Conditions: Adult Hepatocellular Carcinoma Advanced Adult Hepatocellular Carcinoma Endometrial Serous Adenocarcinoma Localized Non-Resectable Adult Liver Carcinoma Lung Carcinoid Tumor Malignant Pancreatic Gastrinoma Malignant Pancreatic Glucagonoma Malignant Pancreatic Insulinoma Malignant Pancreatic Somatostatinoma Metastatic Digestive System Neuroendocrine Tumor G1 Ovarian Carcinosarcoma Ovarian Endometrioid Adenocarcinoma Ovarian Seromucinous Carcinoma Ovarian Serous Surface Papillary Adenocarcinoma Pancreatic Alpha Cell Adenoma Pancreatic Beta Cell Adenoma Pancreatic Delta Cell Adenoma Pancreatic G-Cell Adenoma Pancreatic Polypeptide Tumor Recurrent Adult Liver Carcinoma Recurrent Digestive System Neuroendocrine Tumor G1 Recurrent Fallopian Tube Carcinoma Recurrent Ovarian Carcinoma Recurrent Pancreatic Neuroendocrine Carcinoma Recurrent Primary Peritoneal Carcinoma Recurrent Uterine Corpus Carcinoma Regional Digestive System Neuroendocrine Tumor G1 Stage IIIA Fallopian Tube Cancer Stage IIIA Ovarian Cancer Stage IIIA Primary Peritoneal Cancer Stage IIIA Uterine Corpus Cancer Stage IIIB Fallopian Tube Cancer Stage IIIB Ovarian Cancer Stage IIIB Primary Peritoneal Cancer Stage IIIB Uterine Corpus Cancer Stage IIIC Fallopian Tube Cancer Stage IIIC Ovarian Cancer Stage IIIC Primary Peritoneal Cancer Stage IIIC Uterine Corpus Cancer Stage IV Fallopian Tube Cancer Stage IV Ovarian Cancer Stage IV Primary Peritoneal Cancer Stage IVA Uterine Corpus Cancer Stage IVB Uterine Corpus Cancer Uterine Carcinosarcoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 252
Healthy volunteers: no

Brief summary:
This phase II trial studies how well temsirolimus and bevacizumab work in treating patients with advanced endometrial, ovarian, liver, carcinoid, or islet cell cancer. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of cancer by blocking blood flow to the tumor. Giving temsirolimus together with bevacizumab may kill more tumor cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the response rate and progression-free survival at 6 months in patients with endometrial, ovarian, hepatocellular carcinoma, carcinoid or islet cell cancer.

II. To determine the toxicity of the combination of temsirolimus and bevacizumab in patients with endometrial, ovarian, hepatocellular carcinoma, carcinoid or islet cell cancer.

SECONDARY OBJECTIVES:

I. To collect blood and tumor specimens from all patients entered on the trial for possible future analysis.

OUTLINE:

Patients receive temsirolimus intravenously (IV) on days 1, 8, 15, and 22, and bevacizumab IV over 30-90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 3 years.

Arms:
arm 1: Patients receive temsirolimus IV on days 1, 8, 15, and 22, and bevacizumab IV over 30-90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Bevacizumab intervention 2: Temsirolimus
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV

Protocol document:
Prot_SAP_000.pdf: 
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NCI Protocol # 8233 
Local Protocol # MC0845 
NCI Version Date:  September 6, 2016 
1 
 
 
Title: A Phase II Trial of Temsirolimus and Bevacizumab in Patients with Endometrial, 
Ovarian, Hepatocellular Carcinoma, Carcinoid or Islet Cell Cancer 
Principal Investigator: 
Henry Pitot, M.D. 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
Telephone: (507) 284-2511 
Telefax: (507) 538-5280 
Email: pitot.henry@mayo.edu 
Co-Investigators: 
 
Islet Cell 
Charles Erlichman, M.D. 
Timothy Hobday, M.D. 
Mayo Clinic 
Mayo Clinic 
200 First Street SW 
200 First Street SW 
Rochester, MN 55905 
Rochester, MN 55905 
Telephone: (507) 2842511 
Telephone: (507) 284-2511 
Telefax: (507) 284-5280 
Telefax: (507) 284-5280 
Email: erlichman.charles@mayo.edu 
Email: hobday.timothy@mayo.edu 
Endometrial Cancer 
Ovarian Cancer 
Mark Einstein, M.D. 
Robert Morgan, M.D. 
Albert Einstein College of Medicine 
City of Hope Cancer Center 
1695 Eastchester Road, Suite 601 
1500 East Duarte Road 
Bronx, NY 10461 
Duarte, CA 91010 
Telephone: (718) 405-8082 
Telephone: (626) 256-4673 
Telefax: (718) 405-8087 
Email: rmorgan@coh.org 
Email: meinstei@aecome.yu.edu 
Hepatocellular Carcinoma 
Carcinoid Tumors 
Jennifer Knox, M.D. 
Manisha Shah, M.D. 
Princess Margaret Hospital Consortium 
The Ohio State University 
610 University Avenue 
320 West Tenth Avenue 
Toronto, Ontario M5G 2M9 
Columbus, Ohio 43210 
Telephone: (416) 946-2399 
Telephone: (614) 293-8629 
Telefax: (416) 946-6546 
Telephone: (614) 293-3112 
Email: jennifer.knox@uhn.on.ca 
Email: manisha.shah@osumc.edu 


NCI Protocol # 8233 
Local Protocol # MC0845 
NCI Version Date:  September 6, 2016 
2 
 
 
 
Participating Consortium 
Mayo Clinic Phase 2 Consortium (Coordinating Center – Ops Office) 
University of California/ Davis Phase 2 Consortium 
University of Chicago Phase 2 Consortium 
Albert Einstein College of Medicine, Montefiore Medical Center Phase 2 Consortium 
Memorial Sloan Kettering Phase 2 Consortium 
Princess Margaret Hospital Phase 2 Consortium 
Ohio State University Phase 2 Consortium 
Lee Moffitt Cancer Center and Research Institute Phase 2 Consortium 
 
Statistician: 
Jun (Vivien) Yin, Ph.D. 
Mayo Clinic Cancer Center 
Telephone: (507) 538-6252 
Email: yin.jun@mayo.edu 
 
P2C Protocol Coordinator: 
Sanna McKinzie, M.S. 
Mayo Clinic Cancer Center 
Telephone: (507) 538-6646 
Email: mckinzie.sanna@mayo.edu 
 
 
NCI-Supplied Agent: 
Bevacizumab (NSC 704865, IND 7921) 
Temsirolimus (NSC 683864, IND 61010) 
IND Sponsor: DCTD, NCI. 
 
Document History 
Effective Date 
Document History 
Effective Date 
Activation 
September 8, 2009 
Addendum 9 
July 18, 2012 
Addendum 1 
February 22, 2010 
Addendum 10 
October 8, 2012 
Addendum 2 
June 8, 2010 
Addendum 11 
June 4, 2013 
Addendum 3 
August 23, 2010 
Addendum 12 
November 6, 2013 
Addendum 4 
February 8, 2011 
Addendum 13 
April 11, 2014 
Addendum 5 
June 21, 2011 
Addendum 14 
July 10, 2014 
Addendum 6 
June 21, 2011 
Addendum 15 
Pending 
Addendum 7 
December 22, 2011 
Addendum 8 
March 6, 2012 


NCI Protocol # 8233 
Local Protocol # MC0845 
NCI Version Date:  September 6, 2016 
3 
 
 
 
 
This trial is supported by the NCI Cancer Trials Support Unit (CTSU). 
Participation is restricted to NCI-supported Phase 2 Contract (N01) sites. 
All Phase 2 Contractors will participate through the CTSU mechanism as 
outlined below. 
• All participating investigators and research staff must be registered members of the CTSU and 
have an active CTEP IAM account (https://eapps-ctep.nci.nih.gov/iam). To ensure timely 
communication between the clinical site and the CTSU, it is critical that a CTSU Site 
Administrator and Data Administrator be designated at each site and that their CTEP IAM contact 
information remains current. Instructions on obtaining a CTEP IAM account and registering with 
the CTSU are outlined in the Registration Procedures section of this protocol. 
 
• The study protocol and all related forms and documents may be downloaded from the 8233 
Web page located under the Phase 2 Consortia Trials section of the CTSU Members’ side of the 
web-site. Protocol document access is confined to the investigators and associates at Phase 2 
contract sites (main members and affiliates). Go to http://www.ctsu.org, sign on with your 
username and password on the left hand side, click on the Protocols tab, then click on “Phase 2 
Consortia Trials” and select trial 8233. 
 
• Send site registration documents to the CTSU Regulatory Office in Philadelphia as outlined in 
the Registration Procedures section of this protocol. 
 
• Patient enrollments will be facilitated by the CTSU. Fax patient enrollment documents to the 
CTSU Patient Registration desk as outlined in the Registration Procedures section of this 
protocol. 
 
• Data management activities will be performed by CTSU Data Operations. This is a CTSU 
Remote Data Capture (RDC) study. All sites will submit CRF data electronically using the RDC 
system. Discrepancy management will be handled through the discrepancy management 
component of the RDC system. The RDC Production Application is for those individuals who 
have completed their training in the RDC system. Please go to the CTSU Members’ side of the 
website (https://www.ctsu.org) and click on the “Clinical Data” tab at the top of your screen, 
followed by the “Remote Data Capture” link on the left-hand side of your screen. Select the 
"Training" tab to request a training account. Clinical reports should be submitted to CTSU Data 
Operations via fax. Details are outlined in the protocol section Data Submission to Data 
Operations Center (CTSU). 
Cancer Trials Support Unit (CTSU) Address and Contact Information 
 
 
Mail or FAX site registration documents to: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone - 1-866-651-CTSU (1-866-651-2878) 
Fax – 215-569-0206 


NCI Protocol # 8233 
Local Protocol # MC0845 
NCI Version Date:  September 6, 2016 
4 
 
 
FAX patient enrollment forms to the CTSU Patient Registration desk as outlined in the 
Registration Procedures section of this protocol. 
For answers to patient eligibility or treatment-related questions: 
Please contact: 
Manisha H. Shah, MD (Carcinoid Tumor) manisha.shah@osumc.edu 
Timothy Hobday, M.D. (Islet Cell) hobday.timothy@mayo.edu 
Mark H. Einstein, M.D. (Endometrial Cancer) meinstei@aecom.yu.edu 
Robert Morgan, M.D. (Ovarian Cancer) RMorgan@coh.org 
Jennifer Knox, M.D. (Hepatocellular Carcinoma) jennifer.knox@uhn.on.ca 
All other questions (including forms-specific and remote data capture system questions) should be 
communicated by phone or e-mail to the CTSU Help Desk at: 
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
CTSU Help Desk hours are 9:00 am – 5:30 pm. E.T. Mon-Fri  (excluding holidays) 
The CTSU Web-site is located at: Https://www.ctsu.org 
NCI IDB contacts: 
Helen Chen, M.D. (bevacizumab) Helen_Chen@nih.gov 
L. Austin Doyle, M.D. (temsirolimus) doylela@mail.nih.gov 


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NCI Protocol # 8233 
Local Protocol # MC0845 
NCI Version Date:  September 6, 2016 
6 
 
–
TABLE OF CONTENTS 
SCHEMA ................................................................................................................................5 
TABLE OF CONTENTS .........................................................................................................6 
1. 
OBJECTIVES ...................................................................................................................9 
1.1 
Primary Objectives .....................................................................................................9 
1.2 
Secondary Objectives..................................................................................................9 
2. 
BACKGROUND...............................................................................................................9 
2.1 
Bevacizumab ..............................................................................................................9 
2.2 
Temsirolimus (CCI-779, Torisel)............................................................................... 16 
3. 
PATIENT SELECTION .................................................................................................. 27 
3.1 
Inclusion Criteria - All Patients ................................................................................. 27 
3.2 
Inclusion Criteria – Endometrial Cancer .................................................................... 29 
3.3 
Inclusion Criteria 
Hepatocellular Cancer................................................................. 29 
3.4 
Inclusion Criteria - Islet Cell Cancer and Carcinoid Tumor ........................................ 30 
3.5 
Exclusion Criteria - All Patients ................................................................................ 31 
3.6 
Exclusion Criteria – Endometrial Cancer ................................................................... 33 
3.7 
Exclusion Criteria - Hepatocellular Cancer ................................................................ 33 
3.8 
Exclusion Criteria - Ovarian Cancer .......................................................................... 33 
3.9 
Exclusion Criteria – Carcinoid Cancer ....................................................................... 33 
4.0 
REGISTRATION PROCEDURES ............................................................................... 34 
4.1 
Investigator / Research Associate Registration ........................................................... 34 
4.2 
Site Registration ....................................................................................................... 34 
4.3 
Patient Registration................................................................................................... 36 
5. 
TREATMENT PLAN...................................................................................................... 37 
5.1 
Study Drug Administration ....................................................................................... 37 
5.2 
Ancillary Treatment/Supportive Care ........................................................................ 37 
5.3 
Duration of Therapy.................................................................................................. 39 
5.4 
Duration of Follow Up .............................................................................................. 39 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ................................................................ 40 
6.1 
Bevacizumab Related Adverse Events ....................................................................... 40 
6.2 
Temsirolimus Related Adverse Events....................................................................... 42 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................... 44 
7.1 
CTCAE v 3.0............................................................................................................ 44 
7.2 
Expedited Adverse Event Reporting Requirements .................................................... 45 
7.3 
Exclusions from Expedited Reporting........................................................................ 46 
7.4 
Adverse Events to be Graded .................................................................................... 48 
8. 
PHARMACEUTICAL INFORMATION ......................................................................... 49 
8.1 
Temsirolimus (Torisel®) (NSC # 683864) .................................................................. 49 
8.2 
Bevacizumab (Avastin®) (NSC 704865) .................................................................... 59 


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NCI Version Date:  September 6, 2016 
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8.3 
Agent Ordering/Accountability ................................................................................. 67 
9. 
CORRELATIVE/SPECIAL STUDIES............................................................................. 68 
9.1 
Laboratory Correlative Studies .................................................................................. 68 
10. STUDY CALENDAR...................................................................................................... 72 
11.0 
TREATMENT EVALUATION USING RECIST (VERSION 1.1) CRITERIA[93]........ 73 
11.1 
Schedule of Evaluations ........................................................................................ 73 
11.2 
Definitions of Measurable and Non-Measurable Disease ........................................ 73 
11.3 
Guidelines for Evaluation of Measurable Disease ................................................... 73 
11.4 
Measurement of Effect .......................................................................................... 75 
11.5 
Response and Disease Progression ......................................................................... 78 
12. 
DATA REPORTING / REGULATORY CONSIDERATIONS ..................................... 78 
12.1 
Data Reporting ...................................................................................................... 78 
12.2 
CTEP Multicenter Guidelines ................................................................................ 79 
12.3 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA)............................................................................................................... 79 
13. 
STATISTICAL CONSIDERATIONS .......................................................................... 81 
13.1 
Study Overview .................................................................................................... 81 
13.2 
Statistical Design................................................................................................... 83 
13.3 
Analysis Plan ........................................................................................................ 89 
13.4 
Inclusion of Women and Minorities ....................................................................... 92 
14. 
DESCRIPTIVE FACTORS .......................................................................................... 94 
14.1 
Islet Cell Cancer Patients Only .............................................................................. 94 
14.2 
Carcinoid Cancer Patients Only ............................................................................. 94 
14.3 
Ovarian Cancer Patients Only ................................................................................ 94 
14.4 
Hepatocellular Carcinoma Patients Only ................................................................ 94 
14.5 
Carcinoid and Islet Cell Cancer Patients Only ........................................................ 94 
15. PATHOLOGY CONSIDERATIONS ............................................................................... 94 
16. 
DATA SUBMISSION TO DATA OPERATIONS CENTER (CTSU)............................ 94 
16.1 
Schedule of Data Submission................................................................................. 95 
16.2 
Event Monitoring .................................................................................................. 95 
16.3 
Data Entry/Submission Timetable .......................................................................... 96 
17. 
GROUPING FACTOR................................................................................................. 98 
18. 
FUNDING CONSIDERATIONS ................................................................................ 98 
18.1 
Costs Charged to Patient........................................................................................ 98 
18.2 
Tests to be Research Funded.................................................................................. 98 
18.3 
Support from N01 P2C Contract ............................................................................ 98 
REFERENCES ...................................................................................................................... 98 


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APPENDIX A: ECOG PERFORMANCE STATUS.............................................................. 104 
APPENDIX B: CTEP MULTICENTER GUIDELINES ........................................................ 105 
APPENDIX C: CHILD-PUGH CLASSIFICATION OF HEPATIC FUNCTIONAL RESERVE 
...............................................................................................................................................     107 
APPENDIX D: KNOWN INHIBITORS AND INDUCERS OF CYP3A4 .............................. 108 
APPENDIX E: PERCENT BONE MARROW ...................................................................... 108 
APPENDIX F: NEW YORK HEART ASSOCIATION CLASSIFICATIONS ....................... 110 
APPENDIX G: SPECIMEN SUMMARY ............................................................................. 111 


NCI Protocol # 8233 
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1. 
OBJECTIVES 
1.1 
Primary Objectives 
1.11 
To determine the response rate and progression-free survival at 6 months in patients with 
endometrial, ovarian, hepatocellular carcinoma, carcinoid or islet cell cancer. 
1.12 
To determine the toxicity of the combination of temsirolimus and bevacizumab in 
patients with endometrial, ovarian, hepatocellular carcinoma, carcinoid or islet cell 
cancer. 
1.2 
Secondary Objectives 
1.21 
To collect blood and tumor specimens from all patients entered on the trial for possible 
future analysis. 
2. 
BACKGROUND 
2.1 
Redacted 
 
 
 
 
Redacted 
 
 


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Redacted 
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Redacted 


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Redacted 
Redacted 
 
 
 
 
 
Redacted 
 
 
 
Redacted 


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Redacted 
Redacted 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2 
Temsirolimus (CCI-779, Torisel) 
Temsirolimus (CCI-779, sirolimus 42-ester with 2,2-bis(hydroxymethyl) propionic-acid), 
an ester of the macrocyclic immunosuppressive agent sirolimus (rapamycin, 
Rapamune™), is a cytostatic cell cycle inhibitor with antitumor properties. The agent 
specifically inhibits the mammalian target of rapamycin (mTOR), a Ser/Thr kinase 
involved in the initiation of mRNA translation (reviewed in Dancey, 2002). 
Temsirolimus has been shown to inhibit the growth of a wide range of histologically 
diverse tumor cells, with the greatest sensitivity shown by cells derived from the central 
nervous system (CNS) cancers, leukemia (T-cell), breast cancer, prostate cancer, and 
melanoma [25]. Temsirolimus is being developed as a cytostatic agent to delay the time 
to tumor recurrence or progression or to increase survival in patients with various 
malignancies. Key features of this agent include its good tolerability, unique mechanism 
of action, ability to arrest cells in the G1 phase, and ability to induce apoptosis. 
Intermittent schedules of temsirolimus administration have been evaluated in clinical 
studies because nonclinical data suggest such schedules minimize the agent’s 
Redacted 


NCI Protocol # 8233 
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NCI Version Date:  September 6, 2016 
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immunosuppressive effects while maintaining antitumor activity. 
Mechanism of Action 
The observed antitumor and immunosuppressive properties of rapamycin analogs are due 
to their ability to disrupt the mTOR-dependent signaling pathway [26].  mTOR, a 
member of the phosphatidylinositide 3’-kinase (PI3K)-related family, is located 
predominantly in the nuclear fraction of both neoplastic and normal cells [27]. mTOR 
activation triggers resting cells to increase the translation of a subset of mRNAs whose 
proteins are required for cell cycle progression from G1 to S phase. mTOR regulates 
essential signal transduction pathways and is involved in the coupling of growth stimuli 
with cell cycle progression.  Experimental data indicate that mTOR acts downstream of 
the PI3K/Akt pathway and is phosphorylated in response to mitogenic signals [26]. Early 
studies reported that mTOR was dedicated to initiating mRNA translation in response to 
favorable nutrient environments [28]. In fact, cells treated with rapamycin undergo 
changes that are strikingly similar to those observed during conditions of starvation. 
These include mTOR inactivation, down regulation of translation, G1 arrest, 
accumulation of glycogen stores and altered transcription patterns [28]. More recent 
studies have demonstrated that mTOR is involved in regulating many aspects of cell 
growth, including organization of the actin cytoskeleton, membrane traffic, protein 
degradation, protein kinase C (PKC) signaling, ribosome biogenesis, and transcription 
(reviewed in Schmelzle and Hall, 2000). 
Temsirolimus reacts with the ubiquitous intracellular FK506-binding protein 12 
(FKBP12), forming a temsirolimus/FKBP12 complex that is a potent inhibitor of the 
highly conserved kinase mTOR [29]; [30]. Inhibition of mTOR leads to suppression of 
several downstream signaling effectors, including the ribosomal subunit p70S6k and the 
eukaryotic initiation factor 4 binding protein 1 (4E-BP1) [31]. These two proteins play 
key roles in ribosomal biogenesis and cap-dependent translation, respectively [32]. The 
extent of phosphorylation of these two downstream proteins (p70S6 kinase and 4E-BP1) 
may therefore serve as indicators of temsirolimus biologic activity in vivo. Inhibition of 
the synthesis of ribosomal proteins and elongation factors, required to accelerate the 
process of cell division, are thought to contribute to the anti-proliferative effects of 
rapamycin analogs [33]. While temsirolimus inhibits the translation of only a subset of 
mRNAs, inhibition of mTOR can lead to a substantial decrease (~15%) in overall protein 
synthesis [34]. 
Tumors that rely on paracrine or autocrine stimulation of receptors that constitutively 
stimulate the PI3K/Akt/mTOR pathway or tumors with mutations that activate the 
PI3K/Akt signal transduction pathway may depend on rapamycin-sensitive pathways for 
growth and therefore may be particularly sensitive to rapamycin analogs. The tumor 
suppressor gene PTEN is known to play a major role in embryonic development, cell 
migration, and apoptosis (reviewed in Yamada and Araki, 2001). PTEN acts as a lipid 
phosphatase that regulates major signal transduction pathways and effectively terminates 
PI3K-mediated signaling [35]. PTEN mutation is associated with constitutive activation 
of the PI3K/Akt pathway, resulting in tumors that are generally resistant to apoptosis. 
PTEN status in tumor cells may therefore be an important predictor of sensitivity to 


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rapamycin analogs [26]. Preliminary evidence suggests that breast cancer cell lines 
containing PTEN mutations are sensitive to growth inhibition by rapamycin [36]. 
Additional studies in PTEN-deficient human tumor cell lines and PTEN knockout mice 
have demonstrated sensitivity to growth inhibition by temsirolimus. Temsirolimus 
produced remarkable sensitivity to G1 arrest (ID50 < 1nM) in PTEN-deficient myeloma 
cell lines, while myeloma cells containing wild type PTEN were at least 1000-fold less 
sensitive to the agent [37]. Also, studies of glioblastoma cell lines indicated that low 
PTEN protein expression was strongly linked with sensitivity to temsirolimus-mediated 
growth arrest [38]. Together, these studies indicate that the molecular identification of 
PTEN mutations or other mutations that lead to constitutive activation of the pathway 
within tumor cells might be predictive of sensitivity to temsirolimus therapy [39]. 
Summary of Clinical Studies 
Temsirolimus safety, pharmacokinetics, and preliminary antitumor effects were evaluated 
in a phase 1 dose-escalation study with doses of 7.5-220 mg/m2 given as a weekly 
intravenous (IV) infusion to 24 patients with advanced malignancies [40]. Although the 
maximum tolerated dose (MTD) was not reached, 220 mg/m2 appeared to be the 
maximum acceptable dose, with thrombocytopenia being dose limiting with repeated 
dosing.  No clinically relevant immunosuppressive effects were observed during 
treatment, although herpes simplex infections were observed in five patients. The most 
frequent drug-related adverse events were acneiform maculopapular rashes and 
mucositis/stomatitis (18 of 24 patients, 75%). Confirmed partial responses (PRs) were 
observed in 2 of 24 patients evaluated, one each with renal cell carcinoma (RCC) and 
breast cancer. 
Data from in vitro studies of A498 human renal cell lines indicated that temsirolimus had 
a median growth inhibitory concentration (IC50) of 5 ng/mL [25]. Predicted modeling of 
IC50 (humans receiving doses as low as 10 mg) suggests that whole blood concentrations 
would be above the range of 1 ng/mL throughout the entire 1-week dose interval and 
above 5 ng/mL for the majority of this time period. It is expected that mTOR inhibition 
would be attained with a 25 mg dose. 
Clinical pharmacokinetic data are available in patients with cancer receiving 
temsirolimus both IV daily x 5 days every 2 weeks, once weekly schedules, and orally 
daily x 5 every 2 weeks. These data indicate that there is no appreciable drug 
accumulation between cycles and that distribution is extensive. With increasing dose, 
exposure (AUC) increases in a less than proportional fashion. The mean volume of 
distribution at steady state (Vdss) is large (57 L after 2 mg IV dose; 900 L following a 250 
mg IV dose) and increases with dose. Exposure to the hydrolytic product sirolimus is 
substantial with mean values of approximately 1.5-2.3-fold greater than those seen with 
temsirolimus following IV administration. Clearance (CL) of temsirolimus from whole 
blood increases with increasing dose from approximately 5.2L/h after a 2 mg dose to 
100L/h after a 250 mg dose.  Intersubject variability in CL at a given dose was modest 
and ranged from 16-27%. The terminal half-life (t1/2) following temsirolimus doses of 25 
to 250 mg is approximately 15 hours. 


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Pharmacokinetic results from the initial phase 1 study showed that the AUC increased 
proportionally with doses up to 150 mg, but doses higher than 300 mg yielded high 
AUCs and low CL in some patients [40]. The mean Vdss was large with mean values of 
127-384 L, while the temsirolimus mean terminal t1/2 decreased from 22 hours (34 
mg/m2) to 13 hours (220 mg/m2) as the dose increased.  Similar pharmacokinetic data 
were reported for 16 patients following their initial dose of temsirolimus of 25, 75, or 250 
mg delivered as a weekly 30-minute IV [41]. 
Phase II studies of single agent temsirolimus evaluating different doses of 25 mg, 75 mg, 
and/or 250 mg weekly IV have been undertaken in broad range of tumor histologies. The 
most promising activity has been seen in mantle cell lymphoma [42]; [43], other B-cell 
lymphomas [38] and endometrial carcinoma [44] with objective tumor response rates of 
25-40%.  Moderate activity has been reported in breast [45] and renal cell carcinoma 
[41]. Minimal to modest single agent activity has been seen in SCLC [46], melanoma 
[47] and GBM [48], [49] and multiple myeloma [50]. In general, lower doses appear to 
be as active as higher doses with better tolerability. 
Recently, a phase 3 trial of temsirolimus, temsirolimus with interferon versus interferon 
in poor prognosis patients with RCC has been reported [51]. Of the 626 patients, overall 
survival of patients treated with temsirolimus was significantly prolonged compared to 
those treated with interferon (median 10.9 months versus 7.3 months, HR = 0.73, p = 
0.0069). The combination of interferon and temsirolimus did not confer greater benefit 
than interferon alone, possibly due to compromised dose delivery of the agent(s). 
Temsirolimus +Bevacizumab 
It is clear that many of the new, targeted agents may not be of significant clinical benefit 
when used alone. Interfering with (multiple) pathways that affect the tumor cells and the 
tumor microvasculature may be a potentially promising strategy that can be of benefit for 
patients with renal cell cancer. Based on the mechanisms of action of both drugs, we 
hypothesize that the combination of temsirolimus and bevacizumab would induce stable 
disease in patients with progressive NET, ovarian cancer, HCC and endometrial cancer. 
Temsirolimus targets essential regulatory functions in the tumor cells as well as cells of 
the tumor stroma, and bevacizumab, by neutralizing VEGF, will target the tumor 
endothelium. Preclinical studies have suggested that the combination of the mTOR 
inhibitor rapamycin with a monoclonal antibody against VEGF is associated with 
enhanced antitumor effects in a pancreatic cancer model, compared to each agent alone 
[52]. The combination also was associated with a more potent in vivo antiangiogenic 
effect, as measured by tumor microvessel density, and enhanced apoptosis. This 
combination is at least additive, and may be synergistic (experiments to assess synergy 
were not possible in this in vivo model). This has led to a phase I/II trial of bevacizumab 
combined with temsirolimus in renal cancer which is being performed by the Mayo 
Clinic consortium. The trial reported at ASCO 2007 has demonstrated that the DLT was 
grade 3 hypertriglyceridemia. One patient also experienced a grade 3 mucositis. Other 
grade 3 adverse events that were not DLTs included hypertension, proteinuria, 
hemorrhage, nausea/vomiting, dehydration, anorexia, pneumonitis, anemia, and 
hypophosphatemia. The best responses in the 12 evaluable patients included 7 PRs and 3 


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SDs. This combination will be evaluated in both a company sponsored trial and by 
ECOG in first-line renal cancer. The RP2D from that trial is proposed for this multi- 
tumor phase 2 trial. 
Endometrial Cancer 
Endometrial cancer affects 40,000 women in the US each year and long-term outcomes in 
patients with advanced stage or recurrent disease is poor[53]. Endometrial cancer deaths 
are also rising, increasing over 100% during the past 20 years [54]. Approximately 40% 
of stage II/III tumors will recur and many of these will result in death. Investigations 
focusing on new approaches to improve outcomes in this patient population are 
warranted. 
There have been several randomized controlled studies performed by the Gynecologic 
Oncology Group (GOG) and others addressing the issue of optimal therapy for patients 
with recurrent endometrial cancer. These studies have focused on three active agents 
identified in phase II trials: doxorubicin, platinum agents, and paclitaxel. Doxorubicin 
alone has been shown to have a 38% overall response rate with 26% of patients achieving 
a complete clinical response [55]. In GOG-107, 281 women were randomized to 
doxorubicin alone (60 mg/m2) vs. doxorubicin (60 mg/m2) plus cisplatin (50 mg/m2) 
(AP) which resulted in an improved response rate to combination therapy (25% vs. 42%, 
p=0.004) and PFS (3.8 vs. 5.7 months); however, there was no difference in overall 
survival (9 vs 9.2 months) [56]. It has been shown that Paclitaxel has significant single 
agent activity with a response rate of 36% in recurrent or advanced endometrial cancer 
[57]; however, in the randomized trial comparing paclitaxel with doxorubicin or the 
standard arm of AP, there was no difference in RR, PFS, or OS between the two arms 
[58]. In GOG 177, patients were randomized to AP versus TAP, which had significantly 
worse toxicity despite an improved ORR (57% vs. 34%; p<0.01), PFS (8.3 vs. 5.3 
months; p<0.01) and OS (15.3 vs. 12.3 months; p=0.037) [59]. 
There is evidence that angiogenesis plays a significant role in endometrial cancer 
prognosis and disease progression [60]; [61]; [62]; [63]. Angiogenesis biomarkers 
correlate with endometrial cancer response to therapy and appear to have a prognostic 
role as well [64]. Bevacizumab has been shown to have overall clinical activity in 
previously treated patients with endometrial cancer. In a small study of 11 patients with 
recurrent endometrial cancer and leiomyosarcoma who had multiple sites of recurrence 
and have been treated with prior cytotoxic therapy, 2 had a PR and 3 had SD [65]. 
Temsirolimus and other mTOR inhibitors have shown single agent activity in patients 
who have recurrent or metastatic endometrial cancer [44]; [66]. In an NCIC trial of 27 
patients with recurrent and metastatic endometrial cancer previously treated with 
hormones only who received single agent temsirolimus, a response rate of 25% and 
median progression free survival of 6 months were observed. [44]. Seven of 19 patients 
benefited from a different mTOR inhibitor AP25373 in a patient population who had 
progressed on chemotherapy. [66]. 
Due to the single agent activity of both temsirolimus and bevacizumab in endometrial 


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cancer patients who have been previously treated, this trial will combine these two agents 
to determine the efficacy of the combination as first line therapy. 
Ovarian Cancer 
Therapeutic targets including vascular endothelial growth factor (VEGF) and mammalian 
target of rapamycin (mTOR) have been shown to be important in the regulation of 
ovarian cancer. RAD001 (everolimus) [67] has been shown to play a central role in the 
regulation of ovarian cancer cell growth and cell cycle progression, to delay tumor onset 
and progression in a transgenic mouse model of ovarian cancer.[68]. Expression levels of 
Bcl-2 and CCND1/CDK4 may be predictive of the cellular effects of these agents in 
human ovarian carcinoma.[69]. VEGF expression in cell lines and murine models has 
been shown to be important in ovarian cancer cell growth and in stimulation of ascites 
production with increased production of VEGF leading to rapid ascites accumulation and 
inhibition of VEGF expression decreasing ascites production and cell growth. [70]. 
Furthermore, circulating levels of VEGF in mice has been shown to correlate with tumor 
response and response to therapy. [71] Administration of bevacizumab and rapamycin in 
combination in a mouse model of intraperitoneal cancer has been shown to inhibit of 
tumor growth more than either agent alone. [72] 
While clinical activity of mTOR inhibitors have not yet been reported in human subjects 
with ovarian cancer, the activity of bevacizumab has been documented in phase II trials 
of the single agent alone and in combination with cytotoxic chemotherapy or other 
targeted agents. [73] treated forty-four patients with platinum-resistant ovarian cancer 
and reported a partial response in seven patients (15.9%). The median progression-free 
survival was 4.4 months and the median survival duration was 10.7 months. 
Bevacizumab-associated grade 3 or 4 adverse events included hypertension (9.1%), 
proteinuria (15.9%), bleeding (2.3%), and wound-healing complications (2.3%) and GI 
perforations (11.4%). The incidence of perforation was related to prior therapy as this 
complication was observed in 23.8% of patients receiving three prior chemotherapy 
regimens, compared with 0% of patients receiving two prior chemotherapy regimens (P < 
.01). It is also possible that heavily pretreated patients have a greater degree of tumor 
involvement, which may more directly contribute to the risk of perforation 
The Gynecology Oncology Group reported a separate single agent trial of bevacizumab 
in persistent or recurrent ovarian cancer. [74]. Sixty-two patients having a median age of 
57 years were treated. 66.1% received two prior regimens and 41.9% were considered 
platinum resistant.  Two complete and eleven partial responses (21% ORR) were 
observed with a median response duration of 10 months. Twenty-five patients (40.3%) 
survived progression-free for at least 6 months. The median PFS and overall survival 
were 4.7 and 17 months, respectively. There was no significant association of prior 
platinum sensitivity, age, number of prior chemotherapeutic regimens, or performance 
status with the hazard of progression or death. Grade 3 adverse events included 
myelosuppression, gastrointestinal, hypertension, thromboembolism, allergy, hepatic, 
pain, coagulation, constitutional, and dyspnea. Grade 4 adverse events included one 
incident of pulmonary embolus, vomiting and constipation, and proteinuria. 


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Combinations of bevacizumab with metronomic cyclophosphamide and with erlotinib 
have also been reported. The California Cancer Consortium in collaboration with the 
Princess Margaret and Chicago Phase II Consortia [75] treated seventy patients with 
bevacizumab 10 mg/kg every two weeks with oral cyclophosphamide, 50 mg daily. The 
progression-free survival at 6 months was 56% with a median time to progression of 7.2 
months. Partial responses were observed in 17 patients (24%). Grade 3 and 4 adverse 
events included hypertension, fatigue, and pain. Four episodes of gastrointestinal 
perforation or fistula were observed. In addition, two episodes each of CNS ischemia and 
pulmonary hypertension, and one episode each of gastrointestinal bleeding and wound 
healing complication were observed. There were three treatment-related deaths.  Levels 
of VEGF, E-selectin, and thrombospondin-1 were not associated with clinical outcome. 
The Chicago Phase II Consortium in collaboration with the California Cancer 
Consortium and the Princess Margaret Consortium treated 13 patients with bevacizumab 
15 mg/kg every three weeks with erlotinib 150 mg orally daily. [76] There were two 
major objective responses, one complete response of 16+ month duration and one partial 
response of 11 month (ORR 15%). Seven patients had a best response of stable disease. 
Grade 3 or 4 adverse events included anemia (1), nausea (2), vomiting (1), hypertension 
(1), and diarrhea (2).  Two patients had fatal gastrointestinal perforations. 
Based on this pre-clinical and clinical data suggesting additive or synergistic activity of 
these agents in epithelial ovarian cancer the efficacy of the combination of bevacizumab 
and temsirolimus in patients with persistent or recurrent ovarian cancer will be evaluated. 
Hepatocellular carcinoma 
Hepatocellular carcinoma (HCC) is the 5th most common cancer worldwide with a rising 
incidence in the USA over the past three decades [77], [78], [79]. Worldwide, HCC is the 
third leading cause of cancer death after lung cancer and gastric cancer. The most 
common risk factors for development of HCC are chronic Hepatitis B or Hepatitis C 
infection and alcoholic cirrhosis. Many patients will have poor underlying liver function 
as a result of these co-morbidities [80]. 
The prognosis of HCC is poor. At presentation the majority of patients (70-85%) already 
have unresectable disease. Patients who present with localized disease (solitary nodule 
<5cm or up to 3 nodules <3cm each) may be eligible for surgical resection, 
transplantation or loco regional therapy such as chemoembolization or radiofrequency 
ablation (RFA) [81]. However, for those who do receive potentially curative surgery, 
recurrence rates are up to 50% within 2 years. For these patients who do relapse or 
progress, and for those patients who present with advanced disease, the prognosis is poor 
with survival measured in months. Poor underlying liver function in many patients, and 
the lack of effective systemic therapies are the main factors leading to poor survival in 
these patients [79, 82]. In advanced disease, systemic chemotherapy has not been shown 
to prolong survival. A 1997 meta-analysis of 27 chemotherapy trials concluded that non- 
surgical therapies were either ineffective or minimally effective [83]. 
Expectations for advancement in drug therapy for HCC patients lie with targeted agents. 
It is well recognized that many mutations and aberrant cell pathways drive primary liver 


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tumorigenesis. Even when comparing HCCs with similar etiologies there is tremendous 
molecular heterogeneity, suggesting that therapeutic advancements may require 
simultaneous targeting of more than one molecular pathway [84]. Targeting VEGF and 
mTOR pathways are 2 of the most promising strategies currently in HCC drug 
development. 
VEGF is over-expressed in HCC, and the level of expression correlates with tumor grade. 
[85], and reviewed in [84]. Targeting angiogenesis is therefore an attractive approach in 
treating HCC, and anti-angiogenesis drugs such as sorafenib or bevacizumab have 
already demonstrated activity. 
Sorafenib is a multikinase inhibitor with anti-angiogenic, pro-apoptotic and Raf kinase 
inhibitory activity. Following a phase II trial suggesting efficacy of sorafenib in HCC 
[86], a phase III randomized, placebo controlled trial in patients with advanced HCC with 
preserved liver function (Child-Pugh A) was performed. Treatment with sorafenib was 
associated with a statistically significant improvement in overall survival (10.7 versus 7.9 
months, Hazard Ratio for death 0.69, 95% confidence interval [CI] 0.55-0.87, p<0.001), 
time to radiologic progression (5.5 versus 2.8 months, p<0.001) and disease control rate 
(43% versus 32%, p-0.002).[87]. In both the phase II and phase III studies, partial 
responses were uncommon (<5%) and no complete responses were observed. Therefore it 
appears that sorafenib works primarily as a cytostatic agent. In a subsequent Asian- 
Pacific phase III trial presented by Leung et al at ASCO 2008, sorafenib also impacted 
significantly survival in these very advanced HCC patients. These trials established 
sorafenib as a new reference standard of care in advanced HCC and serve to help validate 
the targeted agent approach in this disease. However given the absolute benefit for HCC 
patients is quite modest, further drug development is needed. 
Bevacizumab has shown promising activity in a single arm phase II trial (NCI protocol 
number 5611) in advanced HCC patients [88]. The study included 46 patients, of whom 6 
had objective responses (13%, 95% CI: 3-23%), and 65% were progression-free at 6 
months.  Median PFS was 6.9 months (95% CI: 6.5-9.1 months); overall survival was 
53% at 1 year, 28% at 2 years, and 23% at 3 years. Grade 3-4 adverse events included 
hypertension (15%), thrombosis (6%, including 4% arterial thrombosis); Grade 3 or 
higher hemorrhage occurred in 11% of patients, including one fatal variceal bleed, 
although more rigorous screening for risk of bleeding appeared to reduce the incidence of 
these complications. Bevacizumab was associated with significant reductions in tumor 
enhancement by DCE MRI, and reductions in circulating VEGF-A and SDF-1 levels. 
The response rate of 13% in HCC with single agent bevacizumab suggests it is one of the 
more active agents studied to date in HCC and as good or better than seen in many other 
solid tumors where the drug has proven benefit. 
The study of drugs that target mTOR are still preliminary in HCC but single agent phase 
I/II trials are underway. Studies in HCC animal models suggest mTOR is a promising 
therapeutic target in HCC [89], [90]. These models also suggest additive tumor control 
with dual m-TOR and VEGF targeting. The recognized toxicity profile of temsirolimus 
at the dose and schedule used in this study is likely to be quite manageable in an HCC 
population with preserved liver function (Child-Pugh A) and good PS. 


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As mTOR inhibitors have pre-clinical evidence in HCC and VEGF inhibitors have 
proven benefit, there is a good foundation to combine these 2 drug classes to study 
potential additive or synergistic benefit to patients with HCC. In addition there is a strong 
scientific rationale that combining bevacizumab with temsirolimus will maximize 
pathway inhibition by concurrently targeting parallel signaling mechanisms.  Based on 
the current safety data that temsirolimus can be safely combined with bevacizumab this 
combination is very attractive to take forward in HCC patients. 
Islet Cell Carcinoma 
Metastatic Islet cell carcinoma (ICC) has few effective and tolerable therapies. Although 
potentially responsive to chemotherapy, response rates are generally in the range of 30- 
40% with systemic chemotherapy.  Interferon is a toxic and minimally effective therapy. 
These tumors are very vascular clinically. Expression of VEGF and its receptors has 
been demonstrated in tumor tissue. Multi-center phase II trials of the receptor TKIs 
sunitinib and sorafenib have demonstrated anti-tumor efficacy in islet cell carcinoma. 
These agents are felt to work predominantly through an anti-angiogenic mechanism. 
Sunitinib demonstrated a 17% response rate and sorafenib resulted in an 11% partial 
response rate, with an additional 14% having a minor response (20-29% reduction in 
tumor size by RECIST). In addition, bevacizumab has demonstrated anti-tumor activity 
in closely related carcinoid tumors, and is currently undergoing evaluation in a 
randomized phase III trial along with Sandostatin versus interferon and Sandostatin. 
However bevacizumab has not been evaluated as a single agent in islet cell tumors. 
There is also evidence for a role for the mTOR pathway in ICC. Patients with tuberous 
sclerosis who have a mutation in the TSC2 gene which regulates mTOR tend to develop 
ICC. Increased IGF-1 expression is common in ICC and this may stimulate the mTOR 
pathway as well. A phase 2 trial of oral everolimus was reported with a 27% response 
rate, and there is a randomized phase III trial of everolimus vs best supportive care for 
ICC ongoing. A multi-center trial of temsirolimus was conducted in metastatic 
neuroendocrine tumors. A multi-center trial of CCI-779 was conducted in metastatic 
neuroendocrine tumors. Although a response rate of only 7% was observed, many 
patients had some tumor regression short of a PR, some with clinical improvement in 
symptoms, and an impressive median time-to progression of 10.6 months was 
demonstrated. 
Given the experience of efficacy and tolerability for both anti-angiogenic and anti-mTOR 
therapy in ICC, this combination warrants evaluation in islet cell cancer. 
Addendum: 
Rationale for additional cohort of patients to be treated with bevacizumab alone: 
Phase III trials of sunitinib and everolimus compared to placebo have now been 
completed and published.  Both trials enrolled patients with progressive disease within 


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the previous 12 months and demonstrated clinically and statistically significant 
improvements in PFS compared to placebo. Both agents have been approved by the US 
FDA and become standard therapy for pancreatic NET (islet cell carcinoma). 
However, in these trials, where the population could have a longer time than in our study 
to show disease progression (and thus potentially more indolent disease) and were 
candidates for placebo, the objective response rates were low; 5% for everolimus and 9% 
for sunitinib. Patients in both trials would not have received prior VEGF TKI pathway or 
mTOR inhibitors. (refs: Yao et al NEJM 2/10/2011; 514-23; Raymond et al NEJM 
2/10/2011; 501-13). 
In the protocol specified interim analysis of the first 25 patients with ICC on this trial 
(MC0845), a confirmed response rate of 52% was documented. This is very promising 
activity in this disease, and suggests clinical synergy of this regimen, as compared with 
either single class of agent alone. There are no good data at this time regarding the single 
agent activity of bevacizumab in ICC, and this may be important to interpreting the 
results of the current combination trial as well as CALGB 80701 (see below). 
 
CALGB 80701 is an open intergroup trial that evaluates further the combined 
mTOR/VEGF pathway. This trial is a randomized phase II trial of either everolimus or 
everolimus combined with bevacizumab in patients with progressive metastatic ICC. 
Prior VEGFR TKI is allowed, but not mandated in this trial. Patients with prior mTOR 
inhibitor are excluded. This trial may provide further information regarding the activity 
of the combined targeted agents. If there are sufficient patients enrolled with prior anti 
VEGFR therapy, it may also provide some information regarding the activity in these 
previously treated patients. 
Given the efficacy and safety data of the combination in this trial to date, we propose to 
add an additional cohort of patients to explore the activity of single-agent bevacizumab in 
ICC. This may provide information that informs future trial design in ICC in addition to 
that from our current trial and CALGB 80701. These patients will be treatment naïve for 
both mTOR inhibitor and VEGFR TKI. 
Addendum: Due to the widespread use of everolimus and sunitinib as first line therapy 
for these patients, enrollment of treatment naïve patients has proven difficult. We will 
expand the eligibility to include patients with prior mTOR inhibitor use, but not Anti- 
VEGFR TKI which will reflect the practice patterns currently in place. 
Carcinoid Tumors 
Hypervascularity of the tumors is the hallmark characteristic of carcinoid tumors and 
VEGF is found to be a critical pro-angiogenic factor in carcinoid tumors. Using 
immunohistochemistry, strong, weak, and negative VEGF expression was observed in 
32%, 54%, and 14% respectively among 50 cases of human gastrointestinal 
neuroendocrine tumors [27]. Furthermore, VEGF expression in this study was associated 
with poor progression free survival (P = .02).  In the pre-clinical studies, bevacizumab 


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did not inhibit the growth of human carcinoid cells in vitro but significantly reduced 
tumor angiogenesis and impaired tumor growth in animal model of carcinoids. Based on 
this rationale for targeting angiogenesis in carcinoid tumors, a phase II clinical trial using 
bevacizumab was conducted in patients with carcinoid tumors and showed promising 
antitumor activity [91]. Forty-four patients on stable doses of octreotide were randomly 
assigned to 18 weeks of treatment with bevacizumab or PEG interferon alpha-2b. At 
disease progression (PD) or at the end of 18 weeks (whichever occurred earlier), patients 
received bevacizumab plus PEG interferon until progression. Bevacizumab in this trial 
was administered at dose of 15 mg/kg IV every 3 weeks in combination with standard 
dose of long acting octreotide. Among 22 patients enrolled in the “bevacizumab first” 
arm, 18% partial response and 77% stable disease was noted with 18-week progression 
free survival of 95% during the bevacizumab alone phase. In addition to clinical activity, 
49% and 28% decrease in tumor blood flow assessed by functional CTs at day 2 and 
week 18 was noted in these patients. Common grade 3-4 AEs included hypertension 
(36%), fatigue (18%), headache (5%) and vomiting (5%). 
In a phase II study of temsirolimus in 37 patients with advanced progressive 
neuroendocrine carcinoma (NEC), 21 patients with carcinoid tumors received intravenous 
weekly doses of 25 mg of temsirolimus [92]. Partial response rate of 5%, median time to 
progression of 6 months and 6-month progression free survival rate of 45% were noted in 
carcinoid tumor patients. The most frequent drug-related AE of all grades included: 
fatigue (78%), hyperglycemia (69%) and rash/desquamation (64%). Pharmacodynamic 
analysis revealed effective mTOR pathway down regulation. 
Based on the safety and moderate anti-tumor activity of single agent bevacizumab and 
temsirolimus in patients with carcinoid tumor, activity of combination therapy in patients 
with metastatic carcinoid tumors will be evaluated. 


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3. 
PATIENT SELECTION 
3.1 
Inclusion Criteria - All Patients 
3.11 
Histologically or cytologically confirmed endometrial (endometrioid, uterine 
papillary serous carcinoma, and carcinosarcoma), ovarian (primary 
peritoneal/fallopian tube, serous, endometrioid, mixed, and poorly differentiated 
epithelial ovarian cancers (for purposes of eligibility, carcinosarcoma is 
considered a poorly differentiated carcinoma)), hepatocellular carcinoma , 
carcinoid or islet cell (neuroendocrine: well- or moderately-differentiated 
neuroendocrine) cancer which are locally advanced, recurrent or metastatic.(see 
HCC criteria for histology and or clinical diagnosis section 3.31). 
3.12 
18 years of age. 
3.13 
Patients must have measurable disease as defined in Section 11.0. Patients 
having only lesions measuring ≥1 cm to <2 cm must use spiral CT 
imaging for both pre- and post-treatment tumor assessments. Patients who 
have had prior palliative radiotherapy to metastatic lesion(s) must have at 
least one measurable lesion(s) that have not been previously irradiated. 
3.14 
Radiation therapy (adjuvant or palliative) must be completed ≥4 weeks 
prior to registration, if applicable. 
3.15 
Required laboratory values obtained  7 days prior to registration: 
• 
Absolute Neutrophil 
 1500/mm3 
Count (ANC) 
• 
Platelets 
 75,000/ mm3 
• 
Hemoglobin 
> 9.0 g/dL 
• 
Total bilirubin 
< 1.5 x upper limit of normal (ULN) 
Note: total bilirubin and INR for HCC 
patients allowed as per Child-Turcotte- 
Pugh scoring see section 3.32 and 
appendix C 
• 
Alkaline phosphatase 
 2.5 x ULN (≤ 5 x ULN if liver metastasis 
is present or patient is in HCC cohort) 
• 
SGOT(AST) 
 2.5 x ULN (≤ 5 x ULN if liver metastasis is 
present or patient is in HCC cohort) 
• 
Creatinine 
< 1.5 x ULN 
• 
Urinalysis 
< 2+ protein* 
• 
Fasting serum cholesterol ≤ 350mg/dL (≤ 9.0 mmol/L) 
• 
Triglycerides 
≤ 1.5 x ULN (mg/dL or mmol/L)** 
• 
International Normalized 
Ratio (INR) 
≤ 1.5 (unless the patient is on full dose 
warfarin see section 3.19a) 


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3.17 
 
*Urine protein should be screened by dipstick or urine analysis.  For proteinuria 
> 2+, 24-hour urine protein should be obtained and the level should be < 2 g for 
patient enrollment. 
**Patients with Triglyceride levels > 1.5 x ULN can be started on lipid 
lowering agents and reevaluated within 1 week. If levels go to≤ 1.5 x ULN, 
they can be considered for the trial and continue the lipid lowering agents. 
NOTE: Cholesterol and triglyceride measurement and management are not 
required for single-agent bevacizumab cohort with Islet Cell carcinoma 
 
 
3.16 
ECOG Performance Status (PS) 0-1 (Appendix A). 
Capable of understanding the investigational nature, potential risks and 
benefits of the study and able to provide valid informed consent. 
 
3.17 
Negative serum pregnancy test done ≤7 days prior to registration, for 
women of childbearing potential only. NOTE: Patients and their partners 
should be practicing an effective form of contraception during the study 
and for at least 3 months following the last dose of this combined therapy. 
3.18 
Full-dose anticoagulants, if a patient is receiving full-dose anticoagulants 
(except carcinoid tumors – see section 3.91), the following criteria should 
be met for enrollment: the subject must have an in-range INR (usually 
between 2 and 3) on a stable dose of warfarin or on stable dose of LMW 
heparin. 
3. 19a Prior systemic treatments for metastatic disease are permitted, including 
targeted therapies, biologic response modifiers, chemotherapy, hormonal 
therapy, or investigational therapy. 
Exception: In the case of endometrial cancer no prior chemotherapy 
for metastatic or recurrent disease is allowed. Prior planned adjuvant 
chemotherapy is allowed. 
3.19 b Patients who have had prior anthracycline must have a normal ejection 
fraction on LVEF assessment by MUGA or Echo ≤ 4 weeks prior to 
registration. 
3.19c Availability of tissue if applicable (from the primary tumor or metastases) 
for tumor studies for banking. 
Note: In the case of hepatocellular cancer if diagnosed by clinical and 
radiologic criteria only, availability of tissue not applicable. 
3.19d Willingness to donate blood for biomarker studies related to the type of 
therapies used in this trial and the tumor types being treated. 


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3.2 
Inclusion Criteria – Endometrial Cancer 
Note: This group is permanently closed to enrollment 
3.21 
Any hormonal therapy directed at the malignant tumor is allowed. NOTE: 
Therapy must be discontinued at least one week prior to registration. 
3.22 
Prior systemic therapy including biologic and immunologic agents as 
adjuvant treatment must be discontinued at least 3 weeks prior to 
registration. 
3.23 
Recurrent or persistent endometrial adenocarcinoma, uterine papillary 
serous carcinoma and carcinosarcoma which is refractory to curative 
therapy or established treatments. NOTE: Histologic or cytologic 
confirmation of original primary tumor is required. 
3.3 
Inclusion Criteria – Hepatocellular Cancer 
Note: This group is permanently closed to enrollment 
3.31 
HCC confirmed by biopsy OR diagnosed by clinical and radiologic 
criteria. All of the following criteria must be met or a biopsy is required: 
• 
Known cirrhosis or chronic HBV or HCV infection, 
• 
Hypervascular liver masses >2 cm, and either serum AFP > 400 
ng/ml, or 
• 
AFP >three times normal and doubling in value in the antecedent 3 
months. 
3.32 
Child-Pugh A (≤6 points) or better liver status (see appendix C for 
calculating score). 
3.33 
Prior regional treatments for liver metastasis are permitted including: 
• 
selective internal radiation therapy such as brachytherapy, 
cyberknife, radiolabelled microsphere embolization, etc. 
• 
hepatic artery chemoembolization 
• 
hepatic artery embolization 
• 
hepatic artery infusional chemotherapy 
• 
radiofrequency ablation. 
NOTE: Patients must be > 4 weeks from treatment and show progressive 
disease in the liver after regional therapy or must have measurable disease 
outside the liver. 
3.34 
Concomitant anti-viral therapy is allowed. 
3.35 
History of prior varices or evidence of varices on pre-study CT/MRI 
imaging is required to undergo endoscopy ≤ 4 weeks prior to registration. 


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Those who had received specific therapy (banding and/or sclerotherapy) 
and had not bled within the prior 6 months are eligible. 
3.36 
Suitably recovered from prior localized therapy, in the opinion of the 
investigator. 
3.4 
Inclusion Criteria - Islet Cell Cancer and Carcinoid Tumor 
Note: The Carcinoid group is permanently closed to enrollment 
3.41 
Patient has evidence of progressive disease as documented by RECIST ≤7 
months prior to study entry. 
 
 
3.41.1 Carcinoid tumor cohort: Prior and concurrent long-acting 
somatostatin analogue therapy is required. Patient has to be on a 
stable dose of a long-acting somatostatin analogue ≥ 2 months prior 
to study entry with documentation of progressive disease on 
current dose. 
3.41.2 Islet cell tumor cohort: Prior and/or concurrent long-acting 
somatostatin analogue therapy is allowed, but not required. If 
patient is continued on a long-acting somatostatin analogue, a 
stable dose for ≥ 2 months prior to study entry is required with 
documentation of progressive disease on current dose. 
. 
3.42 
Prior therapies allowed include: 
• 
≤2 prior cytotoxic chemotherapy regimens. 
• 
Prior interferon ≥4 weeks prior to registration 
• 
Radiolabelled octreotide therapy (Patients with prior radiolabelled 
octreotide therapy should have progressive disease after such 
therapy) 
• 
Other investigational therapy. 
NOTE: Islet Cell Single Agent Bevacizumab Cohort: Prior mTOR 
inhibitor is allowed 
3.43 
Prior regional treatments for liver metastasis are permitted including: 
• 
selective internal radiation therapy such as brachytherapy, 
cyber knife, radiolabelled microsphere embolization, etc. 
• 
hepatic artery chemoembolization 
• 
hepatic artery embolization 
• 
hepatic artery infusional chemotherapy 
• 
Radiofrequency ablation. 


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NOTE: Patients must be > 12 weeks from treatment and show progressive 
disease in the liver after regional therapy or must have measurable disease 
outside the liver. 
 
3.5 
Exclusion Criteria - All Patients 
3.51 
Prior therapy with VEGFR targeting agents or mTOR inhibitors (except as 
in HCC-see section 3.76 and in the Islet cell single agent bevacizumab 
alone cohort where prior mTOR inhibitor is allowed).  NOTE:  Prior use 
of bevacizumab is not allowed in any cohort. 
3.52 
Invasive procedures defined as follows: 
• Major surgical procedure, open biopsy or significant traumatic 
injury ≤ 4 weeks prior to registration. 
• Anticipation of need for major surgical procedures during the 
course of the study. 
• Core biopsy ≤ 7 days prior to registration. 
3.53 
Serious or non-healing wound, ulcer or bone fracture. 
3.54 
History of abdominal fistula, gastrointestinal perforation or intra- 
abdominal abscess ≤ 180 days prior to first date of bevacizumab therapy. 
3.55 
Evidence of bleeding diathesis or coagulopathy in the absence of 
therapeutic anticoagulation. 
3.56 
Evidence of a history bleeding ≤ 6 months such as hemoptysis, or 
cerebrovascular accident ≤ previous 6 months, or peripheral vascular 
disease with claudication on < 1 block, or history of clinically significant 
bleeding, because of the potential bleeding and/or clotting risk with 
bevacizumab. 
3.57 
Untreated central nervous system (CNS) metastases. Exceptions: Patients 
with known CNS metastases can be enrolled if the brain metastases have 
been adequately treated and there is no evidence of progression or 
hemorrhage after treatment as ascertained by clinical examination and 
brain imaging (MRI or CT) ≤ 12 weeks prior to registration and no 
ongoing requirement for steroids,. 
• Anticonvulsants (stable dose) are allowed. 
• Patients who had surgical resection of CNS metastases or brain 
biopsy ≤ 3 months prior to registration will be excluded. 
3.58 
Significant cardiovascular disease defined as congestive heart failure 
(New York Heart Association Class II, III or IV), angina pectoris 
requiring nitrate therapy, or recent myocardial infarction (≤ 6 months prior 
to registration) (Appendix F). 


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3.59 a Uncontrolled hypertension (defined as a blood pressure of >150 mmHg 
systolic and/or ≥ 90 mmHg diastolic). 
3.59b Patient is on ACE inhibitors (benazapril, captopril, enalapril, fosinopril, 
lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril). 
(Patients may have an alternate antihypertensive substituted). 
NOTE: ACE Inhibitors are allowed in single agent bevacizumab cohort 
3.59c   Currently active, second malignancy other than non-melanoma skin 
cancers. NOTE: Patients are not considered to have a ‘currently active’ 
malignancy if they have completed anti-cancer therapy and are 
considered by their physician to be at less than 30% risk of relapse. 
3.59 d Any of the following, as this regimen may be harmful to a developing 
fetus or nursing child: 
• 
Pregnant women 
• 
Breastfeeding women 
• 
Men or women of childbearing potential or their sexual partners 
who are unwilling to employ adequate contraception (diaphragm, 
birth control pills, injections, intrauterine device [IUD], surgical 
sterilization, subcutaneous implants, or abstinence, etc.) 
NOTE: The effects of the agent(s) on the developing human fetus at the 
recommended therapeutic dose are unknown. 
3.59e Known hypersensitivity to other recombinant human antibodies or 
Chinese hamster ovary cell products. 
3.59f Other uncontrolled serious medical or psychiatric condition (e.g. cardiac 
arrhythmias, diabetes, etc.). 
3.59g Current therapy with a CYP3A4 inhibitor or inducer (See Appendix D for 
list of inhibitors and inducers). NOTE: These agents are allowed in the 
single-agent bevacizumab Islet cell carcinoma cohort. 
3.59h   Active infection requiring antibiotics. 
3.59i 
Active bleeding or pathological conditions that carry high risk of bleeding 
(e.g. tumor involving major vessels, known varices). 
3.59j 
Known HIV-positive. 


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3.6 
Exclusion Criteria – Endometrial Cancer 
Note: This group is permanently closed to enrollment 
3.61 
Received prior radiotherapy to any portion of the abdominal cavity or 
pelvis OTHER THAN for the treatment of endometrial cancer. 
3.62 
Any chemotherapy for metastatic or recurrent cancer. 
3.63 
Radiation therapy to > 25% of marrow bearing areas (Appendix E). 
 
3.7 
Exclusion Criteria - Hepatocellular Cancer 
Note: This group is permanently closed to enrollment 
3.71 
Child-Pugh B or C classification (Appendix C). 
3.72 
Grade > 3 hemorrhage ≤ 4 weeks prior to registration. 
3.73 
Prior liver transplant with evidence of recurrent or metastatic disease. 
3.74 
Patients on an active liver transplant list and considered likely to receive a 
liver transplant ≤ 6 months following registration. 
3.75 
Clinical evidence of encephalopathy. 
3.76 
Prior treatment with sorafenib or other VEGF inhibitors. 
NOTE: Exceptions allowed for patients unable to tolerate the agent. 
Intolerance is defined in this protocol as a discontinued agent due to side 
effects with an exposure < to 4 weeks of drug, at any dose level. 
 
3.8 
Exclusion Criteria - Ovarian Cancer 
Note: This group is permanently closed to enrollment 
3.81 
Clinical signs and symptoms of GI obstruction and require parental 
hydration/nutrition or tube feeding. 
3.82 
Evidence of free abdominal air not explained by paracentesis or recent 
surgical procedures. 
3.83 
Received more than two prior cytotoxic chemotherapy regimens for 
persistent or recurrent disease. 
3.9 
Exclusion Criteria – Carcinoid Cancer 
Note: This group is permanently closed to enrollment 
3.91 
Patients on anticoagulant therapy. 


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4.0 
REGISTRATION PROCEDURES 
4.1 
Investigator / Research Associate Registration 
4.11 
Obtaining a CTEP-IAM account 
All participating investigators and research staff must be registered 
members of the CTSU. Access to the CTSU members’ web site is 
managed through the Cancer Therapy and Evaluation Program - Identity 
and Access Management (CTEP-IAM) registration system. To register: 
 
• Go to the CTSU web-site at https://www.ctsu.org and click on the 
Register tab on the upper right of your screen and follow links to the 
CTEP-IAM application, OR, go directly to https://eapps- 
ctep.nci.nih.gov/iam/ and click on the “New Registration” link on the 
left hand side of your screen and click on “Request New Account”. 
● Complete CTEP-IAM application instructions 
● You will receive an email from the CTSU providing the status of your 
application within 2 to 3 business days. Once you receive your email 
from the CTSU, you may use your new CTEP-IAM username and 
password to access the CTSU Members side of the web site. 
4.12 
(Investigators Only) Obtaining an NCI Investigator number 
Before the recruitment of a patient for this study, investigators must be 
registered members of the CTSU. Each investigator must have an NCI 
investigator number and must maintain an “active” investigator 
registration status through the annual submission of a complete 
investigator registration packet (FDA Form 1572 with original signature, 
current CV [signed and dated], Supplemental Investigator Data Form with 
signature, and Financial Disclosure Form with original signature) to the 
Pharmaceutical Management Branch, CTEP, DCTD, NCI. These forms 
are available on the CTSU Web-site (logon to https://www.ctsu.org; then 
click on the Register tab) or by calling the PMB at 301-496-5725 Monday 
through Friday between 8:30 a.m. and 4:30 p.m. Eastern time. 
4.2 
Site Registration 
4.21 
IRB Approval 
Each investigator or group of investigators at a clinical site must obtain 
IRB approval for this protocol and submit all regulatory documents to the 
CTSU Regulatory Office in Philadelphia before patient enrollments may 
commence. 
4.22 
Downloading Regulatory Documents for 8233 


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Site registration forms can be downloaded from the 8233 Web page 
located under the Phase 2 Contractors section of the CTSU Members’ side 
of the web site. 
● Go to https://www.ctsu.org 
● Sign in on the left hand side with the CTEP-IAM username and 
password 
● Click on the Protocols tab in the upper left of your screen 
● Click on the Phase 2 Consortia link 
● Select trial #8233 
● Click on the Site Registration Documents link 
● Download and complete the following forms: 
o CTSU IRB/Regulatory Transmittal 
o CTSU IRB Certification Form 
● Mail or FAX completed forms to the CTSU Regulatory Office in 
Philadelphia along with a copy of your IRB Approved Model Consent 
(stamped, or signed and dated) 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone - 1-866-651-2878 
FAX – 215-569-0206 
4.23 
Checking Your Site’s Registration Status 
Check the status of your registration packets by querying the RSS site 
registration status page of the CTSU Members’ side of the web site. 
● Go to https://www.ctsu.org 
● Sign in on the left hand side using the CTEP-IAM username and 
password 
● Click on the Regulatory tab at the top of your screen 
● Click on the Site Registration tab 
● Enter your 5-character CTEP Institution Code and click on Go 
Note: If possible, please allow three working days for site registration 
approval before attempting to enroll your first patient. 
4.24 
Order Blood Specimen Collection Kits 
Order collection kits for blood draws at least 2 weeks prior to enrolling a 
patient. To request a kit, download the MML Fax Supply Order Form 
posted under the Site Registration Documents section of the 8233 Web 
page and fax as directed on the form. The form can also be found in the 
Forms Packet. See section 9.1 for details on blood sample collection and 
shipment. 


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4.3 
Patient Registration 
4.31 
Contact the CTSU Patient Registration Office at 1-888-462-3009 and 
leave a voicemail to alert the CTSU Patient Registrar that an enrollment is 
forthcoming. Registration hours are between 9:00 a.m. and 5:00 p.m. 
Eastern Time, Mon-Fri. Registrations received after 5:00 p.m. Eastern 
Time will be handled the next business day. For immediate registration 
needs (e.g. enrollments that must be completed within approximately one 
hour or other extenuating circumstances) call the registrar cell phone at 1- 
301-704-2376. 
4.32 
Complete the following forms: 
 
• CTSU Patient Enrollment Transmittal Form 
• Eligibility Checklist 
4.33 
Fax these forms to the CTSU Patient Registrar at 1-888-691-8039. 
Registration desk hours are between 9:00 a.m. and 5:00 p.m. Eastern 
Time, Mon-Fri. Registrations received after 5:00 p.m. Eastern Time will 
be handled the next business day. 
4.34 
The CTSU Patient Registrar will check the investigator and site 
information to ensure that all regulatory requirements have been met. The 
registrar will also check that forms are complete and will follow-up with 
the site to resolve any discrepancies. 
4.35 
Once investigator eligibility is confirmed and enrollment documents are 
reviewed for compliance, the CTSU Patient Registrar will forward patient 
enrollment documents to the Mayo P2C Registration Office to verify 
patient eligibility and perform the enrollment. The CTSU will convey the 
Mayo-assigned patient ID to the enrolling site followed by a confirmation 
of registration e-mail or fax. 
4.36 
Treatment on this protocol must commence at a N01 contract holder 
institution under the supervision of a physician investigator registered with 
NCI Pharmaceutical Management Branch (PMB) and CTSU. 
4.37 
Treatment cannot begin prior to registration and must begin within 7 
days after registration. 
4.38 
Pretreatment tests/procedures must be completed within the guidelines 
specified on the test schedule. 
4.39 a All required baseline symptoms (see Section 7.4) must be documented and 
graded. 
4.39 b   At the time of registration/randomization, the following will be recorded: 


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• Patient has/has not given permission to keep tissue for future 
research to learn about, prevent, or treat cancer. 
• Patient has/has not given permission to keep tissue for future 
research to learn about, prevent or treat other health problems 
(for example: diabetes, Alzheimer’s disease, or heart disease). 
• Patient has/has not given permission for tissue and blood to be 
used for genetic research (about diseases that are passed on in 
families) in the future. 
• Patient has/has not given permission to be contacted in the future 
to take part in more research. 
 
 
5. 
TREATMENT PLAN 
5.1 
Study Drug Administration 
5.1a 
Study Drug Administration 
Agent 
Dose 
Route 
Day 
ReRx 
TEMSIROLIMUS 
25 mg IV q week IV* 
1,8,15,22 
Q 28 days 
(+/-3 days) 
bevacizumab 
10 mg/ kg IV q 2 
weeks 
IV** 
1,15 
Q 28 days 
(+/-3 days) 
*Pre-Medication: Diphenhydramine 25-50 mg I.V. (or comparable antihistamine) approximately 
30 minutes before starting temsirolimus infusion. 
**The first dose of bevacizumab should be given over 90 minutes. If well tolerated, second dose 
may be administered over 60 minutes. Again, if well tolerated, subsequent doses may be 
administered over 30 minutes. 
Temsirolimus will be given first followed by bevacizumab on days 1 and 15 of each cycle. 
One cycle is defined as 4 weeks (i.e. 28 days) of treatment. 
5.1 b 
Study Drug Administration single agent Bevacizumab Islet cell cohort 
Agent 
Dose 
Route 
Day 
ReRx 
bevacizumab 
10 mg/ kg IV q 2 
weeks 
IV** 
1,15 
Q 28 days 
(+/-3 days) 
 
**The first dose of bevacizumab should be given over 90 minutes. If well tolerated, second dose 
may be administered over 60 minutes. Again, if well tolerated, subsequent doses may be 
administered over 30 minutes. 
 
5.2 
Ancillary Treatment/Supportive Care 
5.21 Requirement for radiation therapy during treatment is not allowed, as it is 
an indication of progressive disease. 


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5.22 Pain medications are allowed. 
5.23 Antiemetic therapy is allowed. 
5.24 Zoledronic acid can be continued in patients with bone metastases and/or 
hypercalcemia if it was started prior to treatment initiation. 
5.25 Bevacizumab specific general patient monitoring and supportive care 
guidelines: 
5.251 
Patients should be carefully monitored during the treatment phase 
and then followed appropriately.  Prior to each treatment, the 
patient should be carefully assessed, with special attention to blood 
pressure and bleeding events as well as other adverse events. 
Decisions for retreatment or dose modifications/interruption should 
follow the guidelines in Section 6.0. 
5.252 
Patients who have an on-going study agent-related serious adverse 
event upon study completion or at discontinuation from the study 
will be contacted by the investigator or his/her designee 
periodically until the event is resolved or determined to be 
irreversible. 
5.253 
Hypertension: Blood pressure should be assessed at least weekly 
during the first cycle and before each administration of 
bevacizumab. High blood pressure may require initiation or 
increase in hypertensive medication according to routine practice. 
Bevacizumab treatment modifications due to hypertension should 
follow instructions in Section 6.0. 
5.254 
Therapeutic anticoagulation: For patients on therapeutic 
anticoagulation, PT INR or PTT (which ever appropriate) should 
be monitored closely during bevacizumab therapy. Bevacizumab 
should be held if the coagulation parameters are higher then the 
intended therapeutic range (see Section 6.0). 
5.255 
Surgery and wound complication issues and surgery: The 
appropriate interval from discontinuation of bevacizumab to 
subsequent elective surgery required to reduce the risk of impaired 
wound healing has not been determined. Decision on such an 
interval should take into consideration the half-life of 
bevacizumab. It is generally recommended that bevacizumab 
should be discontinued at least 4-8 weeks prior to major elective 
surgery. In addition, bevacizumab should not be restarted until at 
least 4 weeks after major surgery provided that the wound has 
adequately healed; in cases of high risk procedures such as liver 


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resection, thoracotomy or neurosurgery, it is recommended that 
bevacizumab be resumed no earlier than 8 weeks after surgery. 
5.26 Temsirolimus specific general patient monitoring and supportive care 
guidelines: 
5.261 
Temsirolimus is a CYP3A4 substrate. Avoid concomitant 
treatment of temsirolimus with potent CYP3A4 inhibitors and 
agents that have CYP3A4 induction potential.  (Appendix D) 
 
5.3 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s) felt to be study drug- 
related, treatment may continue until one of the following criteria applies: 
▪ 
Disease progression, 
▪ 
Intercurrent illness that prevents further administration of treatment, 
▪ 
Unacceptable adverse event(s), 
▪ 
Treatment delay of greater than 4 weeks 
▪ 
Withdrawn consent 
▪ 
Changes in the patient’s condition render the patient unacceptable for 
further treatment in investigator’s judgment. 
▪ 
Need for radiation therapy for symptomatic disease. 
 
5.4 
Duration of Follow Up 
Patients will be followed for three years from registration or until death, whichever 
occurs first. Patients removed from treatment for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. 


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6. 
DOSING DELAYS/DOSE MODIFICATIONS 
**Strictly follow the modifications in this table for all cycles** 
ALERT: 
ADR reporting may be required for some adverse events (See Section 7) 
6.1 
Bevacizumab Related Adverse Events 
 
CTCAE 
CATEGORY 
ADVERSE EVENT 
DOSAGE CHANGE 
Hemorrhage/ 
Bleeding 
Hemorrhage: CNS or 
pulmonary 
Grade 1 on anticoagulation 
Discontinue bevacizumab 
Hemorrhage: CNS or 
pulmonary 
≥ Grade 2 
Discontinue bevacizumab 
Any Grade 3 other than CNS or 
pulmonary 
• Patients who are also receiving full-dose anticoagulation should 
discontinue bevacizumab 
• All other patients should have bevacizumab omitted until ALL of the 
following criteria are met: 
• The bleeding has resolved and Hb is stable. 
• There is no bleeding diathesis that would increase the risk of 
therapy 
There is no anatomic or pathologic condition that could increase the 
risk of hemorrhage recurrence 
• Patients who experience recurrence of G3 hemorrhage should 
discontinue study therapy 
Any Grade 4 other than CNS 
pulmonary 
Discontinue bevacizumab 
Vascular 
Grade 3 or 
Omit bevacizumab treatment.  If the planned duration of full-dose 
Asymptomatic Grade 4: 
anticoagulation is ≤2 weeks, bevacizumab should be omitted until the full- 
dose anticoagulation period is over. 
If the planned duration of full-dose anticoagulation is >2 weeks, 
bevacizumab may be resumed during the period of full-dose 
anticoagulation if all of the following criteria are met: 
- The subject must not have pathological conditions that carry high risk 
of bleeding (e.g. tumor involving major vessels or other conditions) 
- The subject must not have had hemorrhagic events while on study 
- The subject must on stable dose of heparin or have an in-range INR 
(usually 2-3) on a stable dose of warfarin prior to restarting 
bevacizumab. 
Discontinue bevacizumab 
Symptomatic Grade 4: 
Coagulation 
APTT (INR) 
For patients on therapeutic anticoagulation, PT INR or PTT (which ever 
appropriate) should be monitored closely during bevacizumab therapy. 
bevacizumab should be omitted if the coagulation parameters are higher 
then the intended therapeutic range 


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Cardiac general Hypertension 
Grade ≤ 3 
Grade 4 
Hypertension should be treated with anti-hypertensive medication as per 
general practice. 
For controlled hypertension: continue therapy. 
For persistent or symptomatic hypertension: omit bevacizumab therapy. 
If treatment is delayed for > 4 weeks due to uncontrolled hypertension, 
patients should discontinue bevacizumab. 
Congestive Heart Failure 
Grade 3 (symptomatic) 
Grade 4 
Discontinue bevacizumab 
Discontinue bevacizumab 
Metabolic/ 
Laboratory 
Proteinuria should be monitored by urine analysis for urine protein prior to 
every other dose of bevacizumab 
< 2 g/24 hours 
• 
Continue bevacizumab. 
≥ 2 g/24 hours 
• 
Omit bevacizumab until urine protein recovers to ≤ 2 g/24 hours 
Grade 4: (nephrotic syndrome) 
Discontinue bevacizumab 
Dermatology/ 
skin 
Wound complication, non- 
infectious Wound dehiscence 
requiring medical or surgical 
intervention: Any Grade 
Discontinue bevacizumab 
Gastrointestinal Bowel perforation, fistula or GI 
leak: any grade (GI or any other 
organ) 
Discontinue bevacizumab 
Bowel obstruction 
Grade 2 (requiring medical 
intervention) 
Omit bevacizumab until complete resolution 
Grade 3-4 
Omit bevacizumab until complete resolution. 
If surgery is required, patient may restart bevacizumab after full recovery 
from surgery, and at investigator’s discretion 
Neurology 
Symptoms and signs of RPLS 
Omit pending workup and management, including control of blood 
pressure. Discontinue if RPLS diagnosed. Resumption of bevacizumab 
may be considered in patients who have documented benefit from the 
agent, provided that RPLS was mild and has completely resolved 
clinically and radiographically within 2-4 weeks; decision to resume 
bevacizumab in these patients must be discussed with the study chair and 
approved by the sponsor. 
Other 
Grade 3 -non-hematological 
(except nausea and vomiting) 
Grade 4 non-hematological 
(except nausea/vomiting) 
Grade 4 hematological (any 
cause) 
If a patient develops any grade 3 non-hematological adverse events. 
bevacizumab should be omitted until symptoms resolve to ≤grade 1. If a 
grade 3 adverse event persists for >4 weeks or recurs after resumption of 
the therapy, discontinue bevacizumab and patient should go to event 
monitoring. 
The patient should discontinue bevacizumab. 
Omit until recover to 
§   ANC >1.0 × 109/L (1000 cells/mm3) 


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▪ 
Platelet count >50 × 109/L (50,000 cells/mm3) 
 
6.2 
Temsirolimus Related Adverse Events 
 
NCI CTC Grade 
TEMSIROLIMUS 
0-2 Hematological or Non-hematological Toxicity 
100% 
Grade 2 adverse events that are persistent and intolerable ≥ 7 
days (i.e. stomatitis) can result in omission or dose 
reductions to the next lower dose level 
3 Hematological or non-hematological Toxicity 
Omit until recovery to 
§   ANC >1.0 × 109/L (1000 cells/mm3) 
▪ Platelet count >50 × 109/L (50,000 cells/mm3) 
▪ Or NCI CTC Grade 0-2 for non-hematologic 
If recovery occurs within 3 weeks after treatment has been 
omitted, dose should be reduced 1 level 
4 Hematological or non-hematological Toxicity 
Omit until recover to 
§   ANC >1.0 × 109/L (1000 cells/mm3) 
▪ Platelet count >50 × 109/L (50,000 cells/mm3) 
▪ Or NCI CTC Grade 0-2 for non-hematologic 
If recovery occurs within 3 weeks after treatment has been 
omitted, dose should be reduced 2 levels 
Metabolic/Laboratory 
Cholesterol, serum high 
(hypercholesterolemia) 
≥ Grade 3 
Triglyceride, serum high 
(hypertriglyceridemia) 
Grade 1 and 2 
May continue treatment. Start or adjust dosage of 
antihyperlipidemic agents. If baseline levels, < grade 2 
hypertriglyceridemia, or ≤ grade 2 hypercholesterolemia, 
whichever is higher, are not achieved after 8 weeks, discontinue 
agent. 
Triglyceride, serum high 
(hypertriglyceridemia) 
> Grade 3 
Omit temsirolimus for 1 week. Therapy with a triglyceride- 
lowering agent will be initiated. Triglycerides will be re- 
assessed at the end of the week, and temsirolimus will be 
resumed if the triglycerides level is reduced to Grade ≤ 2. If 
triglycerides remain at grade 3 or 4 levels, temsirolimus will be 
omitted another week, with serum triglycerides re-assessed one 
week later. If a patient’s triglyceride levels remain at CTCAE 
grade 3-4 for two weeks despite triglyceride-lowering therapy, 
discontinue agent. If Grade 3 or 4 hypertriglyceridemia recurs 
after re-challenge, dose interruption will be managed as above, 
and the patient will resume therapy at a dose reduction of 2 dose 
levels if the hypertriglyceridemia resolves to a Grade ≤ 2 level 
within 2 weeks. 
Hemorrhage 
CNS/Pulmonary 
hemorrhage 
≥ Grade 2 
Discontinue temsirolimus 
Pulmonary/Upper Respiratory 
Addendum 1 
pneumonitis 
Patients with cough and dyspnea should have temsirolimus 
omitted pending investigation and permanently discontinued if 
the diagnosis is confirmed and thought to be related to 
temsirolimus. 
Vascular 
Grade 3 or 
Omit temsirolimus treatment.  If the planned duration of full- 
Asymptomatic Grade 4: 
dose anticoagulation is ≤2 weeks, temsirolimus should be 
omitted until the full-dose anticoagulation period is over. 
If anticoagulation of > 2 weeks then temsirolimus may be 


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Dose Reductions for temsirolimus Related Adverse Event 
Dose Level 
temsirolimus Dose (mg) 
Starting dose 
25 
-1 
20 
-2 
15 
-3 
10 
Patients requiring dose reductions should not have the dose re-escalated with 
subsequent treatments. 
If one of the agents is discontinued, patients can continue on study and 
receive the other agent. 
HCC Patients only: 
 
Decompensation to 
Child-Pugh B or C 
liver status 
If thought likely to be drug related bevacizumab and temsirolimus should be 
omitted until patient returns to Child-Pugh A status. (All appropriate 
supportive care offered) bevacizumab can be re-started at full dose while 
temsirolimus will restart at 1 further dose reduction. 
If decompensation due to progressive disease patient will come off treatment 
and go to event monitoring. 
restarted when patients have been on a stable dose of 
anticoagulant for at least 1 week. 


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7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
 
7.1 
CTCAE v 3.0 
This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) 
v3.0 for adverse event (AE) monitoring and reporting. The CTCAE v3.0 can be 
downloaded from the CTEP home page (http://ctep.info.nih.gov/reporting/ctc.html). All 
appropriate treatment areas should have access to a copy of the CTCAE v3.0. 
7.11 
Adverse event monitoring and reporting is a routine part of every clinical 
trial. First, identify and grade the severity of the event using the CTCAE. 
Next, determine whether the event is expected or unexpected (as reflected 
with the CTEP Agent Specific Adverse Event List [ASAEL], see Section 
7.12) and if the adverse event is related to the medical treatment or 
procedure (see Section 7.13).  With this information, determine whether 
an adverse event should be reported as an expedited report (see Section 
7.2) or as part of the routinely reported clinical data (see Sections 7.2 and 
16.3). AEs reported as expedited must also be reported in routine study 
data submissions. 
Expedited adverse event reporting under a CTEP Investigational New 
Drug Application (IND) requires submission of an CTEP Adverse Event 
Expedited Reporting System (CTEP-AERS) report(s). Other expedited 
reporting requirements and systems may also apply. Expedited reports are 
to be completed within the timeframes and via the mechanisms specified 
in Section 7.2. 
In the rare occurrence when Internet connectivity is lost, an AE report may 
be submitted using CTEP’s Adverse Event Expedited Report-Single Agent 
or Multiple Agent paper template (available at http://ctep.cancer.gov) and 
faxed to 301-230-0158. A 24-hour notification is to be made to CTEP by 
telephone at 301-897-7497, only when Internet connectivity is disrupted. 
Once Internet connectivity is restored, an AE report submitted on paper or 
a 24-hour notification phoned in must be entered electronically into 
CTEP-AERS by the original submitter at the local institution. 
ALL expedited reports submitted via the secure CTEP-AERS application 
must also be copied to the P2C Coordinating Center Quality Control 
Specialist for this protocol (for MC0845) via fax (507-266-7240). 
Those AEs that do not require expedited reporting will be reported to 
CTEP in routine (CDUS) study data submissions by the CTSU Data 
Operations Center. Therefore, AEs reported through CTEP-AERS must 
also be reported in routine study data submissions to CTSU Data 
Operations Center (see Sections 7.2 and 16.3). 
7.12 Expected vs. Unexpected Events 


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Agents provided under a CTEP IND: 
• Expected AEs for expedited reporting purposes are listed on the 
ASAEL. The ASAEL is a component of the Comprehensive Adverse 
Events and Potential Risks List (CAEPR). Refer to Section 15.0 of 
this protocol to locate the CAEPR for the CTEP IND agent(s). 
• Unexpected AEs are those not listed in the ASAEL. 
 
7.13 
Assessment of Attribution 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
Definite - The adverse event is clearly related to the investigational 
agent(s). 
Probable - The adverse event is likely related to the investigational 
agent(s). 
Possible - The adverse event may be related to the investigational 
agent(s). 
Unlikely - The adverse event is doubtfully related to the investigational 
agent(s). 
Unrelated - The adverse event is clearly NOT related to the investigational 
agent(s). 
 
7.2 
Expedited Adverse Event Reporting Requirements 
7.21 
CTEP Expedited AE Investigational Agent Reporting Requirements 
Phase 2 and 3 Trials Utilizing an Agent under a CTEP IND: CTEP-AERS 
Reporting Requirements for Adverse Events That Occur Within 30 Days 1 of the 
Last Dose of the Investigational Agent 
 
Grade 1 
Grade 2 
Grade 2 
Grade 3 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected 
and 
Expected 
Unex- 
pected 
Expected 
Unexpected 
with 
without 
Hospitali-   Hospitali- 
zation 
zation 
Expected 
with 
without 
Hospitali-  Hospitali- 
zation 
zation 
Unex- 
pected 
Expected 
Unrelated 
Unlikely 
Not 
Requi red 
Not 
Requi red 
Not 
Requi red 
10 
Not 
Calendar 
Requi red 
Days 
10 
Not 
Calendar 
Requi red 
Days 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Proba ble 
Definite 
Not 
Requi red 
10 
Calendar 
Days 
Not 
Requi red 
10 
10 
Calendar 
Calendar 
Days 
Days 
Ca 
10
dar 
Not 
len 
Requi red 
Days 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last 
dose of treatment with an agent under a CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
• Grade 4 and Grade 5 unexpected events 
CTEP-AERS 10 calendar day report: 
• Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• Grade 5 expected events 
2  Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full report 


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Note: All deaths on study must be reported using expedited reporting regardless of 
causality.  Attribution to treatment or other cause should be provided. 
• Expedited AE reporting timelines defined: 
➢ “24 hours; 5 calendar days” – The investigator must initially report the AE via 
CTEP-AERS within 24 hours of learning of the event followed by a complete 
CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
➢ “10 calendar days” - A complete CTEP-AERS report on the AE must be submitted 
within 10 calendar days of the investigator learning of the event. 
• Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-specific expedited adverse event 
reporting exclusions. 
• Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs 
following treatment with an agent under a CTEP IND. 
• Use the NCI protocol number and the protocol-specific patient ID provided during 
trial registration on all reports. 
ALL expedited reports submitted to CTEP must be simultaneously copied to the 
Coordinating Center Control Specialist (for MC0845) via fax (507-266-7240). 
 
7.22 
Other Required Reporting 
EVENT 
REPORTING PROCEDURE 
Secondary 
AML/MDS 
Reporting for this event required during and after 
completion of study treatment. 
Submit the NCI/CTEP Secondary AML/MDS Report 
form within 10 days via fax to the Coordinating Center 
Quality Control Specialist (for MC0845) (507-266-7240). 
Other Grade 4 or 5 
Events and/or Any 
Hospitalizations 
During Treatment 
Not Otherwise 
Reportable 
Complete a Notification Form: Grade 4 or 5 Non-AER 
Reportable Events/Hospitalization Form within 5 working 
days. 
If CTEP-AERS or other expedited report has been 
submitted, this form does not need to be submitted. 
Fax to the Coordinating Center Quality Control 
Specialist (MC0845)via fax (507-266-7240). 
 
7.3 
Exclusions from Expedited Reporting 
For this protocol, the following adverse events are specifically excluded from expedited 
AE reporting: 
is required as outlined in the table. 
December 15, 2004 


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CTCAE Category 
Adverse Event 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Comments 
Blood/Bone marrow 
Hemoglobin, leukocytes (total 
WBC), lymphopenia, neutrophils/ 
granulocytes (ANC/AGC), 
platelets 
1-3 
No 
These AEs do not require 
expedited reporting unless 
patient is hospitalized for 
management 
1-3 
Yes 
Hospitalization for grade 3 
AEs does not require 
expedited reporting. 
Complications from these 
Gastrointestinal 
Diarrhea, nausea, vomiting, 
stomatitis 
GI adverse events such as 
dehydration, and electrolyte 
abnormalities do not 
require expedited reporting 
unless grade 4 and patient 
hospitalized for 
management 
Metabolic/laboratory 
Hyperchol este rol em i a, 
hyperglycemia, 
hypertriglyceridemia 
1-3 
No 
These AEs do not require 
expedited reporting unless 
patient is hospitalized for 
management 


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7.4 
Adverse Events to be Graded 
Pretreatment symptoms/conditions to be evaluated at baseline and each evaluation per 
Common Terminology Criteria for Adverse Events (CTCAE) v3.0 grading unless 
otherwise stated in the table below: 
 
Category 
Adverse Events/Symptoms 
Baseline 
Each 
evaluation 
Cardiac- general 
Hypertension 
X 
Cardiac ischemia/infarction 
X 
Hemorrhage 
/Bleeding 
Hematoma 
X 
Hemorrhage, GI 
-Lower GI NOS 
-Upper GI NOS 
X 
X
Petechiae/purpura 
(hemorrhage/bleeding into skin or 
mucosa) 
X 
Hemorrhage, pulmonary/upper 
respiratory 
-Lung 
X 
Infection 
Febrile neutropenia (fever of 
unknown origin without clinically 
or microbiologically documented 
infection) (ANC <1.0 x 109/L, fever 
≥38.5°C) 
X 
Metabolic/ 
laboratory 
Bilirubin (hyperbilirubinemia) 
X 
X 
Cholesterol, serum-high 
(hypercholesteremia) 
X 
X 
Proteinuria
X
X
Neurology 
Leukoencephalopathy (radiographic 
findings) 
X 
Vascular 
Thrombosis/thrombus/embolism 
X 
X* 
* Specify venous or arterial. 
7.41 
Documentation of the following AEs, when experienced by a participant 
but not specified in Section 7.3, are to be submitted using data collection 
mechanisms described in Section 16.0: 
7.411 Grade 1 and 2 AE’s deemed possibly, probably, or definitely 
related to the study treatment or procedure. 
7.412 Grade 3 and 4 AE’s regardless of attribution to the study treatment 
or procedure. 
7.413   Grade 5 AE’s (Deaths) 
7.4131 Any death within 30 days of a patient’s last treatment, 
regardless of relationship to study treatment or procedure. 
7.4132 Any death more than 30 days after the participant's last 
study treatment or procedure which is felt to be at least 


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possibly treatment related must also be submitted as a 
Grade 5 AE, with a CTCAE type and attribution assigned. 
7.42 
Refer to the instructions in the Forms Packet (or electronic data entry 
screens, as applicable) regarding the submission of late occurring AE’s 
following completion of the Active Monitoring Phase (i.e., compliance 
with Test Schedule Section 10.0). 
 
 
8. 
PHARMACEUTICAL INFORMATION 
8.1 
Temsirolimus (Torisel®) (NSC # 683864) 
Pharmaceutical Information 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 8.13. 
Temsirolimus (Torisel®) (NSC 683864) 
Chemical Name: 
Sirolimus 42-ester with 2,2-bis (hydroxymethyl)-propionic acid 
Other Names: 
temsirolimus, Torisel®, Rapamycin analog, WAY-130779 
Classification: 
Cell cycle inhibitor 
Molecular Formula: C56H87NO16 
M.W.: 1030.30 Daltons 
Mode of Action: 
Temsirolimus [an ester of the immunosuppressive compound 
sirolimus, (rapamycin, Rapamune®)] blocks cell cycle progression 
from the G1 to the S phase by binding to the intracellular 
cytoplasmic protein, FK506 binding protein (FKBP) 12. This 
complex inhibits activity of the enzyme mTOR (mammalian target 
of rapamycin), inhibiting translation of several key proteins that 
regulate progression through the G1 phase in response to growth 
factors. Sirolimus, temsirolimus’ s major metabolite, also binds to 
FKBP12. 
How Supplied: 
TORISEL (temsirolimus) is supplied as a commercially labeled kit 
consisting of the following: 
▪ 
TORISEL (temsirolimus) injection (25 mg/mL). The 
TORISEL vial includes an overfill of 0.2 mL. Inert 
ingredients in the drug vial include dehydrated alcohol, d,l- 
alpha-tocopherol, propylene glycol, and anhydrous citric 
acid. 


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▪ 
DILUENT for TORISEL. The DILUENT vial includes a 
deliverable volume of 1.8 mL. The diluent vial contains 
polysorbate 80 NF, polyethylene glycol 400 NF, and 
absolute alcohol USP. 
 
Preparation: 
These mixing instructions apply to commercial TORISEL only. 
The investigationally labeled product is mixed differently. 
Protect from excessive room light and sunlight during preparation. 
Follow this two step dilution process (TORISEL should only be 
diluted with the supplied diluent): 
Step 1 
Inject 1.8 mL of DILUENT for TORISEL into the vial of 
TORISEL injection (25 mg/mL). Due to the intentional 0.2 mL 
overfill in the TORISEL injection vial, the resulting drug 
concentration will be 10 mg/mL. A total volume of 3 mL will be 
obtained. Mix well by gentle inversion of the vial. DO NOT 
SHAKE. Allow sufficient time for air bubbles to subside. 
Step 2 
Withdraw the required amount of TORISEL from the 10 mg/mL 
drug solution/diluent mixture prepared in Step 1. Further dilute 
with 0.9% sodium chloride injection immediately in glass or 
polyolefin containers to a final concentration between 0.04 mg/mL 
and 1 mg/mL. 
Storage: 
Refrigerate intact TORISEL kit at 2º-8ºC and protect from light. 
Stability: 
The 10 mg/mL drug solution/diluent mixture is stable for 24 hours 
at room temperature. 
Administer within 6 hours of the final dilution in 0.9% NaCl. 
 
Route of 
Administration: 
Intravenous with an appropriate in-line filter (i.e. 0.2 to 5 micron) 
for all temsirolimus doses equal to or greater than 10 mg. Do not 
use an inline filter for temsirolimus doses less than 10 mg. Do not 
expose to direct sunlight during administration. 
Incompatibilities: 
Avoid contact of the diluted product with polyvinyl chloride 
(PVC) equipment or devices that are plasticized with di- (2- 
ethylhexyl)pthalate (DEHP) to prevent DEHP leaching. Store 
diluted temsirolimus solutions in bottles (glass) or plastic bags 
(polyolefin or polypropylene). 


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Temsirolimus is compatible with most infusion sets that are acceptable with paclitaxel. 
Infusion sets which have been qualified for use with temsirolimus include the 
following: 
•Baxter vented paclitaxel set 
•Baxter unvented paclitaxel set 
•Abbott #11947 tubing set 
•Alaris #72953 tubing set 
 
Other non-PVC tubings can be used with the following in-line filters: 
•IV 6200 Disposable I.V. Filter 0.2 micron by EPS®, Inc 
•IV 6120 Disposable I.V. Filter 1.2 micron by EPS®, Inc 
•LV 5000 Large Volume 5 micron Conical Filter by B.Braun 
•Baxter Paclitaxel IV 0.2 micron filter set (2C7555) 
•Codan 5 micron monofilter 
•Alaris extension filter set #20350E 
Other polyethersulfone filters may be used. 
Potential Drug Interactions: 
The combination of temsirolimus and sunitinib resulted in dose limiting toxicity 
at low doses of both agents. Avoid concomitant sunitinib during temsirolimus 
treatment. 
Temsirolimus and warfarin may interact to increase INR. Monitor warfarin 
patient’s PT/INR after starting and stopping temsirolimus. 
The combination of temsirolimus and ACE inhibitors resulted in angioedema-type 
reactions (including delayed reactions occurring up to 2 months after initiation of 
therapy). 
Patient Care Implications: 
For hypersensitivity prophylaxis, give diphenhydramine 25-50 mg orally or by 
I.V. (or comparable antihistamine) approximately 30 minutes before starting 
temsirolimus infusion.  Infuse over 30 minutes. 
If a patient develops a hypersensitivity reaction despite diphenhydramine 
pretreatment, stop the infusion and wait 30 to 60 minutes (depending upon the 
reaction severity). At the physician’s discretion, it may be possible to resume 
treatment by administering an H2 blocker approximately 30 minutes before 
restarting the infusion. The manufacturer recommends famotidine 20 mg IV, 
rather than cimetidine, because it lacks reported drug interactions. Re-attempt 
infusion at a slower rate, possibly over one hour. 


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Vaccinations:  Avoid the use of live vaccines during temsirolimus treatment. 
8.12 
Availability 
temsirolimus 
Temsirolimus is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
Temsirolimus is provided to the NCI under a Cooperative Research and 
Development Agreement (CRADA) between Wyeth Pharmaceuticals, Inc. 
and the DCTD, NCI. 
8.13 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Temsirolimus (CCI-779, NSC 683864) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI via CTEP-AERS (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further 
clarification. Frequency is provided based on 1927 patients. Below is the CAEPR for temsirolimus (CCI- 
779, Torisel). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
Version 2.4, July 2, 20131 
Adverse Events with Possible 
Relationship to Temsirolimus (CCI-779, Torisel) 
(CTCAE 4.0 Term) 
[n= 1927] 
 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
Anemia (Gr 3) 
Febrile neutropenia 
Febrile neutropenia (Gr 3) 
ENDOCRINE DISORDERS 
 
Endocrine disorders - Other 
(decreased testosterone) 
Endocrine disorders - Other 
(decreased testosterone) (Gr 2) 
GASTROINTESTINAL DISORDERS 
 
Abdominal distension 
Abdominal distension (Gr 2) 
Abdominal pain 
Abdominal pain (Gr 3) 
Anal mucositis2 
Anal mucositis2 (Gr 2) 
Constipation 
Constipation (Gr 3) 


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Diarrhea 
Diarrhea (Gr 3) 
Gastrointestinal fistula3 
 
Gastrointestingal perforation4 
Gastrointestinal perforation4 (Gr 2) 
Mucositis oral2 
M ucositis oral2 (Gr 3) 
Nausea 
Nausea (Gr 3) 
Rectal mucositis2 
Rectal mucositis2 (Gr 2) 
Small intestinal mucositis2 
Small intestinal mucositis2 (Gr 2) 
Vomiting 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Chills 
Chills (Gr 2) 
Edema face 
Edema face (Gr 2) 
Edema limbs 
Edema limbs (Gr 3) 
Fatigue 
Fatigue (Gr 3) 
Fever 
Fever (Gr 2) 
Flu like symptoms 
Flu like symptoms (Gr 2) 
Non-cardiac chest pain 
Non-cardiac chest pain (Gr 2) 
Pain 
 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction5 
Allergic reaction5 (Gr 2) 
INFECTIONS AND INFESTATIONS6 
 
Infection7 
Infection7 (Gr 3) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
Wound dehiscence8 
Wound dehiscence8 (Gr 2) 
INVESTIGATIONS 
 
Alanine aminotransferase 
increased 
Alanine aminotransferase increased 
(Gr 3) 
Alkaline phosphatase 
increased 
Alkaline phosphatase increased (Gr 2) 
Aspartate aminotransferase 
increased 
Aspartate aminotransferase increased 
(Gr 3) 
Cholesterol high9 
Cholesterol high9 (Gr 4) 
Creatinine increased 
Creatinine increased (Gr 3) 
Fibrinogen decreased 
Fibrinogen decreased (Gr 2) 
GGT increased 
GGT increased (Gr 2) 
Lymphocyte count decreased 
Lymphocyte count decreased (Gr 4) 
Neutrophil count decreased10 
Neutrophil count decreased10 (Gr 4) 
Platelet count 
decreased10 
Platelet count decreased10 (Gr 4) 
Weight loss 
Weight loss (Gr 3) 
White blood cell decreased 
White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
 
Acidosis 
Acidosis (Gr 2) 
Anorexia 
Anorexia (Gr 3) 
Glucose intolerance11 
Glucose intolerance11 (Gr 2) 
Hyperglycemia11 
Hyperglycemia11 (Gr 3) 
Hypertriglyceridemia9 
Hypertriglyceridemia9 (Gr 4) 
Hypocalcemia 
Hypocalcemia (Gr 3) 
Hypokalemia 
Hypokalemia (Gr 4) 
Hypophosphatemia 
Hypophosphatemia (Gr 3) 
Metabolism and nutrition 
disorders - Other 
(hyperlipidemia)9 
M etabolism and nutrition disorders - 
Other (hyperlipidemia)9 (Gr 4) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
Arthralgia (Gr 2) 
Back pain 
Back pain (Gr 2) 


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Myalgia 
M yalgia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
 
Depressed level of 
consciousness 
Depressed level of consciousness 
(Gr 2) 
Dysgeusia 
Dysgeusia (Gr 2) 
Headache 
Headache (Gr 3) 
PSYCHIATRIC DISORDERS 
 
Depression 
Depression (Gr 2) 
Insomnia 
Insomnia (Gr 2) 
Libido decreased 
Libido decreased (Gr 2) 
RENAL AND URINARY DISORDERS 
Acute kidney injury12 
 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
Erectile dysfunction 
Erectile dysfunction (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
Cough (Gr 2) 
Dyspnea 
Dyspnea (Gr 3) 
Epistaxis 
Epistaxis (Gr 2) 
Laryngeal mucositis2 
Laryngeal mucositis2 (Gr 2) 
Pharyngeal mucositis2 
Pharyngeal mucositis2 (Gr 2) 
Pleural effusion 
Pleural effusion (Gr 3) 
Pneumonitis13 
Pneumonitis13 (Gr 3) 
Sinus disorder 
Sinus disorder (Gr 2) 
Tracheal mucositis2 
Tracheal mucositis2 (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Dry skin 
Dry skin (Gr 2) 
Pruritus 
Pruritus (Gr 2) 
Rash acneiform 
Rash acneiform (Gr 2) 
Rash maculo-papular 
Rash maculo-papular (Gr 3) 
Skin and subcutaneous tissue 
disorders – Other (nail 
disorder/nail changes)15 
Skin and subcutaneous tissue 
disorders – Other (nail disorder/nail 
changes)15 (Gr 2) 
Urticaria 
Urticaria (Gr 2) 
VASCULAR DISORDERS 
 
Hypertension 
Hypertension (Gr 3) 
Hypotension 
Hypotension (Gr 3) 
Thromboembolic event 
Thromboembolic event (Gr 4) 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2Mucositis/stomatitis: Gingivitis, mucositis/stomatitis, ulcers in mouth and throat, pharyngitis, and 
dysphagia have been reported in subjects receiving temsirolimus. 
3Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Enterovesical fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, 
Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS 
SOC. 
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC. GI perforation (including fatal outcome) 
has been observed in subjects who received temsirolimus. 


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5Hypersensitivity /infusion reactions (including some life threatening and rare fatal reactions), including 
and 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 early during infusion and appropriate supportive care should be available. 
Temsirolimus infusion should be interrupted in all patients with severe infusion reactions and appropriate 
medical care administered. A risk-benefit assessment should be done prior to the continuation of 
temsirolimus therapy in patients with severe life-threatening reactions. 
6Infections:  Bacterial and viral infections including opportunistic infections have been reported in 
subjects. Infections may originate in a variety of organ systems/body regions and may be associated with 
normal or grade 3-4 neutropenia. Bacterial and viral infections have included cellulitis, herpes zoster, 
herpes simplex, bronchitis, abscess, pharyngitis, urinary tract infection (including dysuria hematuria, 
cystitis, and urinary frequency), rhinitis folliculitis, pneumonia, and upper respiratory tract infection. 
7Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
8Wound Dehiscence: The use of temsirolimus has been associated with abnormal wound healing. 
Therefore, caution should be exercised with the use of temsirolimus in the perisurgical period. 
9Cholesterol High: The use of temsirolimus in subjects has been associated with increases in serum 
levels of triglycerides and cholesterol. This may require initiation of or increase in the dose of lipid- 
lowering agents. 
10Thrombocytopenia and Neutropenia: Grades 3 and 4 thrombocytopenia and/or neutropenia have been 
observed at higher frequency in subjects with mantle cell lymphoma (MCL). 
11Hyperglycemia/Glucose Intolerance: The use of temsirolimus in subjects was associated with increases 
in serum glucose level. This may result in the need for an increase in the dose of, or initiation of, insulin 
and/or oral hypoglycemic agent therapy. 
12Acute Kidney Injury: Renal failure (including fatal outcome) has been observed in subjects receiving 
temsirolimus for advanced RCC and/or with pre-existing renal insufficiency. 
13Interstitial Lung Disease: There have been cases of nonspecific interstitial pneumonitis, including rare 
fatal reports. Some subjects were asymptomatic with pneumonitis detected on computed tomography 
scan or chest radiograph. Others presented with symptoms such as dyspnea, cough, and fever. Some 
subjects required discontinuation of temsirolimus or treatment with corticosteroids and/or antibiotics, while 
some subjects continued treatment without additional intervention. 
14Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
15Nail Disorder/Nail Changes includes Nail discoloration, Nail loss, and Nail ridging under the SKIN AND 
SUBCUTANEOUS TISSUE DISORDERS SOC. 
Also reported on temsirolimus (CCI-779, Torisel) trials but with the relationship to temsirolimus 
(CCI-779, Torisel) still undetermined: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(coagulopathy); Hemolysis; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Chest pain - cardiac; Heart failure; 


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Left ventricular systolic dysfunction; Myocardial infarction; Pericardial effusion; Right ventricular 
dysfunction; Sinus tachycardia; Supraventricular tachycardia; Ventricular fibrillation; Ventricular 
tachycardia 
EAR AND LABYRINTH DISORDERS - Vertigo 
ENDOCRINE DISORDERS - Endocrine disorders - Other (Cushing's syndrome); Endocrine disorders - 
Other (diabetes mellitus) 
EYE DISORDERS - Blurred vision; Cataract; Conjunctivitis; Dry eye; Eye disorders - Other (diplopia); Eye 
pain; Flashing lights; Photophobia; Retinopathy 
GASTROINTESTINAL DISORDERS - Anal pain; Anal ulcer; Ascites; Bloating; Colitis; Colonic 
obstruction; Colonic ulcer; Dry mouth; Duodenal ulcer; Dyspepsia; Dysphagia; Enterocolitis; Esophageal 
pain; Esophageal ulcer; Esophagitis; Flatulence; Gastritis; Gastrointestinal disorders - Other (anal 
fissure); Gastrointestinal disorders - Other (gastroenteritis); Gastrointestinal disorders - Other (mouth 
ulceration); Gastrointestinal hemorrhage14, Hemorrhoids; Ileus; Oral pain; Pancreatitis; Periodontal 
disease; Proctitis; Rectal pain; Small intestinal obstruction; Stomach pain; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema trunk; Facial pain; Gait 
disturbance; Injection site reaction; Localized edema; Malaise; Multi-organ failure; Sudden death NOS 
HEPATOBILIARY DISORDERS - Hepatic failure 
IMMUNE SYSTEM DISORDERS - Anaphylaxis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Fracture; Postoperative 
hemorrhage; Vascular access complication; Wound complication 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin increased; CD4 
lymphocytes decreased; INR increased (potential interaction with Coumadin); Investigations - Other (BUN 
increased); Investigations - Other (lactic dehydrogenase increased); Lipase increased; Lymphocyte count 
increased; Serum amylase increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hyperuricemia; Hypoalbuminemia; Hypoglycemia; Hypomagnesemia; 
Hyponatremia; Metabolism and nutrition disorders - Other (albuminuria) ; Metabolism and nutrition 
disorders - Other (blood urea increased); 
Metabolism and nutrition disorders - Other (hypoproteinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Avascular necrosis; Bone 
pain; Chest wall pain; Generalized muscle weakness; Joint effusion; Muscle weakness lower limb; 
Musculoskeletal and connective tissue disorder - Other (muscle cramps); Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Leukemia 
secondary to oncology chemotherapy; Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) - Other (carcinoma of the lung); Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) - Other (lymphoma); Treatment related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Dizziness; Dysesthesia; 
Hydrocephalus; Intracranial hemorrhage; Lethargy; Neuralgia; Paresthesia; Peripheral motor neuropathy; 
Peripheral sensory neuropathy; Reversible posterior leukoencephalopathy syndrome; Seizure; 
Somnolence; Spasticity; Stroke; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Mania; Psychiatric disorders - Other (bipolar 
disorder); Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Cystitis noninfective; Hematuria; 
Hemoglobinuria; Proteinuria; Renal hemorrhage; Urinary frequency; Urinary retention; Urinary tract pain; 
Urinary urgency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Female genital tract fistula; Hematosalpinx; 
Irregular menstruation; Menorrhagia; Ovarian hemorrhage; Prostatic hemorrhage; Spermatic cord 
hemorrhage; Testicular disorder; Testicular hemorrhage; Testicular pain; Uterine hemorrhage; Vaginal 
discharge; Vaginal dryness; Vaginal fistula; Vaginal hemorrhage; Vaginal inflammation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Allergic rhinitis; Bronchopulmonary hemorrhage; Bronchospasm; Hiccups; Hypoxia; Nasal congestion; 
Pharyngolaryngeal pain; Pleuritic pain; Productive cough; Pulmonary edema; Pulmonary fibrosis; 
Pulmonary hypertension; Respiratory failure; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Erythema multiforme; Hyperhidrosis; 
Pain of skin; Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Skin and subcutaneous 
tissue disorders - Other (angioneurotic edema); Skin ulceration; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Flushing; Phlebitis; Superficial thrombophlebitis; Visceral arterial ischemia 


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Note: Intracerebral Bleeding: Subjects with central nervous system (CNS) tumors (primary CNS tumors 
or metastases) and/or receiving anticoagulation therapy may be at an increased risk of intracerebral 
bleeding (including fatal outcomes) while receiving therapy with temsirolimus (CCI-779, Torisel). 
Note: Temsirolimus (CCI-779, Torisel) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
 
8.14 
Drug procurement: temsirolimus may be requested by the Principal 
Investigator (or their authorized designees) at each participating institution. 
Pharmaceutical Management Branch (PMB) policy requires that the agent be 
shipped directly to the institution where the patient is to be treated. PMB does 
not permit the transfer of agents between institutions (unless prior approval 
from PMB is obtained). Completed Clinical Drug Requests (NIH-986) should 
be submitted to the PMB by fax (301) 480-4612 or mailed to the 
Pharmaceutical Management Branch, CTEP, DCTD, NCI, 9000 Rockville 
Pike, EPN Rm. 7149, Bethesda, MD 20892. 
The Investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Drug Accountability Record Form. See 
the CTEP home page for Policy and Guidelines for Accountability and 
Storage of Investigational Drugs 
(http://ctep.info.nih.gov/Policies/AcctabilitystorageInvDrugs.htm). 
8.15 
Nursing guidelines 
8.151 Hypersensitivity reactions have been observed in some patients 
shortly after beginning the temsirolimus infusion (and ending 
shortly after stopping the infusion). Signs and symptoms have 
included flushing of the face and neck (and in some cases also 
involving the extremities and trunk), description of feeling hot, 
uncomfortable, and/or anxious, chest pain/tightness, shortness of 
breath, decrease in oxygen saturation and cyanosis, hypotension, 
lightheadedness, periorbital puffiness, description of feeling like 
the patient’s head was swelling, nausea, back pain, numbness and 
tingling of hands/feet/face, and difficulty speaking. Some patients 
have been able to receive subsequent infusions following pre- 
medication with diphenhydramine with or without corticosteroids 
and/or histamine H2-receptor antagonist. Pre-medication with 
diphenhydramine now is being used in all new patients to try to 
prevent the occurrence of these reactions. If a patient begins to 
develop a hypersensitivity reaction despite pretreatment with 
diphenhydramine, the infusion should be stopped. It may be 
possible to resume treatment after waiting at least 30-60 minutes 
(depending upon the severity of the reaction) by administering a 


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histamine H2-receptor antagonist approximately 30 minutes before 
restarting the temsirolimus infusion. Famotidine 20 mg IV is the 
recommended agent. The rate of the temsirolimus infusion also 
may be slowed, administered over 1 hour. All patients should be 
monitored closely while receiving the temsirolimus infusion. 
8.152 Treat stomatitis symptomatically – may try dabbing vitamin E oil 
on lesions. Do not swallow oil. Advise frequent and careful oral 
hygiene. 
8.563 Drug may cause hypocalcemia and/or hypophosphatemia. Instruct 
patient to report any persistent muscle aching, muscle weakness, 
nocturia, or polyuria.  Encourage hydration. 
 
8.154 Monitor CBC closely. Instruct patient to report any signs or 
symptoms of infection. The degree of immunosuppression may be 
enhanced if corticosteroids are being used concurrently. 
8.155 Instruct patient to report any unusual and/or persistent bruising or 
bleeding to the health care team. 
8.156 Headache may occur. Tylenol may benefit. Instruct patient to 
report any headache that is not relieved. 
8.157 Libido may be affected and sexual performance may be affected. 
Patients and their partners may wish to discuss intimacy issues. 
8.157 Assess patient’s list of medications (including OTC drugs) closely. 
Patient should avoid taking any medications that inhibit or induce 
the CYP3A pathway of the P450 system. Instruct patient that they 
should check with the health care team before starting any new 
medication, including over the counter medications. 
8.159 Nausea and vomiting may occur. Administer antiemetics as 
ordered and assess for their effectiveness. 
8.160 Diarrhea may also occur. Administer antidiarrheals as needed and 
assess for their effectiveness. 
8.161 Monitor cholesterol and triglyceride levels. 
8.162 Instruct diabetic that hyperglycemia may occur. Blood glucose 
should be monitored closely and any uncontrolled episodes of 
hyperglycemia should be reported to the health care team 
immediately. 


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8.163 
Instruct patient to report rash to the health care team immediately. 
 
8.164 
Instruct patient to report any cough, shortness of breath or chest 
pain to the health care team. 
 
8.165 
Because the risk of cardiovascular events is still undetermined, 
vital signs should be monitored prior to, during, and after the 
infusion closely, per  individual institution  guidelines. 
 
8.166 
Monitor liver and renal function tests. 
 
8.167 
Patient may develop dry skin and or dry eyes. Advise patient to 
use  moisturizing lotions and/or tears. 
 
8.168 
Instruct patients to report episodes of epistaxis.  Minor episodes 
may be dealt with at home by applying ice packs, and keeping 
head back. More serious episodes may have to be dealt with in the 
ER. 
 
8.2 
Bevacizumab (Avastin®) (NS C 704865 ) 
 
 
Oth e r Na mes: 
Classification: 
rhuMAb VEGF, Avastin® 
 
Recombinant humanized monoclonal antibody 
Molecular Weight: 
Approximate molecular weight is 149,000 Daltons 
 
Mode of Action: 
 
 
Description: 
 
 
 
 
How Supplied: 
Bevacizumab blocks the binding of vascular endothelial growth factor 
(VEGF) to its receptors  resulting in inhibition  of angiogenesis. 
 
Bevacizumab is a recombinant humanized anti-VEGFmonoclonal 
antibody consisting of 93% human and 7% murine amino acid sequences. 
The agent is composed of human IgG framework and murine antigen- 
binding  complementarity-determining regions 
 
Bevacizumab is supplied as a clear to slightly opalescent, sterile liquid for 
parenteral administration. 
Each 400 mg (25mg/ml -  16 mL fill) glass 
vial contains bevacizumab with phosphate, trehalose, polysorbate20, and 
Sterile Water for Injection, USP. 
 
Preparation: Vials contain no preservativesand are intended for single use only. Place the 
calculated dose in 100 mL of 0.9% sodium chloride for injection. 
 
Storage: 
Upon receipt, refrigerate bevacizumab (2 
to 8 
C).  Do not freeze.  Do 
not shake. 


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Stability: 
Shelf-life studies of rhuMAb VEGF are ongoing.  The sterile single use 
vials contain no antibacterial preservatives. Discard vials 8 hours after 
initial entry. 
Once diluted in 0.9% sodium chloride, administer solutions of 
bevacizumab within 8 hours. 
Route of Administration: 
Intravenous 
Method of Administration: 
Administer the initial dose over a minimum of 90 minutes. If no 
adverse reactions occur, administer the second dose over a minimum of 60 minutes. If no 
adverse reactions occur after the second dose, administer subsequent doses over a minimum of 
30 minutes. If infusion-related adverse reactions occur, all subsequent infusions should be 
administered over the shortest period that was well tolerated. 
To insure complete delivery of bevacizumab, flush the IV infusion line with 0.9% sodium 
chloride. The following are two recommended methods for flushing the bevacizumab IV 
infusion line: 
1. When the bevacizumab infusion is complete, add an additional 50mL of 0.9% sodium 
chloride for injection to the bevacizumab infusion bag. Continue the infusion until a volume 
equal to that of the volume contained in the tubing has been administered. 
2. Replace the empty bevacizumab infusion bag with a 50mL bag of 0.9% sodium chloride for 
injection and infuse a volume equal to the volume contained in the tubing. 
Please note: the flush is not included in the total recommended infusion times. 
 
8.22 
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8.23 
Nursing Guidelines: 
 
8.231 Monitor patients closely for infusion type reactions, including 
fever, chills, myalgias, rigors, or other allergic reactions.  While 
this is less likely given that bevacizumab is a humanized antibody, 
there still exists the potential for severe allergic reactions. If these 
signs or symptoms occur stop the infusion immediately and contact 
MD. Have emergency equipment nearby and be prepared to 
administer emergency treatment as ordered by MD. 
8.232 Monitor urine dipstick per protocol test schedule. 
8.233 Evaluate IV site regularly for signs of infiltration. 
8.234 Bleeding in the absence of thrombocytopenia is a dose limiting 
toxicity. Monitor patient closely for hemorrhagic events, including 
CNS hemorrhage, epistaxis, hematemesis and hemoptysis. Most 
cases of bleeding have occurred at the tumor site. Advise patient 
about the potential for bleeding or thrombosis. 
8.235 In patients receiving treatment for lung cancer, hemoptysis and 
pulmonary hemorrhage occurred in up to 10% of patients in one 
study.  Monitor these patients especially closely. 
8.236 Patient may experience grade 1-2 nausea, however vomiting is 
uncommon. Medicate as ordered and monitor for effectiveness. 
8.237 Monitor for skin rash, instruct patient to report to MD. 
8.238 a Monitor blood pressure. Administer antihypertensives as ordered 
by MD. 
8.239 aMonitor for signs and symptoms of deep vein thrombosis (DVT) or 
pulmonary embolism (PE), or myocardial infarction (MI) including 
new or worsening angina. These have been reported with therapy. 
Instruct patient to report any calf pain, chest pain or SOB to MD 
immediately. 
8.239b Asthenia and headache were reported during therapy (in up to 70% 
and 50% of patients respectively). Administer acetaminophen as 
needed.  Monitor for its effectiveness.  Avoid the use of aspirin, or 
Redacted 


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ibuprofen as this may interfere with the coagulation cascade and 
further add to the risk of bleeding. 
8.239c Monitor CBC, including platelets. Instruct patient to report signs 
and symptoms of infection, unusual bruising or bleeding to the 
MD. 
8.239d Patient receiving warfarin therapy for thrombosis should have their 
PT or INR monitored weekly until two stable therapeutic levels are 
attained: for patients on warfarin for venous access prophylaxis, 
routine monitoring is satisfactory. 
8.239e A rare but serious complication of bevacizumab is wound 
dehiscence. Patients who have had recent surgery or have other 
open wounds should be monitored carefully. 
8.239f Gastrointestinal perforation with or without abdominal abscess is 
rare but possible. This may present itself as vague abdominal pain 
associated with constipation and vomiting.  Instruct patient to 
report abdominal pain to the MD. 
8.239g Reversible Posterior Leukoencephalopathy Syndrome (RPLS) is a 
rare (<1%) but serious condition. Presenting symptoms may 
include changes in mental status, visual disturbance, seizure, or 
other CNS changes. Patients with this syndrome generally had 
HTN as well, therefore BP monitoring is important. Instruct 
patient to report any mental status changes, visual changes, 
seizures, or other CNS changes to the MD immediately. These 
may be a sign of RPLS or more serious condition, such as 
hemorrhagic event in the CNS. 
8.3 
Agent Ordering/Accountability 
8.31 
Agent Ordering 
NCI supplied agents may be requested by the Principal Investigator (or 
their authorized designee) at each participating institution. Pharmaceutical 
Management Branch (PMB) policy requires that agent be shipped directly 
to the institution where the patient is to be treated. PMB does not permit 
the transfer of agents between institutions (unless prior approval from 
PMB is obtained.) The CTEP assigned protocol number must be used for 
ordering all CTEP supplied investigational agents. The responsible 
investigator at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form 
(IDF), and Financial Disclosure Form (FDF). If there are several 
participating investigators at one institution, CTEP supplied 


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investigational agents for the study should be ordered under the name of 
one lead investigator at that institution. 
Agent may be requested by completing a Clinical Drug Request (NIH- 
986) and mailing it to the Pharmaceutical Management Branch, DCTD, 
NCI, 9000 Rockville Pike, EPN Room 7149, Bethesda, MD 20892-7422 
or faxing it to (301) 480-4612.  For questions call (301) 496-5725. 
8.32 
Agent Accountability 
Agent Inventory Records – The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of the 
inventory and disposition of all agents received from DCTD using the NCI 
Drug Accountability Record Form (DARF). (See the CTEP home page at 
http://ctep.cancer.gov for the Procedures for Drug Accountability and 
Storage and to obtain a copy of the DARF and Clinical Drug Request 
form.) 
9. 
CORRELATIVE/SPECIAL STUDIES 
A number of laboratory correlates could be proposed to be incorporated in this trial. 
However at this stage it is unclear whether there is added value in performing such 
studies. The primary rationale for performing such studies to determine whether there are 
potential predictive markers of clinical activity or toxicity for this combination. Since we 
do not know whether there will be sufficient activity of the combination that would 
enable such an analysis it is premature to propose the actual studies to be performed. 
Furthermore, there is little information available about the sensitivity, specificity, 
precision, day to day, within patient and between patient variability in clinical samples 
for many of the biomarkers one may wish to propose. Nevertheless, data on the assay 
characteristics of a number of such biomarkers may be gleaned from ongoing studies 
where biomarker analysis is being performed such as the kidney cancer trial being 
performed by the Mayo Clinic Consortium. Other single agent trials being performed 
under NCI auspices may generate additional information that may inform the assay 
characteristics.  Thus we propose to collect, process and store genomic DNA, plasma, 
and archival tissue samples that will enable informed decisions to be made about what 
biomarkers would merit analysis. The actual analysis could be done by investigators who 
have obtained additional funding through a peer reviewed process. Such an application 
would have the information at hand of the clinical activity and/or toxicity of the 
combination. Possible markers that could be considered for analysis can include but are 
not limited to, tumor PTEN status, phospho Akt, serum VEGF, and sFLT levels, S6K and 
phospho S6K, cyclin D1, polymorphisms in drug metabolizing exzymes such as 
CYP3A4/5 and eNOS. 
9.1 
Laboratory Correlative Studies 
9.1.1 Paraffin-embedded Blocks and Slides of primary tumors/metastases: 
9.1.1.1 The clinical investigator and the submitting pathologist have the 
responsibility for submitting representative materials for the goals cited 


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in the protocol.  The following materials are required for this protocol: 
 
• 
At least one (two if possible) H&E stained slides with 
representative tumor. 
• 
At least one (three, if possible) paraffin-embedded blocks with 
representative tumor. 
• 
If an institution is unable to release tissue paraffin-embedded tissue 
blocks, they must be willing to submit 12 consecutive unbaked, 
unstained sections cut at 10 microns mounted on charged slides. 
9.1.2 
Blood sample collection 
9.1.2.1 Samples will be collected processed and stored for biomarker studies 
related to the type of therapies used in this trial and the tumor types being 
treated. . One 7 ml EDTA tube of blood will be collected and centrifuged 
within 15 minutes. Plasma removed and stored at -70 until shipped. Buffy 
coat will be removed and stored at -70 until shipped. EDTA plasma and 
buffy coat should be shipped frozen on dry ice. 
9.1.3 
Sample Shipment 
All specimens should be correctly labeled with patient initials, P2C study-specific 
subject ID number, date of birth, P2C protocol number, and date of collection. 
NOTE: In the event that baseline specimens are available but the patient is not 
successfully registered to the protocol, do not submit the patient's specimens. 
Specimens should be shipped frozen on a cold pack and must be shipped for 
express/overnight delivery. 
Blood and Tissue Specimens: 
Kits are required for the collection of blood and tissue specimens. 
The kit contains supplies and instructions for collecting, processing, and 
shipping specimens. Collect and process all blood/blood products and 
tissue, according to specific kit instructions 
Participating institutions may obtain kits by completing and faxing 
the Supply Order Form (found in both the Forms Packet) to the 
number listed on the form. Fill out the site address to where the kits 
will be shipped on the Fax Supply form. Because we are now being 
charged for all outgoing kits, a small, but sufficient, supply of the 
specimen collection kits should be ordered prior to patient entry. Do 
not send the unused kits back to MML. 
Kits will be sent via FedEx® Ground at no additional cost to the 
participating institutions. Allow at least two weeks to receive the kits. 
Kits will arrive inside the shipping boxes. 


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Kits will not be sent via rush delivery service unless the participating 
institution provides their own FedEx® account number or alternate billing 
number for express service. Mayo Clinic Cancer Center will not cover 
the cost for rush delivery of kits. 
All samples must be collected Monday-Thursday ONLY. 
Label specimen tube(s) with protocol number, patient ID number, and 
time and date blood is drawn. 
The MML kits will contain a smart shipper label (white barcoded 
label) affixed to the shipping boxes. The smart shipper label is a pre- 
addressed return label, which replaces the need for an airbill. 
Shipping costs will be covered by Mayo Clinic Cancer Center if this 
box is used fro shipping specimens to MML 
Shipping blood specimens 
Complete the Blood Specimen Submission Form, as appropriate, to 
document specimen submission in the study database. 
Complete and verify ALL sections of the Blood Specimen Submission 
Form (see Forms Packet), MML Requisition Form (provided in kit), and 
specimen collection labels are completed and filled in correctly. 
Blood specimens must be shipped the same day they are drawn. If 
specimens are collected on a Friday or a holiday, samples must be frozen 
at −20ºC or colder and shipped on the next normal working day (e.g., 
Monday).  Avoid using a frost-free freezer, unless this is your only option. 
Ship plasma and buffy coat specimens via Priority Overnight service, 
Monday – Thursday ONLY, to Mayo Medical Laboratories (MML) 
according to kit instructions. Do not send samples on weekends or just 
prior to federal holidays. 
 
Processing of Blood Specimens 
MML will receive the samples and immediately forward specimens to the 
Biospecimens Accessioning and Processing (BAP) Shared Resource, 
Stabile 13-10A, Attention: BAP Supervisor. 
BAP will process specimens according to Appendix G instructions. 
Shipping and Processing of Paraffin-embedded Blocks and/or Slides: 


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Complete the Tissue Specimen Submission Form, as appropriate, to 
document specimen submission in the study database. 
Verify ALL sections of the Tissue Specimen Submission Form (see 
Forms Packet), MML Requisition Form (provided in kit), and 
specimen collection labels are completed and filled in correctly. 
Ship ambient paraffin-embedded blocks and/or slides according to the 
kit instructions and via ground service to the following address: 
P2C Operations Office 
Attn: PC Office (Study MC0845) 
RO_FF_03_24-CC/NW Clinic 
200 First Street SW 
Rochester MN 55905 
Phone 507-293-3928 
When an appropriate request is submitted, the Pathology Coordinator will 
forward the block/slides to the appropriate lab for processing. 


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NCI Pro
10. STUDY CALENDAR 
This schedule is based on currently available information regarding the study regimen and specifies the minimum 
procedures, exams, testing, etc., necessary to determine eligibility (baseline) and to evaluate safety and plan dose 
adjustments at subsequent cycles. The frequency of procedures may be increased or additional procedures 
performed as clinically indicated at physician discretion. 
 
Active Monitoring Phase 
Tests and procedures 
7 days prior 
to registration 
During interval 
between 
treatment 
Prior to 
subsequent 
cycles 
At PD, 
withdrawal or 
removal 
History and exam, wt, PS, BP6 
X 
X 
X 
Height 
X 
Hematology group 
WBC, ANC, Hemoglobin, platelets 
X 
X3, 12 
X 
X 
Coagulation 
Prothrombin time, activated partial thromboplastin 
time, INR, fibrinogen 
X 
X4 
Chemistry group (fasting): glucose, total bilirubin, 
creatinine, alkaline phosphatase, SGOT (AST), 
ALT, Na, K, Ca,  cholesterol, triglycerides,13 
X 
X 
X 
Urinalysis 5 
X5 
X 5 
LVEF assessment, if applicable8 
X 
Chest x-ray (not required if chest CT was done) 
X 
X4 
Tumor Measurement/ 
Evaluation of indicator lesion (CT, MRI, etc.)2 
X 
X2 
Tumor Samples7 
X 
Blood samples for banking 10, R 
X 
Serum pregnancy test1 
X 
Islet cell and Carcinoid Cohorts Only: 
Measurement of relevant elevated circulating 
hormone level if applicable to each patient (e.g. 
serum glucagon, gastrin, Insulin, VIP, ACTH, 
chromagranin A, or 24 hr urinary 5-HIAA11) 
X 
X9 
HCC Cohort: albumin, AFP 
X 
X 
X 
Ovarian Cohort: Mg, CA125 
X 
X 
X 
1. For women of childbearing potential only. 
2. Baseline assessment may be 21 days prior to registration. Use the same method throughout the study. 
Followup scans to be performed every other cycle (8 weeks). If tumor measurement made by physical 
examination, must document prior to each cycle. Repeat measurements are required 4 weeks following a PR or 
CR. See Section 11.0 for full RECIST criteria. For Carcinoid cohort and Islet Cell cohort, Triple phase CT scan 
abd/pelvis or MRI of abdomen are recommended. 
3. To be performed weekly (+/- 1 day). 
4. As clinically indicated 
5. Subjects discovered to have >2+ proteinuria at baseline or during study must undergo a 24-hour urine 
collection. This must be an adequate collection and must demonstrate <2 g of protein/24 hr to allow 
participation in the study. If proteinuria is found during the study, please see Table 6.1 for dose modification 
guidelines. 
6. 
At least weekly during cycle 1, and prior to each administration of bevacizumab (per Section 5). 
7. 
Tumor sample may be used from a previous surgery. 
8. 
LVEF assessment ≤4 weeks prior to registration: required for patients who have received prior anthracycline, 
including doxorubicin and/or liposomal doxorubicin. 
9. To be collected after every other cycle of treatment. 
10. Collected after registration but prior to treatment. 
11. 5-HIAA can be done 28 days 


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12. Hematology group not needed between cycles for patients in single agent bevacizumab Islet Cell Carcinoma 
cohort 
13. Cholesterol and Triglycerides are not required for the Islet Cell-Bevacizumab only cohort. 
R.   Research funded. 
 
11.0 
Treatment Evaluation Using RECIST (version 1.1) Criteria[93] 
11.1 
Schedule of Evaluations 
For the purposes of this study, patients should be reevaluated every 8 weeks. 
Determination of progression will be made according to the RECIST (version 1.1) 
criteria. 
11.2 
Definitions of Measurable and Non-Measurable Disease 
11.21 Measurable disease is defined as at least one lesion whose longest diameter 
can be accurately measured as 2.0 cm with chest X-ray or as ≥1.0 cm with 
CT scan, CT component of a PET/CT, or MRI.  Clinical lesions will only 
be considered measurable when they are superficial (e.g., skin nodules, 
palpable lymph nodes).  Lesions on chest x-ray are acceptable as 
measurable lesions when they are clearly defined and surrounded by 
aerated lung.  However, CT is preferable. 
11.22 Nodes with a short axis of >1.5 cm by CT are considered measurable and 
assessable as target lesions. Only the short axis measurement should be 
included in the sum of lesions in calculation of tumor response. Nodes that 
shrink to <1.0 cm short axis are considered normal. 
 
11.23 All other lesions (or sites of disease), including small lesions (longest 
diameter <2.0 cm with chest X-ray or as <1.0 cm with CT scan, CT 
component of a PET/CT, or MRI) are considered non-measurable disease. 
Bone lesions leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal 
masses (not followed by CR or MRI), and cystic lesions are all non- 
measurable. 
11.3 
Guidelines for Evaluation of Measurable Disease 
11.31 Measurement Methods: All measurements should be recorded in metric 
notation (i.e., decimal fractions of centimeters) using a ruler or calipers. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during 
follow-up. For patients having only lesions measuring at least 1 cm to less 
than 2 cm must use spiral CT imaging for both pre- and post-treatment 
tumor assessments. Imaging-based evaluation is preferred to evaluation by 
clinical examination when both methods have been used at the same 
evaluation to assess the antitumor effect of a treatment. 


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11.32 Acceptable imaging modalities for measurable disease: CT scan 
(conventional and spiral), MRI, chest x-ray, and physical examination. 
 
• Conventional CT and MRI should be performed with cuts of 1.0 cm or 
less in slice thickness contiguously. 
• Spiral CT must be performed using a 5 mm contiguous reconstruction 
algorithm. This specification applies to tumors of the chest, abdomen, 
and pelvis, while head and neck tumors and those of the extremities 
require specific procedures. 
11.33 Measurement at Follow-up Evaluation: 
 
• A subsequent scan must be obtained 4 weeks following initial 
documentation of an objective status of either complete response (CR) 
or partial response (PR). 
• In the case of stable disease (SD), follow-up measurements must have 
met the SD criteria at least once after study entry at a minimum 
interval of 8 weeks (see Section 11.44). 
• 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. 
• Cytologic and histologic techniques can be used to differentiate 
between PR and CR in rare cases (e.g., residual lesions in tumor types 
such as germ cell tumors, where known residual benign tumors can 
remain.) 
• New lesions on the basis of FDG-PET imaging can be identified 
according to the following: 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up 
is a sign of PD based on a new lesion. 
No FDG-PET at baseline and a positive FDG-PET at follow- 
up: 
If the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD. 
If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT scans are needed to determine 
if there is truly progression occurring at that site (if so, the date of PD 
will be the date of the initial abnormal FDG-PET scan). 
If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD. 
(A ‘positive’ FDG-PET scan lesion means one which is FDG avid 
with an uptake greater than twice that of the surrounding tissue) on the 
attenuation corrected image. 


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11.4 
Measurement of Effect 
11.41 Target Lesions 
All measurable lesions (as defined in Section 11.21) up to a maximum of 5 
lesions representative of all involved organs should be identified as target 
lesions and recorded and measured at baseline. If the protocol specified 
studies are performed, and there are fewer than 5 lesions identified (as there 
often will be), there is no reason to perform additional studies beyond those 
specified in the protocol to discover new lesions. For any one organ, no 
more than 2 lesions need 
to be measured. Target lesions should be selected on the basis of their size 
(lesions with the longest diameter) and their suitability for accurate 
repetitive measurements (either by imaging techniques or clinically). 
 
 
Baseline Sum of Diameters (BSD): A sum of the diameters [longest for 
non-nodal target lesions (see 11.21), short axis for target lymph nodes 
(see.11.22)] for all target lesions will be calculated and reported as the 
baseline sum of diameters. The BSD will be used as reference to further 
characterize any objective tumor response in the measurable dimension of 
the disease. 
Post-Baseline Sum of the Diameters (PBSD): A sum of the diameters 
[longest for non-nodal target lesions (see 11.21), short axis for target lymph 
nodes (see.11.22)] for all target lesions will be calculated and reported as 
the post-baseline sum of diameters. If the radiologist is able to provide an 
actual measure for the target lesion, that should be recorded, even if it is 
below 0.5 cm.  If the target lesion is believed to be present and is faintly 
seen but too small to measure, a default value of 0.5 cm should be assigned. 
If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 cm. 
The minimum sum of the diameters (MSD) is the minimum of the BSD and 
the PBSD. 


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11.42 Non-Target Lesions 
All other lesions (or sites of disease) should be identified as non-target 
lesions and should also be recorded at baseline. Measurements are not 
required, and these lesions should be followed in accord with 11.433. 
11.43 Response Criteria 
11.431 All identified sites of disease must be followed on re-evaluation. 
Specifically, a change in objective status to either a PR or CR 
cannot be done without rechecking all identified sites (i.e., target 
and non-target lesions) of pre-existing disease. 
11.432 Evaluation of Target Lesions 
• Complete Response (CR): All of the following must be true: 
a) Disappearance of all non-nodal target 
lesions 
b) Each target lymph node must have 
reduction   in short axis to < 1.0 cm. 
Partial Response (PR): 
At least a 30% decrease in the sum of 
the longest diameter of the non-nodal 
target lesions and the short axis of the 
target lymph nodes taking as reference 
the BSD (Section 11.41) 
• Progression (PD): 
At least one of the following must be 
true: 
a) At least one new malignant lesion 
or a lymph node whose short axis 
has increased to > 1.5 cm. 
b) At least a 20% increase in the sum 
of diameters of target lesions 
taking as reference the MSD. In 
addition, the sum must also 
demonstrate an absolute increase 
of at least 0.5 cm. 
c) See Section 11.33 for details in 
regards to the requirements for PD 
via FDG-PET imaging. 
• Stable Disease (SD): 
Neither sufficient shrinkage to qualify 
for PR nor sufficient increase to 
qualify for PD taking as references 
the smallest sum LD. 


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11.433 Evaluation of Non-Target Lesions 
• Complete Response (CR): All of the following must be true: 
a) Disappearance of all non-nodal 
non-target lesions 
b) Each non-target lymph node must 
have reduction in short axis to < 1.0 
cm. 
 
• Stable Disease (SD): 
Persistence of one or more non-target 
lesions 
• Progression (PD): 
At least one of the following must be true: 
a) At least one new malignant lesion 
b) Unequivocal progression of existing 
non-target lesions.  (Note: 
Unequivocal progression should not 
normally trump target lesion status. It 
must be representative of overall 
disease status change, not a single 
lesion increase.) 
c) See Section 11.33 for details in 
regards to the requirements for PD via 
FDG-PET imaging. 
 
NOTE:  Although a clear progression of “non-target” lesions only 
is exceptional, in such circumstances, the opinion of the treating 
physician will prevail, and the progression status will be confirmed 
at a later time by the study chair or a review panel. 
11.44 Overall objective status 
The overall objective status for an evaluation is determined by combining 
the patient’s status on target lesions, non-target lesions, and new disease as 
defined in the following table. 
 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Objective 
Status 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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11.45 Residual Disease: In some circumstances it may be difficult to distinguish 
residual disease from normal tissue. When the evaluation of complete 
response depends upon this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
11.46 Symptomatic Deterioration: Patients with global deterioration of health 
status requiring discontinuation of treatment without objective evidence of 
disease progression at that time, and not either related to study treatment or 
other medical conditions, should be reported as PD due to “symptomatic 
deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment due to symptomatic 
deterioration: 
• Weight loss >10% of body weight. 
• Worsening of tumor-related symptoms. 
• Decline in performance status of >1 level on ECOG scale. 
11.5 
Response and Disease Progression 
Formal statistical definitions of analysis variables involving response and disease 
progression are contained in Section 13.0. 
 
12. 
DATA REPORTING / REGULATORY CONSIDERATIONS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
12.1 
Data Reporting 
12.11 Method 
This study will be monitored by the Clinical Data Update System (CDUS) 
version 3.0. Cumulative CDUS data will be submitted quarterly to CTEP by 
electronic means.  Reports are due January 31, April 30, July 31, and October 
31. Instructions for submitting data using the CDUS can be found on the 
CTEP web site (http://ctep.cancer.gov/reporting/cdus.html). 
12.12 Responsibility for Submissions 
Study participants are responsible for submitting CDUS data and/or data 
forms to the CTSU Data Operations Center quarterly by April 1, July 1, 
October 1 and January 1 to allow time for CTSU compilation, Principal 
Investigator review, and timely submission to CTEP (see Section 12.11.). 


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The CTSU Data Operations Center is responsible for compiling and 
submitting CDUS data to CTEP for all participants and for providing the data 
to the Principal Investigator for review. 
12.2 
CTEP Multicenter Guidelines 
This protocol will adhere to the policies and requirements of the CTEP Multicenter 
Guidelines. The specific responsibilities of the Principal Investigator and the 
Coordinating Center (Study Coordinator) and the procedures for auditing are 
presented in Appendix B. 
 
• The Principal Investigator/Coordinating Center is responsible for distributing 
all IND Action Letters or Safety Reports received from CTEP to all 
participating institutions for submission to their individual IRBs for action as 
required. CTSU Operations will facilitate this process via email broadcasts 
and web postings. 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
agents directly from CTEP. Agents may be ordered by a participating site only after the initial 
IRB approval for the site has been forwarded to the CTSU Regulatory Office in Philadelphia for 
entry in the Regulatory Support System (RSS) and transmission to CTEP. 
12.3 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA) 
The agent bevacizumab and temsirolimus, supplied by CTEP, DCTD, NCI, used in 
this protocol is provided to the NCI under a Collaborative Agreement (CTA-Clinical 
Trials Agreement) between the Pharmaceutical Company(ies) [hereinafter referred to 
as “Collaborator”] and the NCI Division of Cancer Treatment and Diagnosis. 
Therefore, the following obligations/guidelines, in addition to the provisions in the 
Intellectual Property Option to Collaborator contained within the terms of award, 
apply to the use of  Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the 
clinical study.  Collaborator(s) data for Agent(s) are confidential and proprietary 
to Collaborator(s) and shall be maintained as such by the investigators. The 
protocol documents for studies utilizing investigational agents contain 
confidential information and should not be shared or distributed without the 
permission of the NCI. If a copy of this protocol is requested by a patient 
participating on the study or patient’s family member, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from 
http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in 
combination with (an)other investigational Agent(s), each the subject of different 
collaborative agreements, the access to and use of data by each Collaborator shall 


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be as follows (data pertaining to such combination use shall hereinafter be 
referred to as "Multi-Party Data”.): 
a. NCI must provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NIH, the design of the proposed combination protocol, and the existence of 
any obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow 
said other Collaborator to develop, obtain regulatory approval, or 
commercialize its own investigational agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use 
the Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own investigational agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and 
the FDA, as appropriate and unless additional disclosure is required by law or 
court order. Additionally, all Clinical Data and Results and Raw Data will be 
collected, used and disclosed consistent with all applicable federal statutes and 
regulations for the protection of human subjects, including, if applicable, the 
Standards for Privacy of Individually Identifiable Health Information set forth in 
45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
5. Any data provided to Collaborator(s) for phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP for immediate delivery to Collaborator(s) for advisory review and comment 
prior to submission for publication. Collaborator(s) will have 30 days from the 
date of receipt for review. Collaborator shall have the right to request that 
publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected. Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible 
and preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings.  Press releases and 


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other media presentations must also be forwarded to CTEP prior to release. 
Copies of any manuscript, abstract, and/or press release/ media presentation 
should be sent to: 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, MD 20892 
FAX 301-402-1584 
E-mail: anshers@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/proprietary information. 
 
13. 
STATISTICAL CONSIDERATIONS 
13.1 
Study Overview 
This is a study in multiple tumor types treated with the combination of 
temsirolimus and bevacizumab. The five tumor types are of endometrium, ovary, 
hepatocellular, islet cell and carcinoid. The phase II trial is designed to assess 
treatment efficacy in terms of both tumor response and 6-month progression free 
survival. A modified two-stage Simon design[94] with fixed sample size is 
adopted for each of the five tumor groups respectively. This design will permit 
early stopping of the trial if there is strong evidence that the study regimen is 
inactive. 
13.11 Primary Endpoints 
The primary endpoint of this trial is treatment efficacy evaulated using 
both the tumor response rate and the 6-month progression free survival 
rate. Tumor response rate is the proportion of confirmed tumor responses. 
RECIST criteria will be used for response assessments.  A confirmed 
tumor response is defined to be either a CR or PR noted as the objective 
status on 2 consecutive evaluations at least 8 weeks apart. The tumor 
response rate is defined as the total number of efficacy-evaluable patients 
who achieved a complete or partial response according to the RECIST 
criteria divided by the total number of efficacy-evaluable patients enrolled 
on study. All patients meeting the eligibility criteria who have signed a 
consent form and have begun treatment will be evaluable for response. 
The 6-month progression free survival rate is the proportion of efficacy- 
evaluable patients progression-free 6 months from registration. The 6- 
month progression-free rate is defined as the total number of efficacy- 
evaluable patients on study without documentation of disease progression 
6 months from registration divided by the total number of efficacy- 


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evaluable patients enrolled on study. Patients who died without 
documentation of progression will be considered to have progressed on the 
date of their death. All patients meeting the eligibility criteria who have 
signed a consent form and have begun treatment will be evaluable for 6- 
month progression-free survival. 
13.12 Sample Size 
A maximum of 275 patients will be accrued to this trial if sufficient 
successes occur in all tumor types to be studied. The minimum number of 
patients to be accrued if there is insufficient activity to go to the second 
stage in any tumor type is 138. These estimates include an allowance for 
an extra 10% of patients to replace those deemed not evaluable due to 
ineligibility, major treatment violation, or cancellation. 
Specifically, we will accrue a maximum of 55 patients [25 (Stage 1) + 25 
(Stage 2) + 5 (10% over accrual)] for patients from each tumor group. 
The maximum sample size will be increased to 299 patients after the 
addition of 24 [ 21 plus 3 (10% over accrual)] islet cell cancer who will 
receive single-agent bevacizumab. 
13.13 Accrual Time and Study Duration 
Based on accrual history in these diseases at each of the N01 participating 
consortia, we anticipate accruing approximately 25 eligible patients (ie, 5 
–endometrial cancer, 6 –ovarian cancer, 5 – hepatocellular carcinoma, 4 – 
islet cell, 5 – carcinoid) per month. This estimate accounts for 10% over 
accrual for patients declared not evaluable due to ineligibility, major 
treatment violation, or cancellation. We expect the trial to be completed in 
17 months for endometrial cancer, 16 months for ovarian cancer, 17 
months for hepatocellular carcinoma, 20 months for islet cell cancer, 17 
months for carcinoid, which includes a 6-month temporary suspension 
once the initial stage of accrual is met and to allow patients to become 
evaluable for the primary endpoint. Accrual will be temporarily closed 
during the interim analysis only if patient accrual is rapid. However, 
temporarily closure for interim analysis for one tumor group should not 
affect the status of other tumor groups. The final analyses will begin 
approximately 17 months, 16 months, 17 months, 20 months, 17 months 
after accrual is opened to endometrial cancer, ovarian cancer, 
hepaocellular carcinoma, islet cell and carcinoid patients respectively. 
The accrual rate of islet cell patients treated with single agent 
bevacizumab is estimated to be 3 per month. We expect the accrual and 
analysis to be completed in 8 months for this additional cohort of islet cell 
cancer. 


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13.2 
Statistical Design 
A two-stage phase II clinical trial design has been chosen for each of the tumor 
groups such that under the assumption that tumor response and 6-month progression 
free survival are uncorrelated, there will be approximately 87%--92% chance of 
detecting the target tumor response rate or the target 6-month progression free 
survival rate at a 10% significance level. Instead of pursuing the optimal or minmax 
sample size as in Simon optimal design[94], a fixed sample size of 50 and a first stage 
sample size of 25 are used to assess efficacy for each of the five tumor groups. 
13.21a Endometrial Cancer Decision Rule 
A response rate of 25% and median progression free survival of 6 months 
were observed in the single agent activity of temsirolimus in patients who 
have recurrent or metastatic endometrial cancer [44]. To evaluate endometrial 
cancer, the largest response rate where the proposed treatment regimen would 
be considered ineffective in this population is 25%, and the smallest that 
would warrant further subsequent studies is 45%; the largest 6-month 
progression free survival rate where the proposed treatment regimen would be 
considered ineffective in this population is 50%, and the smallest that would 
warrant further subsequent studies is 70%. The following modified two-stage 
Simon design (Simon, 1989) uses 25 or 50 patients to test the null hypothesis 
that the true tumor response rate in the given patient population is at most 
25% AND the true 6-month progression-free survival rate is at most 50%. 
 
STAGE 1: Enter 25 patients into this study. If more than 7 of the first 25 evaluable 
patients enrolled achieved a confirmed tumor response during the first 6 
cycles of treatment OR more than 13 of the first 25 evaluable patients 
enrolled were progression free at 6 months then enrollment would continue 
to the second stage. If not, patient accrual will be terminated and the 
regimen would be considered inactive in this patient population. 
STAGE 2: Enter an additional 25 patients into this study. If at least 18 of the 
first 50 evaluable patients enrolled achieve a confirmed tumor 
response OR at least 31 of the first 50 evaluable patients enrolled are 
progression free at 6 months, consideration would be given to 
recommending this treatment for further testing in this patient 
population. 
13.21b Ovarian Cancer Decision Rule 
The Gynecology Oncology Group reported a single agent trial of bevacizumab 
in persistent or recurrent ovarian cancer [74], where the response rate was 
21% and 40.3% patients were progression-free for at least 6 months. To 
evaluate ovarian cancer, the largest response rate where the proposed 
treatment regimen would be considered ineffective in this population is 20%, 
and the smallest that would warrant further subsequent studies is 40%; the 
largest 6-month progression free survival rate where the proposed treatment 


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regimen would be considered ineffective in this population is 40%, and the 
smallest that would warrant further subsequent studies is 60%. The following 
modified two-stage Simon design[94] uses 25 or 50 patients to test the null 
hypothesis that the true tumor response rate in the given patient population is 
at most 20% AND the true 6-month progression-free survival rate is at most 
40%. 
STAGE 1: Enter 25 patients into this study. If more than 6 of the first 25 
evaluable patients enrolled achieved a confirmed tumor response 
during the first 6 cycles of treatment OR more than 10 of the first 25 
evaluable patients enrolled were progression free at 6 months then 
enrollment would continue to the second stage. If not, patient accrual 
will be terminated and the regimen would be considered inactive in 
this patient population. 
STAGE 2: Enter an additional 25 patients into this study. If at least 15 of 
the first 50 evaluable patients enrolled achieve a confirmed tumor 
response OR at least 26 of the first 50 evaluable patients enrolled 
are progression free at 6 months, consideration would be given to 
recommending this treatment for further testing in this patient 
population. 
13.21c Hepatocellular Carcinoma Decision Rule 
A single arm phase II trial of bevacizumab[88]reported an objective response 
rate 13% and 65% patients were progression-free at 6 months. Similarly, to 
evaluate hepatocellular carcinoma, the largest response rate where the 
proposed treatment regimen would be considered ineffective in this 
population is 10%, and the smallest that would warrant further subsequent 
studies is 25%; the largest 6-month progression free survival where the 
proposed treatment regimen would be considered ineffective in this 
population is 65%, and the smallest that would warrant further subsequent 
studies is 85%. The following modified two-stage Simon design[94] uses 25 
or 50 patients to test the null hypothesis that the true tumor response rate in 
the given patient population is at most 10% AND the true 6-month 
progression-free survival rate is at most 65%. 
 
STAGE 1: Enter 25 patients into this study. If more than 2 of the first 25 
evaluable patients enrolled achieved a confirmed tumor response 
during the first 6 cycles of treatment OR more than 18 of the first 25 
evaluable patients enrolled were progression free at 6 months then 
enrollment would continue to the second stage. If not, patient accrual 
will be terminated and the regimen would be considered inactive in 
this patient population. 


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STAGE 2: Enter an additional 25 patients into this study. If at least 9 of the 
first 50 evaluable patients enrolled achieve a confirmed tumor 
response OR at least 39 of the first 50 evaluable patients enrolled are 
progression free at 6 months, consideration would be given to 
recommending this treatment for further testing in this patient 
population. 
13.21d Islet Cell Cancer Decision Rule 
A multi-center trial of temsirolimus was conducted in metastatic 
neuroendocrine tumors with an observed response rate of 7% and an median 
time-to progression of 10.6 months[92]. Assuming a constant hazard rate, the 
median time-to progression of 10.6 months can be converted to an 
approximately 67.5% progression free rate at 6 months. Since some patients 
may be died from other causes than islet cell cancer, we estimate that 
progression free survival at 6 months would be a little lower at 60%. To 
evaluate islet cell cancer, the largest response rate where the proposed 
treatment regimen would be considered ineffective in this population is 5%, 
and the smallest that would warrant further subsequent studies is 20%; the 
largest 6-month progression free survival rate where the proposed treatment 
regimen would be considered ineffective in this population is 60%, and the 
smallest that would warrant further subsequent studies is 80%. The following 
modified two-stage Simon design[94]uses 25 or 50 patients to test the null 
hypothesis that the true tumor response rate in the given patient population is 
at most 5% AND the true 6-month progression-free survival rate is at most 
60%. Due to the slow progression of islet cell cancer, we will not temporarily 
close to patient accrual after Stage 1 unless patient accrual is very rapid or 
severe toxicity occurred. 
 
STAGE 1: Enter 25 patients into this study. If more than 2 of the first 25 
evaluable patients enrolled achieved a confirmed tumor response 
during the first 6 cycles of treatment OR more than 15 of the first 25 
evaluable patients enrolled were progression free at 6 months then 
enrollment would continue to the second stage. If not, patient accrual 
will be terminated and the regimen would be considered inactive in 
this patient population. 
STAGE 2: Enter an additional 25 patients into this study. If at least 6 of the 
first 50 evaluable patients enrolled achieve a confirmed tumor 
response OR at least 36 of the first 50 evaluable patients enrolled are 
progression free at 6 months, consideration would be given to 
recommending this treatment for further testing in this patient 
population. 
13.21e Carcinoid Decision Rule 


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A phase II clinical trial using bevacizumab was conducted in patients with 
carcinoid tumors showed promising antitumor activity [91] of a 18% partial 
response rate. A phase II study of temsirolimus in 37 patients with advanced 
progressive neuroendocrine carcinoma [92] reported a partial response rate of 
5% and 6-month progression free survival rate of 45% noted in carcinoid 
tumor patients. To evaluate carcinoid, the largest response rate where the 
proposed treatment regimen would be considered ineffective in this 
population is 15%, and the smallest that would warrant further subsequent 
studies is 35%; the largest 6-month progression free survival rate where the 
proposed treatment regimen would be considered ineffective in this 
population is 45%, and the smallest that would warrant further subsequent 
studies is 65%.  The following modified two-stage Simon design[94]uses 25 
or 50 patients to test the null hypothesis that the true tumor response rate in 
the given patient population is at most 15% AND the true 6-month 
progression-free survival rate is at most 45%. Due to the slow progression of 
Carcinoid, we will not temporarily close to patient accrual after Stage 1 unless 
patient accrual is very rapid or severe toxicity occurred. 
 
STAGE 1: Enter 25 patients into this study. If more than 5 of the first 25 
evaluable patients (evaluable patients are defined as patients who 
have received any dose of study drug on this trial) enrolled 
achieved a confirmed tumor response during the first 6 cycles of 
treatment OR more than 12 of the first 25 evaluable patients enrolled 
were progression free at 6 months then enrollment would continue to 
the second stage. If not, patient accrual will be terminated and the 
regimen would be considered inactive in this patient population. 
STAGE 2: Enter an additional 25 patients into this study. If at least 12 of the 
first 50 evaluable patients enrolled achieve a confirmed tumor 
response OR at least 28 of the first 50 evaluable patients enrolled are 
progression free at 6 months, consideration would be given to 
recommending this treatment for further testing in this patient 
population. 
13.21 f  Islet Cell Cancer Single Agent Bevacizumab Cohort Decision Rule 
The efficacy of single agent Bevacizumab will be compared against 
Sunitinib, an approved anti-VEGF therapy. Tumor response will be 
considered as the sole primary endpoint for this single agent 
Bevacizumab cohort of ICC patients. A phase II clinical trial of 
Sunitinib reported a median PFS of 7.7 months and response rates of 
16% (Kulke et al JCO, 2008). A randomized phase III clinical trial of 
Sunitinib vs placebo reported a median PFS of 11.4 months (71% PFS 
at 6 month) and response rate of 9%. (Raymond et al NEJM, 2011). To 
evaluate the efficacy of single agent Bevacizumab, we have modified 
the null and alternative hypothese to reflect that fact we are testing the 


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Response
superiority of Bevacizumab over Sunitinib. The largest response rate 
where the proposed treatment regimen would be considered ineffective 
in this population is 10%, and the smallest that would warrant further 
subsequent studies is 30%. The single-stage design uses 21 patients to 
test the null hypothesis that the true tumor response rate in the given 
patient population is at most 10%. We will reject the null hypothesis if 
we have at least 7 confirmed responses. 
 
 
13.22 
Power and Significance Level 
Assuming that the number of confirmed tumor responses and the number 
of 6-month progression-free survivors are binomially distributed and 
uncorrelated, the significance level is at most 10% and the probability of 
declaring that this regimen warrants further studies (i.e. statistical power) 
under various success proportions and the probability of stopping accrual 
after the first stage can be tabulated as a function of the true success 
proportion as shown in the following tables. 
Endometrial : probability of stopping accrual at stage 1: 
True 6-month Progression-Free Survival Rate 
50% 
55% 
60% 
65% 
70% 
True Tumor 
Response 
Rate 
25% 0.479 
0.328 
0.194 
0.091 
0.033 
30% 0.333 
0.233 
0.138 
0.096 
0.022 
35% 0.201 
0.141 
0.081 
0.038 
0.014 
40% 0.099 
0.071 
0.041 
0.019 
0.007 
45% 0.041 
0.030 
0.017 
0.008 
0.003 
Endometrial Cancer: probability of declaring that the regimen warrents further 
studies: 
True 6-month Progression-Free Survival Rate 
50% 
55% 
60% 
65% 
70% 
True Tumor 
Response 
Rate 
25% 0.099 0.224 
0.451 
0.714 
0.901 
30% 0.237 0.338 
0.538 
0.758 
0.915 
35% 0.481 0.548 
0.681 
0.836 
0.941 
40% 0.732 0.768 
0.831 
0.915 
0.970 
45% 0.895 0.911 
0.938 
0.967 
0.988 
 
Ovarian Cancer: probability of stopping accrual at stage 1: 
True 6-month Progression-Free Survival Rate 
50% 
55% 
60% 
65% 
70% 
True Tumor 
Rate 
20% 0.514 
0.351 
0.207 
0.097 
0.034 
25% 0.368 
0.258 
0.152 
0.069 
0.024 
30% 0.223 
0.155 
0.092 
0.042 
0.015 
35% 0.116 
0.078 
0.047 
0.022 
0.008 
40% 0.047 
0.034 
0.020 
0.009 
0.003 


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e 
mo 
Ovarian Cancer: probability of declaring that the regimen warrents further 
studies: 
True 6-month Progression-Free Survival Rate 
50% 
55% 
60% 
65% 
70% 
True Tumor 
Response 
Rate 
20% 0.097 0.221 
0.450 
0.714 
0.903 
25% 0.255 0.355 
0.547 
0.764 
0.919 
30% 0.509 0.573 
0.700 
0.845 
0.948 
35% 0.753 0.785 
0.849 
0.921 
0.974 
40% 0.905 0.917 
0.942 
0.970 
0.989 
Hepatocellular Carcinoma: probability of stopping accrual at stage 1: 
True 6-month Progression-Free Survival Rate 
65% 
70% 
75% 
80% 
85% 
True 
Tumor 
Response 
Rate
10% 0.444 
0.353 
0.235 
0.119 
0.037 
15% 0.210 
0.168 
0.111 
0.057 
0.018 
20% 0.080 
0.067 
0.043 
0.020 
0.007 
25% 0.027 
0.021 
0.014 
0.007 
0.002 
Hepatocellular Carcinoma: probability of declaring that the regimen warrents 
further studies: 
True 6-month Progression-Free Survival Rate 
65% 
70% 
75% 
80% 
85% 
True 
Tumor 
Response 
Rate
10% 0.082 0.164 
0.368 
0.663 
0.904 
15% 0.340 0.401 
0.544 
0.758 
0.929 
20% 0.687 0.715 
0.784 
0.882 
0.966 
25% 0.899 0.909 
0.930 
0.964 
0.989 
Islet Cell: probability of stopping accrual at stage 1: 
True 6-month Progression-Free Survival Rate 
60% 
65% 
70% 
75% 
80% 
True 
Tumor 
Response 
Rate
5% 0.505 
0.320 
0.166 
0.062 
0.015 
10% 0.307 
0.200 
0.102 
0.038 
0.009 
15% 0.143 
0.096 
0.048 
0.018 
0.004 
20% 0.056 
0.037 
0.018 
0.007 
0.002 
Islet Cell: probability of declaring that the regimen warrents further studies: 
True 6-month Progression-Free Survival Rate 
60% 
65% 
70% 
75% 
80% 
True 
Tumor 
Response 
Rate
5% 0.080 0.202 
0.454 
0.743 
0.933 
10% 0.333 0.425 
0.606 
0.814 
0.953 
15% 0.685 0.731 
0.814 
0.912 
0.977 
20% 0.889 0.903 
0.936 
0.969 
0.992 
 
 
Carcinoid: probability of stopping accrual at stage 1: 
True 6-month Progression-Free Survival Rate 
45% 
50% 
55% 
60% 
65% 
Tru 
Tu 
15% 0.582 
0.420 
0.259 
0.129 
0.049 
20% 0.427 
0.305 
0.192 
0.092 
0.038 


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Response 
 
25% 0.269 
0.191 
0.118 
0.059 
0.024 
30% 0.136 
0.096 
0.058 
0.029 
0.011 
35% 0.058 
0.040 
0.024 
0.013 
0.006 
 
Carcinoid: probability of declaring that the regimen warrents further studies: 
True 6-month Progression-Free Survival Rate 
45% 
50% 
55% 
60% 
65% 
True Tumor 
Rate 
15% 0.111 0.249 
0.483 
0.728 
0.902 
20% 0.271 0.383 
0.577 
0.779 
0.920 
25% 0.535 0.607 
0.732 
0.862 
0.949 
30% 0.771 0.808 
0.866 
0.931 
0.975 
35% 0.908 0.922 
0.948 
0.973 
0.991 
In this design, we assume that tumor response and 6-month progression-free 
survival are uncorrelated. Through investigating past NCCTG phase II 
metastatic breast cancer trials (N0032, N0234, and 98-32-53), tumor response 
and 6-month progression-free survival may have significantly non-zero 
positive correlation of roughly 0.50 in some settings.  Through simulation 
with various distributional assumptions and correlation levels, the significance 
level under the assumption of uncorrelated binary endpoints appears to be 
conservative (i.e. worst-case scenario) and the power under alternative 
hypothesis of tumor response rate and 6-month progression free survival rate 
appears greater than the specified level regardless of the level of correlation. 
For islet cell patient cohort treated with single agent bevacizumab, we have 
set the significance level around 10% and still maintain the the probability of 
declaring that this regimen warrants further studies (i.e. statistical power) 
above 80%. The sample size of 21 evaluable patients will be sufficient for 
testing Bevacizumab only based on the one-sided exact test of single 
proportion of 10% vs. 30%. 
13.23 
Other Considerations 
Adverse events, duration of response, overall survival, and the pace of 
accrual as well as other scientific discoveries or changes in standard of 
care will be taken into account in any decision to terminate this study 
earlier than designed. 
 
13.3 
Analysis Plan  
The following analyses will be conducted for each of the five tumor 
groups respectively except for a possible exploratory meta analysis at the 
very end of the study. However, the final conclusion of the study will be 
based on each of the separate analysis of the tumor groups. 
 
13.31 Primary Endpoint: 
All patients meeting the eligibility criteria who have signed a consent 
form and begun treatment will be considered evaluable for estimation of 


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the success probability. Those who die within 6 months will be 
considered to have had disease progression unless documented evidence 
clearly indicates no progression has occurred. 
In the event that such evidence is obtained, or in the case of major 
treatment violation, the patients’ response data will be considered 
censored at the date the patient was withdrawn from treatment. 
The true tumor response rate will be estimated by proportion of efficacy- 
evaluable patients who achieved a confirmed CR or PR by the RECIST 
criteria. A 95% confidence interval for the true response rate will be 
constructed using the Duffy-Santner approach[95]. 
The true 6-month progression-free survival rate will be estimated by the 
proportion of efficacy-evaluable patients on study without documentation 
of disease progression 6 months from registration. A 95% confidence 
interval for the true response rate will be constructed using the Duffy- 
Santner approach[95]. However, Kaplan-Meier methodology will be used 
to estimate the final success proportion (i.e. progression free at 6 months 
with a 95% confidence interval) if there are censored patients. 
13.32 Definitions and Analyses of Secondary Endpoints: 
13.321 Overall survival 
Survival time will be defined as the time from registration to death. 
Time to event distributions will be estimated using the Kaplan- 
Meier method[96]. 
13.322 Duration of response 
Duration of response is defined for all evaluable patients who have 
achieved an objective response as the date at which the patient’s 
objective status is first noted to be either a CR or PR to the date 
progression is documented. Median duration of response and the 
confidence interval for the median duration will be computed. 
13.323 Time to disease progression 
Time to progression is defined as the time from registration to 
disease progression. Patients who died without documentation of 
progression will be considered to have progressed on the date of 
their death. If a patient starts treatment and fails to return for 
evaluation, that patient will be censored for progression of disease 
at day one post-registration. 
13.324 Time to treatment failure 


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Time to treatment failure is defined as the time from study entry to 
the date patients end treatment. These analyses will include those 
patients who go off treatment in the first cycle as well as those 
included in the efficacy analyses. Time to treatment failure will be 
evaluated using the method of Kaplan-Meier. 
13.325 Translational endpoints 
Various correlative assays and markers may be explored in an 
independent study as indicated under laboroatory correlates. Thus 
we cannot propose a method of analysis for any data generated 
from samples collected on this trial at this time. 
13.33 Adverse events 
All eligible patients that have initiated treatment will be considered 
evaluable for adverse event analyses.  The maximum grade for each type 
of adverse event will be recorded for each patient, and frequency tables 
will be reviewed to determine adverse event patterns. As per NCI CTCAE 
Version 3.0, the term toxicity is defined as adverse events that are 
classified as either possibly, probably, or definitely related to study 
treatment. The maximum grade for each type of toxicity will be recorded 
for each patient, and frequency tables will be reviewed to determine 
toxicity patterns. In addition, we will review all adverse event data that is 
graded as 3, 4, or 5 and classified as either “unrelated or unlikely to be 
related” to study treatment in the event of an actual relationship 
developing. Adverse events and toxicities will be evaluated using all 
patients who have received any study treatment as well as summarizing 
those who have been included in the efficacy analyses. 
13.34 Over Accrual 
If more than the target number of patients are accrued, the additional 
patients will not be used to evaluate the stopping rule or used in any 
decision making processes; however, they will be included in final point 
estimates and confidence intervals as though they were accrued in the final 
stage. 
13.35 Monitoring 
The principal investigator(s) and the study statistician will review the 
study periodically (at least twice a year) to identify accrual, adverse 
events, and any endpoint problems that might be developing. This study 
will also be monitored by the Mayo Clinic Cancer Center Data and Safety 
Monitoring Board (DSMB) at least semiannually, or more frequently as 
warranted. 
13.36 Adverse Events Stopping Rule 


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Overall, if 5 or more of the first 25 patients (or 20% of all patients after 25 
are accrued) experience grade 4/5 non-hematologic adverse events that are 
probably, possibly, or definitely related to study treatment, accrual to the 
study will be suspended to allow for investigation. For the single-agent 
bevacizumab cohort for islet cell patients, a separate but similar adverse 
events stopping rule will be applied. If 2 or more of the first 10 patients or 
20% of all patients after 10 patients are accrued experience grade 4/5 non- 
hematologic adverse events that are probably, possibly, or definitely 
related to study treatment, accrual to the study will be suspended to allow 
for investigation. After consideration by the study team (study chair[s], 
statistician, etc.) and the primary data safety monitoring board, a decision 
will be made as to whether accrual can be resumed.  In addition, all 
adverse event patterns will be monitored by an independent Mayo Clinic 
Data Safety Monitoring Board on a bi-annual basis. 
13.37 Meta Analysis 
Treating five tumor groups with the combination of temsirolimus and 
bevacizumab under one protocol will provide a standardized platform for 
carrying out a possible exploratory meta analyses. Pooling patients of 
different tumor data in the meta analyses will increase precision of 
estimation and allow borrowing strength across tumor groups. We will 
explore such a meta analysis when all data are mature across all five 
patient tumor groups. 
13.4 
Inclusion of Women and Minorities 
13.41 This study will be available to all eligible patients, regardless of race, 
gender, or ethnic origin. 
13.42 There is no information currently available regarding differential effects of 
this regimen in subsets defined by race, gender, or ethnicity, and there is 
no reason to expect such differences to exist. Therefore, although the 
planned analysis will, as always, look for differences in treatment effect 
based on racial and gender groupings, the sample size is not increased in 
order to provide additional power for subset analyses. 
13.43 The geographical region served by N01 consortia, has a population 
mirrors of general U.S. population. 
This includes approximately 25% minorities. Based on prior NCCTG 
studies involving similar disease sites, we expect about 25% of patients 
will be classified as minorities by race and about 100% of patients will be 
women for Endometrial and Ovary cancer patients, 50% for Carcinoid, 
Islet Cell and Hepatoma. Expected sizes of racial by gender subsets are 
shown in the following table: 


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Accrual Estimates by Gender/Ethnicity/Race for All Phase 2 and 3 Studies 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
19 
9 
0 
28 
Not Hispanic or Latino 
188 
83 
0 
271 
Ethnic Category: Total of all subjects* 
207 
92 
0 
299* 
Racial Category 
American Indian or Alaskan Native 
2 
1 
0 
3 
Asian 
6 
3 
0 
9 
Black or African American 
19 
8 
0 
27 
Native Hawaiian or other Pacific Islander 
2 
1 
0 
3 
White 
178 
79 
0 
257 
Racial Category: Total of all subjects* 
207 
92 
0 
299* 
*These totals must agree.  Enter actual estimates (not percentages) 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central American, or 
other Spanish culture or origin, regardless of race. The term “Spanish origin” can also be used in 
addition to “Hispanic or Latino.” 
 
Racial 
Categories: 
Not Hispanic or Latino 
American Indian or Alaska Native – a person having origins in any of the original peoples of 
North, Central, or South America, and who maintains tribal affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, Southeast Asia, or 
the Indian subcontinent including, for example, Cambodia, China, India, Japan, Korea, Malaysia, 
Pakistan, the Philippine Islands, Thailand, and Vietnam. (Note: Individuals from the Philippine 
Islands have been recorded as Pacific Islanders in previous data collection strategies.) 
Black or African American – a person having origins in any of the black racial groups of Africa. 
Terms such as “Haitian” or “Negro” can be used in addition to “Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the original 
peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle East, or 
North Africa. 


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14. 
Descriptive Factors 
14.1 
Islet Cell Cancer Patients Only 
Functioning (hormone producing) vs. non-functioning (non-hormone producing) 
14.2 
Carcinoid Cancer Patients Only 
Functioning (hormone producing) vs. non-functioning (non-hormone producing) 
14.3 
Ovarian Cancer Patients Only 
Platinum-sensitive vs. platinum resistant (defined as recurrence within six months 
of completing initial platinum-based chemotherapy). 
14.4 
Hepatocellular Carcinoma Patients Only 
Chronic liver disease: Yes vs. No 
If yes, specify from the following: Hepatitis B vs. Hepatitis C vs. Hepatits B & C 
vs. Alcoholic cirrhosis vs. Alcoholic cirrhosis + Hepatitis B vs. Alcoholic 
cirrhosis + Hepatitis C vs. Alcoholic cirrhosis + Hepatitis B & C vs. 
Hematochromatosis vs. Cirrhosis NOS vs. Other, (specify). 
14.5 
Carcinoid and Islet Cell Cancer Patients Only 
Did patient have progressive disease based on RESCIST in preceding 6 months: 
Yes vs No vs N/A. 
 
15. PATHOLOGY CONSIDERATIONS 
Histologic or cytologic confirmation of disease will be the responsibility of each 
center independently without central review. Copies of pathology reports are to 
be sent to the CTSU Data Operations within two weeks of study entry (see 
Section 16.3). 
16. 
DATA SUBMISSION TO DATA OPERATIONS CENTER (CTSU) 
 
Clinical Data Submission via Remote Data Capture 
All participating sites will submit patient data via the CTSU’s Remote Data Capture 
(RDC) system. The CTSU RDC system allows sites to enter patient data into an Oracle 
Clinical ® (OC) database over a secure Internet connection. The RDC system also allows 
for data correction at the point of entry, and is used to communicate and resolve issues 
relating to discrepant data. The Remote Data Capture (RDC) Production Application is 
for those individuals who have completed their RDC training and are ready to enter 
actual patient data into the system. If you have not yet received training in the RDC 
system, please go to the CTSU Members’ side of the website (https://www.ctsu.org) and 
click on the “Clinical Data” tab at the top of your screen, followed by the “Remote Data 
Capture” link on the left-hand side of your screen. Select the "Training" tab to request a 
training account. 


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16.1 
Schedule of Data Submission 
Data is to be submitted ≤ 2 weeks following each evaluation of the patient and 
according to the scheduled in Section 16.3 
After the patient discontinues treatment, follow–up will continue as specified in 
the following section(s): 
16.2 
Event Monitoring 
Follow-up data will be collected and entered via the remote data entry system 
according to the schedule in Section 16.3.  If patient is still alive after 3 years 
have elapsed from on-study date, no further follow-up is required by this protocol. 
16.21 If a patient does not receive treatment (and is classified as a cancel), it is 
not necessary to provide follow-up information. On-study material, End 
of active treatment/cancel notification form and Off Study Form are to be 
submitted.  No further follow-up information is necessary. 
16.22 If a patient declared to be ineligible, all on-study and study treatment 
materials are to be submitted. The patient will enter the event monitoring 
phase of this study and will be followed for a maximum of 3 years or until 
death. 
Clinical Report Submission via Fax 
In addition to submitting patient data electronically via the RDC system, sites may be 
required to submit faxed clinical reports to CTSU. Clinical reports (e.g. operative and 
pathology reports) must be faxed to the CTSU Data Operations Center accompanied by a 
properly completed study-specific CTSU Data Transmittal Form. (Data submitted 
improperly or without a completed CTSU Data Transmittal Form will not be processed. 
Site will receive e-mail notification for any unsuccessful data receipt, including a data 
resubmission memo which will provide details and instructions for re-submission). 
Include the Patient ID and protocol number on all pages of the report and redact the 
patient’s name. CTSU fax number is: 1-301-545-0406. 
Data Submission Questions 
The CTSU help desk is available to answer questions regarding data submission at 1-888- 
823-5923 or by email at ctsucontact@westat.com. Hours are between 9:00 A.M. and 5:30 
P.M. Eastern Time, Monday through Friday (excluding holidays). 


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16.3 
Data Entry/Submission Timetable 
 
 
 
 
Forms/Other 
Active Monitoring Phase 
(Compliance with Test Schedule) 
Event-Monitoring Phase2 
(Completion of Active Monitoring Phase) 
At Each Occurrence 
Initial 
Material 
Subsequent material 
£2 weeks after 
registration 
At each 
evaluation 
At end of treatment 
q. 3 months 
until PD2 
At PD2 
After PD 
q. 6 mos.2 
Death 
All Grade 4/5 AEs 
All Hospitalizations 
During 
Treatment 
Secondary 
AML/MDS 
New 
Primary 
Late 
Adverse 
Event 
On-Study Form 
X 
Baseline Adverse Events Form 
X 
Measurement Form 
X 
X4 
X4 
Paths & Op Reports1 
X 
Biochemical Laboratory Form 
X7 
X7 
X8 
Event Monitoring 
Form 
X 
X4 
X4 
X 
X 
X 
X 
Evaluation/Treatment 
Form 
X 
X 
Nadir/Adverse Event Form 
X 
X 
Blood Specimen Submission 
Form 
X 
Tissue Specimen Submission 
form (Section 9.1) 
X 
Notification Form, Grade 4/5 
X 
End of Active Treatment/Cancel 
Notification Form 
X5 
X 
Off Study Form 
X6 
X6 
AE Reporting per Section 7.0 
X3 
X 
CTEP Report 
Variables Form 
X 
1. Submit copy of pathology reports via fax or mail to the CTSU Data Operations via fax (1-301-545-0406) and a pathology report must be submitted 
along with tissue submission form when the samples are sent to Mayo Clinic. 
2. If a patient is still alive 3 years after registration, no further follow-up is required. 
3. Reminder: Adverse events that necessitate expedited reporting are also to be reported via the routine clinical data (i.e. Nadir/Adverse Event Form, etc.) 
submitted with each evaluation. 


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4. Submit copy of documentation of response, recurrence, or progression to the CTSU Data Operations via fax (1-301-545-0406). 
5. 
Submit if withdrawal/refusal prior to beginning protocol therapy occurs. 
6. Off study form would be completed if patient is a cancel, still alive 3 years after registration, at the time of death, lost to follow-up or refused follow-up. 
7. Submit only for the Carcinoid, Islet Cell, Hcc and Ovarian Cohorts only 
8. Submit only for the HCC and Ovarian Cohorts at PD, withdrawal or removal. 


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17. 
GROUPING FACTOR 
Disease Site: Endometrial vs. ovarian vs. hepatocellular vs. carcinoid vs. islet cell 
(combined therapy) vs. islet cell -single –agent bevacizumab). 
18. 
FUNDING CONSIDERATIONS 
18.1 
Costs Charged to Patient 
All routine clinical care. temsirolimus and Bevacizumab will be provided by the 
NCI. The patient or the patient’s health plan/insurer will be responsible for 
charges associated with supplies and procedures necessary for administration of 
the study drug(s), as well as all other drugs or treatment given to help control 
adverse events as well as the cost of tests or exams to evaluate possible adverse 
events. 
18.2 
Tests to be Research Funded 
The cost of the collection and shipment of samples will be requested from the 
TBD. P2C institutions are responsible for other local costs associated with 
research specimen collection, processing, and shipment. 
18.3 
Support from N01 P2C Contract 
This study is supported by The Phase 2 Consortium (P2C) through its contract 
with the National Cancer Institute (N01 CM62205). 
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(CCI-779) in patients with metastatic or recurrent endometrial cancer--NCIC IND 160. 
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heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin 
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46. 
Pandya, K.J., et al., A randomized, phase II ECOG trial of two dose levels of 
temsirolimus (CCI-779) in patients with extensive stage small cell lung cancer in 
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2005. 23(16_suppl): p. 7005-. 
47. 
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50. 
Farag, S.S., et al., Phase II trial of temsirolimus (CCI-779) in patients with relapsed or 
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24(18_suppl): p. 7616-. 
51. 
Hudes, G., et al., A phase 3, randomized, 3-arm study of temsirolimus (TEMSR) or 
interferon-alpha (IFN) or the combination of TEMSR + IFN in the treatment of first-line, 
poor-risk patients with advanced renal cell carcinoma (adv RCC). ASCO Meeting 
Abstracts, 2006. 24(18_suppl): p. LBA4-. 
52. 
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Therapy in an Orthotopic Model of Human Pancreatic Cancer 
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55. 
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Fleming, G.F., et al., Phase III trial of doxorubicin plus cisplatin with or without 
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61. 
Holland, C.M., et al., Expression of the VEGF and angiopoietin genes in endometrial 
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62. 
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1(KDR) receptor" pathway in patients with endometrial carcinoma: prognostic and 
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APPENDIX A: ECOG PERFORMANCE STATUS 
 
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. 


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APPENDIX B: CTEP MULTICENTER GUIDELINES 
If an institution wishes to collaborate with other participating institutions in performing a 
CTEP sponsored research protocol, then the following guidelines must be followed. 
Responsibility of the Protocol Chair 
• 
The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO). The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments. The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair. 
There will be only one version of the protocol, and each participating institution will use 
that document. The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol. 
• 
The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress. All reporting requirements to CTEP are the 
responsibility of the Protocol Chair. 
• 
The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• 
The Protocol Chair will be responsible for the review of and timely submission of data 
for study analysis. 
Responsibilities of the Coordinating Center 
• 
Each participating institution will have an appropriate assurance on file with the Office 
for Human Research Protection (OHRP), NIH. The Coordinating Center is responsible 
for assuring that each participating institution has an OHRP assurance and must maintain 
copies of IRB approvals from each participating site. 
• 
Prior to the activation of the protocol at each participating institution, an OHRP form 
310 (documentation of IRB approval) must be submitted to the CTEP PIO. 
• 
The Coordinating Center is responsible for central patient registration. The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site. 
• 
The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Protocol Chair. 
• 
The Coordinating Center will maintain documentation of AE reports. There are two 
options for AE reporting: (1) participating institutions may report directly to CTEP with a 
copy to the Coordinating Center, or (2) participating institutions report to the 
Coordinating Center who in turn report to CTEP. The Coordinating Center will submit 
AE reports to the Protocol Chair for timely review. 


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• 
Audits may be accomplished in one of two ways: (1) source documents and research 
records for selected patients are brought from participating sites to the Coordinating 
Center for audit, or (2) selected patient records may be audited on-site at participating 
sites. If the NCI chooses to have an audit at the Coordinating Center, then the 
Coordinating Center is responsible for having all source documents, research records, all 
IRB approval documents, NCI Drug Accountability Record forms, patient registration 
lists, response assessments scans, x-rays, etc. available for the audit. 
Inclusion of Multicenter Guidelines in the Protocol 
• 
The protocol must include the following minimum information: 
➢ The title page must include the name and address of each participating institution and 
the name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
➢ The Coordinating Center must be designated on the title page. 
➢ Central registration of patients is required. The procedures for registration must be 
stated in the protocol. 
➢ Data collection forms should be of a common format. Sample forms should be 
submitted with the protocol. The frequency and timing of data submission forms to 
the Coordinating Center should be stated. 
➢ Describe how AEs will be reported from the participating institutions, either directly 
to CTEP or through the Coordinating Center. 
➢ Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions. 
Agent Ordering 
• 
Except in very unusual circumstances, each participating institution will order DCTD- 
supplied agents directly from CTEP. Agents may be ordered by a participating site only 
after the initial IRB approval for the site has been forwarded by the Coordinating Center 
to the CTEP PIO. 


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APPENDIX C: CHILD-PUGH CLASSIFICATION OF HEPATIC FUNCTIONAL 
RESERVE 
 
Child-Turcotte-Pugh Scoring System 
 
Parameter 
1 Point 
2 Points 
3 Points 
Score 
INR* 
<1.7 
1.7 - 2.3 
>2.3 
Prothrombin 
Time (PT)* 
(seconds over 
control) 
<4 
4-6 
>6 
Albumin 
>35 g/L, 
(> 3.5 
g/dL) 
28-35 g/L, 
(2.8-3.5 g/dL) 
<28 g/L 
(< 2.8 g/L) 
Bilirubin 
<34 
µmol/L 
(<1.8 
mg/dL) 
34-50 µmol/L 
(1.8-2.6 mg/dL) 
>50 µ/L 
(>2.6 
mg/dL) 
Ascites 
Absent 
Slight 
Or controlled by diuretics 
Moderate 
Encephalopathy 
None 
1-2 
3-4 
Total Score (A=5-6; B=7-9; C=10-15) 
*For scoring purposes, both PT and INR are not required. Either test can be used for scoring 
but in the case that both tests are drawn, use the higher score of the 2. 
Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the esophagus 
for bleeding esophageal varices. Br J Surg 1973; 60:646-649 
Clinical Stages of Hepatic Encephalopathy 
 
Stage Mental State 
0 
Normal 
1 
Mild confusion, euphoria or depression, decreased attention, slowing of ability to 
perform mental tasks, irritability, disorder of sleep pattern. 
2 
Drowsiness, lethargy, gross deficits, inability to perform mental tasks, obvious 
personality changes, inappropriate behavior, intermittent disorientation (usually for 
time). Asterixis. 
3 
Somnolent but rousable, unable to perform mental tasks, disorientation with respect to 
time and/or place, marked confusion, amnesia, occasional fits of rage, speech present 
but incomprehensible. Asterixis. 
4 
Coma 


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APPENDIX D: KNOWN INHIBITORS AND INDUCERS OF CYP3A4 
 
 
 
Inducers 
Carbamazepine 
Phenytoin 
Dexamethasone 
Primidone 
Ethosuximide 
Progesterone 
Glucocorticoids 
Rifabutin 
Griseofulvin 
Rifampin 
Nafcillin 
Rofecoxib (mild) 
Nelfinavir 
St John’s wort 
Nevirapine 
Sulfadimidine 
Oxcarbazepine 
Phenobarbital 
Phenylbutazone 
Sulfinpyrazone 
Troglitazone 
Inhibitors 
Amiodarone 
Anastrozole 
Azithromycin 
Cannabinoids 
Cimetidine 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delavirdine 
Dexamethasone 
Diethyldithiocarbamate 
Diltiazem 
Dirithromycin 
Disulfiram 
Entacapone (high dose) 
Erythromycin 
Ethinyl estradiol 
Fluconazole (weak) 
Fluoxetine 
Fluvoxamine 
Gestodene 
Grapefruit juice 
Indinavir 
Isoniazid 
Itraconazole 
Ketoconazole 
Metronidazole 
Mibefradil 
Miconazole (moderate) 
Nefazodone 
Nelfinavir 
Nevirapine 
Norfloxacin 
Norfluoxetine 
Omeprazole (weak) 
Oxiconazole 
Paroxetine (weak) 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin and dalfopristin 
Ranitidine 
Ritonavir 
Saquinavir 
Sertindole 
Sertraline 
Troglitazone 
Troleandomycin 
Valproic acid (weak) 
Verapamil 
Zafirlukast 
Zileuton 
 
 
APPENDIX E: PERCENT BONE MARROW 
Page 1 of 1 


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Local Protocol # MC0845 
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APPENDIX F: NEW YORK HEART ASSOCIATION CLASSIFICATIONS 
 
Clinical Evaluation of Functional Capacity of Patients 
with Heart Disease in Relation to Ordinary Physical Activity 
 
 
Class 
Cardiac Symptoms 
Limitations 
Need for 
Additional Rest* 
Physical Ability 
to work** 
I 
None 
None 
None 
Full time 
 
II 
Only moderate 
Slight 
Usually only slight 
or occasional 
Usually full 
time 
 
III 
Defined, with 
less than 
ordinary activity 
Marked 
Usually moderate 
Usually part 
time 
 
IV 
May be present 
even at rest, 
and any activity 
increases discomfort 
Extreme 
Marked 
Unable to work 
 
* 
To control or relieve symptoms, as determined by the patient, rather than as advised by the physician. 
** 
At accustomed occupation or usual tasks. 
 
 
 
Reference: Bruce, R. A.: Mod. Concepts Cardiovasc. Dis. 25:321, 1956. (Modified from New York Heart 
Association, 1953). 


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Local Protocol # MC0845 
NCI Version Date:  September 6, 2016 
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APPENDIX G: SPECIMEN SUMMARY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. All specimens will be stored in BAP until further research is defined. 
Collection 
Tube 
Description 
and /or 
additive 
(color of 
tube top 
Volume to 
be collected 
per tube 
(number of 
tubes to be 
collected) 
Blood product 
to be 
processed 
Visit 
Description 
£7 Days 
Prior to 
Registration 
Further 
Processing 
by BAP 
Shipping 
Conditions 
EDTA 
(purple) 
7 mL 
(1) 
Plasma, Buffy 
Coat 1 
X 
No 
Frozen