A Phase II Study of Bevacizumab Alone or in Combination With TRC105 for Advanced Renal Cell Cancer
Phase: PHASE2
Conditions: Clear Cell Renal Cell Carcinoma, Recurrent Renal Cell Carcinoma, Stage IV Renal Cell Cancer, Type 1 Papillary Renal Cell Carcinoma, Type 2 Papillary Renal Cell Carcinoma
Sponsor: National Cancer Institute (NCI)

NCI# 9144, PhII-121 
September 23, 2014  
i 
SUMMARY OF CHANGES 
 
Date:  
 
September 23, 2014 
Document: 
NCI Protocol #9144, PhII-121: “A Phase II Study of Bevacizumab Alone 
or in Combination with TRC105 for Advanced Renal Cell Cancer.” 
Note: 
The following is a Summary of Changes between the 6.20.14 and 9.23.14 
versions of protocol 
Section 
Description of Change (v. 6.20.14 to v. 9.23.14) 
Footer 
Changed protocol version to September 23, 2014.  Dates in the footers were also changed 
to 9.23.14v.  
8.1.1 
Updated the pharmaceutical information per the request for amendment for TRC105 
5.1 
Added the following per the request for amendment for TRC105 “Although there is not a 
weight restriction for enrollment purposes, the maximum weight for dose calculation in 
this study is 85 kg for women and 100 kg for men such that the administered dose should 
not exceed 850 mg for women and 1,000 mg for men.” 

NCI# 9144, PhII-121 
September 23, 2014  
1
 
NCI Protocol #: 
9144 
 
Local Protocol #:  
PhII-121 
 
TITLE:  A Phase II Study of Bevacizumab Alone or in Combination with TRC105 for 
Advanced Renal Cell Cancer 
 
Coordinating Center: 
      California Cancer Consortium Data Coordinating Center 
 
City of Hope  
 
1500 E. Duarte Road 
 
Duarte, CA 91010 
 
Phone:  626-256-HOPE (4673) x 65928 
 
Fax:      626-256-8654 
 
Email:   cccp@coh.org  
 
*Principal Investigator: 
Tanya B. Dorff, M.D. 
 
USC Norris Cancer Center 
 
1441 Eastlake Ave. #3440 
 
Los Angeles, CA 90033 
 
Phone:  323-865-3900 
 
Fax:      323-865-0061 
 
Email:  dorff@usc.edu  
 
Co-Investigators: 
Sumanta Pal, M.D. 
 
City of Hope  
 
1500 E. Duarte Rd. 
 
Duarte, CA 91010  
 
Phone:  (626)256-HOPE (4673) 
 
Fax:       (626)301-8233 
 
Email:  spal@coh.org  
 
 
Primo Lara, M.D. 
 
UC Davis Cancer Center 
 
4501 X Street 
 
Sacramento, CA 95817 
 
Phone:  (916)734-3771 
 
Fax:      (916)734-7956 
 
Email:  primo.lara@ucdmc.ucdavis.edu 
 
 
Chandra P. Belani, MD 
Pennsylvania State Cancer Institute 
500 University Dr., H072 
Hershey, PA 17033 
Phone: 717-531-1078 
Fax: 
717-531-0002 
E-mail:  cbelani@psu.edu  
 
 
 
 

NCI# 9144, PhII-121 
          September 23, 2014 
 
 
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Rahul A Parikh MD PhD  
University of Pittsburgh Cancer Center  
5150 Centre Ave.  
Pittsburgh PA 15215  
Phone: (412) 648-6466 
Fax: (412) 648-6579  
E-mail: parikhr@upmc.edu  
  
 
Ulka Vaishampayan, M.D. 
 
Wayne State University 
 
Karmanos Cancer Institute 
 
4100 John R. 
 
Detroit, MI 48201 
 
Phone:  (313) 576-8715 
 
Fax:     (313) 576-8487 
 
E-mail: vaishamu@karmanos.org 
 
 
Nizar Tannir, M.D. 
 
University of Texas 
 
MD Anderson Cancer Center 
 
1515 Holcombe Blvd. Box 1374 
 
Houston, TX  77030 
 
Phone:  (713)563-6969 
 
E-mail: ntannir@mdanderson.org 
 
Charles Erlichman, M.D. 
Mayo Clinic 
Mayo Clinic Cancer Center 
Phone:  507-266-3200 
Fax: 507-538-6290 
E-mail: erlichman.charles@mayo.edu  
 
Daniel Vaena, MD 
University of Iowa Hospitals & Clinics 
200 Hawkins Drive, 5972 JPP 
Iowa City, IA 52242 
Phone:  319-356-2757 
Fax:  319-353-8383 
Email: daniel-vaena@uiowa.edu  
 
Joel Picus, M.D. 
Siteman Cancer Center 
Washington University School of Medicine 
660 S. Euclid, Box 8056 
St. Louis, MO 

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          September 23, 2014 
 
 
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Phone:  314-362-5740 
Fax:  314-747-1534 
Email: jpicus@dom.wustl.edu 
 
Daniel Anderson 
Metro MN CCOP 
3800 Park Nicollet Blvd 
St. Louis Park, MN 55416 
Phone:  651-254-3572  
Fax:  952-993-1550  
 
Elaine Lam, MD 
University of Colorado  
12801 East 17th Ave  
Mail Stop 8117   
Aurora, Co 80045  
Phone:  720-848-0273 
Fax: 303-724-3889  
Email: Elaine.Lam@ucdnever.edu 
 
Stephen Koehler, MD  
City of Hope Medical Group, Inc., 
209 Fair Oaks Avenue 
South Pasadena, CA 91030 
Phone:  626-396-2900 
Email: Skoehler@cohmg.com  
 
Jaime R. Merchan, M.D. 
University of Miami  
Sylvester Comprehensive Cancer Center 
1475 NW 12th Avenue 
Miami, FL 33136 
Phone:  305-243-0865 
Email:  jmerchan@med.miami.edu  
 
CTRG – National Taiwan University Hospital (NTUH)  
P.I. – Dr. Chia-Chi (Josh) Lin 
Address: Department of Oncology 
National Taiwan University Hospital 
7 Chung-Shan S Road 
Taipei 10002 
Taiwan 
Contact Nos.: 
Phone:  886 2 23123456 ext 67680 
Fax: 886 2 23711174 
Email:  cclin1@ntu.edu.tw  

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          September 23, 2014 
 
 
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CTRG – Sydney Cancer Center (SCC) 
P.I.: Dr. Michelle Harrison 
Address: Royal Prince Alfred Hospital, Missenden Road, 
Camperdown,                                   
Sydney, NSW, Australia 2050 
Phone:  02 9515 5494 
Fax:  02 9519 1546 
Email:  Michelle.Harrison@sswahs.nsw.gov.au  
 
  
 
 
   
      University of Chicago 
Walter Stadler, M.D. 
University of Chicago 
5841 S. Maryland, MC 2115 
Telephone: 773-702-4150 
Fax: 773-702-3163 
Email: wstadler@medicine.bsd.uchicago.edu  
 
    
      University of  Maryland, 
Arif Hussain, MD 
University of Maryland 
Marlene and Stewart Greenebaum Cancer Center 
22 S Greene St 
Baltimore, MD 21201  
Phone: 410-328-7225 
E-mail: ahussain@umm.edu 
 
  
 
  
 
      Fort Wayne Oncology/Hematology 
Sreenivasa Nattam, MD 
11143 Parkview Plaza Drive, Suite 100 
Fort Wayne, IN 46815 
Phone: 206-484-8830 
E-mail:  snattam@fwmoh.com 
Fort Wayne Medical Oncology/Hematology, Inc. 
Dr. Sunil Babu, MD 
7910 West Jefferson Blvd. Suite 108 
Fort Wayne, IN 46804 
Ph: 260-436-0800 
Email:  sunilbabumail@yahoo.com  
 
      Decatur Memorial Hospital 
James L. Wade III, MD 
2300 N. Edward Street 
Decatur, IL 62526 
Phone: 217- 876- 6600 
E-mail:  JLWADE3@sbcglobal.net      

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NorthShore University HealthSystem 
Britt Hanson, DO (Daniel Shevrin, MD will be Co-I) 
Kellogg Cancer Center  
2180 Pfingsten Rd., Ste. 1000 
Glenview, IL 60026 
Phone: (847) 503-1000 
Fax: (847) 832-6183 
E-mail: bhanson@northshore.org 
 
Mayer Fishman, MD PhD 
Moffitt Cancer Center 
12902 Magnolia Drive  
Tampa, FL 33612 
Phone: 813-745-8343 
Fax: 813-449-8246 
E-mail:  mayer.fishman@moffitt.org 
 
Craig Swainey, MD  
Virginia Commonwealth University  
1101 E. Marshall St.  
Richmond, VA  23298-0230  
804-828-9723 (t)  
804-828-5406 (f)  
E-mail:  cswainey@mcvh-vcu.edu  
 
Igor Puzanov, M.D., M.S.C.I., F.A.C.P. 
Vanderbilt University Medical Center 
2220 Pierce Avenue, 777 Preston Research Building 
Nashville, TN 37232-6307 
Tel:   615.936.6398 
Fax:  615.343.7602 
E-mail:  igor.puzanov@Vanderbilt.Edu 
 
Mark Stein, M.D. 
Rutgers Cancer Institute of New Jersey 
195 Little Albany Street 
New Brunswick, NJ 08903-2681 
Phone-732-235-6031 
Fax- 732.235.6797 
E-mail: steinmn@cinj.rutgers.edu 
 
Mark F. Kozloff, MD 
Ingalls Memorial Hospital 
One Ingalls Drive, W740 
Harvey, IL 60426 

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Phone:  708-915-6119 
Fax:  708-915-5156 
Email:  mfkozloff@aol.com 
 
Ajjai Shivaram Alva, MD 
University of Michigan 
1500 E. Medical Center Drive, SPC 5848 
Ann Arbor, MI, 48109 
Phone: (734) 936-0091/ (734) 647-8921 
Fax:     (734) 647-8792 
Email: ajjai@med.umich.edu 
 
 
Statistician: 
Jeff Longmate, Ph.D. 
City of Hope 
1500 E. Duarte Road 
Duarte, CA 91010 
Phone:  (626)256-HOPE (4673) 
Fax:       (626)301-8233 
Email:  jlongmate@coh.org  
 
NCI Supplied Agent: 
TRC105 NSC 754227(IND# 115362)  
 
Commercially available Agent:  
Bevacizumab (Genentech) 
 
Protocol Type / Version # / Version Date: 
December 1, 2011 – initial protocol 
February 7, 2012 – Response to Consensus 
Review 
March 6, 2012 – Response to Follow Up 
Review 
May 14, 2012 – Amendment  
May 29, 2012 – Response to Follow Up Review 
(Disapproved) 
June 11, 2012 – Response to Follow Up Review 
July 12, 2012 – Disapproved 
July 26, 2012 – Response to disapproval 
July 30, 2012 – Respond to recommendations 
November 19, 2012 –  disapproved 
December 13, 2012 – Response to disapproval 
March 7, 2013 – Amendment 
July 2, 2013 – RRA Amendment 
July 31, 2013 – Amendment 
January 13, 2014 - Amendment 
June 10, 2014 – Disapproved 
June 20, 2014 – Response to disapproval 
September 23, 2014 – Amendment request 

NCI# 9144, PhII-121 
          September 23, 2014 
 
 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
n=88 
n=88 
*Bevacizumab should be administered 
 over 90 minutes the first time,  
 60 minutes the second time, then all 
 subsequent infusions may occur over 
 30 minutes (provided there is no  
 infusion reaction).
Metastatic 
RCC 
1-3 prior 
therapies 
randomize   
1:1 
Arm A: 
Bevacizumab* 10 mg/kg IV Days 1 and 15 every 
28 day cycle 
 
Arm B: 
Bevacizumab* 10 mg/kg IV Days 1 and 15 every 28 
day cycle 
+TRC105 10 mg/kg IV q week  
Days 1, 8, 15, 22 every 28 day cycle  
 
 
 
 
 

NCI# 9144, PhII-121 
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TABLE OF CONTENTS 
 
1. 
OBJECTIVES ..................................................................................................................10 
1.1. 
Primary Objectives ..........................................................................................................10 
1.2. 
Secondary Objectives.......................................................................................................10 
2. 
BACKGROUND AND RATIONALE ...........................................................................10 
2.1. 
Renal Cancer ....................................................................................................................10 
2.2. 
TRC105 .............................................................................................................................12 
2.3. 
Bevacizumab .....................................................................................................................12 
2.4. 
Rationale ...........................................................................................................................13 
2.5. 
Correlative Studies Background ....................................................................................14 
3. 
PATIENT SELECTION .................................................................................................15 
3.1. 
Eligibility Criteria ............................................................................................................15 
3.2. 
Exclusion Criteria ............................................................................................................17 
3.3. 
Inclusion of Women and Minorities ...............................................................................18 
4. 
REGISTRATION PROCEDURES ................................................................................19 
4.1. 
General Guidelines...........................................................................................................19 
4.2. 
Registration Process.........................................................................................................19 
5. 
TREATMENT PLAN ......................................................................................................20 
5.1. 
Agent Administration ......................................................................................................20 
5.2. 
General Concomitant Medication and Supportive Care Guidelines ..........................22 
5.3. 
Duration of Therapy ........................................................................................................22 
5.4. 
Duration of Follow Up .....................................................................................................22 
5.5. 
Criteria for Removal from Study ...................................................................................22 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ............ Error! Bookmark not defined. 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ......................23 
7.1. 
Comprehensive Adverse Events and Potential Risks List (CAEPR) ..........................23 
7.2. 
Adverse Event Characteristics........................................................................................30 
7.3. 
Expedited Adverse Event Reporting ..............................................................................31 
7.4. 
Routine Adverse Event Reporting ..................................................................................33 
7.5. 
Secondary Malignancy ....................................................................................................33 
7.6. 
Second Malignancy ..........................................................................................................33 
8. 
PHARMACEUTICAL INFORMATION ......................................................................33 
8.1. 
CTEP-provided agent:  TRC105  NSC 754227  (IND# TBD).......................................33 
8.2. 
Bevacizumab .....................................................................................................................35 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ...................................35 
9.1. 
Background on Correlative Studies ...............................................................................35 
9.2. 
Correlative Studies: instructions ....................................................................................37 
9.3. 
Outcome measures for correlative studies .....................................................................39 
10. 
STUDY CALENDAR ......................................................................................................41 
11. 
MEASUREMENT OF EFFECT ....................................................................................42 
11.1. Antitumor Effect – Solid Tumors ...................................................................................42 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS .....................................50 
12.1. Data Reporting .................................................................................................................50 
12.2. CTEP Multicenter Guidelines ........................................................................................50 
12.3. Collaborative Agreements Language .............................................................................50 

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13. 
STATISTICAL CONSIDERATIONS ...........................................................................52 
13.1. Study Design/Endpoints ..................................................................................................52 
13.2. Sample Size/Accrual Rate ...............................................................................................53 
13.3. Stratification Factors .......................................................................................................53 
13.4. Analysis of Secondary Endpoints ...................................................................................53 
13.5. Reporting and Exclusions ...............................................................................................55 
13.6. Safety Monitoring ............................................................................................................55 
14. 
DATA AND SAFETY MONITORING PLAN .............................................................55 
14.1. Oversight of CCCP Phase I and Phase II Trials ...........................................................55 
REFERENCES .................................................................................................................59 
APPENDIX A:  Performance Status Criteria ...............................................................62 
APPENDIX B: CTEP MULTICENTER GUIDELINES .............................................63 
APPENDIX C:  INFORMATION ON POSSIBLE INTERACTIONS WITH 
OTHER AGENTS FOR PATIENTS AND THEIR CAREGIVERS 
AND NON-STUDY HEALTH CARE TEAM ...................................................65 
APPENDIX D:  CCCP REGISTRATION PROCEDURES FOR PHASE II 
TRIALS .................................................................................................................66 
APPENDIX E:  INFORMATION ABOUT CORRELATIVE STUDIES ..................67 
APPENDIX F:  CCCP SPECIMEN SUBMISSION FORM........................................68 
APPENDIX G:  Laboratory Manual for TRC105 Pharmacokinetic & 
TRC105 HAMA/HACA Sample Collection.......................................................69 
 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
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1. OBJECTIVES 
 
1.1. 
Primary Objectives 
 
To compare the progression-free survival at 12 and 24 weeks for bevacizumab alone 
or in combination with TRC105. 
 
1.2. 
Secondary Objectives 
Secondary endpoints will include toxicity and RECIST response rate for the 
combination compared to single agent bevacizumab.  
Correlative endpoints: 
To evaluate tumor tissue expression of CD105, TGFβ-RII, ACVRL1 and TGFBR1 
kinase from pre- and post-treatment tissue samples in order to determine whether 
CD105 and stem cell activation occurs after exposure to anti-VEGF therapy as 
predicted by laboratory models, and whether exposure to TRC105 affects these 
changes.  A primary goal of tissue analysis will be to generate preliminary data to 
correlate levels of CD105, TGFβ-RII, ACVRL1 and TGFBR1 in tissue with response 
to bevacizumab in combination with TRC105 compared to bevacizumab alone.  To 
compare the soluble CD105 levels at baseline and after treatment between the group 
receiving bevacizumab alone and the group receiving bevacizumab in combination 
with TRC105. 
To compare TGFβ-RII levels at baseline and after treatment between the group 
receiving bevacizumab alone and the group receiving bevacizumab in combination 
with TRC105. 
To evaluate whether circulating tumor cells (CTCs) can be detected in this patient 
population using parylene membrane filter technology, and whether changes in CTC 
counts and CD105 expression on CTCs during therapy correspond to imaging and 
clinical response. 
 
2. BACKGROUND AND RATIONALE 
 
2.1. 
Renal Cancer 
Renal cell cancer (RCC) causes over 13,000 deaths annually in the United States, and 
the incidence is rising [Jemal].  Standard chemotherapy has not been associated with 
significant responses, and the responses associated with immune therapies such as 
Interleukin-2 and interferon-α are limited by toxicity and low overall response rates 
[MRC, Linehan].  Targeting the unique biology of von Hippel Lindau inactivation (pro-
angiogenic vascular endothelial growth factor, VEGF, and mammalian target of 
rapaycin, mTOR, activity) has led to the emergence of far more successful therapies 
which prolong progression-free survival and favorably impact overall survival. As a 
result of research involving VHL related proteins, bevacizumab, everolimus, 
pazopanib, sorafenib, sunitinib, temsirolimus have all been incorporated as standard 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
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therapies in RCC.  Nevertheless, many RCC patients fail to respond to VEGF or mTOR 
inhibition, and in responders resistance inevitably develops such that the disease 
ultimately progresses. Additional therapies are therefore needed, and there is particular 
interest in targeting angiogenic pathways that could allow continued proliferation in 
the presence of VEGF inhibition.  CD105 represents one such target.  
CD105 is a transmembrane receptor, a member of the TGFβ receptor family, which 
plays an important role in angiogenesis. It is induced by hypoxia via Hif1, and confers 
protection to cells against apoptosis triggered by hypoxia [Li].  While it is not expressed 
in vasculature of normal tissues, it is overexpressed in the neovasculature of malignant 
tissues, making it an attractive target. [Fonsatti].  Activation of CD105 by TGFβ results 
in stimulation of endothelial cell proliferation through the TBR-II/ACVRL1/TGFBR1 
heterotetrameric receptor complex. [Lebrin]  In addition, tumor cells themselves can 
express CD105, in particular renal cancer cells [Sandlund], and higher expression is 
associated with poorer outcomes [Dallas] Furthermore, the presence of CD105 may be 
a marker of an aggressive, tumor-generating population of RCC cells.  When injected 
into SCID mice, CD105+ RCC cells generated tumors 100% of the time, compared to 
10% for CD105- cells [Bussolati].  When grown clonally, CD105+ cells expressed 
other characteristic stem cell markers, including CD44, CD90, CD146, CD73, CD29, 
vimentin, nestin, nanog, musashi, oct4 and the renal embryonic marker Pax2; they did 
not express pan-cytokeratin, nor the endothelial marker vonWillebrand factor.  Thus, 
CD105 represents an independently valuable therapeutic target that may facilitate 
elimination of more resistant RCC.   
 
 
[From the TRC105 investigator brochure] 
 
 
 
* Note  ALK1 is also known as ACVRL1.  ALK5 is also known as TGFBR1 
 

 
NCI# 9144, PhII-121 
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2.2. 
TRC105 
 
TRC105 is a chimeric (human:murine) IgG1 kappa monoclonal antibody against 
CD105.  It is composed of two light chains of 213 amino acids each and its molecular 
weight is approximately 148 kDa. 
 
50 patients were treated in the phase I study of TRC105.  HAMA and HACA 
formation was rare in patients treated with the NS0-derived product but did not occur 
in those treated with the CHO-produced antibody. For the NS0-derived product, the 
dose was escalated from 0.01 to 1 mg/kg every 2 weeks. The CHO-derived product 
was used to complete dose escalation from 0.3 to 15 mg/kg every two weeks and then 
10 and 15 mg/kg weekly and is the clinical material being used in continued 
development of TRC105.  Serum concentrations expected to saturate CD105 binding 
were continuously achieved at 15 mg/kg every 2 weeks.  Accumulation was noted at 
the dose level of 15 mg/kg/week and was associated with hypoproliferative anemia.  
This has led to the selection of the dose of 10 mg/kg weekly as the single agent 
recommended Phase 2 dose.  Dose escalation with bevacizumab was reported at 
ASCO 2012.  TRC105 and bevacizumab were dosed in 19 patients at TRC105 doses 
of 3 mg/kg, 6 mg/kg and 8 mg/kg weekly with the approved dose of bevacizumab.  
Tolerability (i.e., a decreased frequency of headaches) was improved when the initial 
dose of TR105 was delayed one week following the initial dose of bevacizumab and 
split into two doses during the first week of administration.  Following ASCO, dose 
escalation continued to the single agent recommended Phase 2 dose of 10 mg/kg of 
TRC105, which was administered safely and without dose limiting toxicity in 
combination with the approved dose of bevacizumab of 10 mg/kg.   
 
Early evidence for significant activity was noted in the phase I trial, with one 
complete PSA response associated with bone scan normalization and pain resolution 
in a man with metastatic castration-resistant prostate cancer that has been durable for 
>3 years.  There was an additional minor response in a patient with uterine cancer, 
and several patients experienced prolonged disease stabilization.  Antitumor activity 
was also observed in the Phase Ib trial of TRC105 and bevacizumab.  Tumor marker 
reductions and radiographic responses were noted in multiple patients who 
progressed after prior bevacizumab treatment, who were then treated with TRC105 
weekly and 10 mg/kg bevacizumab every two weeks.  
 
2.3. 
Bevacizumab 
 
Bevacizumab was approved by the FDA for the treatment of metastatic RCC after 
two randomized, phase III trials documented significantly longer progression-free 
survival for patients treated with  bevacizumab + interferon-α compared to interferon-
α alone [Escudier, Rini]; overall survival is also favorably affected.  
 
While bevacizumab was approved in combination with interferon, early studies with 
the agent in RCC documented efficacy as a single agent. In a randomized phase II 

 
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          September 23, 2014 
 
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trial comparing placebo to 3 mg/kg or 10 mg/kg of bevacizumab in metastatic RCC 
patients, the progression-free survival at 4 months was 64% for the 10 mg/kg dose 
compared to 39% for 3 mg/kg and 20% for placebo and the hazard ratio for time to 
disease progression was 2.55 (p<0.001) representing significant prolongation [Yang].  
This more-than-doubling reflects the magnitude of effect seen in the interferon 
combination trial though the absolute duration cannot be compared across trials, 
especially since the phase II trial included cytokine pre-treated patients, whereas the 
registrational trial [Escudier] was in therapy-naïve patients.  Further evidence in 
support of single-agent bevacizumab as an appropriate control arm comes from the 
fact that intergroup CTSU E2804 trial had bevacizumab alone as its control arm 
[NCT00378703].   
 
The most common side effects related to bevacizumab in RCC patients treated at the 
dose of 10 mg/kg every 2 weeks included hypertension (14% overall; 8% grade 3), 
proteinuria (25% overall; 3% grade 3), malaise (13%, only grade 1 and 2), and 
epistaxis (8%, only grade 1 and 2) [Yang].  In the registrational trial combining 
bevacizumab with interferon adverse effects must be put in the context of the high 
rate of events in the placebo plus interferon arm; the toxicities which were 
significantly greater in the bevacizumab plus interferon arm included bleeding (33% 
compared to 9% for placebo, and 3% grade 3 or worse), proteinuria (18% compared 
to 3% for placebo, and 7% was grade 3 or worse), hypertension (26% compared to 
9% for placebo and 3% grade 3 or worse), and thromboembolic events (3% compared 
to <1% for placebo and 2% grade 3 or worse) [Escudier].  Gastrointestinal perforation 
was a rare but serious adverse event seen only in the bevacizumab-treated patients.  In 
this trial we have chosen to utilize bevacizumab without interferon as our control 
arm, in part to minimize toxicity, but also for simplicity and to isolate the added 
effect of TRC105. 
 
2.4. 
 Rationale 
 
One escape mechanism that may allow RCC to progress despite VEGF inhibition is 
signaling through other proliferative pathways which are upregulated by the 
expression of HIF-1α, such as expression of the CD105 receptor [Sanchez-Elsner].  
Specifically, the expression of CD105 has been shown to be upregulated after cancer 
cells are exposed to treatment with a VEGF antibody [Bochner, Davis]. This escape 
mechanism makes targeting of CD105 attractive. In addition, the upregulation of 
CD105 as a result of VEGF ligand inhibition may allow TRC105 to be more effective 
by increasing the density of CD105 expression on the cell surface. In vitro data 
indicates that combined use of TRC105 and bevacizumab is more effective than 
either agent alone in VEGF stimulated tumor cell sprouting studies. (unpublished 
data) This makes the combination of CD105 inhibition with VEGF inhibition highly 
attractive in RCC. 
 
We will evaluate the combination of TRC105, a monoclonal antibody against CD105, 
plus bevacizumab compared to bevacizumab alone in pre-treated metastatic renal 
cancer patients with a primary endpoint of progression-free survival at 12 and 24 

 
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14 
weeks. The doses were chosen based on results from a phase Ib trial combining 
bevacizumab and TRC105. Seven patients were treated at the top dose level (10 
mg/kg bevacizumab + 10 mg/kg TRC105) without the development of DLT. Thus, 
this is a safe dosing schema for phase II study. 
 
2.5. 
Correlative Studies Background 
Hypoxia is known to upregulate CD105 expression [Li], which increases signaling 
via the TGFβ-RII and activin-like receptor kinase ACVRL1/TGFBR1 heterodimer.  
Higher CD105 expression (measured by immunohistochemistry) has been associated 
with higher risk of metastasis and death in several solid tumors [Schimming, Mineo, 
Dales]. While subjects with high expression of CD105 may have poorer prognosis, 
we anticipate that subjects with higher expression of CD105 activity will be more 
likely to respond to TRC105 and less likely to respond to bevacizumab alone.   
In addition to the importance of being inducible by CD105, TGFβ signaling via 
TGFBR1 has taken on new significance as it is identified as one of the pathways for 
epithelial-to-mesenchymal transition (EMT) [Kalluri], a hallmark of aggressive cancer.  
Increased expression of TGFβ mRNA in kidney cancer tissue compared to normal kidney 
tissue may indicate that this is an autocrine growth pathway [Gomella].  Tumor tissue 
will be evaluated for expression of TGFβ-RII activity using immunohistochemistry 
and immunofluorescence. Given that CD105 and other hypoxia-induced growth factors 
signal via this receptor, and it has been implicated in the epidermal to mesenchymal 
transition (EMT), we hypothesize that higher expression will be associated with a poorer 
overall prognosis.  Since it may represent an escape pathway for VEGF inhibition, we 
hypothesize that elevated baseline expression will be associated with a higher likelihood 
of response to TRC105 and lower likelihood of response to bevacizumab alone.   
Given that TGF can signal via TGFBR1 to activate angiogenesis or through alternate 
receptor pathways including ACVRL1 to reduce angiogenesis, the differential expression 
of these proteins may prove markers of which cancers are more angiogenesis-driven.  We 
postulate that elevated baseline tissue expression of TGFBR1 would be associated with a 
better prognosis due to higher likelihood of response to bevacizumab, but that higher 
expression of ACVRL1 would be associated with lower overall treatment response. 
  
Measuring VEGF after exposure to bevacizumab has proven difficult, since the agent 
interferes with the assay [Kindler], though immunodepletion may allow detection of a 
decrease despite an apparent increase related to antibody-bound ligand [Loupakis].  
Thus, finding other molecular changes induced during response or progression on 
bevacizumab remains a high priority.   Suppression of VEGF signaling in preclinical 
models results in upregulation of CD105 expression.  CD105 is an integral 
component of TGFβ signaling; suppression of CD105 may result in a compensatory 
increase in its upstream activator TGFβ. This compensatory increase could represent 
a surrogate marker for effective CD105 suppression and tumor response. Circulating 
sCD105 has been found at high levels in metastatic solid tumors [Takahashi].  We 
will explore serum levels of sCD105 and TGFβ in metastatic RCC patients, and 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
15 
correlate baseline levels with prognosis and likelihood of response to TRC105.  We 
anticipate that subjects assigned to combination therapy (Arm B) will have lower 
levels of sCD105 and TGFβ at post-treatment time points compared to Arm A, where 
we expect serum levels of both factors to increase..  
 
Although circulating tumor cells (CTCs) have not yet been validated as a prognostic 
marker in RCC, they have proved to be strongly prognostic for prostate and breast 
cancer patients [deBono, Cristofanilli].  Using CD45 autoMACS depletion, 
investigators have been able to identify  CTCs in a high percentage of patients with 
localized RCC undergoing nephrectomy, which correlated with presence of nodal  
involvement and synchronous metastases [Bluemke]. Given that targeted therapy for 
RCC results primarily in disease stabilization rather than dramatic regression of 
tumor burden, it can be difficult to measure the degree of response or benefit.  
Reduction in CTCs could be a very useful objective measure by which to gauge 
response in this setting.  We will use blood samples from baseline and after 6 weeks 
and 12 weeks to enumerate CTCs using a parylene membrane filter technology 
developed by USC in conjunction with CalTech [Zheng].  We will evaluate whether 
changes in CTC counts reflect subsequent changes on radiographic imaging to 
determine whether changes in CTC counts could predict for ultimate radiographic 
response versus progression.  In addition, CTCs will be evaluated for CD105 
expression by IHC to investigate whether exposure to TRC105 has an effect on 
CD105 expression.  Reduction in CTCs which express CD105 could correspond to 
elimination of cancer cells with more “stem-like” properties, a population resistant to 
standard therapy, which could account for resistance to VEGF-targeted therapy in 
RCC.   
 
3. PATIENT SELECTION 
 
3.1. 
Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed Renal Cancer  
 
 
 
 
 
All histologic subtypes will be eligible 
 
3.1.2   Patients must have metastatic disease which is measurable, defined as at least 
one lesion that can be accurately measured in at least one dimension (longest 
diameter to be recorded for non-nodal lesions and short axis for nodal lesions) 
to ≥ 20 mm in the long axis by chest x-ray, ≥ 10 mm in the long axis by spiral 
CT, MRI, calipers, or clinical exam, or ≥ 15 mm in the short axis for lymph 
nodes.  See Section 11 for the evaluation of measurable disease. 
 
3.1.3 Patients must have received at least 1 prior systemic therapy for renal cancer 
but no more than 4 prior therapies.  They must have documented intolerance 
to or progression despite at least 1 systemic therapy. 
 
 
Therapy administered in the adjuvant setting counts toward the prior systemic 
therapy total.  If adjuvant therapy is the patient’s only prior therapy the 
disease must have recurred during treatment or within 3 months of 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
16 
discontinuation. 
 
 
 
Allowable prior therapies include VEGF TKIs, mTOR inhibitors, and 
cytokine therapy (ex: IL2). 
 
 
 
 
 
 
At least 2 weeks must have elapsed from the last dose of the prior systemic 
therapy for biologics and 4 weeks for chemotherapy (6 weeks for nitrosoureas 
or mitomycin C).”  Also note that at least 3 weeks should have elapsed since 
prior TKI administration.. 
 
 
3.1.4 Age >18 years.  Because no dosing or adverse event data are currently 
available on the use of  TRC105   and anti-angiogenic therapy would be 
anticipated to have uniquely adverse effects in growing tissues, patients <18 
years of age, children are excluded from this study. 
 
3.1.5 ECOG performance status <2 (see Appendix A). 
 
3.1.6 Life expectancy of greater than 6 months. 
 
3.1.7 Patients must have normal organ and marrow function as defined below: 
 
− leukocytes  
 
 
 
 
>3,000/mcL 
− absolute neutrophil count  
>1,500/mcL 
− platelets  
 
 
 
 
 
>100,000/mcL 
− total bilirubin 
 
 
 
 
< institutional upper limits of normal  
                                                    (except for Gilbert’s) 
− AST(SGOT)/ALT(SGPT)  
<2.5 X institutional upper limit of normal  
− (except subjects with liver metastases, who can have AST/ALT < 5xULN) 
− Creatinine 
 
 
 
 
 
GFR (calculated or measured) >50 mL/min 
− Hemoglobin  
 
 
 
 
>9 g/dL 
 
3.1.8 The effects of TRC105 and bevacizumab on the developing human fetus are 
unknown.  For this reason and because anti-angiogenic agents are known to be 
teratogenic, women of child-bearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation.  
Should a woman become pregnant or suspect she is pregnant while she or her 
partner is participating in this study, she should inform her treating physician 
immediately.  Men treated or enrolled on this protocol must also agree to use 
adequate contraception prior to the study, for the duration of study 
participation, and 6 months after completion of TRC105 or bevacizumab 
administration. 
 
3.1.9 Ability to understand and the willingness to sign a written informed consent 
document. 
 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
17 
3.2. 
Exclusion Criteria 
 
3.2.1 Patients who have had systemic biologic therapy or radiotherapy within 2 
weeks prior to entering the study or those who have not recovered from 
adverse events related to their prior therapy. 
 
3.2.2 Patients who have previously been treated with bevacizumab.   
 
3.2.3 Patients who have previously been treated with TRC105. 
 
3.2.4 Patients who are receiving any other investigational agents. 
 
3.2.5 Known CNS disease except for treated brain metastasis.  Treated brain 
metastases are defined as having no ongoing requirement for steroids and no 
evidence of progression or hemorrhage after treatment for at least 3 months, 
as ascertained by clinical examination and brain imaging (MRI or CT).  
(Stable dose of anticonvulsants are allowed).  Treatment for brain metastases 
may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma 
Knife, LINAC, or equivalent) or a combination as deemed appropriate by the 
treating physician.  Patients with CNS metastases treated by neurosurgical 
resection or brain biopsy performed within 3 months prior to Day 1 will be 
excluded.      
 
 
3.2.6 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to TRC105 or bevacizumab. 
 
3.2.7 Patients on full-dose anticoagulation will be excluded due to the risk of 
bleeding.  Antiplatelet therapy will not be exclusionary. 
 
3.2.8 Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, unhealed wound, gastrointestinal fistula, symptomatic 
congestive heart failure, unstable angina pectoris, myocardial infarction, 
cerebrovascular accident   
 
3.2.9 Pregnant women are excluded from this study TRC105 and bevacizumab are  
anti-angiogenic agents with significant potential for teratogenic or 
abortifacient effects.  Because there is an unknown but potential risk for 
adverse events in nursing infants secondary to treatment of the mother with   
TRC105 and bevacizumab, breastfeeding should be discontinued if the mother 
wishes to participate in the study.   
 
3.2.10 Patients with a history of bleeding diathesis or inherited coagulopathy are 
excluded due to the risk of bleeding and thrombosis associated with 
bevacizumab.  In addition, those with a history of DVT or pulmonary embolus 
within 1 year and still requiring active anticoagulation will be excluded; those 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
18 
with a more remote history of DVT or pulmonary embolus may be eligible but 
the risk of recurrent thrombosis should be considered. 
 
3.2.11 Patients with history of hereditary hemorrhagic telangiectasias (HHT-1 and 
HHT-2). 
 
 
3.2.12 Serious or non-healing wound, ulcer, or bone fracture OR history of 
abdominal fistula, gastrointestinal perforation or intra-abdominal abscess 
within 6 months prior to day 1.  
 
3.2.13 Invasive procedures defined as follows: 
• Major surgical procedure, open biopsy or significant traumatic injury 
within 28 days prior to Day 1 therapy 
• Anticipation of need for major surgical procedures during the course 
of the study 
• Core biopsy within 7 days prior to D1 therapy 
 
3.2.14 Patients with clinically significant cardiovascular disease are excluded. 
• Inadequately controlled HTN (SBP >160mmHg and/or DBP >90 
mmHg despite antihypertensive medication) 
• History of CVA within 6 months  
• Myocardial infarction or unstable angina within 6 months  
• New York heart association grade II or greater congestive heart failure  
• Serious and inadequately controlled cardiac arrhythmia 
• Significant vascular disease (e.g. aortic aneurysm, history of aortic 
dissection) 
• Clinically significant peripheral vascular disease  
. 
3.2.15 Patients with known hypersensitivity to Chinese hamster ovary cell products 
or other recombinant human antibodies. 
 
3.2.16 Patients with psychiatric illness/social situations that would limit compliance 
with study requirements will be excluded. 
 
3.3. 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.   
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
7 
+ 
12 
= 
19 
Not Hispanic or Latino 
19 
+ 
50 
= 
69 
Ethnic Category: Total of all subjects 
26 
 
(A1) 
+ 
62 
 
(B1) 
= 
88 
 
(C1) 

 
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          September 23, 2014 
 
19 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
4 
+ 
7 
= 
11 
Black or African American 
1 
+ 
3 
= 
4 
Native Hawaiian or other Pacific Islander 
0 
+ 
0 
= 
0 
White 
21 
+ 
52 
= 
73 
Racial Category: Total of all subjects 
26 
 
(A2) 
+ 
62 
 
(B2) 
= 
88 
 
(C2) 
 
4. REGISTRATION PROCEDURES 
 
4.1. 
General Guidelines 
 
Eligible patients will be entered on study centrally at the California Cancer Consortium 
Data Coordinating Center at the City of Hope.  All sites should call the Data 
Coordinating Center at (626) 256-4673 extension 65928 to verify study status. 
  
Following registration, patients should begin protocol treatment within 5 business days 
to allow for drug shipment via Priority Mail.  Issues that would cause treatment delays 
should be discussed with the Principal Investigator.  If a patient does not receive 
protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Data Coordinating Center should be notified of cancellations as soon as 
possible. 
 
Each participating institution will order DCTD-supplied agents directly from CTEP, 
DCTD.  Agents may be ordered by a participating site only after the initial IRB 
approval for the site has been forwarded to the City of Hope Data Coordinating Center 
(DCC) FAX (626-256-8654). 
 
4.2. 
Registration Process 
 
To register a patient, the following documents should be completed by the research 
nurse or data manager and faxed to the data coordinating center for the California 
Cancer Consortium (626) 256- 8654.     
• Copy of required laboratory tests (labs, CT, x-ray, pathology, etc) 
• Signed patient consent form 
• HIPAA authorization form 
• Eligibility Screening Worksheet  
• Registration Form 
 
The research nurse or data manager at the participating site will then call (626)256-
4673 ext 65928 the Study Coordinator to verify eligibility.  To complete the 
registration process, the Coordinator will 
• assign a patient study number 
• register the patient on the study 

 
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          September 23, 2014 
 
20 
• assign the patient a dose 
• fax or e-mail the patient study number and dose to the participating site 
• call the research nurse or data manager at the participating site and verbally 
confirm registration. 
 
5. TREATMENT PLAN 
 
 
 
 
5.1. 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events 
and potential risks are described in Section 7.  Appropriate dose modifications are 
described in Section 6.  No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the 
patient's malignancy. 
 
 
 
 
 
TREATMENT ARM A 
Agent 
Premedications 
Precautions 
Dose 
Route 
Schedu
le 
Cycle 
Length 
Bevacizumab none 
 
10 mg/kg in 
100 mL NS 
IV over 90 minutes the 1st  
time, 60 minutes for the 2nd 
infusion, then 30 minutes 
for all subsequent infusions 
Days 1 
and 15  
28 days  
(4 
weeks) 
 
 
 
TREATMENT ARM B 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Bevacizumab none 
 
10 mg/kg 
in 100 mL 
NS 
IV over 90 minutes 
the 1st  time, 60 
minutes for the 2nd 
infusion, then 30 
minutes for all 
subsequent 
infusions 
Days 1 and 
15  
28 days  
(4 weeks) 
TRC105* 
Dexamethasone 
Acetaminophen 
Famotidine 
Diphenhydramine 
(or equivalent) 
10 mg/kg 
in 500 mL 
NS 
All doses IV Days 
1, 8, 15, 22 every 
28 day cycle 
(except Cycle 1 
Day 1) 
Days 1, 8, 
15, 22 
 
(cycle 1 
day 8) will 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
21 
 
Use PVC/DEHP-
free tubing with 
0.22 micron low 
protein-binding in-
line filter 
be split into 
two doses: 
3 mg/kg 
cycle 1 day 
8 and 7 
mg/kg 
cycle 1 day 
11. 
) 
• Start and stop times for infusion of study drug will not be captured, however it is 
recommended that infusion times occur as delineated, with a +/- 10 minute window. 
* Although there is not a weight restriction for enrollment purposes, the maximum weight for 
dose calculation in this study is 85 kg for women and 100 kg for men such that the 
administered dose should not exceed 850 mg for women and 1,000 mg for men. 
 
5.1.1 TRC105 
 
Patients should be encouraged to drink abundant fluid prior to the first treatment.  IV 
hydration prior to and during therapy is left to the discretion of the Investigator, but 
should be considered for patients that may be volume depleted. Vital signs should be 
monitored every 30 minutes during the TRC105 infusion (+/- 10 minutes). 
 
 
 
The following TRC105 premedications should be administered 2 hours to 30 minutes 
prior to the start of each infusion:   
 
 
TRC105 will be administered intravenously utilizing an infusion pump.  TRC105 must be 
administered using a low protein binding, non-DEHP infusion set with a 0.2 micron 
downstream filter.  The attachment of the infusion pump administration set to the i.v. bag 
and transport of the TRC105 study drug to the patient will be performed as per standard 
study site procedures.  
 
Because the study opened with a lower starting dose of TRC105 (8 mg/kg) there may be 
patients who start treatment at the lower dose.  Once the amendment to use full dose 
TRC105 (10 mg/kg) has been approved by the IRB, subjects who are on treatment may 
be offered dose escalation of TRC105 to the 10 mg/kg dose for subsequent cycles. 
 
 
5.1.2 Bevacizumab 
 
No premedications are required.  While infusion reactions are possible, they 
are extremely rare.  nevertheless, the recommended infusion time is no shorter 
than 30 minutes, and standard practice frequently includes administering the 
first dose over 90 minutes, the 2nd over 60 minutes, and then all subsequent 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
22 
infusions over 30 minutes, provided no infusion reactions are noted.  
 
In Arm B, when bevacizumab and TRC105 are administered on the same day, 
the bevacizumab is given first followed by TRC105 premeds followed by 
TRC105.  The first time both drugs will be given on the same day should be 
study day Cycle 1 Day 15. 
 
5.2. 
General Concomitant Medication and Supportive Care Guidelines 
 
There are no known drug-drug interactions for the study medications.  However, 
because these are vascular-targeted therapies, caution is warranted with 
anticoagulation.  Full-dose anticoagulation will exclude patients from enrollment in 
the study; if a subject develops an indication for full-dose anticoagulation, the 
appropriateness of their continuation on study therapy should be carefully assessed in 
consultation with the principal investigator. 
 
5.3. 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 
up to 12 cycles, or until one of the following criteria applies: 
 
• 
Disease progression, 
 
• 
Intercurrent illness that prevents further administration of treatment, 
 
• 
Unacceptable adverse event(s), specifically arterial thrombotic event, 
symptomatic grade 4 venous thrombosis, grade 4 hemorrhage, grade 4 
hypertension, grade 4 proteinuria, GI perforation or wound dehiscence. 
 
• 
Patient decides to withdraw from the study, or 
 
• 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
• 
Pregnancy 
 
5.4. 
Duration of Follow Up 
 
Patients will be followed for 4 weeks after removal from study or until death, 
whichever occurs first.  Patients removed from study for unacceptable adverse 
event(s) will be followed until resolution or stabilization of the adverse event. 
 
5.5. 
Criteria for Removal from Study 
 

 
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          September 23, 2014 
 
23 
Patients will be removed from study when any of the criteria listed in Section 5.3 
applies.  The reason for study removal and the date the patient was removed must be 
documented in the Case Report Form. 
 
 
6. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) 
will determine whether the event requires expedited reporting (via CTEP-AERS) in addition 
to routine reporting.   
 
6.1. 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 
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 of AEs, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text.  The 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/default.htm#adverse_events_CTEP-
AERS for further clarification. Frequency is provided based on 123 patients.. Below 
is the CAEPR for TRC105. 
 
NOTE:  The highest grade currently reported is noted in parentheses next to the AE 
in the SPEER.  Report ONLY AEs higher than this grade expeditiously via CTEP-
AERS.  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. 
 
 
 
 
7.1.2 CAEPRs for Bevacizumab (rhuMAb VEGF, NSC 704865) 
 
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 3540 patients. Below is the CAEPR for 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
24 
bevacizumab (rhuMAb VEGF). 
 
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 2.3, August 1, 20131 
 
 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 4.0 Term) 
[n= 3540] 
 
 
 
 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) 
 
 
Blood and lymphatic system 
disorders - Other (renal 
thrombotic 
microangiopathy) 
  
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 3) 
CARDIAC DISORDERS 
  
 
 
Acute coronary syndrome2 
  
 
Cardiac disorders - 
Other (supraventricular 
arrhythmias)3 
 
 Cardiac disorders - Other 
(supraventricular arrhythmias)3 
(Gr 3) 
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
 
Myocardial infarction2 
  
 
 
Ventricular arrhythmia 
  
 
 
Ventricular fibrillation 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Colitis 
 
 Colitis (Gr 3) 
 
Constipation 
 
 Constipation (Gr 3) 
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
 
Gastrointestinal fistula4 
  
 
Gastrointestinal 
hemorrhage5 
 
 Gastrointestinal hemorrhage5 
(Gr 2) 
 
 Gastrointestinal 
 
  

 
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          September 23, 2014 
 
25 
obstruction6 
 
 
Gastrointestinal perforation7   
 
 
Gastrointestinal ulcer8 
  
 
Ileus 
 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
 
Nausea 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
  
 
Fatigue 
 
 Fatigue (Gr 3) 
 
Infusion related reaction 
 Infusion related reaction (Gr 2) 
 
Non-cardiac chest pain  
 Non-cardiac chest pain (Gr 3) 
 
Pain 
 
 Pain (Gr 3) 
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
 
 Allergic reaction (Gr 2) 
 
 
Anaphylaxis 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection9 
 
 Infection9 (Gr 3) 
 
 
Infections and infestations - 
Other (necrotizing fasciitis) 
  
 
Infections and 
infestations - Other 
(peri-rectal abscess) 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Injury, poisoning and 
procedural complications – 
Other (anastomotic leak)10 
  
 
Wound complication 
 
 Wound complication (Gr 2) 
 
Wound dehiscence 
 
 Wound dehiscence (Gr 2) 
INVESTIGATIONS 
  
 
Alanine 
aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase 
increased 
 
 Alkaline phosphatase increased 
(Gr 3) 
 
Aspartate 
aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Blood bilirubin 
increased 
 
 Blood bilirubin increased (Gr 2) 
 
Cardiac troponin I 
increased 
 
  
Neutrophil count  
 
 Neutrophil count decreased (Gr 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
26 
decreased 
3) 
 
Platelet count decreased  
 Platelet count decreased (Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 3) 
 
White blood cell 
decreased 
 
 White blood cell decreased (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 3) 
 
Musculoskeletal and 
connective tissue 
disorder -  Other (bone 
metaphyseal 
dysplasia)11 
 
  
 
Myalgia 
 
 Myalgia (Gr 3) 
 
Osteonecrosis of jaw12  
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
 
 
Intracranial hemorrhage 
  
 
 
Ischemia cerebrovascular2 
  
 
Peripheral sensory 
neuropathy13 
 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
 
Syncope 
 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
 
Hematuria 
 
 Hematuria (Gr 3) 
 
Proteinuria 
 
 Proteinuria (Gr 2) 
 
 
Renal and urinary disorders - 
Other (Nephrotic Syndrome) 
  
 
 
Urinary fistula 
 
  
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
Reproductive 
system and breast 
disorders - Other 
(ovarian failure)14 
 
 
  
 
 
Vaginal fistula 
  
 
Vaginal hemorrhage 
 
 Vaginal hemorrhage (Gr 3) 

 
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          September 23, 2014 
 
27 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Allergic rhinitis 
 
 Allergic rhinitis (Gr 3) 
 
 
Bronchopleural fistula 
  
 
 
Bronchopulmonary 
hemorrhage 
  
 
Cough 
 
 Cough (Gr 3) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Epistaxis 
 
 Epistaxis (Gr 3) 
 
Hoarseness 
 
 Hoarseness (Gr 3) 
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(nasal-septal perforation) 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(tracheo-esophageal fistula) 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
 
Urticaria 
 
 Urticaria (Gr 2) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event  
 Thromboembolic event (Gr 3) 
 
 
Vascular disorders - Other 
(arterial thromboembolic 
event)2,15 
  
 
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. 
 
2The risks of arterial thrombosis such as cardiac or CNS ischemia are increased in elderly 
patients and in patients with a history of diabetes. 
 
3Supraventricular arrhythmias may include supraventricular tachycardia, atrial fibrillation and 
atrial flutter. 
 
4Gastrointestinal fistula may include: Anal fistula, Colonic fistula, Duodenal fistula, Esophageal 
fistula, Gastric fistula, Gastrointestinal fistula, Rectal fistula, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
 
5Gastrointestinal hemorrhage may include: Colonic hemorrhage, Duodenal hemorrhage, 
Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal 
hemorrhage, Intra-abdominal hemorrhage, Oral hemorrhage, Rectal hemorrhage, and other sites 

 
NCI# 9144, PhII-121 
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28 
under the GASTROINTESTINAL DISORDERS SOC. 
 
6Gastrointestinal obstruction may include: Colonic obstruction, Duodenal obstruction, 
Esophageal obstruction, Ileal obstruction, Jejunal obstruction, Rectal obstruction, Small 
intestinal obstruction, and other sites under the GASTROINTESTINAL DISORDERS SOC. 
 
7Gastrointestinal perforation may include: Colonic perforation, Duodenal perforation, 
Esophageal perforation, Gastric perforation, Jejunal perforation, Rectal perforation, Small 
intestinal perforation, and other sites under the GASTROINTESTINAL DISORDERS SOC. 
 
8Gastrointestinal ulcer may include: Duodenal ulcer, Esophageal ulcer, Gastric ulcer, and other 
sites under the GASTROINTESTINAL DISORDERS SOC. 
 
9Infection may include any of the 75 infection sites under the INFECTIONS AND 
INFESTATIONS SOC. 
 
10Anastomotic leak may include Gastric anastomotic leak; Gastrointestinal anastomotic leak; 
Large intestinal anastomotic leak; Rectal anastomotic leak; Small intestinal anastomotic leak; 
Urostomy leak; Vaginal anastomotic leak 
 
11Metaphyseal dysplasia was observed in young patients who still have active epiphyseal growth 
plates. 
 
12Cases of osteonecrosis of the jaw (ONJ) have been reported in cancer patients in association 
with bevacizumab treatment, the majority of whom had received prior or concomitant treatment 
with i.v. bisphosphonates. 
 
13Increased rate of peripheral sensory neuropathy has been observed in trials combining 
bevacizumab and chemotherapy compared to chemotherapy alone.  
 
14Ovarian failure, defined as amenorrhea lasting 3 or more months with follicle-stimulating 
hormone (FSH) elevation (≥30 mIU/mL), was increased in patients receiving adjuvant 
bevacizumab plus mFOLFOX compared to mFOLFOX alone (34% vs. 2%).  After 
discontinuation of bevacizumab, resumption of menses and an FSH level <30 mIU/mL was 
demonstrated in 22% (7/32) of these women.  Long term effects of bevacizumab exposure on 
fertility are unknown. 
 
15Arterial thromboembolic event includes visceral arterial ischemia, peripheral arterial ischemia, 
heart attack and stroke. 
 
 
Also reported on bevacizumab (rhuMAb VEGF) trials but with the relationship to 
bevacizumab (rhuMAb VEGF) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (idiopathic thrombocytopenia purpura); Bone marrow hypocellular; 

 
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29 
Disseminated intravascular coagulation; Hemolysis 
CARDIAC DISORDERS - Atrioventricular block complete; Atrioventricular block first degree; 
Cardiac arrest; Myocarditis; Pericardial effusion; Restrictive cardiomyopathy; Right ventricular 
dysfunction 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (tympanic 
membrane perforation); Hearing impaired; Tinnitus; Vertigo 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Extraocular muscle paresis; Eye 
disorders - Other (blindness); Eye disorders - Other (conjunctival hemorrhage); Eye disorders - 
Other (corneal epithelial defect); Eye disorders - Other (floaters); Eye disorders - Other 
(ischemic CRVO); Eye disorders - Other (macular pucker); Eye disorders - Other (transient 
increased IOP > or =30 mm Hg); Eye disorders - Other (vitreous hemorrhage); Eye pain; 
Keratitis; Optic nerve disorder; Photophobia; Retinal detachment; Retinal tear; Retinopathy; 
Watering eyes 
GASTROINTESTINAL DISORDERS - Ascites; Chelitis; Colonic stenosis; Dry mouth; 
Dysphagia; Enterocolitis; Esophageal pain; Esophageal stenosis; Flatulence; Gastrointestinal 
disorders - Other (peritonitis); Oral pain; Pancreatitis; Proctitis; Rectal mucositis; Rectal 
stenosis;Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; 
Edema face; Edema limbs; Edema trunk; Facial pain; Fever; Flu like symptoms; Gait 
disturbance; Injection site reaction; Localized edema; Multi-organ failure; Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Gallbladder necrosis; Gallbladder 
obstruction; Hepatic failure; Hepatic necrosis 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (aseptic meningitis) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; 
Bruising; Burn; Dermatitis radiation; Fracture 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood antidiuretic 
hormone abnormal; CD4 lymphocytes decreased; CPK increased; Carbon monoxide diffusing 
capacity decreased; Electrocardiogram QT corrected interval prolonged; Forced expiratory 
volume decreased; GGT increased; INR increased; Lipase increased; Lymphocyte count 
decreased; Serum amylase increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; 
Hyperglycemia; Hyperkalemia; Hypermagnesemia; Hypernatremia; Hypertriglyceridemia; 
Hyperuricemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; 
Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; 
Bone pain; Chest wall pain; Fibrosis deep connective tissue; Generalized muscle weakness; Head 
soft tissue necrosis; Joint effusion; Muscle weakness lower limb; Muscle weakness upper limb; 
Musculoskeletal and connective tissue disorder - Other (aseptic necrotic bone); Musculoskeletal 
and connective tissue disorder - Other (myasthenia gravis); Musculoskeletal and connective 
tissue disorder - Other (polymyalgia rheumatica); Neck pain; Pain in extremity; Pelvic soft tissue 
necrosis; Soft tissue necrosis lower limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Arachnoiditis; Ataxia; Central nervous system necrosis; 
Cerebrospinal fluid leakage; Cognitive disturbance; Depressed level of consciousness; 

 
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30 
Dysesthesia; Dysgeusia; Dysphasia; Encephalopathy; Extrapyramidal disorder; Facial nerve 
disorder; Hydrocephalus; Leukoencephalopathy; Memory impairment; Nervous system disorders 
- Other (increased intracranial pressure); Paresthesia; Peripheral motor neuropathy; Pyramidal 
tract syndrome; Seizure; Somnolence; Tremor; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Libido 
decreased; Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Chronic kidney disease; Cystitis 
noninfective; Renal and urinary disorders - Other (dysuria); Renal and urinary disorders - Other 
(ureterolithiasis); Renal hemorrhage; Urinary frequency; Urinary incontinence; Urinary 
retention; Urinary tract obstruction; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Erectile 
dysfunction; Irregular menstruation; Pelvic pain; Vaginal discharge 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory 
distress syndrome; Atelectasis; Hypoxia; Nasal congestion; Pulmonary fibrosis; Pulmonary 
hypertension; Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (dry 
nares); Respiratory, thoracic and mediastinal disorders - Other (pulmonary infarction) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; 
Nail loss; Pain of skin; Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Purpura; 
Rash acneiform; Skin and subcutaneous tissue disorders - Other (diabetic foot ulcer); Skin and 
subcutaneous tissue disorders - Other (skin breakdown/ decubitus ulcer); Skin 
hyperpigmentation; Skin induration; Skin ulceration; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Lymphocele; Phlebitis; 
Vasculitis  
 
Note: Bevacizumab (rhuMAb VEGF) 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. 
 
6.2. 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0.  A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
• 
For expedited reporting purposes only:   
o AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed 
in the SPEER column, Section 7.1.1) should be reported through CTEP-AERS 
only if the grade is above the grade provided in the SPEER. 
o Other AEs for the protocol that do not require expedited reporting are outlined 
in section 7.3.4. 
 
• 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 

 
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31 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
6.3. 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse 
EventReporting System), accessed via the CTEP Web site 
(http://ctep.cancer.gov).  The reporting procedures to be followed are 
presented in the “NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” which 
can be downloaded from the CTEP Web site (http://ctep.cancer.gov).  These 
requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour 
notification is to be made to CTEP by telephone at 301-897-7497.  Once 
Internet connectivity is restored, the 24-hour notification phoned in must be 
entered electronically into CTEP-AERS by the original submitter at the site. 
 
7.3.2 CTEP-AERS is programmed for automatic electronic distribution of reports to 
the following individuals:  Study Coordinator of the Lead Organization, 
Principal Investigator, and the local treating physician.  CTEP-AERS provides 
a copy feature for other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines  
 
Use the NCI protocol number and the protocol-specific patient ID assigned 
during trial registration on all reports. 
 
Note:   
“Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 
hours.” 
 
“Any death occurring greater than 30 days after the last dose of the 
investigational agent/intervention requires expedited reporting within 24 hours 
only if it is possibly, probably or definitely related to the investigational 
agent/intervention.” 
 
 
Death due to progressive disease should be reported as Grade 5 “Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other 
(Progressive Disease)” under the system organ class (SOC) of the same 

 
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32 
name.  Evidence that the death was a manifestation of underlying disease 
(e.g., radiological changes suggesting tumor growth or progression: clinical 
deterioration associated with a disease process) should be submitted.  
 
 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 

 
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33 
 
6.4. 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs 
reported through CTEP-AERS must also be reported in routine study data 
submissions and a copy of the report must be sent to the Data Coordinating 
Center at the City of Hope (cccp@coh.org).  
 
6.5. 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy 
(e.g., treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an 
agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should 
also be reported via the routine reporting mechanisms outlined in each protocol.  
 
6.6. 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy).  Second malignancies require ONLY 
routine reporting via CDUS unless otherwise specified.  
 
 
7. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational and 
commercial agents administered in this study can be found in Section 7.1. 
 
7.1. 
CTEP-provided agent:  TRC105  NSC 754227  (IND# TBD) 
 
8.1.1 Descriptive information 
 
Classification:  Chimeric IgG1 kappa monoclonal antibody 
 
M.W.:  Approximately 148 kDa 
 
Mode of Action:  TRC105 is a chimeric IgG1 monoclonal antibody to human 

 
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34 
CD105, a transmembrane receptor that is selectively expressed at high levels on 
proliferating endothelial cells. Upon binding to the endothelial cell CD105 receptor, 
TRC105 changes the downstream signal from a proliferative to a quiescent one.  
TRC105 also induces endothelial cell antibody-dependent cell-mediated 
cytotoxicity and apoptosis.  In addition targeting angiogenesis, TRC105 may have 
direct antitumor activity by inducing ADCC and apoptosis of CD105-positive 
cancer cells. 
 
 
Route of Administration: Intravenous infusion.  
 
 
 
 
 
 
 
 
Availability 
TRC105  is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. 
 
TRC105   is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.1.2 Agent Ordering and Agent Accountability 
 
8.1.2.1 
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 investigational agents for the study should be ordered under the 
name of one lead investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated 
shipping designees and ordering designees can submit agent requests 
through the PMB Online Agent Order Processing (OAOP) application 
(https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to 
OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and 
the maintenance of an “active” account status and a “current” password.   
For questions about drug orders, transfers, returns, or accountability, call 
(240) 276-6575Monday through Friday between 8:30 am and 4:30 pm 
(ET) or email PMBAfterHours@mail.nih.gov anytime 

 
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35 
8.1.2.2 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 NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.) 
 
7.2. 
Bevacizumab 
 
8.2.1 Descriptive information 
 
Bevacizumab (Avastin®, Genentech) is a recombinant humanized monoclonal 
IgG1 antibody that binds to and inhibits the biologic activity of human vascular 
endothelial growth factor (VEGF) in in vitro and in vivo assay systems. 
Bevacizumab contains human framework regions and the complementarity-
determining regions of a murine antibody that binds to VEGF. Avastin has an 
approximate molecular weight of 149 kD. Bevacizumab is produced in a 
mammalian cell (Chinese Hamster Ovary) expression system in a nutrient 
medium containing the antibiotic gentamicin.  Gentamicin is not detectable in the 
final product.  Bevacizumab is FDA approved for the treatment of metastatic 
RCC. 
 
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile, pH 
6.2 solution for intravenous infusion. Bevacizumab is supplied in 100 mg and 400 
mg preservative-free, single-use vials to deliver 4 mL or 16 mL of Bevacizumab 
(25 mg/mL). The 100 mg product is formulated in 240 mg α,α-trehalose 
dihydrate, 23.2 mg sodium phosphate (monobasic, monohydrate), 4.8 mg sodium 
phosphate (dibasic, anhydrous), 1.6 mg polysorbate 20, and Water for Injection, 
USP. The 400 mg product is formulated in 960 mg α,α-trehalose dihydrate, 92.8 
mg sodium phosphate (monobasic, monohydrate), 19.2 mg sodium phosphate 
(dibasic, anhydrous), 6.4 mg polysorbate 20, and Water for Injection, USP. 
 
Bevacizumab is typically administered intravenously over 90 minutes for the first 
infusion, 60 minutes for the second infusion, and 30 minutes for all subsequent 
infusions provided no allergic infusional reactions are noted.  This dosing may be 
adjusted to match institutional standard practices. 
 
8.2.2 Agent ordering and accountability 
 
Bevacizumab is commercially available. 
 
8. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
8.1. 
Background on Correlative Studies 
 
For additional information about techniques,etc please see Appendix E. 
 

 
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36 
Rationale.  The rationale and hypotheses for correlative studies may be found in 
section 2.5 of the protocol.  The correlative studies are exploratory, with markers that 
have been selected rationally based on the mechanism of action of the two drugs being 
administered.  The primary goal of the tissue analyses will be to generate preliminary 
data, potentially identifying a biomarker for  response.  Those who agree to a repeat 
biopsy will give us the opportunity to evaluate for proof of principle, evaluating how 
expression of CD105 and its signaling pathway change after expression to VEGF 
antibody (bevacizumab) alone or with the added blockade of CD105 (TRC105).  We 
will also evaluate for changes in serum factors and CTC expression induced by 
treatment, which will generate preliminary data about whether the agent in fact hits the 
target, and elucidate potential mechanisms of resistance to therapy.  
 
Techniques.  Standard technique will be used for immunohistochemical (IHC) 
analysis, utilizing the commercially available primary murine antibodies against 
CD105 (Abcam) and TGFβ-RII (Abcam), and immunofluorecence using primary 
murine antibodies against ALK-1 and ALK-5 (Santa Cruz Biotech).  Following 
deparaffinization, antigen retrieval will be performed with heating during incubation 
with citrate buffer.  IHC will be visualized using 3,3’- diaminobenzidine (DAB; 
DAKO, Japan) and immunofluorescence with fluorescein antimouse IgG (Invitrogen).  
We have chosen IHC and immunofluorescence because these are the methods  
for assessing CD105, TGFβ-RII, and ALK-1 and ALK-5 which have been reported in 
the literature.  This is also considerably less costly than expression by RT-PCR from 
microdissected paraffin embedded specimens.  Applying ACIS to the interpretation 
will enhance the reproducibility and reliability of the results.   
 
Standard ELISA kits will be used for serum TGFβ and sCD105 (R&D systems, 
Minneapolis, USA) and samples collected throughout the study will be run in batches.  
CTCs will be run on microfilters developed by USC and CalTech. We have chosen this 
platform because it allows for additional sophisticated assays of the captured cells, 
such as interrogation of captured cells for expression by IHC or RNA by PCR [Xu 
2010, Xu 2011].  Also, since enumeration of CTCs by the commercially available 
Veridex (CellSearch®) assay has not been shown to have prognostic value in RCC, it 
is not considered standard, and would not be held as the gold standard for this disease. 
Validation of the USC/CalTech microfilter platform in  
comparison to the Veridex assay has been completed as part of the randomized phase 
III clinical trial SWOG S0421 (results pending).   
 
Competence of the laboratories which will perform the assays.  The Pinski 
laboratory has published multiple studies using immunohistochemistry [Daneshmand, 
Quek, Liu].  The Pinski laboratory has also published studies using ELISA to evaluate 
protein expression [Wang].  Circulating tumor cells will be processed in the circulating 
tumor cell core of the USC Norris Comprehensive  Cancer Center under the guidance 
of Dr. Amir Goldkorn.   
 
Concern for human subjects.  In order to minimize adverse events related to 
venipuncture for the study subjects, every effort will be made to draw study correlative 

 
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37 
bloodwork at the same time as clinically necessary laboratory tests are being 
performed.  Tissue which has previously  
been obtained by biopsy or surgery will be utilized for all subjects, and extra biopsy 
will be an optional part of the study.  Only subjects with safely accessible tumors (ex: 
palpable lymph nodes or subcutaneous nodules) will be considered for participation in 
the extra biopsy.  Results of the correlative studies will not be routinely provided to 
subjects or treating physicians since they have not been validated for clinical decision-
making, however, results may be provided to treating physicians who request the 
results. 
 
Banking of specimens.  In order to maximize the value of clinically annotated 
biological specimens obtained as part of this study, all unused tissue and blood will be 
banked.  However, tissue blocks which are submitted will NOT be banked, but will be 
returned so that they would be available to subjects should they need additional 
analysis of their tissue in the future.  Subjects who participate in the voluntary extra 
biopsy will have those tissue blocks banked.  Banking of specimens will be handled by 
the USC Norris Pathology Core. 
 
8.2. 
Correlative Studies: instructions 
9.2.1   Tissue Studies:  CD105, TGFβ-RII, ACVRL1  and  TGFBR1 using
 
immunohistochemistry and immunofluorescence 
 
 
 
9.2.1.1  
Collection 
 
For all subjects, paraffin-embedded tissue blocks or unstained slides from 
a prior biopsy or nephrectomy specimen will be requested.  Please select a 
section that contains tumor.  If blocks are provided, the USC Norris 
Pathology Core will cut 10 x 5 micron sections and return the blocks.  If 
slides are provided, request 9 unstained slides (5 micron thick) plus 1 
H&E from the same block. 
 
For subjects who agree to a repeat biopsy after therapy in order to 
compare tissue expression before and after treatment, a core needle biopsy 
is required to provide adequate tissue; if a core biopsy cannot be safely 
obtained the subject should not be asked to participate in the optional 
repeat biopsy aspect of the protocol.  Blocks or unstained slides should be 
prepared as above. 
 
 
 
9.2.1.2  
Handling  
 
Blocks should be wrapped in bubble wrap or send in padded envelope.  
Slides should be packaged in slotted plastic box and wrapped in bubble 
wrap or sent in a padded envelope. 
 

 
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38 
9.2.1.3  
Shipping 
 
Blocks or slides should be shipped to: 
 
Dr. Tanya Dorff 
USC Norris Cancer Center 
1441 Eastlake Ave. #3440 
Los Angeles, CA 90033 
 
9.2.2 Serum Studies:  TGFβ and sCD105 levels (ELISA) 
 
9.2.2.1 
Collection 
 
At each correlative time point (baseline, Cycle 2 Day 1, and Cycle 4 Day 1 
(about week 13)), draw 2 x 7.5 mL serum separator tubes. 
 
9.2.2.2 
Handling 
 
The serum separator tubes should be allow blood to clot by standing 
vertically at room temperature for 30 minutes. Then centrifuge specimen 
at 1000-1400xg for 20 minutes. Remove the top layer (serum) by pouring 
into 1 mL aliquots and place in -80oC freezer.  These shipments may be 
batched.  Samples can be placed in a -20oC freezer for short term storage.   
 
9.2.2.3 
Shipping 
 
If shipping a batch of ONLY serum tubes, please ship to the laboratory of 
Jacek Pinski: 
 
 
 
 
Jacek Pinski Laboratory 
 
 
 
USC Norris Cancer Center Room 5432 
 
 
 
1441 Eastlake Ave.  
 
 
 
Los Angeles, CA 90033 
 
9.2.3 Circulating Tumor Cells – DO NOT COLLECT UNTIL FUNDING HAS 
BEEN OBTAINED.  Sites will be notified on when samples can be collected. 
 
9.2.3.1 
Collection 
 
At each correlative time point (baseline, Cycle 2 Day 1, and Cycle 4 Day 1 
(about week 13)) draw 1 x 7.5 mL EDTA-containing tube. 
 
9.2.3.2 
Handling  
 
The EDTA tube should be left unspun and shipped immediately on ice.  
Please alert the Goldkorn laboratory when samples have been collected 

 
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39 
(323) 442-7721. 
 
Note: there has been no noted difference in yield of CTCs from samples 
processed immediately compared to those processed after shipment. 
 
9.2.3.3 
Shipping  
 
Blood samples should be shipped to the laboratory of Dr. Amir Goldkorn 
if they contain any EDTA tubes.   
 
 
 
 
Amir Goldkorn Laboratory 
 
 
 
9171 HSC  
 
 
 
NRT 6505 
 
 
 
Los Angeles, CA 90033 
 
9.2.4 Pharmacokinetics and Immunogenicity (Arm B only) 
 
9.2.4.1.1 Collection   
 
Immunogenicity samples will be collected at cycle 1 day 8 (before dose), 
end of study, and end of study +28 days (when possible). 
 
Pharmacokinetics will be collected pre- and post-dose of TRC105 on cycle 
1 day 15, cycle 2 day 1, end of study, and end of study +28 days (when 
possible).   
 
See Appendix G for processing and shipping samples. 
 
8.3. 
 Outcome measures for correlative studies 
 
All data will be recorded using study ID #s only, without protected health information.  
Data will be recorded in CAFÉ, the electronic database managed by the USC Norris 
Cancer Center Clinical Investigator Support Office (CISO). 
 
Tissue:  IHC will be evaluated for intensity by an experienced pathologist, Dr. Debra 
Hawes, using ACIS.  ACIS, the automated cellular imaging system, provides a 
reproducible quantification of staining, both % of cells staining as well as intensity.  
Both will be recorded.  IHC will be run in batches of 14 subjects intermittently during 
the study duration or within 3 months after study closure.  
 
Serum:  Standard ELISA kits will be used (R&D systems, Minneapolis, USA) and 
samples collected throughout the study will be run in batches during the study duration 
or within 3 months after study closure.  
 
Circulating Tumor Cells:  Because the results are best when specimens are processed 
immediately, CTC samples will be processed on microfilters immediately upon receipt.  
IHC staining for CD105 will occur in batches, however.  The following data will be 

 
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40 
recorded for each time point: number of CTCs detected, expression of CD105 at 
baseline and after therapy.  This will only be done if funding has been obtained to 
collect the CTC samples. 
 
 

 
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41 
9. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy.  
Scans and x-rays must be done < 28 days prior to the start of therapy.  In the event that the 
patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours 
prior to initiation of the next cycle of therapy. Contrast is not required for imaging but is left 
to the discretion of the treating physician.  Visits for Day 8 and Day 11 will only occur for 
patients on Arm B. 
 
Pre- 
Study 
 
Cycle 1 
Day 1 
Cycle 1 
Day 8 
Cycle 1 
Day 11 
Cycle 1  
Day 
15 
Cycle 
1  
Day 
22 
Cycle 
2 
Day 1 
& 15 
Cycle 
2 
Day 8 
& 22 
Cycle 
3 
Day 
1& 15 
Cycle 3  
Day 8 
& 22 
Cycle 4  
Day 1 & 
15 
Cycle 4  
Day 8 & 
22 
Cycles 
5-12  
Day 1& 
15 
Cycles 5-
12  
Day 8& 
22 
Off 
Studyc 
TRC105 
 
 
B  
(3 
mg/kg) 
B 
(7 
mg/kg) 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
 
Bevacizumab 
 
A & B 
 
 
A & B 
 
A & 
B 
 
A & 
B 
 
A & B 
 
A & B 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
 
X 
X 
X   (May be done by telephone for Arm A) 
Physical exam 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Vital signsg 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Performance status 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
CBC w/diff, plts 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum chemistrya 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
LDH 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Urine dipstick OR 
protein & creatinine 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
PT/PTT 
X 
 
 
 
 
Adverse event eval. 
 
 
X 
X 
X (may be done by telephone for patients on Arm A) 
Tumor measurements 
X 
 
 
 
Every 12 weeks 
Radiologic evaluation 
X 
 
 
 
Every 12 weeks 
B-HCG 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative Blood 
Xd * 
 
 
 
 
 
Xe * 
 
 
 
Xf * 
 
 
 
 
Pharmacokinetics 
(Arm B) 
 
 
 
 
X 
 
X 
(day 
1 
only
) 
 
 
 
 
 
 
 
 
Immunogenicity 
(Arm B) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
42 
 
 
All treatment, clinical and laboratory observations are +/- 3 days.  Baseline H&P (or cycle 1, day 1 h&p) 
should include tobacco history including number of years smoked, number of cigarettes per day, and 
years since quitting, as applicable. 
 
All imaging is +/- 7 days except for baseline imaging.  Baseline imaging should be done within 28 days 
prior to registration and should consist of at least a CT, CT/PET, or MRI covering the chest, abdomen and 
pelvis.  Bone scans should be done as appropriate. As much as possible, repeat imaging should use the 
same modality as baseline/previous studies so that comparison can be made accurately. 
 
“A” and “B” (as opposed to “X”) denote the treatment group to which the patient is assigned. 
TRC105 = 10 mg/kg IV q week (GROUP B only) 
Bevacizumab = 10 mg/kg IV q 2 weeks (BOTH GROUPS A & B) 
 
a= include electrolytes, creatinine, albumin, total protein, AST/ALT, alkaline phosphatase, and bilirubin 
b = for women of childbearing potential only 
c = off study evaluation 
d= may be drawn at cycle 1, day 1 
e = only on day 1 
 
f = only on day 1 
g = Vital signs should be monitored every 30 minutes during the TRC105 infusion (+/- 10 
minutes). 
 
*At each correlative time point (baseline, Cycle 2 Day 1 (about week 5), and Cycle 4 Day 1 
(about week 13), draw 2 x 7.5 mL serum separator tubes.  Pharmacokinetic samples are to be 
drawn on cycle 1 day 15 before and after TRC105 dose, and cycle 2 day 1 before and after dose 
and off-study, as well as 28 days after off-study if feasible. Immunogenicity samples are to be 
drawn at cycle 1 day 8 and off-study, as well as 28 days after off-study if feasible. 
 
 
 
10. MEASUREMENT OF EFFECT 
 
10.1. Antitumor Effect – Solid Tumors 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the 
largest diameter (unidimensional measurement) of the tumor lesions and the shortest 
diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
 
For the purposes of this study, patients should be re-evaluated for response every 12 
weeks.  In addition to a baseline scan, confirmatory scans should also be obtained 4-6 
weeks following initial documentation of objective response.   
 
Tissue blocks 
/unstained slides 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
43 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment with Bevacizumab alone or with TRC105. 
 
Evaluable for objective response.  Only those patients who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for response.  These 
patients will have their response classified according to the definitions stated 
below.  (Note:  Patients who exhibit objective disease progression prior to the end 
of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, 
have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for non-target disease.  The response 
assessment is based on the presence, absence, or unequivocal progression of the 
lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded, 
except for lymph nodes) as >20 mm by chest x-ray or as >10 mm with CT scan, 
MRI, or calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area will not be 
considered measurable. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and 
measurable, a lymph node must be >15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or involved lymph nodes with ≥10 to <15 mm 
short axis), are considered non-measurable disease.  Bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by CT or MRI), 
are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
44 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum.  The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements of 
these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 4 weeks before the beginning of 
the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm 
diameter as assessed using calipers (e.g., skin nodules).  In the case of skin 
lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
45 
they are clearly defined and surrounded by aerated lung.  However, CT is 
preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less.  If CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables 
involved in MRI, which greatly impact image quality, lesion conspicuity, and 
measurement.  Furthermore, the availability of MRI is variable globally.  As with 
CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of 
disease.  Furthermore, as with CT, the modality used at follow-up should be the 
same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts, 
and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  
Body scans should be performed with breath-hold scanning techniques, if 
possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a diagnostic 
CT (with IV and oral contrast), then the CT portion of the PET-CT can be used 
for RECIST measurements and can be used interchangeably with conventional 
CT in accurately measuring cancer lesions over time.  Note, however, that the 
PET portion of the CT introduces additional data which may bias an investigator 
if it is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement.  Ultrasound examinations cannot be 
reproduced in their entirety for independent review at a later date and, because 
they are operator dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next.  If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is 
advised.  If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to determine 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
46 
relapse in trials where recurrence following complete response (CR) or surgical 
resection is an endpoint. 
 
Tumor markers  There are no tumor markers to be followed for RCC patients. 
 
Cytology, Histology  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.  
 
FDG-PET  While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible 'new' 
disease).  New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
b. 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. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar 
to a biopsy in cases where a residual radiographic abnormality is thought 
to represent fibrosis or scarring.  The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and 
supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
  
 Note:  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. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions.  Any 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
47 
pathological lymph nodes (whether target or 
non-target) must have reduction in short axis 
to <10 mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as 
reference the baseline sum diameters. 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as 
reference the smallest sum on study (this 
includes the baseline sum if that is the 
smallest on study).  In addition to the 
relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 
5 mm.  (Note:  the appearance of one or 
more new lesions is also considered 
progressions). 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for 
PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum 
diameters while on study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All 
lymph nodes must be non-pathological in 
size (<10 mm short axis). 
 
Note:  If tumor markers are initially above 
the upper normal limit, they must normalize 
for a patient to be considered in complete 
clinical response. 
 
Non-CR/Non-PD:  
Persistence of one or more non-target 
lesion(s). 
 
Progressive Disease (PD): 
Appearance of one or more new lesions 
and/or unequivocal progression of existing 
non-target lesions.  Unequivocal 
progression should not normally trump 
target lesion status.  It must be 
representative of overall disease status 
change, not a single lesion increase.     

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
48 
Although a clear progression of “non-target” lesions only is exceptional, 
the opinion of the treating physician should prevail in such circumstances, 
and the progression status should be confirmed at a later time by the 
review panel (or Principal Investigator). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the 
treatment started).  The patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 
    
 
 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-
Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. 
Confirmation** 
CR 
Non-
CR/Non-
PD 
No 
PR 
>4 wks. 
Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or 
CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is 
evidence of a new lesion. 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
49 
** 
Only for non-randomized trials with response as primary 
endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-
target lesions may be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to 
document the objective progression even after discontinuation 
of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is not 
advised 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started, including the baseline 
measurements.  
 
11.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of 
progression or death, whichever occurs first. 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
50 
 
11. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
7.0 (Adverse Events: List and Reporting Requirements). 
 
11.1. Data Reporting 
 
 
 
12.1.1 Method 
 
This study will be monitored by the Clinical Data Update System (CDUS) 
Version 3.0.  Cumulative protocol- and patient-specific CDUS data will be 
submitted electronically to CTEP on a quarterly basis, either by FTP burst of data 
or via the CDS web application.  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).  
 
12.1.2 Responsibility for Data Submission 
 
Study participants are responsible for submitting CDUS data and/or data forms to 
the Coordinating Center for the California Cancer Consortium quarterly.  The date 
for submission to the Coordinating Center one month before the CDUS deadlines 
(i.e. December 31, March 31, June 30, September 30).  CDUS does not accept 
data submissions from the participants on the study.     
11.2.  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. 
 
• 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 (PIO@ctep.nci.nih.gov) 
except for Group studies. 
 
11.3.  Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to 
the NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
51 
Pharmaceutical Company(ies) (hereinafter referred to as “Collaborator(s)”) 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” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained 
within the terms of award, apply to the use of the 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 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 or patient’s family member 
participating on the study, 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 Agent(s), each the subject of different Collaborative 
Agreements, the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as "Multi-
Party Data”): 
 
a.  NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NCI, 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 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 Agent. 
 
3.   Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
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 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
52 
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 by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies 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 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: 
 
Email:  ncicteppubs@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. 
 
12. STATISTICAL CONSIDERATIONS 
 
12.1. Study Design/Endpoints 
The primary endpoint will be progression-free survival, evaluated using the two-point 
analysis (12 and 24 weeks) proposed by [Freidlin].  Secondary endpoints will include 
toxicity, RECIST response rate and investigation of correlative markers. 
The main endpoint of interest will be whether the combination arm has a greater PFS 
than single agent bevacizumab.  Planning is based on the supposition of 12-week PFS 
of 61% on the control arm and 78% on the combination arm.   This improvement of 
17% corresponds to reducing the hazard of progression in half by adding TRC105 to 
Bevacizumab.  The corresponding hypothesized PFS at 24 weeks would be 37% on the 
single-agent arm and 60% on the combination arm.  A randomized design is needed 

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
53 
due to the paucity of data for progression-free survival of bevacizumab in the second 
and third-line setting.   
 
While there are limited data for outcomes with 2nd and 3rd line therapy in RCC, 
published phase II and retrospective data for the use of sunitinib or sorafenib after prior 
VEGF-targeted therapy document median progression-free survival of 16-34 weeks 
[DiLorenzo, Motzer 2006, Zimmerman].   Our planning hypotheses, described above, 
correspond to median PFS of 17 weeks on the single agent arm, and 33 weeks on the 
combination arm.    
 
Enrollment of 88 patients, at a rate of one patient per week, would provide 
approximately 80% power for a one-sided test at the 0.10 level of significance, based 
conservatively on a single evaluation.  We propose to use the two-point analysis (12 
and 24 weeks) proposed by Freidlin et al [Freidlin] for unblinded randomized trials 
using PFS, which will increase power.    An interim analysis for futility will be done 
after 44 patients have been evaluated.  The 1-sided p-value at the interim analysis must 
be less than 0.43 to continue.  There will be no early stopping for efficacy.  With 44 
patients per arm, the fraction of patients progression-free at 12 weeks can be estimated 
with a standard error of approximately 7.5 percentage points, although exact binomial 
lower confidence bounds will be calculated.   
 
In addition to the planned interim analysis for futility, the study will receive routine 
review at monthly meetings of the California Cancer Consortium Data Coordinating 
Center to ensure adequacy of enrollment, tolerability of treatment, and suitability of 
enrolled subjects (e.g. adequate expected survival).  
 
 
 
12.2.  Sample Size/Accrual Rate 
 
The sample size will be 88 patients.  We anticipate accrual of 4 patients per 
month.  Enrollment will be monitored at the regular monthly meetings of the 
consortium Data Coordinating Center.  The protocol PI and consortium contract PI will 
receive a written notification from the DCC if, at 6, 12, 18, or 24 months into the trial, 
enrollment is less than half of the planned rate.  Recognizing that this study may be 
impacted by the current enrollment cap on the N01 contract, plans for dealing with 
underenrollment may include expanding participation to additional sites, or closure of 
the trial. 
 
12.3.  Stratification Factors 
 
Randomization will be blocked and stratified to maintain balance with respect to clear-
cell versus non-clear-cell disease, and ECOG performance status of 0 or 1 versus 2. 
 
12.4. Analysis of Secondary Endpoints 
 
Correlative Endpoints:  The data generated from the correlative studies during this 
protocol will be exploratory in nature.   

 
NCI# 9144, PhII-121 
          September 23, 2014 
 
54 
 
13.4.1 Tissue studies  
Baseline levels of CD105, TGFβ-RII, TGFBR1 and ACVRL1 will be correlated 
with response.   
 
13.4.1.1 
For CD105, the reported median number of cells staining positive per core 
is 5 (range 0-79) and staining in at least one of 2 tissue cores had some 
staining positivity in 75% [Sandlund].  We anticipate that patients whose 
tumors have higher levels of CD105 staining will be more likely to 
respond to TRC105 plus bevacizumab, and may be less likely to respond 
to bevacizumab alone.  If 5 subjects on the combination arm were to 
respond, and all 5 had above-median staining, the association would be 
significant (p=0.024) by a one-sided version of Fisher’s exact test.  While 
this provides an example of a detectable effect, without invoking a 
detailed model, the planned analysis will use a rank-sum test for improved 
power.  Generalized linear models for ordered categorical data will be 
used to address the treatment and staining interaction using the full 
dataset. 
 
13.4.1.2 
For TGFβ-RII, the expression in kidney cancer has not yet been well 
described.  Given that CD105 and other hypoxia-induced growth factors 
signal via this receptor, and it has been implicated in the epidermal to 
mesenchymal transition (EMT), we will explore the associate of this 
receptor’s expression with outcomes in study patients.   
 
13.4.1.3. For TGFBR1 and ACVRL1, again there are not published reports of 
extent of expression in renal carcinoma.  However, given that TGF can 
signal via ALK-5 to activate angiogenesis or through alternate receptor 
pathways including ALK-1 to reduce angiogenesis, the differential 
expression of these proteins may prove markers of which cancers are more 
angiogenesis-driven, which could rationally affect response to therapy 
and/or prognosis. 
 
13.4.2 Serum studies   
 
The change in serum levels of sCD105 will be compared between groups A & B.  
We anticipate that subjects assigned to combination therapy (Arm B) will have 
lower levels of sCD105 at post-treatment time points compared to Arm A, where 
we expect levels to increase. Both baseline levels of sCD105 and changes during 
treatment will be correlated with response, using the approach described above.   
 
(CTCs:  The change in number of CTCs from baseline to repeat time points will 
be correlated with radiographic response.  The change in expression of CD105 on 
CTCs will be compared between groups.) – ON HOLD pending funding   
 

 
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12.5. Reporting and Exclusions 
 
13.5.1 Evaluation of toxicity – All patients will be evaluable for toxicity from the time 
of their first treatment with Bevacizumab and TRC105. 
 
13.5.2 Evaluation of response – All patients included in the study must be assessed for 
response to treatment, even if there are major protocol treatment deviations or if 
they are ineligible.  Each patient will be assigned one of the following 
categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from 
toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).   
 
All of the patients who met the eligibility criteria and were randomized will be 
included in the main analysis of the response rate.  Patients in response 
categories 4-9 will be considered to have a treatment failure (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does 
not result in exclusion from the analysis of the response rate.  
 
Subgroup analyses will include evaluation of progression-free survival among 
those categorized as good risk or intermediate risk by Motzer criteria compared 
to  those categorized as poor risk.  Additionally, clear cell and non-clear cell 
subjects will be analyzed as separate subgroups. 
 
12.6. Safety Monitoring 
 
Safety and toxicity will be reviewed monthly at the CCCP Data Coordinating Meetings, 
in which all toxicities (especially Grade 3+) are assembled and reviewed.  In addition, 
every time a patient dies within 30 days of last treatment, this death will be reviewed to 
ascertain whether the death could be attributed primarily to the treatment, to disease 
progression, or another cause.  If the attribution for the death is most likely due to 
treatment, then  a careful review of the trial data will be mandated.  Based on the review, 
a decision will be made to continue the study unchanged or to modify the regimen and 
amend the protocol.    Finally, at approximately every 6 months, at the time of the DSMC 
review, all deaths on both arms will be tabulated for overall review. 
 
13.   DATA AND SAFETY MONITORING PLAN  
 
13.1. Oversight of CCCP Phase I and Phase II Trials 
 
The Californian Cancer Consortium with Pittsburgh (CCCP) will oversee the 
development and conduct of all Phase I and II trials that are undertaken as part of this 
consortium.  However, it is also the CCCP policy to take advantage of reviews and 
infrastructure provided by CTEP as well as the Protocol Review and Monitoring 
Systems (PRMSs) that are in place at each participating Cancer Center.  In addition to 
these institutional mechanisms for review and oversight, to ensure that the CCCP 

 
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objectives and priorities are addressed and that highest quality clinical research prevails, 
the following policies and procedures are in place. 
 
14.1.1 Review of Trials Prior to Activation 
Prior to developing a protocol, the concept for a Phase I or Phase II trial is 
discussed at a monthly CCCP teleconference.   While this discussion is 
informal, no concept is given the go-ahead without approval by CCCP 
leadership (i.e. the grant PI’s at each of the 4 member institutions, for both 
the Phase I U01 and Phase II N01).  Discussion includes the scientific merit 
of the proposal, the compatibility with the CCCP priorities, and the ability 
to complete the study in a timely fashion. Once the protocol document is 
completed, the protocol is reviewed by the collaborating statistician, by the 
CCCP Project Coordinator (to verify adherence to boilerplate and 
formatting requirements), as well as the CCCP leadership; at this stage, the 
plans to monitor safety and (if appropriate) efficacy are carefully reviewed. 
 
This is done before the document is submitted for review by CTEP and/or 
other sponsors, as well as the CCCP institutional PRMSs and IRBs. 
 
14.1.2 Review of Safety, Conduct, and Data While Trial is Open to Accrual 
 
14.1.2.1 Ongoing Review 
The protocol principal investigator (PI) is responsible for 
monitoring the conduct and progress of this Phase I trial, including 
the ongoing review of accrual, data and toxicities, as well as the 
accumulation of reported adverse events from other trials testing 
the same drug(s).  The participating clinicians and their designees 
are responsible for timely submission of adverse event reports and 
case report forms.  The Data Coordinating Center for the CCCP 
Consortium is responsible for providing the PI with access to the 
submitted case report form data in summary and detail in a timely 
fashion.   Although the PI is responsible for evaluating the 
cumulative reported adverse events and the impact that these have 
on the continued conduct of the trial, it is the Operations Office of 
the CCCP that distributes all submitted SAE reports to the 
appropriate individuals, including the local protocol principal 
investigators, at each of the participating institutions.   
 
The Data Coordinating Center (DCC) posts a summary (accrual, 
toxicities, and responses) of each CCCP initiated trial on the 
CCCP website.  In this way, each PI has access to up-to-date 
information on the status of his or her trial.  In consultation with 
the collaborating statistician, the PI is responsible for review of: 
 
14.1.2.1.1 
For Phase I trials, all dose limiting toxicities and 
decisions regarding dose escalation, expansion, as 

 
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well as decisions to terminate escalation, and  
14.1.2.1.2 
For Phase II trials, the toxicities and therapeutic 
endpoints referred to in the statistical plan.     
 
The DCC meets monthly to review data management and data 
quality issues – completeness of data submissions as well as 
accuracy.  Any issues identified and the corrective plans are 
presented at the next CCCP teleconference meeting for review and 
approval. 
 
14.1.2.2 Oversight 
Oversight of the conduct of CCCP trials occurs at several levels: 
 
14.1.2.2.1 
The Operations Office for the CCCP flags all trials 
that are approaching a decision in terms of toxicity 
(for both Phase I and Phase II trials) or responses (for 
Phase II trials).  Decisions are made by the PI with 
input from the statistician and discussion with the 
principal investigator of the funding mechanism 
(U01 Cooperative Agreement or N01 Contract, as 
appropriate) or his or her designee, and are 
communicated to the participating centers by the 
CCCP Operations Office. 
14.1.2.2.2 
At the monthly teleconferences, the status of each 
open protocol is reviewed. 
14.1.2.2.3 
For CTEP sponsored Phase I trials, data are reported 
to the NCI-designated clinical trials monitoring 
service (CTMS) which will audit patients’ records on 
each protocol – at each CCCP institution;  this audit 
is initiated by CTEP.  For all other CCCP trials, the 
CCCP will contract with Theradex to audit patient 
records at each CCCP institution. 
14.1.2.2.4 
An independent CCCP DSMC will review CCCP 
trials every 6 months. This DSMC will consist of 4 
voting 
members 
(2 
medical 
oncologists 
or 
hematologists involved in Phase I/II cancer clinical 
trials but not participating in CCCP studies, a 
statistician, and a patient advocate) and a non-voting 
CCCP statistician.   
14.1.2.2.4.1 
DSMC meetings will take place twice 
a year.  Additional meetings will be 
convened if necessary.  
14.1.2.2.4.2 
This DSMC will review each CCCP 
trial 
in 
terms 
of 
accrual, 
toxicity/safety, and adherence to trial 

 
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design, audit results, and likelihood of 
successful completion. 
14.1.2.2.4.3 
The DSMC will report to the CCCP 
leadership.  The CCCP Operations 
Office will distribute the DSMC 
reports to the PI of each open study 
and the U01 and N01 institutional 
PI’s for submission to local oversight 
committees as required per each 
institution’s policy.  
 
14.1.3 Review of Manuscripts and Abstracts based on CCCP Trials 
All meeting abstracts and manuscripts must be approved, and signed off by 
the collaborating statistician and the CCCP leadership.  Copies of the final, 
published abstracts and manuscripts must be maintained in the CCCP 
operations office – along with a copy of the frozen data files on which the 
analyses were based. 

 
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59 
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Dallas NA, Samuel S, Xia L, Fan F, Gray MJ, Lim SJ, Ellis LM.  Endoglin (CD105) : a marker 
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Kindler HL, Friberg G, Singh DA, Locker G, Nattam S, et al.  Phase II trial of bevacizumab plus 
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Rini B, Halabi S, Rosenberg JE, et al.  Bevacizumab plus interferon alfa compared with  
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Sanchez-Elsner T, Botella LM, Velasco B, Langa C, Bernabeu C.  Endoglin expression is 
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71:1390-1400. 
 
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bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer.  
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Oncology (Karger) 2009; 76:350-4. 

 
 
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62 
APPENDIX A:  Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
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). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 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. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
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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64 
• 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:  
1. 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. 
2. The Coordinating Center must be designated on the title page. 
3. Central registration of patients is required.  The procedures for registration must be 
stated in the protocol. 
4. 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. 
5. Describe how AEs will be reported from the participating institutions, either directly 
to CTEP or through the Coordinating Center. 
6. 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 investigational agents directly from CTEP.  Investigational 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:  INFORMATION ON POSSIBLE INTERACTIONS WITH OTHER 
AGENTS FOR PATIENTS AND THEIR CAREGIVERS AND NON-STUDY HEALTH 
CARE TEAM 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental agent TRC105.  This clinical trial is sponsored by the National Cancer Institute.  
This form is addressed to the patient, but includes important information for others who care for 
this patient.  
 
Because TRC105 is an antibody, it is not known to interact with many other medications.  
However, it does increase the risk of bleeding, and this side effect could be made worse by using 
other drugs which “thin the blood” at the same time.   
 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.   
 
Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s usually big 
and catches your eye.  They also have a generic name—it’s usually small and located above or 
below the brand name, and printed in the ingredient list.  Find the generic name and determine, 
with the pharmacist’s help, whether there could be an adverse interaction.   
 
Other medicines can be a problem with your study drugs.  
 
• You should check with your doctor or pharmacist whenever you need to 
use an over-the-counter medicine or herbal supplement.  
 
• Your regular prescriber should check a medical reference or call your 
study doctor before prescribing any new medicine for you.  Your study 
doctor’s name is _____________________________________ and he or 
she can be contacted at _____________________________________.  
 
 
 
 
 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent 
__________________.  This clinical trial is sponsored by the NCI.  
__________________ interacts with drugs that are processed by your 
liver.  Because of this, it is very important to: 
 Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
 Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
__________________ interacts with a specific liver enzyme called 
CYP______, and must be used very carefully with other medicines 
that interact with this enzyme.  
 Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inducers/inhibitors or substrates of CYP______.” 
 Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis/table.asp for a list 
of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is ______________ and can be 
contacted at ______________.  

 
 
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66 
 
 
APPENDIX D:  CCCP REGISTRATION PROCEDURES FOR PHASE II TRIALS 
 
 
1. 
Registrations for Phase II protocols must be made through the Data Coordinating Center 
(DCC) office at the City of Hope between the hours of 8:30 a.m. to 4:30 p.m. Pacific Time, 
Monday through Friday (except holidays). 
2. 
Patients must be registered within 5 days (to allow for drug shipment via Priority Mail) 
prior to initiation of protocol therapy. 
3. 
A patient failing to meet all protocol requirements may not be registered.  If you have any 
questions regarding eligibility, contact the City of Hope Data Coordinating Center (DCC) 
at (626) 256-HOPE (4673), extension 65928. 
4. 
Prestudy laboratory tests, scans and x-rays must be completed prior to registration 
according to study calendar/protocol. 
5. 
Patients must sign an informed consent prior to registration. 
6. 
Confirm that the patient meets all inclusion and exclusion eligibility criteria for a protocol. 
7. 
Complete the Eligibility Checklist.   
8. 
Verify that all required prestudy tests were performed. 
9. 
Fax the completed Eligibility Checklist, signed and dated informed consent, pathology 
report, and relevant laboratory results to the City of Hope Consortium Coordinator for 
confirmation of eligibility.  The FAX number is (626) 256-8654.  
10. 
Call the City of Hope Consortium Coordinator at (626) 256-HOPE (4673), extension 65928 
to confirm the FAX arrival. If the Consortium Coordinator is not in the office, have them 
paged at (626) 423-5365. 
11. 
If the patient qualifies, the City of Hope Consortium Coordinator will call the registering 
institution to complete the registration/randomization procedure and assign the patient's 
study ID number.   
12. 
Once a patient has been registered, the Data Coordinating Center will provide a 
"Confirmation of Registration" to the center registering the patient via email.  
 
For questions regarding eligibility call City of Hope California Cancer Consortium,  
Data Coordinating Center  
(626) 256-HOPE (4673), extension 65928 
 
 
 
 
 
 
 
 
 
 
 

 
 
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APPENDIX E:  INFORMATION ABOUT CORRELATIVE STUDIES 
 
Immunohistochemistry and Immunofluorescence.   
Deparaffinization will be performed using xylene, followed by rehydration with graded EtOH 
solutions (100%, 95%, 85% for 5 min 3x, 2x, and 1x respectively).  Antigen retrieval will be 
performed in 0.001M citrate buffer (pH 7) and incubation in the pressure cooker for 5 minutes.  
Non-specific protein binding will be performed using albumin for 30 minutes, then endogenous 
peroxidase will be blocked using 3% H2O2 in distilled water.  Commercially available primary 
murine antibodies against CD105 (Abcam) and TGFβ-RII (Abcam) diluted 1:100 will be applied 
and incubated overnight at 4̊ C. For ALK-1 and ALK-5 (Santa Cruz Biotech) primary murine 
antibodies for immunofluorecence will be diluted 1:100 and incubated overnight at 4̊ C.   
 
Secondary antibody diluted 1:500 will be applied (mouse-horseradish peroxidase) and incubated 
for 1 hour at room temperature.  IHC will be visualized using 3,3’- diaminobenzidine (DAB; 
DAKO, Japan) with hematoxylin counter-stain, and immunofluorescence with fluorescein 
antimouse IgG (Invitrogen).  We have chosen IHC and immunofluorescence because these are 
the methods for assessing CD105, TGFβ-RII, and ALK-1 and ALK-5 which have been reported 
in the literature.   
 
Slides will be read by an experienced pathologist (DH), and IHC will be graded 0-2+ based on 
intensity of staining.  The pathologist will also use ACIS, and analysis will be performed using 
the ACIS output which is an arbitrary number from 0-100 which represents the intensity of 
staining.   
 
ELISA. 
Standard ELISA kits will be used for serum TGFβ and sCD105 (R&D systems, Minneapolis, 
USA) and samples collected throughout the study will be run in batches.   
 
Circulating Tumor Cells (CTCs). 
CTCs will be run on microfilters developed by USC and CalTech, using technique which has 
been previously reported [Xu 2010, Xu 2011]. Briefly,  7.5ml peripheral blood will be drawn by 
standard venipuncture into 1 CellSave tube. The tube will be kept at room temperature and 
delivered to the Goldkorn laboratory, where it will be subjected to Ficoll-Paque centrifugation to 
deplete red blood cells and to isolate the “buffy coat” layer containing CTC and white blood cells 
(WBC). Then, the buffy coat will be passed through the slot microfilter using a constant low-
pressure delivery apparatus. The microfilter-captured cells will be fixed in 1% formalin and 
subjected to immunofluorescent staining for cytokeratin ( Cam 5.2, BD), CD105, and DAPI. 
Captured CTC (DAPI+Cam5.2+) will be enumerated by a blinded independent observer using the 
Nuance multispectral imaging platform. Because there are fewer cells anticipated than are 
typically available in tissue samples, percent of cells staining IHC+ will be reported in addition 
to an intensity score.  
 

 
 
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APPENDIX F:  CCCP SPECIMEN SUBMISSION FORM 
 
To be emailed to sites separately once study is activated.   
Please email cccp@coh.org to request the form.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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APPENDIX G:  Laboratory Manual for TRC105 Pharmacokinetic & TRC105 
HAMA/HACA Sample Collection 
 
Please contact the cccp@coh.org for the latest version of the laboratory manual.