls with the 
participating sites at the completion of each cohort or more frequently as needed to discuss risk 
assessment.  The following issues will be discussed as appropriate: 
 
Enrollment information  
 
Cohort updates (i.e. DLTs) 
 
Adverse events (i.e. new adverse events and updates on unresolved adverse events and 
new safety information) 
 
Protocol violations 
 
Other issues affecting the conduct of the study 
10.9 Record Keeping and Record Retention 
The Principal Investigator is required to maintain adequate records of the disposition of the 
drug, including dates, quantity, and use by subjects, as well as written records of the disposition 
of the drug when the study ends.   
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, CHR correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified. 
10.10 Coordinating Center Documentation of Distribution 
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution 
of study documents as well as their receipt (when possible). The HDFCCC recommends that 
the Study Chair maintain a correspondence file and log for each segment of distribution (e.g., 
FDA, drug manufacturer, participating sites, etc.). 
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt. 


 
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Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received. 
At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its 
updates and safety information are distributed. 
10.11 Regulatory Documentation 
Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be approved by 
the UCSF Committee on Human Research (CHR). Prior to implementing this protocol at the 
participating sites, approval for the UCSF CHR approved protocol must be obtained from the 
participating site’s IRB.  
The following documents must be provided to UCSF HDFCCC before the participating site can 
be initiated and begin enrolling participants:  
 
Participating Site IRB approval(s) for the protocol, appendices, informed consent form and 
HIPAA authorization  
 
Participating Site IRB approved consent form  
 
Participating Site IRB membership list  
 
Participating Site IRB’s Federal Wide Assurance number and OHRP Registration number  
 
Curriculum vitae and medical license for each investigator and consenting professional  
 
Documentation of Human Subject Research Certification training for investigators and key 
staff members at the Participating Site  
 
Participating site laboratory certifications and normals  
Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant 
permission to proceed with enrollment. 
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Abou-Alfa, G. K., L. Schwartz, et al. (2006). "Phase II study of sorafenib in patients with 
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Antoch, G., J. Kanja, et al. (2004). "Comparison of PET, CT, and dual-modality PET/CT imaging 
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Baba, H. A., J. Wohlschlaeger, et al. (2009). "Phosphorylation of p70S6 kinase predicts overall 
survival in patients with clear margin-resected hepatocellular carcinoma." Liver Int 29(3): 399-
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Barrera, K., Imagawa DK, Yamamoto M, Katz M, Sanati H, Nguyen A, Nguyen L, Ho J, 
Gebhardt K, Hoang T (2009). Sorafenib for treatment of hepatocellular carcinoma in the Asian-
American population: Does one size fit all? Gastrointestinal Cancers Symposium. 
Bayer (2011). Investigator's Brochure BAY 43-9006: 192. 
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Benjamin, R. S., H. Choi, et al. (2007). "We should desist using RECIST, at least in GIST." J 
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advanced, recurrent hepatocellular carcinoma after liver transplantation: a proof of principle. J 
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Bolondi L., C. W., Bennouna J., et al. (2008). Clinical benefit of sorafenib in hepatitis C patients 
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human HCC." Gastroenterology 130(4): 1117-1128. 
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Chang, Y. S., J. Adnane, et al. (2007). "Sorafenib (BAY 43-9006) inhibits tumor growth and 
vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models." Cancer 
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Cheng, A., Y. Kang, D. Lin, et al. (2011). Phase III trial of sunitinib (Su) versus sorafenib (So) in 
advanced hepatocellular carcinoma (HCC). American Society of Clinical Oncology Annual 
Meeting, Chicago, IL, J Clin Oncol. 
Cheng A., K. Y., Chen C., et al. (2008). Randomized phase III trial of sorafenib versus placebo 
in Asian patients with advanced hepatocellular carcinoma. 2008 ASCO Annual Meeting. 
Cheng, A. L., Y. K. Kang, et al. (2009). "Efficacy and safety of sorafenib in patients in the Asia-
Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, 
placebo-controlled trial." Lancet Oncol 10(1): 25-34. 
Chenivesse, X., D. Franco, et al. (1993). "MDR1 (multidrug resistance) gene expression in 
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Cho, E. H., M. Wendel, et al. (2012). "Characterization of circulating tumor cell aggregates 
identified in patients with epithelial tumors." Phys Biol 9(1): 016001. 
Choi, H. (2005). "Critical issues in response evaluation on computed tomography: lessons from 
the gastrointestinal stromal tumor model." Curr Oncol Rep 7(4): 307-311. 
Cohen, S. J., C. J. Punt, et al. (2008). "Relationship of circulating tumor cells to tumor response, 
progression-free survival, and overall survival in patients with metastatic colorectal cancer." J 
Clin Oncol 26(19): 3213-3221. 
Compagnon, P., S. Grandadam, et al. (2008). "Liver transplantation for hepatocellular 
carcinoma without preoperative tumor biopsy." Transplantation 86(8): 1068-1076. 
Craxi A., P. C., Sangiovani A, et al. (2008). Efficacy and safety of sorafenib in patients with 
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Transplantation 79(7): 855-857. 


 
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3027-3035. 
 


 
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Appendix 1 ECOG Performance Status Criteria 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Symptoms, but ambulatory 
Restricted in physically strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light housework, office work) 
2 
In bed < 50% of the time 
Ambulatory and capable of all self-care, but unable to carry out any work activities 
Up and about more than 50% of waking hours 
3 
In bed > 50% of the time 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
5 
Dead 
 
Appendix 2 Staging Tools 
 
Child-Pugh Score 


 
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http://homepage.mac.com/sholland/contrivances/childpugh.html 
Below is an example of a calculated score: 
 


 
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Barcelona Clinic Liver Cancer (BCLC) Stage 
 
 
Barcelona-Clinic Liver Cancer (BCLC) staging classification and treatment schedule 
Stage 0: Patients with very early HCC are optimal candidates for resection. Stage A: Patients 
with early HCC are candidates for radical therapies (resection and ablation, liver transplantation; 
or percutaneous treatments). Stage B: Patients with intermediate HCC may benefit from 
chemoembolization. Stage C: Patients with advanced HCC may receive new agents in the 
setting of a RCT. Stage D: Patients with end-stage disease will receive symptomatic treatment. 
(Adapted from Llovet JM et al with permission.) 
 
Liver Transplantation Volume 10, Issue S2, pages S115-S120, 30 JAN 2004 DOI: 10.1002/lt.20034 
http://onlinelibrary.wiley.com/doi/10.1002/lt.20034/full#fig1 


 
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Cancer of the Liver Program (CLIP) Score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“Prospective Validation of the CLIP Score: A New Prognostic System for Patients With Cirrhosis and Hepatocellular 
Carcinoma”.The Cancer of The Liver Italian Program (CLIP) Investigators Hepatology Vol. 31, No. 4, 2000 
http://onlinelibrary.wiley.com/doi/10.1053/he.2000.5628/pdf 


 
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Appendix 3 Data and Safety Monitoring Plan for Multicenter Institutional Study 
(Phase 2 or 3 Institutional Study) 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study includes:  
 
Review of subject data 
 
Review of suspected adverse reactions considered “serious” 
 
Monthly monitoring (depending on study accrual) 
 
Minimum of a yearly regulatory audit 
Monitoring and Reporting Guidelines 
All institutional Phase 2 or 3 therapeutic studies are designated with a moderate risk 
assessment. The data is monitored every six months, with twenty percent of the subjects 
monitored (or at least three subjects if the calculated value is less than three). 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial. The UCSF 
Coordinating Center will also coordinate quarterly conference calls with the participating sites to 
communicate the review of adverse events, safety data, and other study matters. 
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. 
The Study Chair is responsible for the overall conduct of the study and for monitoring its safety 
and progress at all participating sites. The Study Chair will conduct continuous review of data 
and subject safety and discuss each subject’s treatment at monthly UCSF Site Committee 
meetings. The discussions are documented in the UCSF Site Committee meeting minutes. 
Multicenter communication 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate, at minimum, monthly conference calls with the 
participating sites at the completion of each cohort or more frequently as needed to discuss risk 
assessment.  The following issues will be discussed as appropriate: 
 
Enrollment information  
 
Adverse events (i.e. new adverse events and updates on unresolved adverse events and 
new safety information) 
 
Protocol violations 
 
Other issues affecting the conduct of the study 
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center, as well as the participating sites.  The DSMC will be responsible for monitoring all data 
entered in OnCore® at the UCSF Coordinating Center and the participating sites.  The data (i.e. 
copies of source documents) from the participating sites will be sent electronically or faxed over 
to the UCSF Coordinating Center prior to the monitoring visits in order for the DSMC to monitor 
the participating site’s compliance with the protocol, patient safety, and to verify data entry. 


 
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Adverse Event Review and Monitoring 
Adverse Event Monitoring 
All Grade 3-5 Adverse Events, whether or not unexpected, and whether or not considered to be 
associated with the use of study drug, will be entered into OnCore®, UCSF’s Clinical Trial 
Management System. 
All Adverse Events will be reported by the participating site to the Coordinating Center (UCSF) 
approximately weekly, as required for weekly review of study data and as per local IRB 
guidelines within the required timeframes. 
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
UCSF Site Committee meetings. All clinically significant adverse events must be reported to the 
UCSF Coordinating Center by the participating sites within 10 business days of becoming aware 
of the event or during the next scheduled quarterly conference call, whichever is sooner. The 
UCSF Site Committee will review and discuss the selected toxicity, the toxicity grade, and the 
attribution of relationship of the adverse event to the administration of the study drug(s) from the 
UCSF Coordinating Center and the participating sites. 
In addition, all suspected adverse reactions considered “serious” must be entered in OnCore® 
and reported to the UCSF Coordinating Center within 1 business day. The suspected adverse 
reactions considered “serious” will be reviewed and monitored by the Data and Safety 
Monitoring Committee on an ongoing basis and discussed at the DSMC meeting, which take 
place every six (6) weeks. 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be related either to the investigational 
drug or any research related procedure, the Study Chair at the UCSF Coordinating Center or 
the assigned designee must be notified within 1 business day from the participating site(s) and 
the Study Chair must then notify the DSMC Chair or qualified alternate within 1 business day of 
this notification. The contact may be by phone or e-mail. 
Increase in Adverse Event Rates 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert), the Study Chair at the UCSF Coordinating Center is 
responsible for notifying the DSMC at the time the increased rate is identified.  The report will 
indicate if the incidence of adverse events observed in the study is above the range stated in 
the Investigator Brochure or package insert. 
If at any time the Study Chair stops enrollment or stops the study due to safety issues, the 
DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail.  The DSMC 
must receive a formal letter within 10 business days and the CHR must be notified. 
Data and Safety Monitoring Committee Contacts: 
 
DSMC Chair:  
 
DSMC Monitors  
Phone:  
Email: 
Address:  
 
 
Box 1705 
UCSF 
San Francisco, CA 94115 
Box 1297 
UCSF Helen Diller Family Comprehensive 
Cancer Center 
San Francisco, CA 94115 
 


 
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3.1 
Cover Sheet for SAE Reporting to NCCN and Research Grant Provider 
 


 
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Appendix 4 Substrates, Inhibitors, and Inducers of CYP3A4 *,** 
Sensitive CYP3A4 substrates as well as those with a narrow therapeutic range (indicated 
in boldface and/or by review with Investigational Pharmacist) are prohibited.13**   
Sensitive CYP3A4 substrates refers to drugs whose plasma AUC values have been shown to 
increase 5-fold or higher when co-administered with a known CYP3A4 inhibitor.  CYP3A4 
substrates with narrow therapeutic range refers to drugs whose exposure-response indicates 
that increases in their exposure levels by the concomitant use of CYP3A4 inhibitors may lead to 
serious safety concerns (such as torsades de pointes).  Other CYP3A4 substrates should be 
avoided or used with caution. 
Strong CYP3A4 inhibitors (indicated in boldface and/or by review with Investigational 
Pharmacist) are prohibited. 
Moderate inhibitors (indicated in underlined text) and weak inhibitors (indicated in italicized text) 
should be avoided, if possible, and their concomitant use must be evaluated by the Study Chair 
or Investigational Pharmacist.  A strong inhibitor is one that caused a ≥ 5-fold increase in the 
plasma AUC values or more than 80% decrease in clearance of CYP3A4 substrates (not limited 
to midazolam, a sensitive CYP3A4 substrate) in clinical evaluations.  A moderate inhibitor is one 
that caused a ≥ 2- but < 5-fold increase in the AUC values or 50-80% decrease in clearance of 
sensitive CYP3A substrates when the inhibitor was given at the highest approved dose and the 
shortest dosing interval in clinical evaluations.  A weak inhibitor is one that caused a ≥ 1.25 - but 
< 2-fold increase in the AUC values or 20-50% decrease in clearance of sensitive CYP3A 
substrates when the inhibitor was given at the highest approved dose and the shortest dosing 
interval in clinical evaluations. 
All CYP3A4 Inducers (indicated in boldface and/or by review with Investigational 
Pharmacist) are prohibited. 
Please note that these lists are not exhaustive, and there may be some cases where a boldface 
drug does not pose significant risk for interaction and may be used with caution (depending on 
dose, interval, mode of administration, etc.).  If investigators are unsure of potential for drug-
drug interaction, the Investigational Pharmacist and Study Chair will be consulted to determine if 
an agent may be used with caution versus discontinued  For the most up to date table of 
cytochrome P450-related drug interactions, please refer to the Indiana University drug 
interaction table at the following website: 
http://medicine.iupui.edu/clinpharm/ddis/ClinicalTable.asp. 
CYP3A4,5,7 Substrates 
Macrolide antibiotics: 
Clarithromycin 
Erythromycin (not 3A5) 
NOT azithromycin 
Telithromycin 
Anti-arrhythmics: 
Quinidine 3OH (not 3A5) 
Benzodiazepines: 
Alprazolam 
Diazepam 3OH 
Miscellaneous: 
Alfentanyl 
Aprepitant 
Aripiprazole 
Budesonide 
Buspirone 
Cafergot 
Caffeine_TMU 
Cilostazol 
Cocaine 
Codeine-Ndemethylation 


 
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CYP3A4,5,7 Substrates 
Midazolam 
Triazolam 
Immune Modulators: 
Cyclosporine 
Sirolimus  
Tacrolimus (FK506) 
HIV Antivirals: 
Indinavir 
Nelfinavir 
Ritonavir 
Saquinavir 
Prokinetic: 
Cisapride 
Antihistamines: 
Astemizole 
Chlorpheniramine 
Terfenadine 
Calcium Channel Blockers: 
Amlodipine 
Diltiazem 
Felodipine 
Lercanidipine 
Nifedipine2 
Nisoldipine 
Nitrendipine 
Verapamil 
HMG CoA Reductase Inhibitors: 
Atorvastatin 
Cerivastatin 
Lovastatin 
NOT pravastatin 
Simvastatin 
Steroid 6beta-OH: 
Estradiol 
Hydrocortisone 
Progesterone 
Testosterone 
Dapsone 
Dexamethasone 
Dextromethorphan 
Diergotamine 
Docetaxel 
Domperidone 
Eletriptan 
Eplerenone 
Ergotamine 
Fentanyl 
Finasteride 
Fluticasone 
Gleevec 
Haloperidol 
Irinotecan 
LAAM 
Lidocaine 
Methadone 
Nateglinide 
Ondansetron 
Pimozide 
Propranolol 
Quetiapine 
Quinine 
Risperidone 
NOT rosuvastatin 
Salmeterol 
Sildenafil 
Tamoxifen 
Taxol 
Terfenadine 
Trazodone 
Vardenafil 
Vincristine 
Zaleplon 
Ziprasidone 
Zolpidem 
 


 
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CYP3A4,5,7 Inducers 
Barbiturates 
Carbamazepine 
Efavirenz 
Glucocorticoids*** 
Modafinil 
Nevirapine 
 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
Pioglitazone 
Rifabutin 
Rifampin 
St. John's Wort 
Troglitazone 
 
CYP3A4,5,7 Inhibitors 
Amiodarone 
Amprenavir 
Aprepitant 
Atazanavir 
Chloramphenicol 
Cimetidine 
Clarithromycin 
Celaviridine 
Diethyldithiocarbamate 
Diltiazem 
Erythromycin (NOT azithromycin) 
Fluconazole 
Fluvoxamine 
Fosamprenavir 
Gestodene 
Grapefruit juice 
Imatinib 
Indinavir 
Itraconazole 
Ketoconazole 
Mibefradil 
Mifepristone 
Nefazodone 
Nelfinavir 
Norfloxacin 
Norfluoxetine 
Ritonavir 
Saquinavir 
Star fruit 
Telithromycin 
Verapamil 
Voriconazole 
 
* Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine 
(2007). Http://medicine.iupui.edu/clinpharm/ddis/table.asp   Accessed 6/12/2009.  
**http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm081
177.htm#cypEnzymes. Accessed 6/17/2009. 
*** Glucocorticoids are permitted for transient use such as for treatment of or premedication for hypersensitivity 
reactions, asthma or chronic bronchitis exacerbations, or nausea.  Chronic use (≥ 2 weeks) is prohibited. 
 


 
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Appendix 5 Substrates of CYP2B6, CYP2C8, and CYP2C9*,** 
Sensitive CYP2B6, CYP2C8, and CYP2C9 substrates as well as those with a narrow 
therapeutic range (indicated in boldface and/or by review with Investigational Pharmacist) are 
prohibited.13  Other CYP2B6, CYP2C8, and CYP2C9 substrates should be avoided or used with 
caution. 
Please note that these lists are not exhaustive, and there may be some cases where a boldface 
drug does not pose significant risk for interaction and may be used with caution (depending on 
dose, interval, mode of administration, etc.).  If investigators are unsure of potential for drug-
drug interaction, the Investigational Pharmacist and Study Chair will be consulted to determine if 
an agent may be used with caution versus discontinued For the most up to date table of 
cytochrome P450-related drug interactions, please refer to the Indiana University drug 
interaction table at the following website: 
http://medicine.iupui.edu/clinpharm/ddis/ClinicalTable.asp 
CYP2B6 Substrates 
CYP2C8 Substrates 
CYP2C9 Substrates 
Bupropion 
Cyclophosphamide 
Efavirenz 
Ifosfamide 
Methadone  
Amodiaquine 
Cerivastatin 
Paclitaxel 
Repaglinide  
Torsemide 
 
Celecoxib 
Diclofenac 
Fluoxetine 
Fluvastatin 
Glibenclamide 
Glimepiride 
Glipizide 
Glyburide 
Ibuprofen 
Irbesartan 
Lornoxicam 
Losartan 
Meloxicam 
Nateglinide 
Phenytoin-4-OH2 
Piroxicam 
Rosiglitazone 
S-naproxen 
Suprofen 
S-warfarin 
Tamoxifen 
Tolbutamide 
Tolbutamide 
Torsemide 
* Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine 
(2007), http://medicine.iupui.edu/clinpharm/ddis/table.asp.  Accessed 6/12/2009.  
**http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm081
177.htm#cypEnzymes. Accessed 6/17/2009. 


 
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Appendix 6 Substrates of UGT1A1 and UGT1A9* 
Substrates of UGT1A1 and UGT1A9 should be used with caution.  If used concomitantly with 
sorafenib, levels of these substrates are expected to increase.  Please note that these lists are 
not exhaustive, and there may be some cases where a boldface drug does not pose significant 
risk for interaction and may be used with caution (depending on dose, interval, mode of 
administration, etc.).  If investigators are unsure of potential for drug-drug interaction, the 
Investigational Pharmacist and Study Chair will be consulted to determine if an agent may be 
used with caution versus discontinued 
 
UGT1A1 Substrates 
UGT1A9 Substrates 
Acetaminophen 
Buprenorphine 
Ethinyl estradiol 
Ibuprofen 
Irinotecan 
Nicotine 
Phenytoin 
Warfarin 
Acetaminophen 
Ibuprofen 
Phenytoin 
Valproate 
Warfarin 
 
* Adapted from GeneMedRx Health Care Provider Information, http://www.genemedrx.com/UGTtable.php.  Accessed 
6/12/09 


 
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Appendix 7 Substrates, Inhibitors, and Inducers of P-glycoprotein (P-gp)* 
In general, inhibitors and inducers of P-gp are to be avoided or used with caution. 
Use of the P-gp substrates digoxin and doxorubicin is prohibited (indicated in boldface 
and/or by review with Investigational Pharmacist).  
Temsirolimus has been shown to inhibit P-gp mediated efflux of digoxin in vitro; sorafenib 
increases concentrations of doxorubicin.  Please note that these lists are not exhaustive, and 
there may be some cases where a boldface drug does not pose significant risk for interaction 
and may be used with caution (depending on dose, interval, mode of administration, etc.).  If 
investigators are unsure of potential for drug-drug interaction, the Investigational Pharmacist 
and Study Chair will be consulted to determine if an agent may be used with caution versus 
discontinued 
P-gp Substrates 
P-gp Inhibitors 
P-gp Inducers 
Aldosterone 
Amprenavir 
Bilirubin 
Cimetidine 
Colchicine 
Cortisol 
CPT-11 
Cyclosporine 
Dexamethasone 
Digoxin 
Diltiazem 
Domperidone 
Doxorubicin 
Erythromycin 
Estradiol-17B-Đ-glucuronide 
Etoposide 
Fexofenadine 
Indinavir 
Itraconazole 
Ivermectin 
Loperamide 
Methylprednisolone 
Morphine 
Nelfinavir 
Paclitaxel 
Quinidine 
Ranitidine 
Rhodamine 
Saquinavir 
Sparfloxacin 
Terfenadine 
Tetracycline 
Vecuronium 
Verapamil 
Vinblastine 
Atorvastatin 
Bromocriptine 
Carvedilol 
Cyclosporine 
Erythromycin 
GF120918 
Itraconazole 
Ketoconazole 
LY335979 
Meperidine 
Methadone 
Nelfinavir 
Pentazocine 
Progesterone 
Quinidine 
Ritonavir 
Saquinavir 
Tamoxifen 
Valspodar 
Verapamil 
Amprenavir 
Clotrimazole 
Dexamethasone 
Indinavir 
Morphine 
Nelfinavir 
Phenothiazine 
Retinoic acid 
Rifampin 
Ritonavir 
Saquinavir 
St. John’s Wort 


 
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* Kim RB: Drugs as P-Glycoprotein Substrates, Inhibitors, and Inducers.  Drug Metabolism Reviews 34 (1&2), 
47-54 (2002) 


 
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Appendix 8 List of Phosphorus-Rich Foods 
Below is a list of common foods that are high in phosphorus. 
Please also refer to USDA National Nutrient Database for a list of foods sorted by their 
elemental phosphorus content:  
http://www.nal.usda.gov/fnic/foodcomp/Data/SR17/wtrank/sr17a305.pdf