Clinical trial NCT01664182
Conditions: Advanced Renal Cell Carcinoma Advanced Sarcomatoid Renal Cell Carcinoma Stage III Renal Cell Cancer AJCC v7 Stage IV Renal Cell Cancer AJCC v7
Sponsor: National Cancer Institute (NCI)
Start date: 2012-08-01; Completion date: 2020-12-07
Enrollment: 41 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well trebananib with or without bevacizumab, pazopanib hydrochloride, sorafenib tosylate, or sunitinib malate works in treating patients with kidney cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Trebananib may stop the growth of tumor cells by blocking blood flow to the tumor. Immunotherapy with monoclonal, such as bevacizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Pazopanib hydrochloride, sorafenib tosylate, and sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the tumor. It is not yet known whether giving trebananib with or without bevacizumab, pazopanib hydrochloride, sorafenib tosylate, or sunitinib malate is more effective in treating kidney cancer.

Detailed description:
PRIMARY OBJECTIVE:

I. To evaluate the overall response rate (complete response \[CR\] + partial response \[PR\]) of trebananib (AMG 386) alone and in combination with continuation of previously administered bevacizumab, pazopanib hydrochloride (pazopanib), sorafenib tosylate (sorafenib), or sunitinib malate (sunitinib) in advanced renal cell carcinoma.

SECONDARY OBJECTIVES:

I. To evaluate progression free survival in each arm. II. To evaluate the tolerance and toxicity of AMG 386 alone and in combination with continuation of the prior VEGF targeted agent.

CORRELATIVE OBJECTIVES:

I. To evaluate the association between pretreatment tumor gene expression levels and response to AMG 386 in combination with continuation of the prior VEGF targeted agent.

II. To evaluate the association between single nucleotide polymorphisms (SNPs) in angiogenic genes and response to AMG 386 in combination with continuation of the prior VEGF targeted agent.

III. To compare changes in circulating angiogenic factors in patients treated with AMG 386 monotherapy to those treated with AMG 386 in combination with VEGF-targeted therapy.

IV. To compare expression of angiogenic genes from archival tumor specimens to the expression in biopsy specimens obtained after progression on anti-VEGF therapy.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive trebananib intravenously (IV) over 30-60 minutes on days 1, 8, 15, 22, 29, and 36. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive trebananib as in Arm I and either bevacizumab IV over 30-90 minutes on days 1, 15, and 29, pazopanib hydrochloride orally (PO) once daily (QD) on days 1-42, sorafenib tosylate PO twice daily (BID) on days 1-42, or sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4-8 weeks.

Arms: arm 1: Patients receive trebananib IV over 30-60 minutes on days 1, 8, 15, 22, 29, and 36. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive trebananib as in Arm I and either bevacizumab IV over 30-90 minutes on days 1, 15, and 29, pazopanib hydrochloride PO QD on days 1-42, sorafenib tosylate PO BID on days 1-42, or sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Bevacizumab intervention 2: Pazopanib Hydrochloride intervention 3: Sorafenib Tosylate intervention 4: Sunitinib Malate intervention 5: Trebananib
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO intervention 3: Given PO intervention 4: Given PO intervention 5: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
i 
PhII-122, NCI# 9048 
8.26.20v 
 
SUMMARY OF CHANGES 
 
Date:  
 
August 26, 2020 
Document: 
NCI Protocol #9048, PhII-122: “A Randomized Phase 2 Study of AMG 
386 with or without Continued Anti-Vascular Endothelial Growth Factor 
(VEGF) Therapy in Patients with Renal Cell Carcinoma Who Have 
Progressed on Bevacizumab, Pazopanib, Sorafenib, or Sunitinib.” 
Note: 
The following is a Summary of Changes between the 12.23.19 and 8.26.20 
versions of protocol 
 
# 
Section 
Comments 
1 
Face Page 
Changed protocol version to August 26, 2020.  Dates in the headers were also changed to 
8.26.20. 
2 
7.1 
Insertion of Revised Sorafenib CAEPR (Version 2.10, June 24, 2020):   
• Increase in Risk Attribution:  
 
• Changed to Rare but Serious from Also Reported on Sorafenib Trials But With 
Insufficient Evidence for Attribution: Injury, poisoning and procedural complications 
- Other, specify (wound healing complication) 
 
• Provided Further Clarification: 
 
• Wound complication reported under (Also Reported on Sorafenib Trials But With 
Insufficient Evidence for Attribution) is now reported as Injury, poisoning and 
procedural complications - Other, specify (wound healing complication) under (Rare 
but Serious). 
 
 


1 
PhII-122, NCI# 9048 
8.26.20v 
 
 
NCI Protocol #: 
9048 
 
Local Protocol #:  
PhII-122 
 
 
TITLE:   
A Randomized Phase 2 Study of AMG 386 with or without Continued Anti-
Vascular Endothelial Growth Factor (VEGF) Therapy in Patients with Renal Cell 
Carcinoma Who Have Progressed on Bevacizumab, Pazopanib, Sorafenib, or 
Sunitinib  
 
 
Coordinating Center: 
 
 
California Cancer Consortium Data Coordinating Center 
 
 
 
 
 
 
 
 
 
City of Hope National Medical Center 
 
 
 
 
 
 
 
 
 
1500 E. Duarte Road, Duarte, California 91010 
 
 
 
 
 
 
 
 
 
Phone: 626-256-HOPE(4673), extension 65928 
 
 
 
 
 
 
 
 
 
Fax: 626-256-8654 
 
 
 
 
 
 
 
 
 
Email: cccp@coh.org  
 
*Principal Investigator: 
Thomas J. Semrad, MD, MAS 
 
University of California Davis Cancer Center 
 
4501 X Street, Sacramento, CA 95817 
 
Phone: (916) 734-3771 
 
Fax: (916) 734-7946 
 
thomas.semrad@ucdmc.ucdavis.edu  
 
Co-Investigators: 
Primo N. Lara, Jr., MD 
 
University of California Davis Cancer Center 
 
4501 X Street, Sacramento, CA 95817 
 
Phone: (916) 734-3771 
 
Fax: (916) 734-7946 
 
primo.lara@ucdmc.ucdavis.edu  
 
 
David Gandara, MD 
 
University of California Davis Cancer Center 
 
4501 X Street, Sacramento, CA 95817 
 
Phone: (916) 734-3771 
 
Fax: (916) 734-7946 
 
david.gandara@ucdmc.ucdavis.edu  
 
 
David I. Quinn, MD, PhD, FRACP 
 
University of Southern California  
 
1441 Eastlake Ave #3453 
 
Los Angeles CA 90033 
 
Phone: 323-865-3956 /323-865-3000 


 
PhII-122, NCI# 9048 
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Fax: 323-865-0061 
 
diquinn@usc.edu  
 
 
Przemyslaw Twardowski, MD 
 
City of Hope  
 
1500 E. Duarte Rd 
 
Duarte, CA 91010 
 
Phone: 626-256-HOPE (4673) x 62307 
 
Fax: 626-301-8233 
 
ptwardowski@coh.org  
 
Sumanta Pal, MD 
City of Hope 
1500E. Duarte Rd. 
Duarte, CA 91010  
Phone: 626-256-HOPE (4673) x 62307 
Fax: 626-301-8233 
spal@coh.org  
 
 
Leonard J. Appleman, MD, PhD 
 
University of Pittsburgh Cancer Institute  
 
UPMC Cancer Pavilion, 5th Floor 
 
5150 Center Avenue 
 
Pittsburgh, PA 15232 
 
Phone: 412-648-6507 
 
Fax: 412-648-6579 
 
applemanlj@upmc.edu  
 
 
 
Ulka Vaishampayan, MD 
 
Karmanos Cancer Institute 
 
Wayne State University 
 
4100 John R, Detroit MI 48201 
 
Phone: (313) 576-8715 
 
Fax: (313) 576-8487 
 
vaishamu@karmanos.org 
 
Chandra P. Belani, MD 
Pennsylvania State Cancer Institute 
500 University Dr., H072 
Hershey, PA 17033 
Phone: 717-531-1078 
Fax: 
717-531-0002 
 
cbelani@psu.edu 
 


 
PhII-122, NCI# 9048 
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Patrick J. Flynn, MD 
 
Metro MN CCOP 
 
3800 Park Nicollet Blvd. 
 
St. Louis Park, MN 55416 
 
Phone:  952-993-1518  
 
Fax:  952-9931550 
 
Email:   
 
 
Brian Costello, MD 
 
Mayo Clinic 
 
200 1st St SW 
 
Rochester, MN 55905 
 
Phone:  507-284-2511 
 
Fax:  507-284-2580 fax 
 
Email:  Costello.brian@mayo.edu 
 
 
Tina Mayer, MD 
 
Rutgers Cancer Institute of New Jersey 
 
195 Little Albany St. 
 
New Brunswick, NJ 08901 
 
Phone: 732-235-6031 
 
Fax: 732-235-8808 
 
Email: mayertm@cinj.rutgers.edu 
 
 
Craig W. Swainey, MD  
 
Massey Cancer Center  
 
Virginia Commonwealth University  
 
P.O. Box 980230  
 
Richmond, VA  23298-0230  
 
Phone: 804-828-9723  
 
Email:  cswainey@mcvh-vcu.edu 
 
 
Dr. W. Kimryn Rathmell 
University of North Carolina at Chapel Hill 
Lineberger Comprehensive Cancer Center 
450 West Drive 
CB 7295 Hematology and Oncology 
C/O Clinical Protocol Office 
Chapel Hill, NC 27599 
Phone:  (919) 966-4432 
Email:  rathmell@med.unc.edu 
 
 
City of Hope Affiliate: 
Stephen Koehler, MD  


 
PhII-122, NCI# 9048 
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4 
City of Hope Medical Group, Inc., 
209 Fair Oaks Avenue 
South Pasadena, CA 91030 
Phone: (626) 396-2900 
skoehler@cohmg.com  
 
Correlative Science: 
Heinz-Josef Lenz, MD 
 
University of Southern California  
 
1441 Eastlake Ave #3453 
 
Los Angeles CA 90033 
 
Phone: 323-865-3956 /323-865-3000 
 
Fax: 323-865-0061 
 
lenz@usc.edu  
 
 
Philip C. Mack, PhD (not a treating physician) 
 
University of California Davis Cancer Center 
 
4501 X Street, Sacramento, CA 95817 
 
Phone: (916) 734-3771 
 
Fax: (916) 734-7946 
 
pcmack@ucdavis.edu  
 
Participating Centers:  
City of Hope National Medical Center, Duarte CA (COH) 
and affiliates 
USC/Norris Comprehensive Cancer Center, Los Angeles (USC) 
University of California, Davis Cancer Center, Sacramento (UCD) 
University of Pittsburgh, Pittsburgh, PA (UOP) 
Pennsylvania State Cancer Institute (PSU) 
Karmanos Cancer Institute, Wayne State University, Detroit, MI 
(KCI) 
Mayo Consortium (Mayo, Metro MN CCOP)  
Moffitt Consortium (Rutgers, Massey, University of North 
Carolina) 
 
Statistician: 
Susan Groshen, PhD  
USC/Norris Cancer Center  
1441 Eastlake Avenue, Suite 3419, Los Angeles, CA 90089 
Phone: (323) 865-0375 
Fax: (323) 865-0133  
susan.groshen@med.usc.edu  
 
NCI Supplied Agent: 
AMG 386 (NSC 751173) 
 
Commercial Agents: 
Patients will use commercial supply of the following agents: 
 
 
Bevacizumab, Genetech/Roche 
 
 
Pazopanib, GlaxoSmithKline  


 
PhII-122, NCI# 9048 
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Sorafenib, Bayer Healthcare/Onyx Pharmaceuticals 
 
 
Sunitinib, Pfizer Pharmaceuticals 
 
 
 
Protocol Type / Version # / Version Date:  Initial Protocol 
January 19, 2012 
Response to Consensus Review 
March 9, 2012 
Response to Follow Up Review 
April 3, 2012 
Amendment 1 
April 17, 2012 
Amendment 2 
August 27, 2012 
Amendment 3                                 March 13, 2013 
Amendment 4 (RRA) - 
disapproved     
June 20, 2013 
Amendment 5  
July 1, 2013 
Amendment 6 
October 17, 2013 
(disapproved) 
 
 
 
                                                      Amendment 7                               November 4, 2013 
 
 
 
 
 
 
Amendment 8 (RRA)  
       April 10, 2014 
 
 
 
 
 
 
Amendment 9 (RA)  
       June 12, 2014 
 
 
 
 
 
 
Amendment 10 (RA)  
       August 26, 2014 
 
 
 
 
 
 
Amendment 11 
 
      December 1, 2014 
 
 
 
 
 
 
Amendment 12 (RRA) 
      March 4, 2015 
 
 
 
 
 
 
Amendment 13 (RA)  
      July 7, 2015 
 
 
 
 
 
 
Amendment 14 (RRA) 
      February 10, 2016 
 
 
 
 
 
 
Amendment 15 (RRA) 
      May 20, 2016 
 
 
 
 
 
 
Amendment 16 (RA)  
      August 18, 2016 
 
 
 
 
 
 
Amendment 17 (RRA) 
      January 19, 2017 
 
 
 
 
 
 
Amendment 18 (RRA) 
      August 4, 2017 
 
 
 
 
 
 
Amendment 19 
 
      March 13, 2018 
 
 
 
 
 
 
Amendment 20 (RRA)  
   September 11, 2018 
 
 
 
 
 
 
Amendment 21 (RA)  
      March 19, 2019 
 
 
 
 
 
 
Amendment 22 (RA)  
      March 29, 2019 
 
 
 
 
 
 
Amendment 23 (RA)      
      July 11, 2019 
 
 
 
 
 
 
Amendment 23 (RRA) 
   December 23, 2019 
 
 
 
 
 
 
Amendment 24 (RRA) 
      August 26, 2020 
 
 
 
                                                       
 
 
 
 
 
 
 
 
 
 


 
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6 
SCHEMA 
 


 
PhII-122, NCI# 9048 
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7 
TABLE OF CONTENTS 
 
 
SCHEMA ........................................................................................................................................6 
1. 
OBJECTIVES ....................................................................................................................9 
1.1. 
Primary Objective ..............................................................................................................9 
1.2. 
Secondary Objectives.........................................................................................................9 
1.3. 
Correlative Objectives .......................................................................................................9 
2. 
BACKGROUND ................................................................................................................9 
2.1. 
Advanced Renal Cell Carcinoma .....................................................................................9 
2.2. 
AMG 386 ...........................................................................................................................11 
2.3. 
Anti-VEGF Agents in Renal Cell Carcinoma ...............................................................22 
2.4. 
Rationale ...........................................................................................................................32 
2.5. 
Correlative Studies Background ....................................................................................33 
3. 
PATIENT SELECTION .................................................................................................36 
3.1. 
Eligibility Criteria ............................................................................................................36 
3.2. 
Exclusion Criteria ............................................................................................................38 
3.3. 
Inclusion of Women and Minorities ...............................................................................40 
4. 
REGISTRATION PROCEDURES ................................................................................41 
4.1. 
General Guidelines...........................................................................................................41 
4.2. 
Registration Process.........................................................................................................41 
4.3. 
Randomization Process ...................................................................................................42 
5. 
TREATMENT PLAN ......................................................................................................42 
5.1. 
Pre-Treatment Tumor Biopsy ........................................................................................42 
5.2. 
Agent Administration ......................................................................................................43 
5.3. 
General Concomitant Medication and Supportive Care Guidelines ..........................47 
5.4. 
Duration of Therapy ........................................................................................................48 
5.5. 
Duration of Follow Up .....................................................................................................48 
5.6. 
Criteria for Removal from Study ...................................................................................48 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................48 
6.1. 
AMG 386 Dose Modification...........................................................................................49 
6.2. 
Bevacizumab Dose Modification ....................................................................................52 
6.3. 
Pazopanib Dose Modification .........................................................................................53 
6.4. 
Sorafenib Dose Modification ...........................................................................................54 
6.5. 
Sunitinib Dose Modification ...........................................................................................55 
6.6. 
Management of Hypertension and Proteinuria ............................................................56 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ......................57 
7.1. 
Comprehensive Adverse Events and Potential Risks Lists (CAEPR).........................57 
7.2. 
Adverse Event Characteristics........................................................................................87 
7.3. 
Expedited Adverse Event Reporting ..............................................................................88 
7.4. 
Routine Adverse Event Reporting ..................................................................................89 
7.5. 
Secondary Malignancy ....................................................................................................90 
7.6. 
Second Malignancy ..........................................................................................................90 
7.7. 
Pregnancy .........................................................................................................................90 
8. 
PHARMACEUTICAL INFORMATION ......................................................................91 


 
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8.1. 
AMG 386 (NSC 751173) ..................................................................................................91 
8.2. 
Commercial Agents ..........................................................................................................94 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ...................................98 
9.1. 
Tumor Tissue-Based Correlative Studies ......................................................................98 
9.2. 
Pharmacodynamic Correlative Studies .........................................................................99 
9.3. 
Pharmacogenetic Correlative Studies ..........................................................................100 
10. 
STUDY CALENDAR ....................................................................................................102 
11. 
MEASUREMENT OF EFFECT ..................................................................................104 
11.1. Antitumor Effect – Solid Tumors .................................................................................104 
11.2. Definitions .......................................................................................................................104 
11.3. Response Criteria ...........................................................................................................108 
11.4. Duration of Response .....................................................................................................111 
11.5. Progression-Free Survival .............................................................................................111 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...................................111 
12.1. Data Reporting ...............................................................................................................111 
12.2. CTEP Multicenter Guidelines ......................................................................................113 
12.3. Collaborative Agreements Language ...........................................................................113 
13. 
STATISTICAL CONSIDERATIONS .........................................................................115 
13.1. Study Design/Endpoints ................................................................................................115 
13.2. Sample Size/Accrual Rate .............................................................................................115 
13.3. Analysis of Secondary Endpoints .................................................................................115 
13.4. Analysis of Correlative Endpoints ................................................................................117 
13.5. Reporting and Exclusions .............................................................................................120 
14. 
CCCP POLICIES FOR MONITORING CONSORTIUM TRIALS .......................120 
APPENDIX A - Performance Status Criteria .........................................................................126 
APPENDIX B - CTEP Multicenter Guidelines .......................................................................127 
APPENDIX C - List of drugs that may have potential CYP3A4 interactions .....................129 
APPENDIX D – Pregnancy Information Form ......................................................................131 
APPENDIX E – Pill Diaries ......................................................................................................133 
APPENDIX F - Specimen Shipment Guidelines .....................................................................136 
APPENDIX G - CCCP Registration Procedures for Phase II Trials ...................................138 
APPENDIX H – AMG 386 Dose Rounding Guideline Tables ...............................................139 


 
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1. OBJECTIVES 
 
1.1. 
Primary Objective 
 
To evaluate the overall response rate (CR + PR) of AMG 386 alone and in 
combination with continuation of previously administered bevacizumab, pazopanib, 
sorafenib, or sunitinib in advanced renal cell carcinoma. 
 
1.2. 
Secondary Objectives 
 
 
1.2.1 To evaluate progression free survival in each arm. 
 
1.2.2 To evaluate the tolerance and toxicity of AMG 386 alone and in combination 
with continuation of the prior VEGF targeted agent. 
 
1.3. 
Correlative Objectives 
 
 
1.3.1 To evaluate the association between pretreatment tumor gene expression 
levels and response to AMG 386 in combination with continuation of the prior 
VEGF targeted agent. 
 
 
 
1.3.2 To evaluate the association between SNPs in angiogenic genes and response 
to AMG 386 in combination with continuation of the prior VEGF targeted 
agent.  
 
1.3.3 To compare changes in circulating angiogenic factors in patients treated with 
AMG 386 monotherapy to those treated with AMG 386 in combination with 
VEGF-targeted therapy. 
 
1.3.4 To compare expression of angiogenic genes from archival tumor specimens to 
the expression in biopsy specimens obtained after progression on anti-VEGF 
therapy. 
 
2.  
BACKGROUND 
 
2.1. Advanced Renal Cell Carcinoma 
 
Over 60,000 new cases of renal cell carcinoma (RCC) will be diagnosed in the United 
States in 2011 and the disease will account for approximately 13,000 deaths (Siegel et 
al. 2011).  Surgery is a potentially curative therapeutic option for localized disease, 
although recurrence after nephrectomy occurs in up to 50% of cases.  No adjuvant 
therapy has been shown to reduce this risk.  Additionally, as many as one-third of 
newly diagnosed patients with RCC have metastases present at the time of diagnosis.  
For these patients, the disease is unlikely to be cured.  In the cytokine era, 
investigators at the Memorial Sloan Kettering Cancer Center (MSKCC) developed a 
prognostic scoring system that is comprised of 2 clinical variables: performance 
status and time from diagnosis to treatment; as well as 3 laboratory variables: the 
levels of lactate dehydrogenase, hemoglobin, and calcium.  Using this system, 
patients can be categorized into three groups according to risk.  Similar risk factors 
were obtained when these analysis were repeated for those receiving anti-vascular 


 
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endothelial growth factor (VEGF) therapy. 
 
Treatment of advanced RCC may involve multiple modalities.  Debulking 
nephrectomy and surgical resection of limited metastatic disease improve outcomes 
in selected cases.  Immune therapy with IL-2 provides a small, but consistent, chance 
of complete response (CR) and prolonged disease free survival.  The development of 
a number of new agents for the treatment of advanced RCC in the past several years 
has resulted from an improved understanding of the molecular underpinnings of the 
disease.  Clear cell RCC is frequently associated with mutations in the von Hippel 
Lindau (VHL) gene that results in deregulated signaling through hypoxia inducible 
factor (HIF).  This potent signaling molecule increases transcription of multiple 
proangiogenic factors including VEGF, platelet-derived growth factor (PDGF), and 
transforming growth factor alpha (TGFα).  With the observation that angiogenic 
signaling was key to the development and progression of advanced RCC, a number of 
anti-angiogenic agents have been developed and tested.   
 
Multiple small molecule kinase inhibitors have recently obtained regulatory approval 
for the treatment of RCC including pazopanib (VotrientTM, GlaxoSmithKline), 
sorafenib (Nexavar®, Bayer/Onyx Pharmaceuticals), and sunitinib (Sutent®, Pfizer 
Corporation).  Although the spectrum of target affinity differs amongst the agents, a 
common feature is inhibition of signaling through the VEGF pathway.  Additionally, 
the 
VEGF-A 
ligand 
sequestering 
antibody 
bevacizumab 
(Avastin®, 
Genentech/Roche), demonstrated benefit in the management of advanced RCC in 
combination with interferon.  One of these anti-VEGF agents is now the standard of 
care for the initial treatment of most patients with newly diagnosed advanced RCC.   
 
Using analogous reasoning, two inhibitors of the mammalian target of rapamycin 
(mTOR) have also recently been developed for the management of patients with 
advanced RCC: temsirolimus (Torisel®, Pfizer Corporation), and everolimus 
(Affinitor®, Novartis Pharmaceuticals).  The mTOR pathway is abnormally regulated 
in RCC, and signaling through the phosphatidlyinositol-3-kinase(PI3K)-Akt-mTOR 
pathway is a important driver of proliferation and angiogenesis in the setting of 
hypoxia.  Temsirolimus is considered a standard initial treatment for patients with 
MSKCC poor prognosis advanced RCC and everolimus is currently an approved 
agent for patients previously treated with sunitinib or sorafenib. 
 
Despite these advances in therapy, the majority of cases of advanced RCC remain 
incurable and therapeutic resistance invariable develops.  Resistance to anti-VEGF 
therapy may develop from selection for or up-regulation of alternative pro-angiogenic 
pathways, recruitment of bone marrow derived vascular progenitors and pro-
angiogenic monocytes, increased involvement of pericytes in blood vessel stability, 
and increased capacity for invasion without metastasis.  The recruitment of 
alternative angiogenic pathways is as a potential mechanism for failure of anti-VEGF 
therapy.  A number of inhibitors of these pathways have been developed and are in 
clinical testing.  Furthermore, it is not presently known whether continued VEGF 
pathway inhibition is required for the clinical efficacy of antiangiogenic agents that 


 
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inhibit these alternative pathways. 
 
2.2. AMG 386 
 
AMG 386 (previously named 2XCon4[C]) is a novel peptide-Fc fusion protein, or 
peptibody.  The molecule is a non-glycosylated homodimer engineered by fusing an 
IgG1 Fc domain to 4 copies of an anti-angiopoietin (Ang)-2 (Ang2) peptide.  AMG 
386 sequesters Ang1 and Ang2, thereby preventing their interaction with Tie2 and 
inhibiting tumor endothelial cell (EC) proliferation and tumor growth.  The 
neutralization potency of AMG 386 is greater against Ang2 (50% inhibitory 
concentration [IC50]=0.023 nM) than Ang1 (IC50=0.9 nM).  The potency against 
Ang2 is similar across species between humans, mice, rats, and cynomolgous 
monkeys, while the potency against Ang1 is similar between mice and humans 
(Investigator's Brochure 2011). 
 
Angiopoietins as targets of anticancer therapy 
 
The Ang family has four members (Ang 1-4), with Ang1 and 2 being the best 
understood (Augustin et al. 2009; Eklund et al. 2006; Huang et al. 2010; Yancopoulos 
et al. 2000).  Ang1 and Ang 2 are ligands of Tie2, a tyrosine kinase (TK) receptor 
expressed on ECs.  Ang1 is mainly derived from perivascular cells (pericytes or 
smooth muscle cells); it acts as an agonist of Tie2 and promotes vascular maturation 
and stabilization.  Ang2 is primarily produced in activated ECs, and is thought to be 
an antagonist of Tie2.  By displacing Ang1 from Tie2, Ang2 induces vascular 
plasticity and renders ECs more responsive to angiogenic signals such as VEGF.  In 
certain contexts, Ang2 may also act as an agonist of Tie2.  The precise signal 
transduction pathway downstream of Ang-Tie2 interaction is unknown; the PI3K-
AKT-mTOR pathway has been implicated in most studies.  While the two 
angiopoietins may seem to have contradictory effects on Tie2, they act 
complementarily in the angiogenesis process, from vascular formation to vascular 
maturation:  Ang2 promotes EC proliferation, sprouting, and neoangiogenesis, while 
Ang1 maintains EC survival, pericyte coverage, and vascular integrity.  
Angiopoietins are also required for the formation of lymphatic vessels.  Ang2 
ablation in mice was compatible with live birth, but most mice died within 2 weeks 
with severe chylous ascites and peripheral lymphedema (Gale et al. 2002).  
Overexpression of Ang was found to be associated with lymph node metastases in 
early gastric (Jo et al. 2009) or breast cancers (Sfiligoi et al. 2003).  In addition, Ang1 
and Ang2 have been shown to interact with integrin (α5vβ3 or α5β1) on ECs or 
nonvascular cells; these interactions were implicated in the survival of certain 
neuronal cells (Dallabrida et al. 2005; Lee et al. 2006), cardiomyocytes, and tumor 
cells (Imanishi et al. 2007), but the precise mechanisms have not be elucidated. 
 
Preclinical studies with Ang1- and Ang2-specific antagonists have suggested that 
Ang2 is involved in EC proliferation and angiogenesis in cancers, and that inhibition 
of Ang2 may have therapeutic benefit (Oliner et al. 2004).  Angiopoietins may also 
promote tumor growth through non-vascular mechanisms.  Recent studies reported 


 
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that Tie2-expressing monocytes (TEMs) can be recruited to tumor sites through the 
chemo-attractant action of angiopoietins (De Palma et al. 2008).  In tumor xenograft 
models, TEMs purified from human tumor specimens markedly promoted 
angiogenesis, suggesting a potentially critical role of TEMs in human cancer 
progression (De Palma et al. 2008; Lewis et al. 2007; Venneri et al. 2007).  
 
Studies with anti-VEGF agents in tumor models suggest that Ang1 and Ang2 may 
play a role in tumor survival under VEGF inhibition.  In an orthotopic tumor model 
(Huang et al. 2009), while an Ang1 agonist did not alter tumor growth by itself, it was 
found to attenuate the antitumor effect of VEGF Trap and protect the tumor vessels 
from regression.  In the U87 glioma model, ectopic expression of Ang2 increased 
vascular density without impact on tumor growth; however, the presence of Ang2 
compromised the activity of a VEGFR2 inhibitor, suggesting that blocking Ang2 
along with VEGF may lead to enhanced therapeutic effect (Chae et al. 2010).  In 
patients with renal cell cancer (RCC), circulating Ang2 levels were initially decreased 
after treatment with sunitinib but subsequently increased at the time of tumor 
progression (Bullock et al. 2010). 
 
Overexpression of Ang1, Ang2, or Tie2 can be found in tumor tissues, but the levels 
and sites of expression (ECs, stromal cells, or tumor cells) are highly variable among 
individual patients and tumor types.  Increased levels of Ang2 in the tumor or in 
circulation have been associated with higher grade, later stage, and poorer survival in 
several malignancies, including melanoma (Helfrich et al. 2009), glioma, gastric 
cancer (Etoh et al. 2001; Jo et al. 2009), breast cancer, bladder cancer (Oka et al. 
2005; Szarvas et al. 2008), and acute myeloid leukemia (AML) (Hou et al. 2008; 
Loges et al. 2005).  In general, Ang2 or Tie2 expression is confined to ECs or stromal 
cells, but ectopic expression in tumor cells has also been reported (e.g., gastric cancer, 
inflammatory breast cancer, and thyroid cancer).  The functional relevance of Tie2 
expression on tumor cells is unclear.  A summary of Ang1, Ang2, and Tie2 
expression data in various human cancers has been published (Augustin et al. 2009). 
 
Nonclinical Studies of AMG 386 
 
In vitro efficacy:  AMG 386 does not alter the in vitro growth of human cancer cell 
lines, including A431 (uterine epidermoid carcinoma) and Colo205 (colon 
carcinoma), indicating that the mechanism of action of AMG 386 is not likely to be 
through a direct antitumor effect (Investigator's Brochure 2011). 
 
In vivo efficacy:  As a single agent, AMG 386 significantly inhibited VEGF-induced 
rat corneal angiogenesis and inhibited the growth of multiple tumor xenografts in 
nude mice, including Colo205, A341, OVCAR-3 SQ3 (ovarian carcinoma), and 
HT29 (colon carcinoma).  The antitumor effect in the Colo205 model was associated 
with a reduction of EC proliferation and significant increases in tumor cell apoptosis 
and necrotic tumor fraction; no increase in EC apoptosis suggests that AMG 386 
prevents tumor growth via inhibition of angiogenesis.  Maximum efficacy in Colo205 
tumor-bearing mice occurred at 0.6 mg/kg administered subcutaneously (SC) twice 


 
PhII-122, NCI# 9048 
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13 
weekly, which resulted in a minimum observed serum concentration (Cmin) of 3 
mcg/mL.  No delay in tumor growth was observed with AMG 386 treatment in 
several tumor models, including U-87 MG (glioblastoma), Calu6 (lung carcinoma), 
Daudi (B-cell lymphoma), and MesSa/Dx5 (uterine sarcoma) (Investigator's Brochure 
2011). 
 
The combination of AMG 386 with VEGF/VEGFR inhibitors was associated with 
greater antitumor activities when compared with each agent alone.  In the HT29 
model, AMG 386 in combination with motesanib (a multi-kinase inhibitor against 
VEGFR/PDGFR/cKit) showed superior antitumor activity in the HT29 model.  
Similarly, the combination of AMG 386 with bevacizumab in Colo205 xenografts 
also resulted in significantly improved efficacy.  In another experiment in the 
Colo205 model, combination of bevacizumab and an Ang2-specific peptide (L1-
7[N]) demonstrated that the enhanced antitumor effect was associated with 
significantly lower vascular sprouting and more profound vascular regression 
(Hashizume et al. 2010). 
 
Combinations of AMG 386 with irinotecan, fluorouracil (5-FU), and docetaxel have 
also been tested in the Colo205 model.  Preliminary data suggest neither antagonism 
of single-agent efficacy nor gross evidence of increased toxicity upon combining the 
agents, but the study design did not allow for conclusions regarding additive activity 
to be made (Investigator's Brochure 2011). 
 
Preclinical pharmacology:  Pharmacokinetics (PK) studies were conducted in 
Sprague-Dawley rats and cynomolgus monkeys (Investigator's Brochure 2011).  
Single-dose intravenous (IV) administration of AMG 386 exhibited dose-linear PK 
over dose ranges of 1 to 100 mg/kg (rats) and 5 to 100 mg/kg (monkeys).  The mean 
terminal elimination half-life (t1/2) was 97.5 and 49.5 hours in rats and monkeys, 
respectively.  The mean volume of distribution value after the first dose (V0) was 
similar to the plasma volume but increased by 4-5 fold steady state (Vss), suggesting 
that AMG 386 distributes extravascularly. 
 
No accumulation of AMG 386 was observed after twice-weekly IV administration to 
rats (3 to 300 mg/kg) and monkeys (25 to 300 mg/kg) for 4 weeks.  After 13 weeks, 
however, moderate accumulation (accumulation ratio [AR] range, 2.03 to 2.77) was 
observed in rats; low accumulation (AR range, 1.19 to 2.09) was observed in 
monkeys. 
 
Unlike full IgG antibodies, the kidneys may contribute to the overall clearance of 
AMG 386.  PK profiles in splenectomized rats indicate that the spleen is not involved 
in the elimination of AMG 386.  In nephrectomized rats, total clearance was 
decreased by approximately 30%.  These values were 14-18 fold higher in the 
neonatal constant region fragment (Fc) receptor (Fc-Rn) knockout mice, indicating 
the Fc-Rn receptor contributes to the sustainability of circulating AMG 386 levels 
after IV administration of 3 and 10 mg/kg to mice (Investigator's Brochure 2011). 
 


 
PhII-122, NCI# 9048 
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Preclinical toxicology:  In preclinical toxicology studies in adult monkeys and dogs, 
AMG 386 was well tolerated, with findings consistent with the mechanisms of action 
(see Investigator’s Brochure, 2011, Section 5.3 for details). 
 
As with other antiangiogenic agents, administration of AMG 386 in developing 
monkeys has shown dose-dependent, premature closure of the physeal growth plate.  
AMG 386 is also detrimental to fetal growth and has potential impact on the 
reproductive system (see Investigator’s Brochure, 2011, Section 5.3 for details). 
 
Clinical Studies of AMG 386 
 
There are a total of 16 studies sponsored by Amgen with AMG 386 as monotherapy 
or in combination regimens.  Two studies have been completed, while 14 are 
ongoing.  The trials (six phase 1, seven phase 2, two phase 3, and one unspecified) 
have included:  1) phase 1 trials for single agent, combination with anti-VEGF agents 
(AMG 706 [motesanib], sorafenib, sunitinib, and bevacizumab), or combination with 
chemotherapy 
(carboplatin/paclitaxel, 
docetaxel, 
paclitaxel/trastuzumab, 
capecitabine/lapatinib, topotecan, and pegylated liposomal doxorubicin [PLD]); 2) 
phase 2 trials for combination with chemotherapy in ovarian, gastric, colorectal, and 
breast cancer; 3) phase 2 trials in combination with VEGFR tyrosine kinase inhibitors 
(TKIs) in RCC and hepatocellular carcinoma (HCC); and 4) phase 3 trials in 
combination with chemotherapy in ovarian cancer (Investigator's Brochure 2011). 
 
PK, immunogenicity, and maximum tolerated dose (MTD) in humans:  In the phase 1 
Study 20040169, 32 patients with advanced solid tumors received AMG 386 
monotherapy in escalating dose cohorts from 0.3 to 30 mg/kg IV weekly.  AMG 386 
exposure was dose proportional, and the total serum clearance appeared to be similar 
across doses, suggesting that AMG 386 exhibited linear PK.  The mean t1/2 was 3.1 to 
6.3 days, and the serum steady state level (Css) was reached after four weekly doses.  
The average minimum observed concentration (Cmin) increased approximately 
proportionately with increasing dose.  At the initially selected phase 2 doses of 3 and 
10 mg/kg IV weekly, the mean Css was 10.2 mcg/mL and 26.6 mcg/mL, respectively.  
Across studies, exposure to weekly IV doses of AMG 386 at 3 and 10 mg/kg (and 15 
mg/kg, based on more limited experience) has been consistent with the approximately 
dose-proportional PK and minimal accumulation observed in Study 20040169.  
Population PK modeling in several studies has identified baseline creatinine clearance 
(CrCl) as a significant covariate for AMG 386 Cl. 
 
No PK alterations of AMG 386 at 10 mg/kg have been demonstrated in 
coadministration with other agents, including VEGF inhibitors (motesanib, sorafenib, 
sunitinib, 
and 
bevacizumab) 
and/or 
chemotherapeutic 
agents 
(FOLFOX-4 
[oxaliplatin, leucovorin, and infusional 5-fluorouracil (5-FU)], FOLFIRI [5-FU, 
leucovorin, and irinotecan], paclitaxel, docetaxel, carboplatin, cisplatin, PLD, 
topotecan, and capecitabine).  Linear interpolation to compare 15 mg/kg of AMG 386 
with monotherapy data additionally suggests no evidence of drug interaction.  There 
has been no conclusive evidence of a marked PK interaction between AMG 386 and 


 
PhII-122, NCI# 9048 
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15 
other targeted or chemotherapeutic agents after coadministration. 
 
As of March 30, 2011, no patients have developed neutralizing antibodies in any 
open-label or blinded AMG 386 studies.  Of the 703 patients across nine studies who 
had serum samples tested for immunogenicity, 32 patients developed binding 
antibodies to AMG386. 
 
At doses up to 30 mg/kg weekly in the first-in-human phase 1 Study 20040169 and 
Japanese phase 1 Study 20060212, the MTD was not reached. 
 
Pharmacodynamics in humans:  There have been limited pharmacodynamic studies 
with AMG 386.  In the completed phase 1 single agent trial (Study 20040169) 
(Herbst et al. 2009), the post-treatment effects of AMG 386 were assessed by DCE-
MRI and 18F-FDG PET, and angiogenic cytokine and apoptosis marker levels in 
blood.  Of the 12 patients with interpretable serial DCE-MRIs, 10 patients were 
treated at 30 mg/kg and the others at 1 mg/kg and 3 mg/kg.  Vascular response, as 
measured by volume transfer constant (Ktrans) and initial area under the curve (IAUC) 
changes, were demonstrated in all patients, but a dose-effect correlation (or lack 
thereof) cannot be made due to small numbers.  A significant vascular effect (i.e., 
≥20% reduction in median Ktrans) was seen in 7/12 patients on Day 2, 3/6 patients at 
Week 4, and 5/8 patients at Week 8. 
 
Serial blood levels of several angiogenic cytokines (e.g., VEGF and placental growth 
factor [PlGF], serum VCAM-1 [sVCAM-1], Ang1, and Ang 2) are being assessed in 
ongoing phase 1b and 2 studies.  Small but significant changes in PlGF and sVCAM-
1 have been observed in response to treatment with AMG 386.  The correlation of 
these and other potential markers with clinical response will require larger studies and 
more optimal sampling time. 
 
Clinical activity of AMG 386: 
 
Phase 1 study of single agent AMG 386 in solid tumors (Study 20040169).  In the 
primary analysis (September 6, 2006), 29 patients were evaluable for tumor response.  
One patient with advanced, refractory ovarian cancer treated at 30 mg/kg achieved a 
partial response (PR) after 68 weeks that lasted up to 156 weeks when she withdrew 
from study; CA125 response occurred earlier, at week 4.  Four patients had stable 
disease (SD) for >16 weeks:  one each with soft tissue sarcoma, thyroid cancer, 
pseudomyxoma, and submandibular adenocarcinoma. 
 
Phase 1 study of single agent AMG 386 in Japanese patients with advanced solid 
tumors (Study 20060212).  Preliminary data have recently been presented (Toshihiko 
et al., 2011).  Among the 18 patients enrolled in three dose cohorts (3, 10, or 30 
mg/kg), two patients achieved PR (one patient with colon cancer treated at 3 mg/kg, 
and one patient with bladder cancer treated at 30 mg/kg); these two patients were 
continuing the study treatment for 56 weeks and 24 weeks, respectively.  Two 
patients had a best response of SD, and 14 patients experienced PD. 


 
PhII-122, NCI# 9048 
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16 
 
Phase 1b dose-escalation study of AMG 386 (3-10 mg/kg weekly) in combination 
with standard phase 2 doses of bevacizumab (15 mg/kg every 3 weeks), sunitinib 
(50 mg daily for 4 out of 6 weeks), or sorafenib (400 mg twice daily [BID]) (Study 
20050170).  A preliminary analysis of efficacy among 30 patients with metastatic 
RCC was conducted using data available as of March 19, 2010.  Of the 15 patients 
who received sorafenib in combination with AMG 386, 5 patients had PRs, 9 patients 
had SD, and 1 patient experienced PD.  Of the 15 patients who received sunitinib in 
combination with AMG 386, 1 patient had a CR, 7 patients had PRs, 6 patients had 
SD, and 1 patient experienced PD.  Two patients with advanced squamous cell 
carcinoma of the head and neck treated with AMG386 and bevacizumab combination 
developed fatal arterial hemorrhage and tumor hemorrhage; the events were thought 
to be due to bevacizumab or the combination. 
 
Phase 2 randomized, double-blind, placebo-controlled study in recurrent 
ovarian cancer patients combining paclitaxel (80 mg/m2 weekly) and AMG 386 
(3 or 10 mg/kg weekly) or placebo (Study 20060342).  The primary analysis (for 
data as of October 21, 2009) showed a strong trend toward progression-free survival 
(PFS) improvement for the paclitaxel + AMG 386 arms (combined) vs. paclitaxel + 
placebo (hazard ratio [HR], 80% CI:  0.761 [0.59, 0.98]; P=0.165); median PFS was 
5.7, 7.2, and 4.6 months in the AMG 386 3 mg/kg, 10 mg/kg, and placebo groups, 
respectively.  Of the 16 subjects from the paclitaxel + placebo arm who crossed over, 
median PFS was 2.6 months.  The ORR was 19%, 37%, and 27% in the AMG 386 3 
mg/kg, 10 mg/kg, and placebo groups, respectively (Karlan et al. 2011).  PK analysis 
revealed a significant correlation between AMG 386 exposure and efficacy (Lu et al., 
2010).  While patients with low steady state AUC (AUCss) (<9.6 mg•h/mL) of AMG 
386 had a modest difference in PFS compared to the control (5.7 vs. 4.6 months, HR 
0.81, P=0.31), those with high AUCss (≥9.6 mg•h/mL) exhibited greater PFS 
improvement above chemotherapy alone (8.1 vs. 4.6 months, HR 0.76, P=0.14).  The 
apparent dose-efficacy and exposure-efficacy relationships observed here prompted 
the exploration of higher doses of AMG 386 in subsequent trials.  Subsequently, a 
dose of 15 mg/kg has been selected to begin the phase 3 trials of AMG 386 and 
chemotherapy in first line ovarian cancer. 
 
Phase 2 randomized, double-blind, multi-center phase 2 study combining 
sorafenib 400 mg orally (PO) BID and weekly AMG 386 (3 or 10 mg/kg) or 
placebo in RCC (Study 20060159).  The primary analysis (for data as of February 
22, 2010) showed no difference in median PFS between individual treatment groups 
(median PFS:  8.5, 9, and 9 months for the AMG 386 3 mg/kg, 10 mg/kg, and placebo 
groups, respectively).  However, the ORR was higher for AMG 386 at 3 mg/kg (37%) 
and 10 mg/kg (38%) vs. placebo (24%).  A phase 2 study of AMG 386 (doses up to 
15 mg/kg) with sunitinib is also ongoing (Study 20080579).  
 
 
Phase 2 randomized, double-blind, placebo-controlled study in gastric cancer 
(Study 20060439).  The primary analysis (for data as of December 15, 2009) showed 


 
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no improvement in PFS for patients on cisplatin 80 mg/m2 and capecitabine 1000 
mg/m2 BID with AMG 386 (3 or 10 mg/kg) or placebo.  Earlier discontinuation of 
study drugs in the AMG 386 arms due to poor tolerability of the combination is likely 
to have contributed to the observed lack of efficacy and decreased median overall 
survival (OS) observed for the chemotherapy + AMG 386 3 mg/kg and chemotherapy 
+ AMG 386 10 mg/kg arms (9.4 and 9.1 months, respectively) vs. the chemotherapy 
+ placebo arm (12.8 months).  Common adverse events leading to discontinuation of 
investigational product included pulmonary embolism (2%, 5%, 4% of patients in the 
groups receiving AMG 386 3 mg/kg, AMG 386 10 mg/kg, and placebo, respectively), 
diarrhea (5%, 2%, 0%), and nausea (3%, 4%, 0%).  No single specific toxicity 
appeared to account for the reduced tolerability of regimens containing AMG 386, 
and no synergistic toxicities were observed between AMG 386 and chemotherapy. 
 
AMG 386 Safety Profile 
 
At the time of study-respective data cutoff dates for safety and efficacy data 
(Investigator's Brochure 2011), a total of 1190 patients had been exposed to either 
AMG 386 or placebo in open-label (343 patients) and unblinded (847 patients) phase 
1 and phase 2 studies.  Analysis pools for potential and identified risks associated 
with AMG 386 administration were comprised of 32 patients from monotherapy 
studies; 293 patients from open label, combination therapy studies; and 847 patients 
(582 administered AMG 386, and 265 administered placebo) from unblinded, 
placebo-controlled, combination therapy studies (Investigator's Brochure 2011).   
 
Overall, AMG 386 up to 10 mg/kg weekly is well tolerated as monotherapy or in 
combination with VEGF inhibitors or chemotherapy.  Single agent use at 30 mg/kg 
also appeared tolerable in the phase 1 trials with a total of 22 patients treated at this 
dose level (Study 20040169 and Study 20060212). 
 
AMG 386 does not appear to cause hypertension as typically observed with anti-
VEGF agents.  A unique adverse effect of AMG 386 is edema, which is believed to 
be due to the target effect on the lymphatic system.  Adverse events of proteinuria 
were not observed in the monotherapy setting, and were reported in 3% and 2% of 
patients who received AMG 386 in combination with other agents in open-label and 
blinded studies, respectively.  Proteinuria was mild to moderate, non-serious, and did 
not result in discontinuation of AMG 386. 
 
Safety data for higher doses of AMG 386 (15 and 30 mg/kg) in combination regimens 
are pending. 
 
A Comprehensive Adverse Events and Potential Risks (CAEPR) list using NCI 
Common Terminology Criteria for Adverse Events (CTCAE) terms is included in 
Section 7.1 of the protocol. 
 
Details of identified risks (edema, ascites, and pleural effusion) and potential risks 
are described below. 


 
PhII-122, NCI# 9048 
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18 
 
Edema (identified risk):  Ang1 and Ang2 contribute to the normal development of the 
lymphatic system; Ang2 knockout mice display defects in the lymphatic system, 
including chylous ascites, hypoplasia of the lymphatic vasculature, and peripheral 
lympedema (Gale et al. 2002).  Edema events occurred in 34% of patients receiving 
AMG 386 monotherapy and in 46% of patients who received AMG 386 in 
combination with other agents in open-label studies.  In each of the five unblinded 
studies, a higher incidence of edema was observed in the AMG 386 arms (combined) 
vs. the placebo arms (Table 2-1). 
 
The most common manifestation is peripheral edema, although facial edema, 
periorbital edema, and penile edema were also reported.  The majority of cases were 
mild to moderate in severity and did not result in permanent discontinuation of 
investigational product.  Current toxicity management guidelines are for investigators 
to continue AMG 386 for Grades 1 and 2 edema, and to discontinue AMG 386 only 
for Grade 3 edema. 
 
Ascites (identified risk):  Approximately 10% of all cases of ascites are due to cancer, 
with the most common primary tumor types being ovarian (37%), pancreaticobiliary 
(21%), gastric (18%), esophageal (4%), colorectal (4%), and breast (3%).  Ascites 
adverse events have been observed for 3% of patients receiving AMG 386 
monotherapy, and 8% of patients receiving AMG 386 in combination with other 
agents in open-label studies.  The incidence of ascites in the five unblinded studies is 
shown in Table 2-1.   
 
Pleural effusion (identified risk):  Historically, pleural effusion has been observed in 
cancer patients with advanced disease.  Pleural effusion has been reported for 6% of 
patients receiving AMG 386 monotherapy, and 6% of patients receiving AMG 386 in 
combination with other agents in open-label studies; 1% of patients in open-label 
studies had events of “malignant pleural effusion.”  The incidence of pleural effusion 
in unblinded studies is shown in Table 2-1.  One fatal event of pleural effusion 
occurred in a patient with RCC and bilateral lymphangitic carcinomatosis (Study 
20080579); the investigator did not consider the event to be related to AMG 386 
treatment. 
 
A number of potential risks have been analyzed in AMG 386 trials.  The findings are 
as follows: 
 
Infusion reaction or allergic response:  Adverse events consistent with possible 
infusion reaction were observed for 6% of patients receiving AMG 386 monotherapy, 
and 2% of subjects who received AMG 386 in combination with other agents in open-
label studies; these events included hypersensitivity, infusion-related reaction, and 
dyspnea and were of severity grade 1 or 2.  In the five unblinded studies, the 
incidence of adverse events consistent with possible infusion reaction was similar or 
less in the AMG 386 (combined) arms vs. the placebo arms; the events included 
bronchospasm, chills, infusion related reaction, pyrexia, dyspnea, hypersensitivity, 


 
PhII-122, NCI# 9048 
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19 
and drug hypersensitivity.  No fatal infusion reactions have been reported.  One 
patient developed grade 3 hypotension as part of a possible infusion reaction (Study 
20080579).  That patient received concomitant methylprednisolone for laryngeal 
spasms and hot flushes. 
 
Proteinuria:  Treatment-emergent adverse events of proteinuria have been observed 
in clinical studies of AMG 386.  Proteinuria has not been reported in patients 
receiving AMG 386 monotherapy, but it was observed in 4% of patients who received 
AMG 386 in combination with other agents in open-label studies.  The incidence of 
proteinuria in the five unblinded studies is shown in Table 2-1.  The majority of 
proteinuria events were mild to moderate, nonserious, and did not result in 
discontinuation of the investigational product. 
 
Gastrointestinal perforation:  No patients receiving AMG 386 monotherapy, and 2% 
of patients who received AMG 386 in combination with other agents in open-label 
studies, experienced gastrointestinal perforation events.  In the five unblinded studies, 
the incidence of gastrointestinal perforation was similar between the AMG 386 arms 
(combined) vs. the placebo arms (Table 2-1). 
 
One event of gastrointestinal perforation occurred in a patient enrolled in a study of 
AMG 102 (anti-hepatocyte growth factor/scatter factor neutralizing antibody) who 
was misdosed by a clinical site and received AMG 386 in addition to AMG 102.  
Another patient with advanced ovarian cancer who was receiving AMG 386 10 
mg/kg in combination with PLD had a fatal event of intestinal perforation. 
 
Hemorrhage:  No subjects receiving AMG 386 monotherapy, and 14% of patients 
who received AMG 386 in combination with other agents in open-label studies, had 
hemorrhage events.  In the five unblinded studies, the incidence of hemorrhage was 
similar or lower in the AMG 386 arms (combined) vs. the placebo arms (Table 2-1).  
The majority of events were mild to moderate in severity.  However, fatal 
hemorrhage has been observed on the AMG 386-containing arms (see below). 
 
The hemorrhage event with the highest incidence overall was epistaxis; incidence 
varied among studies, from 0% in Study 20040169 (AMG 386 monotherapy) to 49% 
in the blinded arms of Study 20060341 (AMG 386 or placebo in combination with 
paclitaxel and bevacizumab). 
 
Five fatal events of hemorrhage have occurred.  Two of the events (hematemesis and 
gastric hemorrhage, in gastric cancer patients receiving chemotherapy + AMG 386 in 
Study 20060439) were not considered by the investigator to be related to AMG 386.  
The other three events were considered possibly related to the study product:  two 
patients with advanced squamous cell carcinoma of the head and neck treated with 
AMG 386 and bevacizumab combination developed fatal arterial hemorrhage and 
tumor hemorrhage (Study 20050170); and the other patient with metastatic breast 
cancer in the lungs treated with AMG 386, paclitaxel, and bevacizumab combination 
developed fatal hemoptysis (Study 20060341).  Since hemorrhage is a recognized 


 
PhII-122, NCI# 9048 
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20 
adverse event of agents targeting VEGF (Avastin(R) Prescribing Information 2011), 
interpreting the relationship of these events to AMG 386 is confounded. 
 
Pulmonary embolism:  No subjects receiving AMG 386 monotherapy, and 1% of 
patients who received AMG 386 in combination with other agents in open-label 
studies, had events of pulmonary embolism.  In most of the five unblinded studies, 
the incidence of pulmonary embolism in the AMG 386 arms (combined) vs. the 
placebo arms (Table 2-1). 


 
PhII-122, NCI# 9048 
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Table 2-1:  Incidence of selected AEs (all grades) of interest in five randomized phase 2 trials that have been unblinded 
 
 
Study 20060342 
(ovarian ca) 
Study 20060159 
(RCC) 
Study 20060439 
(gastric ca) 
Study 20060341 
(Her2- breast ca) 
Study 20070307 
(colorectal ca) 
 
Paclitaxel
+ 
AMG 
386 
(3 or 10 
mg/kg) 
 
Paclitaxel 
Sorafenib 
+ 
AMG 386 
(3 or 10 
mg/kg) 
Sorafenib 
Cisplatin/ 
gemcitabine 
+ 
AMG 386 
(3 or 10 
mg/kg) 
Cisplatin / 
gemcitabine 
Paclitaxel 
+ 
Bevacizumab 
+ 
AMG 386 
(3 or 10 mg/kg) 
 
Paclitaxel 
+ 
Bevacizumab 
 
FOLFIRI 
+ 
AMG 386 
(10 mg/kg) 
FOLFIRI 
Edema 
71% 
35% 
32% 
20% 
32% 
15% 
62% 
29% 
26% 
6% 
Ascites 
10% 
4% 
1% 
0% 
5% 
2% 
2% 
3% 
2% 
4% 
Pleural 
effusion 
6% 
0% 
6% 
0% 
4% 
0% 
7% 
0% 
0% 
0% 
Proteinuria 
7% 
4% 
15% 
8% 
1% 
2% 
4% 
2% 
1% 
0% 
GI 
perforation 
0% 
2% 
2% 
2% 
1% 
2% 
1% 
2% 
1% 
0% 
Hemorrhage 
28% 
24% 
13% 
20% 
12% 
15% 
48% 
55% 
5% 
6% 
Pulmonary 
embolism 
4% 
5% 
2% 
0% 
6% 
15% 
1% 
2% 
1% 
4% 
 
 
 


 
PhII-122, NCI# 9048 
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2.3. Anti-VEGF Agents in Renal Cell Carcinoma 
 
 
 
2.3.1 
Bevacizumab (Avastin®) 
 
Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to 
and inhibits the biologic activity of human 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. 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.  For additional updated information beyond that listed below, 
please refer to the bevacizumab (Avastin®) complete prescribing information 
(package insert). 
 
Clinical Studies in RCC 
 
Patients with treatment-naïve mRCC were evaluated in a multicenter, randomized, 
double-blind, international study comparing bevacizumab plus interferon alfa 2a 
(IFN- α2a) versus placebo plus IFN-α2a (Escudier et al. 2007b).  A total of 649 
patients who had undergone a nephrectomy were randomized (1:1) to receive either 
bevacizumab (10 mg/kg IV infusion every 2 weeks; n = 327) or placebo (IV every 2 
weeks; n = 322) in combination with IFN-α2a (9 MIU subcutaneously three times 
weekly, for a maximum of 52 weeks). Patients were treated until disease progression 
or unacceptable toxicity. The main outcome measure of the study was investigator-
assessed PFS. Secondary outcome measures were ORR and OS. 
 
The median age was 60 years (range 18−82), 96% were white, and 70% were male. 
The study population was characterized by MKSCC scores as follows: 28% favorable 
(0), 56% intermediate (1-2), 8% poor (3-5), and 7% missing. 
 
PFS was statistically significantly prolonged among patients receiving bevacizumab 
plus IFN-α2a compared to those receiving IFN-α2a alone; median PFS was 10.2 
months vs. 5.4 months [HR 0.60 (95% CI 0.49, 0.72), p-value < 0.0001, stratified 
log-rank test]. Among the 595 patients with measurable disease, ORR was also 
significantly higher (30% vs. 12%, p < 0.0001, stratified CMH test). There was no 
improvement in OS based on the final analysis conducted after 444 deaths, with a 
median OS of 23 months in the bevacizumab plus IFN-α2a arm and 21 months in the 
IFN-α2a plus placebo arm [HR 0.86, (95% CI 0.72, 1.04)]. 
 
Safety Profile 
 
In the phase III trial of bevacizumab plus interferon α2a (Escudier et al. 2007b), grade 
3−5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving 
IFN-α plus bevacizumab compared to 304 patients receiving IFN-α plus placebo arm 
were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), 
hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and 


 
PhII-122, NCI# 9048 
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23 
hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm 
ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage 
intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic 
hematoma).  Grade 1−5 adverse events occurring at a higher incidence (≥ 5%) in 
patients receiving IFN-α plus bevacizumab compared to the IFN-α plus placebo arm 
are presented in the following table. 
 
MedDRA version 10.1 term 
IFN-α + 
Placebo 
(n=304) 
IFN-α + 
bevacizumab 
(n=337) 
Gastrointestinal disorders 
 
 
     Diarrhea 
16% 
21% 
 
 
 
General disorders and administration site conditions 
 
 
     Fatigue 
27% 
33% 
 
 
 
Investigations 
 
 
     Weight decreased 
15% 
20% 
 
 
 
Metabolism and nutrition disorders 
 
 
     Anorexia 
31% 
36% 
 
 
 
Musculoskeletal and connective tissue disorders 
 
 
     Myalgia 
14% 
19% 
     Back pain 
6% 
12% 
 
 
 
Nervous system disorders 
 
 
     Headache 
16% 
24% 
 
 
 
Renal and urinary disorders 
 
 
     Proteinuria 
3% 
20% 
 
 
 
Respiratory, thoracic and mediastinal disorders 
 
 
     Epistaxis 
4% 
27% 
     Dysphonia 
0% 
5% 
 
 
 
Vascular disorders 
 
 
     Hypertension 
9% 
28% 
 
 
 
2.3.2 
Pazopanib (VotrientTM) 
 
Pazopanib (VotrientTM) is a tyrosine kinase inhibitor (TKI).  Pazopanib tablets are for 
oral administration.  Each 200 mg tablet of pazopanib (VotrientTM) contains 216.7 mg 
of pazopanib hydrochloride, equivalent to 200 mg of pazopanib free base.  For 
additional updated information beyond that listed below, please refer to the pazopanib 
(VotrientTM) complete prescribing information (package insert). 


 
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Clinical Studies in RCC 
 
The safety and efficacy of pazopanib in renal cell carcinoma (RCC) were evaluated in 
a randomized, double-blind, placebo-controlled, multicenter, Phase 3 study 
(Sternberg et al. 2010).  Patients (N = 435) with locally advanced and/or metastatic 
RCC who had received either no prior therapy or one prior cytokine-based systemic 
therapy were randomized (2:1) to receive pazopanib 800 mg once daily or placebo 
once daily. The primary objective of the study was to evaluate and compare the 2 
treatment arms for progression-free survival (PFS); the secondary endpoints included 
overall survival (OS), overall response rate (RR), and duration of response. 
 
Of the total of 435 patients enrolled in this study, 233 patients had no prior systemic 
therapy (treatment-naïve subgroup) and 202 patients received one prior IL-2 or IFN-
α-based therapy (cytokine-pretreated subgroup). The baseline demographic and 
disease characteristics were balanced between the pazopanib and placebo arms. The 
majority of patients were male (71%) with a median age of 59 years. Eighty-six 
percent of patients were Caucasian, 14% were Asian and less than 1% were other. 
Forty-two percent were ECOG performance status 0 and 58% were ECOG 
performance status 1. All patients had clear cell histology (90%) or predominantly 
clear cell histology (10%). Approximately 50% of all patients had 3 or more organs 
involved with metastatic disease. The most common metastatic sites at baseline were 
lung (74%), lymph nodes (56%), bone (27%), and liver (25%).  A similar proportion 
of patients in each arm were treatment-naïve and cytokine-pretreated. In the cytokine-
pretreated subgroup, the majority (75%) had received interferon-based treatment. 
Similar proportions of patients in each arm had prior nephrectomy (89% and 88% for 
pazopanib and placebo, respectively). 
 
The analysis of the primary endpoint PFS was based on disease assessment by 
independent radiological review in the entire study population.  PFS was significantly 
prolonged with pazopanib compared with placebo in the overall study population 
(median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < 
.0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 
95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median 
PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective 
response rate was 30% with pazopanib compared with 3% with placebo (P < .001). 
The median duration of response was longer than 1 year.  Analysis of overall survival 
was immature. 
 
Safety Profile 
 
Potentially serious adverse reactions with pazopanib include hepatotoxicity, 
hypertension, QT prolongation and torsades de pointes, arterial thrombotic events, 
hemorrhagic events, and gastrointestinal perforation and fistula. 
 
Hepatic Toxicity:  In a controlled clinical study with pazopanib for the treatment of 


 
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RCC, ALT >3 X ULN was reported in 18% and 3% of the pazopanib and placebo 
groups, respectively. ALT >10 X ULN was reported in 4% of patients who received 
pazopanib and in <1% of patients who received placebo.  Concurrent elevation in 
ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline 
phosphatase >3 X ULN occurred in 5/290 (2%) of patients on pazopanib and 2/145 
(1%) on placebo.  
 
Hypertension:  In a controlled clinical study with pazopanib for the treatment of RCC, 
115/290 patients (40%) receiving pazopanib compared with 15/145 patients (10%) on 
placebo experienced hypertension.  Grade 3 hypertension was reported in 13/290 
patients (4%) receiving pazopanib compared with 1/145 patients (<1%) on placebo. 
The majority of cases of hypertension were manageable with anti-hypertensive agents 
or dose reductions with 2/290 patients (<1%) permanently discontinuing treatment 
with pazopanib because of hypertension.  Pazopanib has been associated with 
hypertensive crisis in patients with various cancer types including RCC.  In the 
overall safety population for RCC (N = 586), one patient had hypertensive crisis on 
pazopanib. 
 
QT Prolongation and Torsades de Pointes:  In a controlled clinical study with 
pazopanib, QT prolongation (≥500 msec) was identified on routine electrocardiogram 
monitoring in 3/290 (1%) of patients treated with pazopanib compared with no 
patients on placebo. Torsades de pointes was reported in 2/586 (<1%) patients treated 
with pazopanib in the RCC studies.  
 
Arterial Thrombotic Events:  In a controlled clinical study with pazopanib, the 
incidences of arterial thrombotic events such as myocardial infarction/ischemia 
[5/290 (2%)], cerebral vascular accident [1/290 (<1%)], and transient ischemic attack 
[4/290 (1%)] were higher in patients treated with pazopanib compared to the placebo 
arm (0/145 for each event).  
 
Hemorrhagic Events:  In a controlled clinical study with pazopanib, 37/290 patients 
(13%) treated with pazopanib and 7/145 patients (5%) on placebo experienced at least 
1 hemorrhagic event. The most common hemorrhagic events in the patients treated 
with pazopanib were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal 
hemorrhage (1%). Nine (9/37) patients treated with pazopanib who had hemorrhagic 
events experienced serious events including pulmonary, gastrointestinal, and 
genitourinary hemorrhage. Four (4/290) (1%) patients treated with pazopanib died 
from hemorrhage compared with no (0/145) (0%) patients on placebo.  In the overall 
safety population in RCC (N = 586), cerebral/intracranial hemorrhage was observed 
in 2/586 (<1%) patients treated with pazopanib. 
 
Hypothyroidism:  In a controlled clinical study with pazopanib, more patients had a 
shift from thyroid stimulating hormone (TSH) within the normal range at baseline to 
above the normal range at any post-baseline visit in pazopanib compared with the 
placebo arm (27% compared with 5%, respectively). Hypothyroidism was reported as 
an adverse reaction in 19 patients (7%) treated with pazopanib and no patients (0%) 


 
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in the placebo arm. 
 
Diarrhea:  Diarrhea occurred frequently and was predominantly mild to moderate in 
severity.  
 
Proteinuria:  In the controlled clinical study with pazopanib, proteinuria has been 
reported as an adverse reaction in 27 patients (9%) treated with pazopanib. In 2 
patients, proteinuria led to discontinuation of treatment with pazopanib.  
 
Lipase Elevations:  In a single-arm clinical study, increases in lipase values were 
observed for 48/181 patients (27%). Elevations in lipase as an adverse reaction were 
reported for 10 patients (4%) and were Grade 3 for 6 patients and Grade 4 for 1 
patient. In clinical RCC studies of pazopanib, clinical pancreatitis was observed in 
4/586 patients (<1%). 
 
Cardiac Dysfunction:  Pazopanib has been associated with cardiac dysfunction (such 
as a decrease in ejection fraction and congestive heart failure) in patients with various 
cancer types, including RCC. In the overall safety population for RCC (N = 586), 
cardiac dysfunction was observed in 4/586 patients (<1%). 
 
 
 
2.3.3 
Sorafenib (Nexavar®) 
 
Sorafenib (Nexavar®) is a multi-kinase inhibitor.  Sorafenib tablets are for oral 
administration.  Each red, round sorafenib (Nexavar®) film-coated tablet contains 
sorafenib tosylate (274 mg) equivalent to 200 mg of sorafenib.  For additional 
updated information beyond that listed below, please refer to the sorafenib 
(Nexavar®) complete prescribing information (package insert). 
 
Clinical Studies in RCC 
 
The safety and efficacy of sorafenib in the treatment of advanced renal cell carcinoma 
(RCC) were studied in the following two randomized controlled clinical trials. 
 
The TARGET study was a Phase 3, international, multicenter, randomized, double 
blind, placebo-controlled trial in patients with advanced renal cell carcinoma who had 
received one prior systemic therapy (Escudier et al. 2007a).  Primary study endpoints 
included overall survival and progression-free survival (PFS).  Tumor response rate 
was a secondary endpoint.  The PFS analysis included 769 patients stratified by 
MSKCC prognostic risk category (low or intermediate) and country and randomized 
to sorafenib 400 mg twice daily (N=384) or to placebo (N=385).  Baseline 
demographics and disease characteristics were well balanced for both treatment 
groups. The median time from initial diagnosis of RCC to randomization was 1.6 and 
1.9 years for the sorafenib and placebo groups, respectively. 
 
The median PFS for patients randomized to sorafenib was 167 days compared to 84 
days for patients randomized to placebo. The estimated hazard ratio (risk of 


 
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progression with sorafenib compared to placebo) was 0.44 (95% CI: 0.35, 0.55).  A 
series of patient subsets were examined in exploratory univariate analyses of PFS. 
The subsets included age above or below 65 years, ECOG PS 0 or 1, MSKCC 
prognostic risk category, whether the prior therapy was for progressive metastatic 
disease or for an earlier disease setting and time from diagnosis of less than or greater 
than 1.5 years. The effect of sorafenib on PFS was consistent across these subsets, 
including patients with no prior IL-2 or interferon therapy (N=137; 65 patients 
receiving sorafenib and 72 placebo), for whom the median PFS was 172 days on 
sorafenib compared to 85 days on placebo. 
 
Tumor response was determined by independent radiologic review according to 
RECIST criteria. Overall, of 672 patients who were evaluable for response, 7 (2%) 
sorafenib patients and 0 (0%) placebo patients had a confirmed partial response. Thus 
the gain in PFS in sorafenib -treated patients primarily reflects the stable disease 
population. 
 
At the time of a planned interim survival analysis, based on 220 deaths, overall 
survival was longer for sorafenib than placebo with a hazard ratio (sorafenib over 
placebo) of 0.72. This analysis did not meet the prespecified criteria for statistical 
significance.  
 
A Phase 2 randomized discontinuation trial in patients was also performed in patients 
with RCC (Ratain et al. 2006).  The primary endpoint was the percentage of 
randomized patients remaining progression-free at 24 weeks.  All patients received 
sorafenib for the first 12 weeks. Radiologic assessment was repeated at week 12. 
Patients with <25% change in bi-dimensional tumor measurements from baseline 
were randomized to sorafenib or placebo for a further 12 weeks. Patients who were 
randomized to placebo were permitted to cross over to open-label sorafenib upon 
progression. Patients with tumor shrinkage ≥25% continued sorafenib, whereas 
patients with tumor growth ≥25% discontinued treatment. 
 
Two hundred and two patients with advanced RCC were enrolled into the randomized 
discontinuation trial, including patients who had received no prior therapy and 
patients with tumor histology other than clear cell carcinoma. After the initial 12 
weeks of sorafenib, 79 patients with RCC continued on open-label sorafenib, and 65 
patients were randomized to sorafenib or placebo. After an additional 12 weeks, at 
week 24, for the 65 randomized patients, the progression-free rate was significantly 
higher in patients randomized to sorafenib (16/32, 50%) than in patients randomized 
to placebo (6/33, 18%) (p=0.0077). Progression-free survival was significantly longer 
in the sorafenib group (163 days) than in the placebo group (41 days) (p=0.0001, 
HR=0.29). 
 
Safety Profile 
 
The following additional drug-related adverse reactions and laboratory abnormalities 
were reported from clinical trials of sorafenib (very common 10% or greater, 


 
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common 1 to less than 10%, uncommon 0.1% to less than 1%): 
 
Cardiovascular:  
 Common: congestive heart failure, myocardial ischemia and/or infarction 
Uncommon: hypertensive crisis  
 Rare: QT prolongation 
 
Dermatologic:  
 Very common: erythema  
Common: exfoliative dermatitis, acne, flushing  
Uncommon: folliculitis, eczema, erythema multiforme, 
keratoacanthomas/squamous cell cancer of the skin  
 
Digestive:  
 Very common: increased lipase, increased amylase  
Common: mucositis, stomatitis (including dry mouth and glossodynia), dyspepsia, 
dysphagia  
Uncommon: pancreatitis, gastrointestinal reflux, gastritis, gastrointestinal 
perforations, cholecystitis, cholangitis 
 
 Note that elevations in lipase are very common (41%); a diagnosis of pancreatitis 
should not be made solely on the basis of abnormal laboratory values. 
 
General Disorders:  
 Very common: hemorrhage (including gastrointestinal & respiratory tract and 
uncommon cases of cerebral hemorrhage), asthenia, pain (including mouth, bone, 
and tumor pain)  
Common: decreased appetite, influenza-like illness, pyrexia  
Uncommon: infection 
 
Hematologic:  
 
Very common: leukopenia, lymphopenia  
 
Common: anemia, neutropenia, thrombocytopenia  
 
Uncommon: INR abnormal 
 
Hypersensitivity:  
 
Uncommon: hypersensitivity reactions (including skin reactions and urticaria) 
 
Metabolic and Nutritional:  
 
Very common: hypophosphatemia  
 
Common: transient increases in transaminases 
 Uncommon: dehydration, hyponatremia, transient increases in alkaline 
phosphatase, increased bilirubin (including jaundice), hypothyroidism, 
hyperthyroidism 
 
Musculoskeletal:  


 
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Common: arthralgia, myalgia 
 
Nervous System and Psychiatric:  
 Common: depression  
Uncommon: tinnitus, reversible posterior leukoencephalopathy 
 
Renal and Genitourinary:  
 
Common: renal failure 
 
Reproductive:  
 
Common: erectile dysfunction  
 
Uncommon: gynecomastia 
 
Respiratory:  
 Common: hoarseness  
Uncommon: rhinorrhea, interstitial lung disease-like events (includes reports of 
pneumonitis, radiation pneumonitis, acute respiratory distress, interstitial 
pneumonia, pulmonitis and lung inflammation) 
 
In addition, the following medically significant adverse reactions were uncommon 
during clinical trials of sorafenib: transient ischemic attack, arrhythmia, and 
thromboembolism. For these adverse reactions, the causal relationship to sorafenib 
has not been established. 
 
 
 
2.3.4 
Sunitinib (Sutent®) 
 
Sunitinib (Sutent®) is an oral multi-kinase inhibitor.  Sunitinib is for oral 
administration.  Sunitinib malate (Sutent®) capsules are supplied as printed hard shell 
capsules containing sunitinib malate equivalent to 12.5 mg, 25 mg or 50 mg of 
sunitinib together with mannitol, croscarmellose sodium, povidone (K-25) and 
magnesium stearate as inactive ingredients.  For additional information beyond that 
listed below, please refer to the sunitinib (Sutent®) complete prescribing information 
(package insert). 
 
Clinical Studies in RCC 
 
Treatment-Naïve RCC 
A multi-center, international randomized study comparing single-agent sunitinib with 
IFN-α was conducted in patients with treatment-naïve RCC (Motzer et al. 2007).  The 
objective was to compare PFS in patients receiving sunitinib versus patients receiving 
IFN-α.  Other endpoints included Objective Response Rate (ORR), Overall Survival 
(OS) and safety. Seven hundred fifty (750) patients were randomized (1:1) to receive 
either 50 mg sunitinib once daily on Schedule 4/2 or to receive IFN-α administered 
subcutaneously at 9 MIU three times a week. Patients were treated until disease 
progression or withdrawal from the study.  The ITT population included 750 patients, 
375 randomized to sunitinib and 375 randomized to IFN- α. Demographics were 


 
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comparable between the sunitinib and IFN- α groups with regard to age (59% vs. 
67% <65 years for sunitinib vs. IFN- α, respectively), gender (Male: 71% vs. 72%), 
race (White: 94% vs. 91%, Asian: 2% vs. 3%, Black: 1% vs. 2%, remainder not 
reported), and Performance Status (ECOG 0: 62% vs. 61%, ECOG 1: 38% each arm, 
ECOG 2: 0 vs. 1%). Prior treatment included nephrectomy (91% vs. 89%) and 
radiotherapy (14% each arm). The most common site of metastases present at 
screening was the lung (78% vs. 80%, respectively), followed by the lymph nodes 
(58% vs. 53%, respectively) and bone (30% each arm); the majority of the patients 
had multiple (2 or more) metastatic sites at baseline (80% vs. 77%, respectively). 
 
There was a statistically significant advantage for sunitinib over IFN-α in the 
endpoint of PFS.  In the pre-specified stratification factors of LDH (>1.5 ULN vs. 
≤1.5 ULN), ECOG performance status (0 vs. 1), and prior nephrectomy (yes vs. no), 
the hazard ratio favored sunitinib over IFN-α. The ORR was higher in the sunitinib 
arm. 
 
At the protocol-specified final analysis of OS, the median OS was 114.6 weeks for 
the sunitinib arm and 94.9 weeks for the IFN-α arm [HR= 0.821, 95% CI (0.673, 
1.001)]. The median OS for the IFN-α arm includes 25 patients who discontinued 
IFN- α treatment because of disease progression and crossed over to treatment with 
sunitinib as well as 121 patients (32%) on the IFN-α arm who received post-study 
cancer treatment with sunitinib. 
 
Cytokine-Refractory RCC 
The use of single agent sunitinib in the treatment of cytokine-refractory RCC was 
investigated in a single-arm multi-center study.  In this study, failure of prior cytokine 
therapy was based on radiographic evidence of disease progression defined by 
RECIST or World Health Organization (WHO) criteria during or within 9 months of 
completion of 1 cytokine therapy treatment (IFN-α, interleukin-2, or IFN-α plus 
interleukin-2; patients who were treated with IFN-α alone must have received 
treatment for at least 28 days) (Motzer et al. 2006).  All patients were required to 
have a histological clear-cell component. The primary endpoint was ORR.  Duration 
of Response (DR) was also evaluated. 
 
One hundred six patients (106) were enrolled. Patients received 50 mg sunitinib on 
Schedule 4/2. Therapy was continued until the patients met withdrawal criteria or had 
progressive disease.  There were 36 PRs as assessed by a core radiology laboratory 
for an ORR of 34.0% (95% CI 25.0, 43.8). DR data is premature as only 9 of 36 
patients (25%) responding to treatment had experienced disease progression or died at 
the time of the data cutoff. 
 
Safety Profile 
 
The as-treated patient population for the treatment-naive RCC study included 735 
patients, 375 randomized to sunitinib and 360 randomized to IFN-α (Motzer et al. 
2007).  The median duration of treatment was 11.1 months (range: 0.4 – 46.1) for 


 
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sunitinib treatment and 4.1 months (range: 0.1 – 45.6) for IFN- α treatment.  Dose 
interruptions occurred in 202 patients (54%) on sunitinib and 141 patients (39%) on 
IFN-α. Dose reductions occurred in 194 patients (52%) on sunitinib and 98 patients 
(27%) on IFN-α. Discontinuation rates due to adverse reactions were 20% for 
sunitinib and 24% for IFN-α.  Most treatment-emergent adverse reactions in both 
study arms were Grade 1 or 2 in severity.  Grade 3 or 4 treatment-emergent adverse 
reactions were reported in 77% versus 55% of patients on sunitinib versus IFN- α, 
respectively.  Adverse events are summarized in the table below. 
 
Adverse Reaction, 
n (%) 
Treatment Naïve RCC 
Sunitinib (n=375) 
INF-α (n=360) 
Any 
372 (99) 
290 (77) 
355 (99) 
197 (55) 
Constitutional 
 
 
 
 
  Fatigue 
233 (62) 
55 (15) 
202 (56) 
54 (15) 
  Asthenia 
96 (26) 
42 (11) 
81 (22) 
21 (6) 
  Fever 
84 (22) 
3 (1) 
 134 (37) 
1 (<1) 
  Weight decreased 
60 (16) 
1 (<1) 
60(17) 
3 (1) 
  Chills 
53 (14) 
3 (1) 
111 (31) 
0  
  Chest Pain 
50 (13) 
7 (2) 
24 (7) 
3 (1) 
  Influenza like illness 
18 (5) 
0 
54 915) 
1 (<1) 
Gastrointestinal  
 
 
 
 
  Diarrhea 
246 (66) 
37 (10) 
76 (21) 
1 (<1) 
  Nausea 
216 (58) 
21 (6) 
147 (41) 
6 (2) 
  Mucositis/stomatitis 
178 (47) 
13 (3) 
19 (5) 
2 (<1) 
  Vomiting 
148 (39) 
19 (5) 
62 (17) 
4 (1) 
  Dyspepsia 
128 (34) 
9 (2) 
16 94) 
0 
  Abdominal pain 
113 (30) 
20 (5) 
42 (12) 
5 (1) 
  Constipation 
85 (23) 
40 (1) 
49 (14) 
1 (<1) 
  Dry mouth 
50 (13) 
0 
27 (7) 
1 (<1) 
  GERD 
47 (12) 
1 (<1) 
3 (1) 
0 
  Flatulence 
52 (14) 
0 
8 (2) 
0 
  Oral pain 
54 (14) 
2 (<1) 
2 (1) 
0 
  Glossodynia 
40 (11) 
0 
2 (1) 
0 
  Hemorrhoids 
38 (10) 
0 
6 (2) 
0 
Cardiac 
 
 
 
 
  Hypertension 
127 (34) 
50 (13) 
13 (4) 
1 (<1) 
  Edema, peripheral 
91 (24) 
7 (2) 
17 (5) 
2 (1) 
  Ejection fraction decreased 
61 (16) 
10 (3) 
19 (5) 
6 (2) 
Dermatology 
 
 
 
 
  Rash 
109 (29) 
6 (2) 
39 (11) 
1 (<1) 
  Hand-foot syndrome 
108 (29) 
32 (8) 
3 (1) 
0 
  Yellow skin 
94 (25) 
1 (<1) 
0 
0 
  Dry skin 
85 (23) 
1 (<1) 
26 (7) 
0 
  Hair color changes 
75 (20) 
0 
1 (<1) 
0 
  Alopecia 
51 (14) 
0 
34 (9) 
0 
  Erythema 
46 (12) 
2 (<1) 
5 (1) 
0 
  Pruritis 
44 (12) 
1 (<1) 
24 (7) 
1 (<1) 
Neurology 
 
 
 
 
  Altered taste 
178 (47) 
1 (<1) 
54 (15) 
0 
  Headache 
86 (23) 
4 (1) 
69 (19) 
0 
  Dizziness 
43 (11) 
2 (<1) 
50 (14) 
2 (1) 
Musculoskeletal 
 
 
 
 


 
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Adverse Reaction, 
n (%) 
Treatment Naïve RCC 
Sunitinib (n=375) 
INF-α (n=360) 
Any 
372 (99) 
290 (77) 
355 (99) 
197 (55) 
  Back pain 
105 (28) 
19 (5) 
52 (14) 
7 (2) 
  Arthralgia 
111 (30) 
10 (3) 
69 (19) 
4 (1) 
  Pain in extremity 
 
 
 
 
Endocrine 
 
 
 
 
  Hypothyroidism 
150 (40) 
19 (5) 
107 (30) 
7 (2) 
Respiratory 
 
 
 
 
  Cough 
100 (27) 
3 (1) 
51 (14) 
1 (<1) 
  Dyspnea 
99 (26) 
24 (6) 
71 (20) 
15 (4) 
  Nasopharyngitis 
54 (14) 
0 
8 (2) 
0 
  Oropharyngeal Pain 
51 (14) 
2 (<1) 
9 (2) 
0 
  Upper respiratory tract 
infection 
43 (11) 
2 (<1) 
9 (2) 
0 
Metabolism/Nutrition 
 
 
 
 
  Anorexia 
182 (48) 
11 (3) 
153 (42) 
7 (2) 
Hemorrhage/Bleeding 
 
 
 
 
  Bleeding, all sites 
140 (37) 
16 (4) 
35 (10) 
3 (1) 
Psychiatric 
 
 
 
 
  Insomnia 
57 (15) 
3 (<1) 
37 (10) 
0 
  Depression 
40 (11) 
0 
51 (14) 
5 (1)  
 
2.4. Rationale 
 
A capacity for neoangiogenesis is a fundamental property of cancer (Hanahan et al. 
2000).  With the clinical application of multiple inhibitors of VEGF signaling, 
angiogenesis is a validated therapeutic target.  However, the overall clinical benefit of 
agents targeting VEGF has been less than what was hoped.  An important mechanism 
of resistance to anti-VEGF therapy is the selection for or up-regulation of alternative 
pro-angiogenic pathways and treatments targeting these alternative angiogenic 
pathways are needed (Abdollahi et al. 2010; Bergers et al. 2008; Ellis et al. 2008).   It 
is not presently known whether continued VEGF pathway inhibition is required for 
the clinical efficacy of alternative antiangiogenic agents. Moreover, biomarkers of 
sensitivity or resistance to antiangiogenic therapies are urgently needed. 
 
The angiopoietin-Tie signaling system is an alternative vascular signaling pathway 
that is involved in vascular development and maintenance.  Angiopoietin 1 (Ang1) 
and Angiopoietin 2 (Ang2) are ligands of Tie2, a receptor tyrosine kinase expressed 
on endothelial cells (Augustin et al. 2009).  While Ang1 and Ang2 have opposing 
effects on the Tie2 receptor in most contexts, they both contribute to vascular 
homeostasis.  High levels of Ang2 have been found in breast cancer, non-small cell 
lung cancer (NSCLC), ovarian cancer, and AML.  In renal cell carcinoma (RCC), 
Ang2 is elevated at the time of progression on VEGF receptor (VEGFR) targeted 
therapy (Bullock et al. 2010).  Thus, angiogenesis through the Ang/Tie system may 
contribute to anti-angiogenic therapy resistance in a subset of patients treated with 
VEGF pathway targeted agents.   
 
In this trial, we hypothesize that 1) inhibition of the angiopoietin-Tie pathway 


 
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either alone or in combination with continued anti-VEGF therapy will result in 
tumor responses in patients with renal cell cancer who have progressed on anti-
VEGF therapy and that 2) pretreatment tumor- and blood-derived biomarkers 
will predict resistance to continued anti-angiogenic treatment in patients who 
have progressed on anti-VEGF therapy. 
 
Bevacizumab, pazopanib, sorafenib and sunitinib are anti-VEGF agents that are 
indicated for the treatment of advanced renal cell cancer.  This trial will evaluate 
AMG 386 alone or AMG 386 plus bevacizumab, pazopanib, sorafenib, or sunitinib 
after progression on at least one line of anti-VEGF therapy for renal cell cancer.  
Preliminary results of Phase 1B study of AMG 386 with sorafenib or sunitinib in 
advanced renal cell carcinoma were recently presented (Appleman et al. 2010).  The 
preliminary efficacy results were encouraging with 1 complete response, 12 
confirmed partial responses, and 15 patients with stable disease in the first 30 
evaluable patients.  Preliminary data from a randomized trial of sorafenib combined 
with AMG 386 or sorafenib plus placebo suggest the possibility of higher responses 
but not improved PFS with the combination (Rini et al. 2011).  This trial will provide 
complementary data by evaluating AMG 386 at a higher dose and in anti-VEGF 
pretreated RCC patients. With this preliminary data, it has not been established 
whether anti-VEGF therapy enhances level of activity of AMG 386 alone, thus 
providing rationale for the randomization in this trial.   
 
A major objective of this trial is to use pretreatment tumor biopsies to explore 
biomarkers of sensitivity and resistance to both angiopoietin inhibition and combined 
angiopoietin/VEGF inhibition in the renal cell cancer cohort.  We hypothesize that 
the expression of angiogenic biomarkers will be influenced by exposure to an anti-
VEGF agent and will therefore compare the expression pattern of biomarkers in the 
study biopsy to results obtained from archival specimens.  The goal of these analyses 
– in addition to better understanding why tumors did or did not respond – is to 
identify a subset of biomarkers which can be further studied in future trials. 
 
2.5. Correlative Studies Background 
 
2.5.1 Overview 
 
 
 This trial design allows for the simultaneous exploration of tumor and blood 
based anti-angiogenic therapy resistance biomarkers as well as the effect of 
combined anti-angiopoietin and anti-VEGF therapy on circulating angiogenic 
factors.  Because archival tumor specimens do not represent the tumor after 
exposure to and progression on a regimen containing an anti-VEGF agent, a 
research biopsy will be performed on all patients immediately prior to treatment 
in order to evaluate angiogenic biomarkers immediately (within 13 weeks) after 
VEGF targeted treatment.  Blood sampling will be performed prior to treatment, 
once per cycle at the completion of the first 2 cycles, and upon progression.   
 


 
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Although AMG 386 targets a VEGF-independent pathway of angiogenesis, its 
activity may still be dependent on alternative pro-angiogenic signaling, 
particularly through the VEGF pathway. Therefore, markers of VEGF-pathway-
mediated angiogenesis, and other complementary factors such as PDGF, FGF and 
IL-8, may be useful to select patients for continued anti-angiogenic therapy.  
Therefore, we will evaluate a) tumor-based biomarkers of resistance and 
sensitivity to anti-angiogenic therapy, b) compare these biomarkers between 
archival specimens and post-VEGF therapy failure specimens, c) evaluate the 
effects of angiopoietin inhibition with and without continued anti-VEGF therapy 
on circulating angiogenic biomarkers and d) evaluate pharmacogenetic correlates 
of anti-angiogenic therapy resistance and sensitivity.  In each of these settings, 
biomarkers will be categorized into those suggestive of VEGF-pathway activity, 
angiopoietin-pathway activity, or of VEGF- and angiopoietin-independent 
angiogenesis.  The goal of these analyses is to identify a subset of these 
biomarkers for future study should this agent or these combinations warrant 
further study.  Our overall hypotheses are that: 
 
 
(1)  
Tumors with evidence of active angiopoietin – Tie2 pathway expression 
will be sensitive to angiopoietin inhibition, 
 
(2)  
Tumors with continued evidence of VEGF pathway activation after anti-
VEGF therapy will be optimally inhibited by continuation of the anti-
VEGF agent,  
 
(3)  
Tumors with evidence of VEGF- and angiopoietin-independent 
angiogenesis will be resistant to AMG 386 + continued anti-VEGF 
therapy, and 
 
(4)  
The expression of angiogenesis related genes will differ in archival and 
pre-treatment tumor biopsy specimens. 
 
2.5.2 Tumor-Based Correlative Studies 
 
 In previous work, we used quantitative PCR on carefully microdissected tumor 
specimens to evaluate angiogenic gene expression levels in patients with 
metastatic colorectal cancer treated with bevacizumab, and suggested that 
elevated VEGFR2 and NRP-1 expression levels were associated with an 
improved overall survival (Zhang et al. 2010).  As some previous research 
looking at tissue-based biomarkers of angiogenic resistance has suffered from the 
lack of validated and quantitative laboratory procedures; our use of quantitative 
real-time PCR allows for reproducible gene expression analyses.  Up-regulation 
of the VEGF pathway genes may suggest that after progression on an anti-VEGF 
agent, continued VEGF-pathway inhibition is required to restrain continued 
angiogenesis.    Thus we will examine the following: 
 
 
• 
The intratumoral expression of the VEGF-pathway genes VEGF, VEGFR1, 
VEGFR2 and NRP-1 as markers of active VEGF-pathway mediated 
angiogenesis.   


 
PhII-122, NCI# 9048 
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• 
The intratumoral expression of Ang1, Ang2, and Tie2 as markers of active 
angiopoietin-pathway mediated angiogenesis.  
 
• 
Alternatively, resistance to anti-VEGF and anti-angiopoietin therapy may 
result from up-regulation of alternative pro-angiogenic pathways. The 
expression of IL-8, VCAM-1 and bFGF will be analyzed as markers of 
VEGF- and angiopoietin-independent angiogenesis.   
 
 Paraffin-embedded tumor blocks will be prepared from 1) archival tumor 
specimens and from 2) tumor biopsies from RCC patients taken at the start of this 
trial.  Gene expression will be measured using a validated mRNA isolation and 
quantization method and normalized to an internal reference gene (Response 
Genetics, Inc.) as previously described (Vallbohmer et al. 2006).  Briefly, each 
block will be reviewed for quality and tumor content by a board-certified 
pathologist.  Ten µm-thick sections will be prepared from identified areas with the 
highest tumor concentration.  If the histology is homogenous and contains more 
than 80% tissue of interest, the samples will be dissected from the slides using a 
scalpel.  Laser capture microdissection will be applied to all other specimens.  
After mRNA isolation and cDNA synthesis, a fluorescence-based real-time 
detection method (Taqman, Applied Biosystems, Foster City, CA) will be used to 
quantitate the expression of each gene of interest and the internal reference gene 
(β-actin).   
 
2.5.3 Pharmacodynamic Correlative Studies 
 
 In order to better understand the success or failure of AMG 386 + continued anti-
VEGF therapy in individual patients, this randomized trial design allows the 
opportunity to compare the effects of AMG 386 monotherapy to AMG 386 + anti-
VEGF therapy on VEGF-pathway, angiopoietin-Tie2 pathway, and VEGF-
angiopoietin-pathway independent circulating angiogenic factors.  Although not 
prospectively validated, a number of circulating biomarkers have been associated 
with the efficacy of antiangiogenic treatments (Jain et al. 2009; Jubb et al. 2010; 
Jubb et al. 2006).  Changes in certain circulating angiogenic factors have been 
associated with the efficacy of VEGF targeted treatment (Hanrahan et al. 2010), 
and certain factors seem to rise upon progression on VEGF targeted therapy 
(Kopetz et al. 2010).  We hypothesize that: 
 
 
(1)  
AMG 386 will exert its anti-angiogenic effect by sequestering both Ang1 
and Ang2, resulting in decreased circulating levels of Ang2. 
 
(2)  
Resistance to AMG 386 + anti-VEGF therapy will be accompanied by 
increases (or lack of decreases) in circulating markers of VEGF- and 
angiopoietin-independent angiogenesis. 
 
Circulating Ang2 and soluble Tie2 will be measured as plasma markers of 
angiopoietin-pathway activity.  Plasma VEGF-A, and soluble VEGFR2 will be 
measured as markers of VEGF-mediated angiogenic activity.  Levels of IL-8, 
PlGF, ICAM1, VCAM1, PDGFα, PDGFβ and FGFR ligands (including FGF2) 


 
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will be measured as markers of VEGF/angiopoietin-independent angiogenesis.  
Samples will be obtained at baseline (prior to cycle 1), prior to cycle 2, prior to 
cycle 3, and at progression.  Plasma levels of selected markers will be performed 
by multiplex bead suspension array.  Soluble VEGFR2 and Tie2 receptors and 
Ang2 will be measured by ELISA.     
 
2.5.4 Pharmacogenetic Correlative Studies 
 
 We and others have shown that single nucleotide polymorphisms (SNPs) in 
VEGF pathway (VEGF and VEGFR2) genes and VEGF-pathway independent 
genes (IL-8, PlGF, ICAM-1, VCAM-1, and FGFR4) can predict the benefit of 
bevacizumab in ovarian cancer (Schultheis et al. 2008), breast cancer (Schneider 
et al. 2008), NSCLC (Zhang et al. 2009), and colorectal cancer patients (Shaye et 
al. 2007).  There are incomplete data regarding the association of polymorphisms 
in Ang1, Ang2, and Tie2 with the development or treatment of malignancies, 
although one study did not show an association between an Ang2 polymorphism 
and ovarian, cervical, or endometrial cancer (Konac et al. 2007).  In this trial, we 
will further explore these polymorphisms as predictors of efficacy of anti-
angiopoietin and combined anti-angiopoietin/anti-VEGF therapy.  Genomic DNA 
will be collected from peripheral mononuclear cells collected from each subject at 
the start of the trial.  Polymorphisms in VEGF, VEGFR2, Ang2, IL-8, PlGF, 
ICAM-1, VCAM-1, and FGFR4 genes will be analyzed by polymerase chain 
reaction-restriction length polymorphism (PCR-RFLP) as previously described 
(Schneider et al. 2008; Schultheis et al. 2008; Shaye et al. 2007; Zhang et al. 
2009).   
 
3. PATIENT SELECTION 
 
3.1. Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed renal cell 
carcinoma except medullary or collecting duct subtypes.  Sarcomatoid 
differentiation will be allowed. 
 
3.1.2 Patients must have measurable disease, 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) as >20 mm 
with conventional techniques or as >10 mm with spiral CT scan, MRI, or 
calipers by clinical exam.  See Section 11 for the evaluation of measurable 
disease. 
 
3.1.3 Patients must have documented radiologic or clinical progressive disease 
following at least one prior anti-VEGF regimen administered either as a single 
agent or in combination with other agents for at least 8 weeks.  The prior anti-
VEGF treatment regimen must have included bevacizumab, pazopanib, 
sorafenib or sunitinib administered not more than 12 weeks before study 


 
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entry.   Note:  Enrollment not more than 8 weeks after the last dose of anti-
VEGF therapy is encouraged.   Nevertheless, intercurrent therapy with an 
mTOR inhibitor (everolimus or temsirolimus) will be allowed if progression 
on that treatment is observed within 12 weeks of the prior anti-VEGF therapy. 
 
3.1.4 Age >18 years.  Because no dosing or adverse event data are currently 
available on the use of AMG 386 alone or in combination in patients <18 
years of age, children are excluded from this study, but will be eligible for 
future pediatric trials. 
 
3.1.5 Any number of prior regimens is allowed.  Prior investigational therapy is 
allowed. 
 
3.1.6 ECOG performance status <1 (Karnofsky > 70%, see Appendix A). 
 
3.1.7 Life expectancy of greater than 3 months. 
 
3.1.8 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 
− AST(SGOT)/ALT(SGPT)  
≤2.5 X institutional upper limit of normal 
− PTT or aPTT 
 
 
 
 
≤ ULN per institutional laboratory range and 
INR ≤1.5 
− creatinine 
 
 
 
 
 
within normal institutional limits 
 
OR 
− creatinine clearance  
 
 
>40 mL/min per 24 h urine collection or 
calculated according to the Cockcroft-Gault 
formula 
 
CrCl (mL/min) 
= 
(140-age) x actual body weight (kg) 
(x 0.85 for females) 
72 x serum creatinine (mg/dL) 
 
− urinary protein  
 
 
 
≤100 mg/dL in urinalysis or ≤1+ on dipstick, 
unless quantitative protein is <1000 mg in a 
24 h urine sample 
 
3.1.9 Generally well-controlled blood pressure with systolic blood pressure ≤140 
mmHg AND diastolic blood pressure ≤90 mmHg prior to enrollment.  The use 
of anti-hypertensive medications to control hypertension is permitted. 
 
 
3.1.10 Patients must have a tumor site amenable to biopsy as determined by the 
treating investigator.  Any questions regarding suitability of a site for biopsy 
will be adjudicated by the principal investigator. 


 
PhII-122, NCI# 9048 
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3.1.11 Patients must be willing to consent to tumor biopsy for research purposes. 
 
 
 
 
3.1.12  Patients should have archival tumor tissue (either unstained slides or tumor 
blocks) available for retrieval.  See section 9.1.2 for specimen shipping 
instructions. 
 
3.1.13 The effects of AMG 386 are known to be detrimental to fetal development.  
For this reason and because inhibitors of angiogenesis as well as other 
therapeutic agents used in this trial 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,for the duration of study participation, and 6 months after completion of 
AMG 386.  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 AMG 386 and 
bevacizumab, pazopanib, sunitinib, or sorafenib administration. 
 
3.1.14 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2. Exclusion Criteria 
 
 
 
 
3.2.1 Intolerance of prior treatment with bevacizumab, pazopanib, sorafenib, or 
sunitinib. 
 
 
 
 
 
 
Note:  Subjects who required a dose reduction of pazopanib, sorafenib, or 
sunitinib during prior therapy MAY be eligible if they tolerated the agent after 
dose level reduction (to a minimum of dose level -2 as defined in this 
protocol; see Section 6 for dose levels). 
 
3.2.2 Central nervous system metastases unless: (1) metastases have been treated 
and have remained controlled for at least two weeks following treatment, 
AND (2) patient has no residual neurological dysfunction off corticosteroids 
for at least one week.  A CT or MRI to evaluate for CNS disease is required 
for symptomatic patients only. 
 
3.2.3 History of venous or arterial thromboembolism within 12 months prior to 
enrollment/randomization. 
 
3.2.4 History of clinically significant bleeding within 6 months of 
enrollment/randomization. 
 
3.2.5 Unresolved toxicities from prior systemic therapy that are CTCAE version 3.0 


 
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or 4.0 ≥ Grade 2 in severity except alopecia. 
 
3.2.6 Currently or previously treated with AMG 386, or other molecules that inhibit 
the angiopoietins or Tie2 receptor. 
 
3.2.7 Clinically significant cardiovascular disease within 12 months prior to 
enrollment/randomization, including myocardial infarction, unstable angina, 
grade 2 or greater peripheral vascular disease, cerebrovascular accident, 
transient ischemic attack, congestive heart failure, or arrhythmias not 
controlled by outpatient medication or placement of percutaneous 
transluminal coronary angioplasty/stent. 
 
3.2.8 Major surgery within 28 days prior to enrollment or still recovering from prior 
surgery. 
 
3.2.9 Minor surgical procedures except placement of tunneled central venous 
access device within 3 days prior to enrollment. 
 
3.2.10  Non-healing wound, ulcer (including gastrointestinal), or fracture. 
 
3.2.11 Subject not consenting to the use of highly effective contraceptive precautions 
(e.g., double barrier method [i.e., condom plus diaphragm]) during the course 
of the study and for 6 months after administration of the last study medication. 
 
3.2.12 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to AMG 386 or the anti-VEGF agent used in study. 
 
3.2.13 History of allergic reactions to bacterially-produced proteins. 
 
3.2.14 Patients who have had anti-VEGFR tyrosine kinase inhibitor within 1 week, 
mTOR inhibitor within 1 week or anti-VEGF antibody therapy within 3 weeks 
prior to entering the study.  Patients who have had other forms of 
chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or 
mitomycin C) prior to entering the study or those who have not recovered 
from adverse events due to agents administered more than 4 weeks earlier. 
 
3.2.15 Patients who have not yet completed at least 21 days (30 days for prior 
monoclonal antibody therapy) since ending other investigational device or 
drug trials, or who are currently receiving other investigational treatments. 
 
3.2.16 Patients receiving any medications or substances that are strong inhibitors or 
inducers of CYP450 3A4 are ineligible due to the potential for interaction 
with pazopoanib, sorafenib, or sunitinib.  Caution is advised for patients 
requiring weak or moderate CYP450 3A4 inhibitors or inducers.  Specifically 
prohibited medicines include indinavir, nelfinavir, ritonavir, clarithromycin, 


 
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itraconazole, ketoconazole,  nefazodone, carbamazepine, phenobarbital, 
phenytoin, pioglitazone, rifabutin, rifampin, St. John's wort, and troglitazone.   
 
 
 
Note: A list of CYP450 3A4 inhibitors and inducers is included in Appendix 
C.  Because the lists of these agents are constantly changing, it is important to 
regularly consult a frequently-updated list such as 
http://medicine.iupui.edu/clinpharm/ddis/table.asp; medical reference texts 
such as the Physicians’ Desk Reference may also provide this information.  
As part of the enrollment/informed consent procedures, the patient will be 
counseled on the risk of interactions with other agents, and what to do if new 
medications need to be prescribed or if the patient is considering a new over-
the-counter medicine or herbal product.   
 
3.2.17 Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would 
limit compliance with study requirements. 
 
3.2.18 Pregnant women are excluded from this study because AMG 386, 
bevacizumab, pazopanib, sorafenib, and sunitinib are inhibitors of 
angiogenesis with the 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 AMG 386, breastfeeding 
must be discontinued if the mother is treated with AMG 386. 
 
3.2.19 HIV-positive patients on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with pazopanib, 
sorafenib, or sunitinib.  In addition, these patients are at increased risk of 
lethal infections when treated with marrow-suppressive therapy.  Appropriate 
studies will be undertaken in patients receiving combination antiretroviral 
therapy when indicated.  
 
3.2.20 Inability to take oral medications on a continuous basis.  Patients who are to 
take pazopanib, sorafenib, or sunitinib and are unable to swallow pills whole 
are ineligible (The pills cannot be crushed or broken).  
 
3.2.21 Any condition which in the investigator’s opinion makes the subject 
unsuitable for study participation 
 
3.3. Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. The 
anticipated accrual in ethnicity/race and gender categories is provided below: 
 
 


 
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Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
8 
9 
17 
Not Hispanic or Latino 
17 
44 
61 
Ethnic Category: Total  
25 
53 
78 
Racial Category 
 
 
American Indian or 
Alaskan Native 
0 
0 
0 
Asian 
2 
4 
6 
Black or African American 
2 
8 
10 
Native Hawaiian or other 
Pacific Islander 
0 
0 
0 
White 
21 
41 
62 
Racial Category: Total  
25 
53 
78 
  
 
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 be scheduled for a research biopsy within 7 
days.  Treatment should be initiated between 3 and 5 working days after the biopsy 
pending full recovery from any biopsy related effects.  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 Study Coordinator 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 research nurse or data manager must complete the 
eligibility/registration form and contact the Consortium office (Data Coordinating 
Center for the California Cancer Consortium) at the City of Hope (626-256-4673, ext. 
65928), FAX a copy of the completed eligibility checklist, required pre-study tests 
(laboratory and pathology report), signed Informed Consent, signed Patients' Bill of 


 
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Rights and HIPAA authorization form. (FAX Number: 626-256-8654). See 
Appendix G (“Registration Procedures”). 
 
The research nurse or data manager at the participating site will then call the Data 
Coordinating Center at Tel# 626-256-4673 extension 65928 to confirm receipt of all 
registration documents. To complete the registration process, the data coordinating 
center coordinator will: 
 
• Verify the eligibility 
• Register the patient on study 
• Assign a patient accession number 
• 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. 
 
4.3. Randomization Process 
 
Statisticians in the Data Coordinating Center will prepare a stratified randomization 
list of treatment assignments, with stratification by participating institution.  This 
process will utilize a random permuted block design, so as to minimize the difference 
in the number of patients assigned to the 2 treatment arms for any given institution. 
The block sizes will be chosen by the Study Biostatistician, and not revealed until 
patient accrual has been completed. 
 
The stratified randomization list will be provided to the Study Coordinator, who will 
be the only other person with access to the list. It will allow for instant determination 
of (randomized) treatment assignment for the patient, as soon as his eligibility has 
been confirmed.  
 
If an additional institution(s) later join(s) the study, an additional stratified 
randomization list(s) will be prepared in a similar manner to accommodate the 
patients to be registered and randomized from that new institution(s). 
 
 
5.  
TREATMENT PLAN 
 
 
 
 
5.1. Pre-Treatment Tumor Biopsy 
 
 
Assent to performing a fresh tumor biopsy is a requirement of this trial.  At the time 
of enrollment, the treating investigator will select a site amenable for tumor biopsy.  
The biopsy should be performed in the first 7 days after registration.  The tumor site 
used for biopsy may be modified in consultation with appropriate specialists (e.g. 
radiologist, interventional radiologist).  If a site is deemed appropriate for biopsy with 
minimal risk to the participant by agreement between the investigators and 
appropriate specialists, a biopsy will be attempted. The use of imaging to facilitate 
biopsies will be decided by appropriately trained specialists and may include an 


 
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ultrasound (US), a computer tomography (CT) scan, or a magnetic resonance imaging 
(MRI) scan.  Should a CT scan be needed for biopsy, the number of scans for each 
procedure will be limited to the minimum number needed to safely obtain a biopsy.  
Tumor biopsies and local anesthesia will be administered only if they are considered 
to be of low risk to the participant, as determined by the investigators and appropriate 
specialists. 
 
Biopsy will be performed by a qualified professional.  It is preferred that a core 
biopsy system be used to obtain at least 2 core biopsies not less than 20 gauge in 
diameter and 1 cm in length.  Tumor biopsies will be obtained with the help of the 
Interventional Radiology team by a percutaneous approach.  When necessary for 
clinical management, one biopsy sample will be sent for pathological review and the 
remainder will be sent for correlative studies; if only a single biopsy is feasible, then 
the sample will be divided.  If not necessary for clinical management, the entire 
specimen will be sent for correlative studies after processing.    
 
5.2. Agent Administration 
 
Treatment will be administered on an outpatient basis.  The first cycle of treatment 
should begin 3-5 working days after the biopsy procedure when feasible and is 
subject to full recovery from any biopsy related complications, and should also begin 
at least 14 days from the last dose of an mTOR inhibitor if the patient was previously 
treated with an mTOR inhibitor.  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.  Those 
randomized to Arm A will receive AMG 386 monotherapy and those randomized to 
Arm B will receive AMG 386 plus their prior anti-VEGF agent as described in the 
tables below. 
 
 
REGIMEN DESCRIPTION FOR ARM A  
(AMG 386 Monotherapy) 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
AMG 386 
Flush the IV line 
with 0.9% NS 
(minimum volume 
is 5 mL) before and 
after the each IV 
infusion. 
15 mg/kg 
IV over 60 
minutesa 
Day 1, 8, 
15, 22, 29, 
and 36 
42 days 
(6 weeks) 
a If the first infusion is well tolerated, subsequent infusions may be delivered over 30 
minutes. 
 
 
 


 
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REGIMEN DESCRIPTION FOR ARM B  
(AMG 386 + continued anti-VEGF therapy) 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
AMG 386 
Flush the IV line 
with 0.9% NS 
(minimum volume 
is 5 mL) before and 
after the each IV 
infusion. 
15 mg/kg 
IV over 60 
minutesa 
Day 1, 8, 
15, 22, 29, 
and 36 
42 days 
(6 weeks) 
ONE of the following anti-VEGF agents will be administered: 
Bevacizumab 
Dilute in 100 mL 
0.9% Sodium 
Chloride Injection, 
USP 
10 mg/kg 
IV over 90 
minutesb 
Day 1, 15, 
and 29 
42 days 
(6 weeks) 
Pazopanib 
At least 1 hour 
before or 2 hours 
after a meal 
800 mg 
once 
dailyd 
Oralc 
Daily, 
Days 1-42 
Sorafenib 
At least 1 hour 
before or 2 hours 
after a meal 
400 mg 
BIDd 
Oralc 
Daily, 
Days 1-42 
42 days 
(6 weeks) 
Sunitinib 
With or without 
food 
50 mg 
once 
dailyd 
Oralc 
Daily, 
Days 1-28 
a If the first infusion is well tolerated, subsequent infusions may be delivered over 30 
minutes. 
b Administer second infusion over 60 minutes if first infusion is tolerated; 
administer all subsequent infusions over 30 minutes if infusion over 60 minutes is 
tolerated. 
c The patient will be requested to maintain a medication diary of each dose of 
medication.  The medication diary will be returned to clinic staff at the end of each 
course. 
d The standard starting dose is given.  Patients may start at a lower dose based on 
toxicity during prior administration.  See section 6 for dose levels. 
 
 
5.2.1 AMG 386 
 
The actual dose of AMG 386 will be based upon the subject’s actual weight (Kg).  
Baseline weight of a subject should be taken prior to the first dose of AMG 386, 
and subsequent weights will be taken on Day 1 of each cycle.  Currently, the 240 
mg vials are being used in all CTEP sponsored protocols.  Once the NCI has 
depleted the 240 mg supply, stop using the dosing table that is currently available 
in the protocol.  All calculated dose in Dose Levels 10mg/kg, 15 mg/kg, and 30 
mg/kg will be rounded to the nearest vial size using 150 mg or/and 600 mg vials.  
Please refer to Appendix H for dose rounding guidelines that use the 150 mg and 


 
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600 mg vials.   
 
Subject’s actual 
weight 
AMG 15 mg/kg 
Weight in kilograms 
(kg) 
AMG 386 dose in 
milligrams (mg) 
35 to 44.9 
600 mg 
45 to 54.9 
750 mg 
55 to 64.9 
900 mg 
65 to 74.9 
1050 mg 
75 to 84.9 
1200 mg 
85 to 94.9 
1350 mg 
95 to 104.9 
1500 mg 
105 kg and above 
Add 150 mg AMG 386 
for each additional 10 kg 
in subject’s weight 
 
 
Every effort should be made to keep the weekly AMG 386 infusions exactly 7 
days apart; however, occasionally a weekly dose may need to be given off 
schedule due to logistical reasons.  Appropriate documentation of AMG 386 
dosing must be maintained in the source documents and Case Report Form. 
 
A physician or medical staff involved in study evaluations must be available 
during the administration of investigational product to assess and treat adverse 
events that may arise during dosing.  Subjects will be monitored in the clinic for 
at least 1 hour after the completion of AMG 386 infusions for any signs of 
adverse events for the first dose of therapy.  For all subsequent dosing, subjects 
will be monitored for at least 30 minutes after the completion of AMG 386. 
 
The first dose of AMG 386 will be administered as an IV infusion using an 
intravenous infusion pump given over a 60-minute period.  Administration of 
AMG 386 by methods other than infusion pump must be discussed and approved 
by the sponsor prior to administration.  If the initial dose administration is well 
tolerated, future administrations of AMG 386 may be given in no less than 30 
minutes at the discretion of the investigator. 
 
Before and after each IV infusion, the IV access will be flushed with a minimum 
of 5.0 mL of sterile 0.9% NaCl suitable for injection.  AMG 386 may be given 
through a peripheral IV or through a central catheter (including but not limited to 
a port-a-cath, Hickman, triple lumen catheter, or PICC line).  Subjects must be 
monitored throughout and immediately after the administration of AMG 386.  If 
AMG 386 extravasates during IV administration, the infusion must be 
immediately stopped.  There is no specific treatment for extravasation of AMG 
386.  Supportive care may be given as per institutional policy and guidelines. The 
subject may also develop a reddened area around the site of infiltration which is 
caused by accumulation of investigational product in the surrounding tissues 


 
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(depot effect).  If this occurs, tell patients to report it to the healthcare research 
team.  The remaining volume of AMG 386 may be administered through a 
separate IV well away from the area of extravasation (or the opposite arm). 
 
5.2.2 Bevacizumab 
 
Bevacizumab will be administered as an intravenous infusion on Day 1, 15, and 
29 in a 42-day Cycle.  Bevacizumab should be administered after AMG 386 on 
the days when these two drugs are both administered.  The initial dose on this trial 
should be administered over a minimum of 90 minutes.  If no adverse reactions 
occur after the initial dose, the second dose should be administered over a 
minimum of 60 minutes.  If no adverse reactions occur after the second dose, all 
subsequent doses should be administered over a minimum of 30 minutes.  If 
infusion-related adverse reactions occur, all subsequent infusions should be 
administered over the shortest period that was well tolerated. 
 
5.2.3 Pazopanib 
 
Pazopanib is supplied as 200 mg tablets.  The initial dose of pazopanib for this 
trial is 800 mg (4 tablets) orally once daily without a scheduled off-treatment 
period.  The dose of pazopanib should not exceed 800 mg per day at any point on 
this trial.  Patients who required a dose reduction to 400 mg orally once daily or 
200 mg orally once daily due to toxicity during prior treatment with pazopanib 
will be treated with that dose.  A lower starting dose is not allowed.  Because 
specific safety data for the combination of pazopanib and AMG 386 is not 
available, extra caution will be applied to the first 5 patients receiving this 
combination.  Toxicity experienced by these 5 patients will be reviewed on 
monthly CCCP conference calls.   
 
Exposure is increased when pazopanib is taken with food.  Therefore, pazopanib 
should be taken without food (at least 1 hour before or 2 hours after a meal).   
 
Pharmacokinetic results indicate that the bioavailability and the rate of absorption 
of pazopanib are increased after administration of the crushed tablet relative to 
administration of the whole tablet.  Do not crush tablets due to the potential for 
increased rate of absorption that may affect systemic exposure. 
 
The patient will be requested to maintain a medication diary (see Appendix E) of 
each dose of medication. The medication diary will be returned to clinic staff at 
the end of each course. Patients will be instructed to record doses as they take 
them (and not to batch entries at a later time) and how to correct errors if they 
occur. 
 
5.2.4 Sorafenib 
 
Sorafenib is supplied as 200 mg tablets.  The initial dose of sorafenib for this trial 


 
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is 400 mg (2 tablets) orally twice a day without a scheduled off-treatment period.  
The dose of sorafenib should not exceed 800 mg per day at any point on this trial.  
Patients who required a dose reduction to 400 mg daily or 400 mg every other day 
due to toxicity during prior treatment with sorafenib will be treated with those 
doses.  A lower starting dose is not allowed. 
 
The bioavailability is reduced when sorafenib is taken with a fatty meal.  
Therefore, sorafenib should be taken twice daily without food (at least 1 hour 
before or 2 hours after a meal). 
 
The patient will be requested to swallow tablets whole (to not chew or crush the 
tablets) and maintain a medication diary (see Appendix E) of each dose of 
medication. The medication diary will be returned to clinic staff at the end of each 
course. Patients will be instructed to record doses as they take them (and not to 
batch entries at a later time) and how to correct errors if they occur. 
 
5.2.5 Sunitinib 
 
Sunitinib is supplied as 50 mg, 25 mg, and 12.5 mg capsules.  The initial dose of 
sunitinib on this trial is one 50 mg oral dose taken once daily, on a schedule of 4 
weeks on treatment followed by 2 weeks off.  The dose of sunitinib should not 
exceed 50 mg per day at any point on this trial.  Patients who required a dose 
reduction to a dose of 37.5 mg or 25 mg due to toxicity during prior treatment 
with sunitinib will be treated with that dose daily for 4 weeks followed by two 
weeks off treatment.  A lower starting dose is not allowed. 
 
Food has no effect on the bioavailability of sunitinib.  Therefore, sunitinib can be 
taken with or without food.  
There may be a yellow discoloration of the skin area following direct contact with 
the capsules.  Patients should wash the exposed area with soap and water 
immediately. 
The patient will be requested to maintain a medication diary (see Appendix E) of 
each dose of medication. The medication diary will be returned to clinic staff at 
the end of each course. Patients will be instructed to record doses as they take 
them (and not to batch entries at a later time) and how to correct errors if they 
occur. 
 
5.3. General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of pazopanib, sorafenib and sunitinib with 
other concomitantly administered drugs through the cytochrome P450 system, the 
case report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies.  The Principal Investigator should be alerted if 
the patient is taking any agent known to affect or with the potential to affect selected 
CYP450 
isoenzymes. 
 
Appendix 
C 
presents 
guidelines 
for 
identifying 
medications/substances that could potentially interact with the study agents. 


 
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Blood pressure should be assessed at least once every 3 weeks for patients receiving 
bevacizumab, pazopanib, sorafenib, or sunitinib. More frequent monitoring may be 
appropriate for patients with a history of elevated blood pressure while taking anti-
VEGF agents and should follow institutional guidelines.  High blood pressure may 
require initiation or increase in hypertensive medication according to routine practice. 
Treatment modifications due to hypertension should follow instructions in Section 
6.6. Patients should not take grapefruit/grapefruit juice while receiving pazopanib, 
sorafenib, or sunitinib.  Supportive care for symptoms related to anti-VEGF agents 
not explicitly defined in this protocol should follow institutional protocol and 
guidelines. 
 
5.4. Duration of Therapy 
 
 
In the absence of treatment delays due to adverse event(s), treatment may continue 
until one of the following criteria applies: 
 
• 
Disease progression, 
 
• 
Intercurrent illness that prevents further administration of treatment, 
 
• 
Treatment delay of greater than 4 weeks for any reason, 
 
• 
Unacceptable adverse event(s), 
 
• 
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. 
 
5.5. Duration of Follow Up 
 
Patients will be followed for approximately 4-8 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. 
 
5.6. Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.4 
applies.  The reason for study removal and the date the patient was removed must be 
documented in the Case Report Form. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 


 
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6.1. AMG 386 Dose Modification 
 
Toxicity will be graded according to CTCAE version 4.0 until March 31, 2018, except 
edema/lymphedema.  CTCAE version 5.0 will be utilized for AE reporting beginning 
April 1, 2018.  There will be no dose reductions for AMG 386. 
 
A special note on Edema/Lymphedema:  A higher incidence of peripheral edema has 
been associated with AMG 386.  To provide a common framework for reporting edema 
(including lymphedema), investigators should report edema and manage their subjects as 
defined in this section. 
 
All AEs of edema/lymphedema must be reported and graded as found in this section and 
NOT per CTCAE v5.0. 
 
Investigators should attempt to ascertain the etiology of edema, which may include, but is 
not limited to, tumor obstruction of lymphatic or blood vessels, congestive heart failure, 
iatrogenic fluid overload, renal insufficiency, nephritic syndrome, or other significant 
hypoalbuminemic states. 
 
• Reporting of Edema/Lymphedema: Edema should be classified, graded, and 
reported on the adverse event eCRF as follows: 
 
1. Classify the extent of edema:  
• LOCALIZED (confined to a single body area, e.g., lower extremities only), 
or  
• GENERALIZED (extending to more than a single body area) 
 
2. Grade the AE (whether localized or generalized edema/lymphedema) as follows: 
 
Edema/Lymphedema 
(grade based on this 
table, NOT per CTCAE 
v5.0) 
Grade 1 (MILD) 
Trace thickening or faint 
discoloration of the affected area 
Grade 2 
(MODERATE) 
Marked discoloration; leathery skin 
texture; papillary formation 
Grade 3 (SEVERE) 
Severe symptoms that may involve 
skin blistering or skin breakdown; 
limitations to activities of daily 
living (ADL) 
Edema of a visceral organ or body cavity (such as pulmonary congestion, ascites, or 
pleural effusion): grading based on CTCAE v5.0 but NOT per this section. 
 
• Pleural Effusion and Ascites: Since AMG 386 is known to cause or worsen pre-
existing pleural effusions and ascites, these adverse events should be managed as in 
the table of AMG 386 dose modification guidelines below. 
 
NOTE: Each invasive procedure required for interventional treatment of pleural effusion 
or ascites should be documented on the appropriate eCRFs. 
 


 
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In subjects without a documented history of malignant pleural effusion or ascites, 
investigators should attempt to exclude disease progression as the cause of any new 
onset, or substantially worsening ascites or pleural effusion.  In some settings, cytology 
of aspirated fluid may help in this determination (RECIST v1.1, cytology and histology 
section). 
 
 
 
 
 
 
 
 
 
Dose modification of AMG 386 for edema and other AEs should follow the table below: 
Treatment Modification for AMG 386-Related Adverse Events (Based on CTCAE v4.0) 
Event 
CTCAE v4 Grade 
(unless noted 
otherwise) 
Action to be Taken 
• In the event that AMG 386 is held for >28 days due to treatment-related toxicity or any other reasons, AMG 386 
will be permanently discontinued. 
• AMG 386 may be held for a maximum of 2 times for treatment-related toxicity.  If AMG 386 needs to be held for 
treatment-related toxicity for a third time, AMG 386 will be permanently discontinued. 
 
Edema/lymphedema:   
Edema should be classified and graded as per instructions above 
 
Grade 1:   
(Trace thickening or 
faint discoloration of 
the affected area) 
Continue AMG 386 dosing per protocol and treat per institutional 
guidelines. 
 
Grade 2: 
(Marked discoloration; 
leathery skin texture; 
papillary formation) 
Continue AMG 386 dosing per protocol and treat per institutional 
guidelines. 
 
Grade 3:   
[(Severe symptoms 
that may involve skin 
blistering or skin 
breakdown; limitations 
to activities of daily 
living (ADL)] 
Discontinue AMG 386 permanently.  Treat edema/lymphedema 
per institutional guidelines. 
Pleural effusion and 
ascites: 
Investigators should document each paracentesis and/or thoracentesis for pleural effusion 
or ascites that occurs while a subject is on study. 


 
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Treatment Modification for AMG 386-Related Adverse Events (Based on CTCAE v4.0) 
Event 
CTCAE v4 Grade 
(unless noted 
otherwise) 
Action to be Taken 
 
Non-life-threatening 
• Treat per institutional guidelines which may include: non-
investigational diuretics, thoracentesis, chest tube drainage, 
paracentesis or pleurodesis 
• If chest tube drainage or pleurodesis is required, AMG 386 
should be held until at least two days after chest tube removal 
and the patient’s condition is stable. 
• If AMG 386 is interrupted more than two times or beyond 28 
days for pleural effusion/ascites, but continuation of AMG386 is 
clinically warranted, consultation with the study chair and 
sponsor (CTEP) is required before resuming AMG386 
 
Life-threatening 
Institute emergency measures per institutional guidelines. 
 
Permanently discontinue AMG 386. 
Hemorrhage (CNS):   
Any grade 
Permanently discontinue AMG 386. 
Hemorrhage:   
≥ Grade 3 
Permanently discontinue AMG 386. 
 
Arterial 
thromboembolic event 
(CVA, myocardial 
ischemia or infarction, 
arterial thrombosis):   
Any grade 
Permanently discontinue AMG 386. 
Venous 
thromboembolic 
events:   
Grade 1 or 2 
Continue AMG 386. 
Subjects who, while on anticoagulation, develop a second venous 
thromboembolic event of Grade 2 or higher, should permanently 
discontinue AMG 386. 
 
Grade 3 or 
asymptomatic Grade 4 
Hold AMG 386. 
• 
If the planned duration of the full-dose anticoagulant is ≤2 
weeks, AMG 386 should be held until the full-dose 
anticoagulation period is over. 
• 
If the planned duration of full-dose anticoagulation is >2 
weeks, AMG 386 may be resumed (at the same dose) during 
the period of full-dose anticoagulation if the following 
criterion is met:  the subject must have an in-range INR 
(usually between 2 and 3) on a stable dose of a coumarin-type 
anticoagulant OR at least 1 week of therapy on a low 
molecular weight heparin (or similar non-coumarin-type 
anticoagulant) prior to restarting AMG 386. 
If VTE recurred or worsened on anti-coagulation: discontinue 
AMG 386. 
 
Symptomatic Grade 4 
VTE 
Discontinue AMG 386. 


 
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Treatment Modification for AMG 386-Related Adverse Events (Based on CTCAE v4.0) 
Event 
CTCAE v4 Grade 
(unless noted 
otherwise) 
Action to be Taken 
Infusion reactions and 
delayed infusion-
related reactions:   
Any potential infusion reaction should be classified based upon severity and time of onset 
relative to the infusion and reported as an infusion reaction and the underlying symptoms 
on the AE CRF. 
*NOTE: infusional reactions usually occur during or within 24 hours of the drug 
administration.  If infusional reactions are suspected more than 24 hours after the dosing of 
AMG 386, the patients should be treated as per institutional guidelines and decision on 
subsequent treatment should be discussed with the study chair. 
 
Mild or moderate 
Temporally hold AMG386, and treat per institutional guidelines.  
AMG 386 dosing may resume; however, all subsequent doses of 
AMG 386 should be administered no faster than over 60 minutes. 
 
Severe or life-
threatening 
Treat per institutional guidelines.  Discontinue AMG386. 
Hypokalemia:   
Subjects should have their serum potassium checked and managed as per local medical 
practice.  If hypokalemia is present, replacement should be managed with either oral and/or 
parenteral replacement, according to institutional practice and to the degree of hypokalemia 
present.  It is recommended that the subject’s serum potassium level should be maintained 
within the normal range, as much as possible, during study treatment. 
Other attributable 
toxicities not specified:   
Grade 3 
When a subject experiences a grade 3 toxicity considered to be 
related to AMG 386, AMG386 will be held until the toxicity 
resolves to ≤ grade 1 or the subject’s baseline. 
Other attributable 
toxicities not specified:   
Grade 4 
If a grade 4 event is considered to be related to AMG386, the 
study should be discontinued. 
Resuming AMG386 may be considered in patients who have 
shown benefit from the protocol and the toxicities have resolved 
to < grade 2, however, approval by the study chair and the sponsor 
is required. 
 
6.2. Bevacizumab Dose Modification 
 
There will be no dose reductions for bevacizumab, only dose delays.  If delay is required, 
bevacizumab should resume at the same dose.  Please see section 6.6 for dose modification 
for hypertension and proteinuria.   
 
Dose modification of bevacizumab should follow the table below: 
Treatment Modification for Bevacizumab-Related Adverse Events (Based on CTCAE v4.0) 
Event 
CTCAE v4 Grade 
Action to be Taken 
Allergic reactions,  
or  
Acute infusional 
reactions:  
Grade 1-2 
Premeds should be given with the next dose, and infusion time 
must not be reduced for the subsequent infusion.   
> Grade 3 
Discontinue bevacizumab. 
Arterial Thrombotic 
Event: 
Any grade 
Discontinue bevacizumab. 


 
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Treatment Modification for Bevacizumab-Related Adverse Events (Based on CTCAE v4.0) 
Event 
CTCAE v4 Grade 
Action to be Taken 
Reversible Posterior 
Leukoencephalopathy 
Syndrome: 
Any grade 
Discontinue bevacizumab. 
Acute Venous 
Thrombosis: 
Grade 1 or 2 
Continue bevacizumab. 
Subjects who develop a second venous thromboembolic event of 
Grade 2 or higher while on anticoagulation should permanently 
discontinue bevacizumab. 
 
Grade 3 or 
asymptomatic Grade 4 
Hold bevacizumab. 
• 
If the planned duration of the full-dose anticoagulant is ≤2 
weeks, bevacizumab should be held until the full-dose 
anticoagulation period is over. 
• 
If the planned duration of full-dose anticoagulation is >2 
weeks, bevacizumab may be resumed (at the same dose) 
during the period of full-dose anticoagulation if the following 
criterion is met:  the subject must have an in-range INR 
(usually between 2 and 3) on a stable dose of a coumarin-type 
anticoagulant OR at least 1 week of therapy on a low 
molecular weight heparin (or similar non-coumarin-type 
anticoagulant) prior to restarting bevacizumab. 
If VTE recurred or worsened on anti-coagulation: discontinue 
bevacizumab. 
 
Symptomatic Grade 4 
VTE 
Discontinue bevacizumab. 
Wound dehiscence 
requiring medical or 
surgical intervention: 
Any grade 
Discontinue bevacizumab. 
GI perforation, GI  
leak or fistula: 
Any grade 
Discontinue bevacizumab. 
Hemoptysis: 
≥ Grade 2 
Discontinue bevacizumab. 
Hemorrhage (CNS):   
Any grade 
Discontinue bevacizumab. 
Hemorrhage:   
≥ Grade 3 
Discontinue bevacizumab. 
Other attributable 
toxicities not specified:  
Grade 3 
Hold bevacizumab for up to 4 weeks until symptoms resolve to ≤ 
Grade 1. 
Other attributable 
toxicities not specified: 
Grade 4 
If a grade 4 event is considered to be related to bevacizumab, the 
study should be discontinued. 
 
Resuming bevacizumab may be considered in patients who have 
shown benefit from the protocol and the toxicities have resolved to 
< grade 2, however, approval by the study chair is required. 
 
6.3. Pazopanib Dose Modification 
 
For patients treated initially with 800 mg pazopanib daily, the initial dose reduction 
should be to 400 mg, and additional dose decrease should be in 200 mg steps based on 
individual tolerability. For patients treated initially with 400 mg daily one dose reduction 
to 200 mg is allowed based on individual tolerability.  The minimum daily dose of 


 
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pazopanib is 200 mg daily and the dose of pazopanib should not exceed 800 mg.  Please 
see section 6.6 for dose modification for hypertension and proteinuria.  Dose 
modification of pazopanib for other toxicities should follow the tables below.   
 
Pazopanib Dose Levels 
Dose Level 
Pazopanib Dose 
1 
800 mg (4 tablets) orally daily 
-1 
400 mg (2 tablets) orally daily 
-2 
200 mg (1 tablet) orally daily 
 
 
Treatment Modification for Pazopanib-Related Adverse Events (Based on CTCAE v4.0) 
Event 
CTCAE v4 Grade 
Action to be Taken 
Other attributable 
toxicities not specified: 
Grade 3 
Hold pazopanib for up to 4 weeks until symptoms resolve to ≤ 
Grade 1. 
Other attributable 
toxicities not specified: 
Grade 4 
If a grade 4 event is considered to be related to pazopanib, the 
study should be discontinued. 
 
Resuming pazopanib may be considered in patients who have 
shown benefit from the protocol and the toxicities have resolved to 
< grade 2, however, approval by the study chair is required. 
 
6.4. Sorafenib Dose Modification 
 
For those treated with 800 mg sorafenib daily, the initial dose reduction should be to 400 
mg.  For patients treated initially with 400 mg daily one dose reduction to 400 mg every 
other day is allowed based on individual tolerability.  Management of suspected adverse 
drug reactions may require temporary interruption and/or dose reduction of sorafenib.  
Please see section 6.6 for dose modification for hypertension and proteinuria.  Dose 
modification of sorafenib for other toxicities should follow the tables below. 
 
 
Sorafenib Dose Levels 
Dose Level 
Sorafenib Dose 
1 
400 mg (2 tablets) orally twice daily 
-1 
400 mg (2 tablets) orally once daily 
-2 
400 mg (2 tablets) orally once every other day 
 
Treatment Modification for Sorafenib -Related Adverse Events (Based on CTCAE v4.0) 
Event 
CTCAE v4 Grade 
(unless noted 
otherwise) 
Action to be Taken 


 
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Treatment Modification for Sorafenib -Related Adverse Events (Based on CTCAE v4.0) 
Event 
CTCAE v4 Grade 
(unless noted 
otherwise) 
Action to be Taken 
Skin Toxicity: 
Grade 1: Numbness, 
dysethesia, 
paresthesia, tingling, 
painless swelling, 
erythema or 
discomfort of the 
hands or feet which 
does not disrupt the 
patients normal 
activity 
Any occurrence 
Institute supportive measures immediately and 
continue sorafenib treatment. 
 
Grade 2: Painful 
erythema and swelling 
of the hands or feet 
and/or discomfort 
affecting the patient’s 
normal activities 
1st occurrence 
Institute supportive measures immediately and 
continue sorafenib treatment.  If no 
improvement in 7 days, see below. 
 
 
No improvement 
in 7 days or 2nd 
or 3rd occurrence 
Interrupt sorafenib treatment for a minimum of 
7 days, until toxicity has resolved to grade 0–1. 
 
When resuming treatment after dose 
interruption, resume sorafenib at a reduced dose 
level. 
 
 
4th  occurrence 
Discontinue sorafenib. 
 
Grade 3:  Moist 
desquamation, 
ulceration, blistering 
or severe pain of the 
hands or feet, or severe 
discomfort that causes 
the patient to be 
unable to work or 
perform activities of 
daily living 
1st  or 2nd 
occurrence 
Interrupt sorafenib treatment for a minimum of 
7 days, until toxicity has resolved to grade 0–1. 
 
When resuming treatment after dose 
interruption, resume sorafenib at a reduced dose 
level. 
 
 
3rd  occurrence 
Discontinue sorafenib. 
Other attributable 
toxicities not specified: 
Grade 3 
Hold pazopanib for up to 4 weeks until symptoms resolve to ≤ 
Grade 1. 
Other attributable 
toxicities not specified: 
Grade 4 
If a grade 4 event is considered to be related to sorafenib, the study 
should be discontinued. 
 
Resuming sorafenib may be considered in patients who have 
shown benefit from the protocol and the toxicities have resolved to 
< grade 2, however, approval by the study chair is required. 
 
6.5. Sunitinib Dose Modification 
 
Dose interruption and/or dose modification of sunitinib in 12.5 mg decrements is 
recommended based on individual safety and tolerability. Please see section 6.6 for dose 
modification for hypertension and proteinuria. Dose modification of sunitinib for other 
toxicities should follow the tables below.   


 
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Sunitinib Dose Levels 
Dose Level 
Sunitinib Dose 
1 
50 mg orally daily 4 weeks on, followed by 2 weeks off 
-1 
37.5 mg orally daily 4 weeks on, followed by 2 weeks off 
-2 
25 mg orally daily 4 weeks on, followed by 2 weeks off 
 
Treatment Modification for Sunitinib-Related Adverse Events (Based on CTCAE v4.0) 
Event 
CTCAE v4 Grade 
Action to be Taken 
Other attributable 
toxicities not specified: 
Grade 3 
Hold sunitinib for up to 4 weeks until symptoms resolve to ≤ 
Grade 1. 
Other attributable 
toxicities not specified: 
Grade 4 
If a grade 4 event is considered to be related to sunitinib, the study 
should be discontinued. 
 
Resuming sunitinib may be considered in patients who have 
shown benefit from the protocol and the toxicities have resolved to 
< grade 2, however, approval by the study chair is required. 
 
 
6.6. Management of Hypertension and Proteinuria 
 
Dose modification guidelines for AMG 386 are listed in Section 6.1.  Below are dose 
modification tables for bevacizumab, pazopanib, sorafenib, and sunitinib for the 
following adverse events:  hypertension and proteinuria.  Blood pressure should be 
measured at least once every 3 weeks for patients receiving bevacizumab, pazopanib, 
sorafenib, or sunitinib.  If a new anti-hypertensive is to be added, the choice of drug is at 
the discretion of treating physician.  Based on prior experience, vasodilators such as 
dihydropyridine calcium channel blockers, angiotensin blockers, and alpha-blockers are 
recommended agents. 
 
Treatment Modification for Hypertension (Based on CTCAE v4.0) 
CTCAE v4 
Grade 
Occurrence 
Action to be Taken 
Grade 1 
Any occurrence 
No dose modification is required. 
Grade 2 
Any occurrence 
The dose of bevacizumab, pazopanib, sorafenib, or sunitinib should be held for 
resting SBP > 150 or resting DBP > 90 at the time of treatment.  Dose should also 
be held for symptomatic hypertension regardless of grade or blood pressure level.  
Dose may be held for up to 4 weeks. 
 
Initiate anti-hypertensive therapy if patient not on any antihypertensive agent.  
Ideal goal for blood pressure is < 140/80.   
Grade 3 
1st occurrence 
Hold bevacizumab, pazopanib, sorafenib, or sunitinib.  Medications should be 
used or added for blood pressure control.  Ideal goal for blood pressure is < 
140/80.  Resume treatment at the same dose when blood pressure controlled to < 
grade 2. 
 
2nd or higher 
occurrence 
Hold bevacizumab, pazopanib, sorafenib, or sunitinib.  Medications should be 
used or added for blood pressure control.  Ideal goal for blood pressure is < 
140/80.   
 
Resume treatment with a one-level dose reduction of pazopanib, sorafenib, or 


 
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Treatment Modification for Hypertension (Based on CTCAE v4.0) 
CTCAE v4 
Grade 
Occurrence 
Action to be Taken 
sunitinib when blood pressure controlled to < grade 2 (the dose of bevacizumab is 
not modified).  
 
If HTN cannot be controlled with medications, remove patient from protocol 
treatment. 
Grade 4 
 
Remove patient from protocol treatment 
 
 
Treatment Modification for Proteinuria  
Proteinuria 
Action to be Taken 
Urine dipstick < 2+ protein 
No action. 
Urine dipstick > 2+ protein 
Collect 24 hour collection for protein and creatinine.  If < 3.5 gm, continue to 
monitor 24-hour urine collection each cycle.   
24-hour urine collection > 3.5gm 
Hold bevacizumab, pazopanib, sorafenib, or sunitinib and repeat 24-hour 
collection in 2 weeks.  Resume treatment if < 3.5 gm.  Discontinue 
bevacizumab, pazopanib, sorafenib, or sunitinib if drug held more than 4 
weeks. 
Grade 4 or nephrotic syndrome 
Discontinue bevacizumab, pazopanib, sorafenib, or sunitinib. 
 
 
7. 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.   
 
7.1. Comprehensive Adverse Events and Potential Risks Lists (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, 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 1556 patients.  Below is the CAEPR for 
AMG 386 (trebananib). 
 
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, 


 
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use the lower of the grades to determine if expedited reporting is required. 
 
7.1.1 CAEPR for AMG 386 (trebananib, NSC 751173) 
Version 2.6, June 4, 20181 
 
 Adverse Events with Possible  
 Relationship to AMG 386 (Trebananib) 
 (CTCAE 5.0 Term) 
[n= 1556] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)   
CARDIAC DISORDERS 
  
 
 
Myocardial infarction2 
  
EYE DISORDERS 
  
 
 
Blurred vision 
  
 
 
Eye disorders - Other (retinal 
vascular thrombosis) 2,3 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
 
Ascites 
  
 
Diarrhea2 
 
 Diarrhea2 (Gr 3) 
 
Nausea 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema face2 
 
 Edema face2 (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 2) 
 
Fatigue2 
 
 Fatigue2 (Gr 3) 
 
Pain 
 
 Pain (Gr 3) 
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction4 
 
 Allergic reaction4 (Gr 2) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction2,4 
 
 Infusion related reaction2,4 (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Hypokalemia 
 
  
RENAL AND URINARY DISORDERS 
  
 
Proteinuria2 
 
 Proteinuria2 (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 
Pleural effusion 
  
 
 
Respiratory failure2 
  
VASCULAR DISORDERS 
  
 
 
Hemorrhage5 
  
 
Hypertension 
 
  
 
 
Thromboembolic event3 
  
 
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. 
 
2These adverse events attributable to AMG 386 (trebaninib) have been reported primarily in 
studies of AMG 386 (trebaninib) in combination with VEGF- and/or tyrosine kinase-inhibitors 


 
PhII-122, NCI# 9048 
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and/or with chemotherapy. Retinal vascular thrombosis (arterial or venous) may result in 
permanent impairment of vision. 
 
3Thromboembolic events, including Cerebral venous thrombosis, Jugular vein thrombosis, 
Peripheral artery thrombosis, Subclavian vein thrombosis, Deep vein thrombosis, Pulmonary 
embolism, Retinal vascular thrombosis, and Intracardiac thrombus have been observed in AMG 
386 (trebananib) trials. 
 
4Symptoms of allergic reactions and/or infusion related reactions may include Fever, Chills, 
Headache, Rash, Flushing, Swelling, and Shortness of breath. Severe allergic reactions can cause 
Dizziness, Hypotension, or Difficulty swallowing and may be life-threatening. 
 
5Hemorrhage events, some of which may be serious, including Cerebral hemorrhage, 
Esophageal varices hemorrhage, Intracranial hemorrhage, Eye hemorrhage, Epistaxis, 
Gastrointestinal hemorrhage, Arterial hemorrhage, Bronchopulmonary hemorrhage, Bladder 
hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Tumor hemorrhage have 
been observed in AMG 386 (trebananib) trials. 
 
6Gastrointestinal obstruction includes Colonic obstruction, Duodenal obstruction, Esophageal 
obstruction, Ileal obstruction, Jejunal obstruction, Obstruction gastric, Rectal obstruction, and 
Small intestinal obstruction under the GASTROINTESTINAL DISORDERS SOC. 
 
7Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and 
Small intestinal perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
 
Adverse events reported on AMG 386 (trebananib) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that AMG 386 (trebananib) 
caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Cardiac arrest; 
Cardiac disorders - Other (atrioventricular block second degree); Cardiac disorders - Other 
(intracardiac thrombus); Chest pain - cardiac; Heart failure; Mitral valve disease; Pericarditis; 
Restrictive cardiomyopathy; Sinus bradycardia; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (inner ear fluid); 
Tinnitus; Vertigo 
ENDOCRINE DISORDERS - Hypothyroidism 
EYE DISORDERS - Eye disorders - Other (blindness); Eye disorders - Other (central arterial 
occlusion); Eye disorders - Other (eye edema); Glaucoma; Papilledema; Uveitis; Vision 
decreased; Watering eyes 
GASTROINTESTINAL DISORDERS - Abdominal distension; Bloating; Colitis; 
Constipation; Dysphagia; Enterocolitis; Fecal incontinence; Flatulence; Gastric ulcer; 
Gastrointestinal disorders - Other (intestinal ischemia); Gastrointestinal fistula; Gastrointestinal 
obstruction6; Gastrointestinal perforation7; Ileus; Mucositis oral; Pancreatitis; Rectal pain  


 
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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills4; 
Disease progression; Fever4; Flu like symptoms; Generalized edema; Localized edema; Malaise; 
Multi-organ failure; Non-cardiac chest pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatobiliary disorders - 
Other (hepatitis toxic) 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (developed anti-
trebananib binding antibodies) 
INFECTIONS AND INFESTATIONS - Abdominal infection; Anorectal infection; 
Appendicitis; Infections and infestations - Other (nasopharyngitis); Kidney infection; Lung 
infection; Sepsis; Skin infection; Urinary tract infection; Wound infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Spinal fracture; Wound 
complication; Wound dehiscence 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; 
Aspartate aminotransferase increased; Blood bilirubin increased; Creatinine increased2; GGT 
increased; INR increased; Lymphocyte count decreased; Neutrophil count decreased; Platelet 
count decreased; Weight gain; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; 
Hyperkalemia; Hypernatremia; Hypoalbuminemia; Hypocalcemia; Hypomagnesemia; 
Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - Other (electrolyte 
imbalance) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back 
pain; Bone pain; Generalized muscle weakness; Muscle cramp; Myalgia; Neck pain; Pain in 
extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Treatment related secondary malignancy; Tumor pain 
NERVOUS SYSTEM DISORDERS - Cerebrospinal fluid leakage; Dizziness4; Dysgeusia; 
Dysphasia4; Edema cerebral; Encephalopathy; Headache4; Hydrocephalus; Ischemia 
cerebrovascular; Muscle weakness left-sided; Nervous system disorders - Other (hemiplegia); 
Nervous system disorders - Other (left-sided hemineglect); Nervous system disorders - Other 
(loss of gag reflex); Paresthesia; Peripheral sensory neuropathy; Seizure; Stroke; Syncope; 
Transient ischemic attacks; Tremor 
PSYCHIATRIC DISORDERS - Confusion; Delirium; Insomnia; Mania; Personality change 
RENAL AND URINARY DISORDERS - Acute kidney injury2; Hematuria; Urinary retention; 
Urinary tract obstruction 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory 
distress syndrome; Apnea; Chylothorax; Cough; Dyspnea4; Hypoxia; Laryngopharyngeal 
dysesthesia; Pneumonitis; Pulmonary edema; Respiratory, thoracic and mediastinal disorders - 
Other (nasal septum perforation); Respiratory, thoracic and mediastinal disorders - Other 
(obstructive airways disorder); Respiratory, thoracic and mediastinal disorders - Other (runny 
nose) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Erythroderma; 
Hyperhidrosis; Nail discoloration; Nail loss; Palmar-plantar erythrodysesthesia syndrome; 
Pruritus; Rash acneiform; Rash maculo-papular4; Skin and subcutaneous tissue disorders - Other 
(abnormal hair growth); Skin ulceration 
VASCULAR DISORDERS - Arterial thromboembolism; Flushing4; Hypotension4; 
Lymphedema; Peripheral ischemia; Vascular disorders - Other (vascular rupture) 


 
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Note: AMG 386 (Trebananib) 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. 
 
7.1.2 Comprehensive Adverse Events and Potential Risks Lists (CAEPR for 
Commercial Agents 
 
 
 
 
7.1.2.1 Bevacizumab 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
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. 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 
bevacizumab (rhuMAb VEGF). 
 
Version 2.5, May 2, 20181 
 
 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 5.0 Term) 
[n= 3540] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia 
 
 
 
Febrile neutropenia 
 
 
 
 
Hemolytic uremic syndrome 
 
CARDIAC DISORDERS 
 
 
Cardiac disorders - Other 
(supraventricular arrhythmias)2  
 
 
 
 
Chest pain - cardiac3 
 
 
 
Heart failure 
 
 
 
Left ventricular systolic 
dysfunction 
 
 
 
Myocardial infarction3 
 
 
 
Ventricular arrhythmia 
 
 
 
Ventricular fibrillation 
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain 
 
 
 
Colitis 
 
 
 
Constipation 
 
 
 
Diarrhea 
 
 
 
Dyspepsia 
 
 
 
 
Gastrointestinal fistula4 
 
 
Gastrointestinal hemorrhage5 
 
 
 
Gastrointestinal obstruction6 
 
 


 
PhII-122, NCI# 9048 
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 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 5.0 Term) 
[n= 3540] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Gastrointestinal perforation7 
 
 
 
Gastrointestinal ulcer8 
 
 
Ileus 
 
 
 
Mucositis oral 
 
 
 
Nausea 
 
 
 
Vomiting 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
 
Fatigue 
 
 
 
Non-cardiac chest pain 
 
 
 
Pain 
 
 
HEPATOBILIARY DISORDERS 
 
 
 
Gallbladder perforation 
 
IMMUNE SYSTEM DISORDERS 
 
 
Allergic reaction 
 
 
 
 
Anaphylaxis 
 
INFECTIONS AND INFESTATIONS 
 
 
Infection9 
 
 
 
 
Infections and infestations - 
Other (necrotizing fascitis) 
 
 
Infections and infestations - Other 
(peri-rectal abscess) 
 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
 
Infusion related reaction 
 
 
 
 
Injury, poisoning and procedural 
complications - Other 
(anastomotic leak)10 
 
 
Wound complication 
 
 
 
Wound dehiscence 
 
 
INVESTIGATIONS 
 
 
Alanine aminotransferase increased  
 
 
Alkaline phosphatase increased 
 
 
 
Aspartate aminotransferase increased  
 
 
Blood bilirubin increased 
 
 
 
Creatinine increased 
 
 
Neutrophil count decreased 
 
 
 
 
Platelet count decreased 
 
 
 
Weight loss 
 
 
 
White blood cell decreased 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
 
 
Dehydration 
 
 
 
Hyperglycemia 
 
 
 
Hypokalemia 
 
 
 
Hyponatremia 
 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
 
Arthralgia 
 
 
 
 
Avascular necrosis11 
 
 
Generalized muscle weakness 
 
 


 
PhII-122, NCI# 9048 
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 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 5.0 Term) 
[n= 3540] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Musculoskeletal and connective 
tissue disorder - Other (bone 
metaphyseal dysplasia)12 
 
 
 
Myalgia 
 
 
 
Osteonecrosis of jaw13 
 
 
NERVOUS SYSTEM DISORDERS 
 
 
Dizziness 
 
 
 
Headache 
 
 
 
 
Intracranial hemorrhage 
 
 
 
Ischemia cerebrovascular 
 
 
Peripheral sensory neuropathy14 
 
 
 
 
Reversible posterior 
leukoencephalopathy syndrome 
 
 
Syncope 
 
 
RENAL AND URINARY DISORDERS 
 
 
 
Acute kidney injury 
 
 
Hematuria 
 
 
 
 
Nephrotic syndrome 
 
 
Proteinuria 
 
 
 
 
Urinary fistula 
 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
 
Reproductive system and breast 
disorders - Other (ovarian 
failure)15 
 
 
 
 
 
Vaginal fistula 
 
 
Vaginal hemorrhage 
 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 
Allergic rhinitis 
 
 
 
 
Bronchopleural fistula 
 
 
 
Bronchopulmonary hemorrhage  
 
Cough 
 
 
 
Dyspnea 
 
 
 
Epistaxis 
 
 
 
Hoarseness 
 
 
 
 
Pulmonary hypertension 
 
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(nasal-septal perforation) 
 
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(tracheo-esophageal fistula) 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Dry skin 
 
 
 
Erythroderma 
 
 
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
 
 
Pruritus 
 
 
 
Rash maculo-papular 
 
 
 
Urticaria 
 
 


 
PhII-122, NCI# 9048 
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 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 5.0 Term) 
[n= 3540] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
VASCULAR DISORDERS 
 
 
 
Arterial thromboembolism3,16 
 
Hypertension 
 
 
 
 
Thromboembolic event 
 
 
 
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. 
 
2Supraventricular arrhythmias may include supraventricular tachycardia, atrial fibrillation, and 
atrial flutter. 
 
3The risks of arterial thrombosis such as cardiac or CNS ischemia are increased in elderly 
patients and in patients with a history of diabetes. 
 
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 
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, and Small 
intestinal perforation. 
 
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. 


 
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11There have been reports of non-mandibular osteonecrosis (avascular necrosis) in patients under 
the age of 18 treated with bevacizumab. 
 
12Metaphyseal dysplasia was observed in young patients who still have active epiphyseal growth 
plates. 
 
13Cases 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. 
 
14Increased rate of peripheral sensory neuropathy has been observed in trials combining 
bevacizumab and chemotherapy compared to chemotherapy alone.  
 
15Ovarian 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. 
 
16Arterial thromboembolic event includes visceral arterial ischemia, peripheral arterial ischemia, 
heart attack, and stroke. 
 
 
Adverse events reported on bevacizumab (rhuMAb VEGF) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that bevacizumab 
(rhuMAb VEGF) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; 
Disseminated intravascular coagulation; Hemolysis; Thrombotic thrombocytopenic purpura 
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 (ischemic CRVO); Eye disorders - Other 
(macular pucker); Eye disorders - Other (transient increased IOP > or =30 mm Hg); Eye pain; 
Floaters; Keratitis; Optic nerve disorder; Photophobia; Retinal detachment; Retinal tear; 
Retinopathy; Vitreous hemorrhage; Watering eyes 
GASTROINTESTINAL DISORDERS - Ascites; Cheilitis; Colonic stenosis; Dry mouth; 
Dysphagia; Enterocolitis; Esophageal pain; Esophageal stenosis; Flatulence; Gastrointestinal 
disorders - Other (peritonitis); Oral pain; Pancreatitis; Proctitis; Rectal mucositis; Rectal 


 
PhII-122, NCI# 9048 
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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 
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; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; 
Hypocalcemia; Hypomagnesemia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; 
Bone pain; Chest wall pain; Fibrosis deep connective tissue; Head soft tissue necrosis; Joint 
effusion; Muscle weakness lower limb; Muscle weakness upper limb; Musculoskeletal and 
connective tissue disorder - Other (polymyalgia rheumatica); Neck pain; Osteonecrosis; 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; 
Dysesthesia; Dysgeusia; Dysphasia; Encephalopathy; Extrapyramidal disorder; Facial nerve 
disorder; Hydrocephalus; Leukoencephalopathy; Memory impairment; Myasthenia gravis; 
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; 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; Respiratory 
failure; Respiratory, thoracic and mediastinal disorders - Other (dry nares); Respiratory, thoracic 
and mediastinal disorders - Other (pulmonary infarction) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Hyperhidrosis; Nail loss; 
Pain of skin; 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 


 
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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. 
 
 
 
 
7.1.2.2 Pazopanib 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
For Pazopanib (Votrient, GW786034, NSC 737754) 
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. 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 2383 patients. Below is the CAEPR for 
pazopanib (Votrient, GW786034). 
 
Version 2.9, November 20, 20191 
 
 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 5.0 Term) 
[n= 2383] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia 
 
 
 
 
Hemolytic uremic 
syndrome2 
 
 
 
Thrombotic 
thrombocytopenic purpura 
 
CARDIAC DISORDERS 
 
 
 
Cardiac disorders - Other 
(Torsades de Pointes) 
 
 
 
Heart failure 
 
 
 
Left ventricular systolic 
dysfunction 
 
 
 
Myocardial infarction 
 
 
Sinus bradycardia 
 
 
ENDOCRINE DISORDERS 
 
 
Hypothyroidism 
 
 
EYE DISORDERS 
 


 
PhII-122, NCI# 9048 
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 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 5.0 Term) 
[n= 2383] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Eye disorders - Other (eye 
hemorrhage, retinal 
hemorrhage) 
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain 
 
 
 
Constipation 
 
 
Diarrhea 
 
 
 
 
Dyspepsia 
 
 
 
 
Gastrointestinal fistula3 
 
 
 
Gastrointestinal 
hemorrhage4 
 
 
 
Gastrointestinal 
perforation5 
 
 
Mucositis oral 
 
 
Nausea 
 
 
 
Vomiting 
 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
 
Edema limbs 
 
 
Fatigue 
 
 
 
 
Fever 
 
 
HEPATOBILIARY DISORDERS 
 
 
 
Hepatic failure 
 
INFECTIONS AND INFESTATIONS 
 
 
 
Infection6 
 
INVESTIGATIONS 
 
 
Activated partial 
thromboplastin time 
prolonged 
 
 
Alanine 
aminotransferase 
increased 
 
 
 
 
Alkaline phosphatase 
increased 
 
 
Aspartate 
aminotransferase 
increased 
 
 
 


 
PhII-122, NCI# 9048 
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 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 5.0 Term) 
[n= 2383] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
Blood bilirubin 
increased 
 
 
 
 
Creatinine increased 
 
 
 
 
Ejection fraction decreased  
 
 
Electrocardiogram QT 
corrected interval 
prolonged 
 
Lymphocyte count 
decreased 
 
 
 
Neutrophil count 
decreased 
 
 
 
Platelet count 
decreased 
 
 
 
 
Weight loss 
 
 
White blood cell 
decreased 
 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 
 
 
Dehydration 
 
 
 
Hypercalcemia 
 
 
Hyperglycemia 
 
 
 
 
Hyperkalemia 
 
 
 
Hypermagnesemia 
 
 
 
Hypernatremia 
 
 
 
Hypoalbuminemia 
 
 
 
Hypocalcemia 
 
 
 
Hypoglycemia 
 
 
 
Hypokalemia 
 
 
 
Hypomagnesemia 
 
 
Hyponatremia 
 
 
 
 
Hypophosphatemia 
 
 
 
 
Tumor lysis syndrome 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
 
Arthralgia 
 
 
 
Back pain 
 
 
 
Myalgia 
 
 
 
Pain in extremity 
 
 


 
PhII-122, NCI# 9048 
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 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 5.0 Term) 
[n= 2383] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL 
CYSTS AND POLYPS) 
 
 
Tumor pain 
 
 
NERVOUS SYSTEM DISORDERS 
 
 
Dizziness 
 
 
 
Dysgeusia 
 
 
 
Headache 
 
 
 
 
Intracranial hemorrhage 
 
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
 
RENAL AND URINARY DISORDERS 
 
 
 
Acute kidney injury 
 
 
 
Hematuria 
 
 
Proteinuria 
 
 
 
 
Urinary fistula 
 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
 
 
 
Reproductive system and 
breast disorders - Other 
(female genital tract fistula) 
 
 
 
Uterine fistula 
 
 
 
Vaginal fistula 
 
 
 
Vaginal hemorrhage 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 
Cough 
 
 
 
Dyspnea 
 
 
 
Respiratory hemorrhage7  
 
 
 
Respiratory, thoracic and 
mediastinal disorders - 
Other (interstitial lung 
disease)8  
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Alopecia 
 
 
Hair color changes 
 
 
 
 
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
 


 
PhII-122, NCI# 9048 
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 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 5.0 Term) 
[n= 2383] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Rash maculo-papular 
 
 
 
Skin hypopigmentation  
 
VASCULAR DISORDERS 
 
 
 
Arterial thromboembolism9  
Hypertension 
 
 
 
 
 
Thromboembolic event9 
 
 
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. 
 
2Thrombotic microangiopathy (TMA) which includes both Hemolytic uremic syndrome (HUS) 
and Thrombotic thrombocytopenic purpura (TTP) has been reported in clinical trials of 
GW786034. 
 
3Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Enterovesical 
fistula, Esophageal fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, 
Oral cavity fistula, Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the 
GASTROINTESTINAL DISORDERS SOC.  
 
4Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic 
hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, 
Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, 
Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic 
hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal 
hemorrhage under the GASTROINTESTINAL DISORDERS SOC.  
 
5Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and 
Small intestinal perforation under the GASTROINTESTINAL DISORDERS SOC.  
 
6Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS 
SOC. 
 
7Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Laryngeal 
hemorrhage, Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under 
the RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS SOC.  
 


 
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8Interstitial lung disease may include, Adult respiratory distress syndrome, Pneumonitis, 
Pulmonary fibrosis, Respiratory, thoracic and mediastinal disorders - Other (Acute respiratory 
distress syndrome), Respiratory, thoracic and mediastinal disorders - Other (Aveolitis), 
Respiratory, thoracic and mediastinal disorders - Other (Bronchiolitis obliterans), Respiratory, 
thoracic and mediastinal disorders - Other (Interstitial fibrosis), Respiratory, thoracic and 
mediastinal disorders - Other (Interstitial pneumonia), Respiratory, thoracic and mediastinal 
disorders - Other (Interstitial pneumonitis), Respiratory, thoracic and mediastinal disorders - 
Other (Organizing pneumonia), Respiratory, thoracic and mediastinal disorders - Other 
(Pulmonary infiltrates), Respiratory, thoracic and mediastinal disorders - Other (Toxic 
pneumonitis). 
 
9These events can result in life-threatening pulmonary, cardiac, cerebral, and other 
complications. 
 
 
Adverse events reported on pazopanib (GW786034) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that pazopanib 
(GW786034) caused the adverse event:  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (sinus arrest); Cardiac 
disorders - Other (supraventricular extrasystoles); Cardiac disorders - Other (Takotsubo [Broken 
Heart Syndrome]); Chest pain - cardiac;  
Pericardial effusion; Supraventricular tachycardia 
ENDOCRINE DISORDERS - Adrenal insufficiency 
EYE DISORDERS - Blurred vision; Dry eye; Eye disorders - Other (asthenopia); Eye disorders 
- Other (foreign body sensation in eyes); Eye pain; Floaters; Glaucoma; Photophobia; Retinal 
tear 
GASTROINTESTINAL DISORDERS - Abdominal distension; Dry mouth; Duodenal 
obstruction; Dysphagia; Esophagitis; Flatulence; Gastroesophageal reflux disease; 
Gastrointestinal disorders - Other (hyperactive bowel); Gastrointestinal disorders - Other 
(pneumatosis intestinalis); Gastrointestinal pain; Oral pain; Pancreatitis; Periodontal disease; 
Proctitis; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema 
face; Malaise; Non-cardiac chest pain; Pain 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Blood lactate dehydrogenase increased; Cardiac troponin T increased; 
Cholesterol high; GGT increased; INR increased; Investigations - Other (blood TSH increased); 
Lipase increased; Serum amylase increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Hypertriglyceridemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Chest 
wall pain; Generalized muscle weakness; Head soft tissue necrosis; Muscle cramp; Muscle 
weakness lower limb; Muscle weakness upper limb; Neck pain 
NERVOUS SYSTEM DISORDERS - Extrapyramidal disorder; Ischemia cerebrovascular; 
Memory impairment; Paresthesia; Peripheral sensory neuropathy; Stroke; Syncope; Transient 
ischemic attacks 


 
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PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Suicide 
attempt 
RENAL AND URINARY DISORDERS - Urinary frequency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation; 
Reproductive system and breast disorders - Other (vaginal necrosis); Vaginal discharge 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Laryngeal edema; 
Oropharyngeal pain; Pharyngolaryngeal pain; Pleural effusion; Pleuritic pain; Pneumothorax; 
Postnasal drip; Sore throat; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Pruritus; 
Purpura; Skin hyperpigmentation; Skin ulceration 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Vasculitis 
 
 
Note: Pazopanib (GW786034) 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. 
 
 
 
 
 
7.1.2.3 Sorafenib 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
For Sorafenib (BAY 43-9006, NSC 724772) 
 
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. 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 2571 patients. Below is the CAEPR for 
sorafenib (BAY 43-9006). 
 
Version 2.10, June 24, 20201 
 
 Adverse Events with Possible  
 Relationship to Sorafenib (BAY 43-9006; Nexavar) 
 (CTCAE 5.0 Term) 
[n= 2571] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia 
 
 
CARDIAC DISORDERS 
 
Chest pain – cardiac 
 
 
 
Heart failure 
 
 
Left ventricular systolic 
dysfunction 


 
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 Adverse Events with Possible  
 Relationship to Sorafenib (BAY 43-9006; Nexavar) 
 (CTCAE 5.0 Term) 
[n= 2571] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Myocardial infarction 
GASTROINTESTINAL DISORDERS 
Abdominal pain 
 
 
 
Ascites 
 
 
Constipation 
 
Diarrhea 
 
 
 
Gastrointestinal hemorrhage2 
 
 
 
Gastrointestinal 
perforation3 
 
Mucositis oral 
 
Nausea 
 
 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Edema limbs 
 
Fatigue 
 
 
 
Fever 
 
HEPATOBILIARY DISORDERS 
 
 
Hepatic failure 
IMMUNE SYSTEM DISORDERS 
 
 
Anaphylaxis 
INFECTIONS AND INFESTATIONS 
 
Infection4 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
 
Injury, poisoning and 
procedural complications 
- Other, specify (wound 
healing complication) 
INVESTIGATIONS 
 
Activated partial thromboplastin 
time prolonged 
 
Alanine aminotransferase 
increased 
 
 
Alkaline phosphatase 
increased 
 
 
Aspartate aminotransferase 
increased 
 
 
Blood bilirubin increased 
 
 


 
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 Adverse Events with Possible  
 Relationship to Sorafenib (BAY 43-9006; Nexavar) 
 (CTCAE 5.0 Term) 
[n= 2571] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
Creatinine increased 
 
 
 
 
Electrocardiogram QT 
corrected interval 
prolonged 
 
GGT increased 
 
INR increased 
 
 
 
Investigations - Other 
(Bicarbonate-serum low) 
 
Lipase increased 
 
 
Lymphocyte count decreased  
 
 
Neutrophil count decreased 
 
Platelet count decreased 
 
 
Serum amylase increased 
 
 
 
 
Thyroid stimulating 
hormone increased 
Weight loss 
 
 
White blood cell decreased 
 
 
METABOLISM AND NUTRITION DISORDERS 
Anorexia 
 
 
 
Hypercalcemia 
 
Hyperglycemia 
 
 
 
Hyperkalemia 
 
 
Hypernatremia 
 
Hypoalbuminemia 
 
 
Hypocalcemia 
 
 
 
Hypoglycemia 
 
 
Hypokalemia 
 
Hyponatremia 
 
 
Hypophosphatemia 
 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 
Back pain 
 
 
Bone pain 
 
 
Muscle cramp 
 
 
Myalgia 
 
 
Pain in extremity 
 


 
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 Adverse Events with Possible  
 Relationship to Sorafenib (BAY 43-9006; Nexavar) 
 (CTCAE 5.0 Term) 
[n= 2571] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) 
 
Treatment related secondary 
malignancy 
 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
 
Headache 
 
 
 
Intracranial hemorrhage 
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
PSYCHIATRIC DISORDERS 
 
Insomnia 
 
RENAL AND URINARY DISORDERS 
 
Acute kidney injury 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 
 
Dyspnea 
 
 
Respiratory hemorrhage5 
 
 
Voice alteration 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Alopecia 
 
 
 
Dry skin 
 
 
 
Erythema multiforme 
Palmar-plantar 
erythrodysesthesia syndrome 
 
 
 
Pruritus 
 
Rash maculo-papular 
 
 
 
 
Stevens-Johnson 
syndrome 
 
 
Toxic epidermal 
necrolysis 
VASCULAR DISORDERS 
 
Hypertension 
 
 
 
Thromboembolic event 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 


 
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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. 
 
2Gastrointestinal hemorrhage may include Anal hemorrhage, Cecal hemorrhage, Colonic 
hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, 
Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, 
Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic 
hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal 
hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
 
3Gastrointestinal perforation may include Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and 
Small intestinal perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
4Infection may include any of the 75 infection sites under the INFECTIONS AND 
INFESTATIONS SOC. 
 
5Respiratory hemorrhage may include bronchopulmonary hemorrhage, epistaxis, laryngeal 
hemorrhage, mediastinal hemorrhage, pharyngeal hemorrhage, and pleural hemorrhage under the 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS SOC. 
 
6Febrile neutropenia is seen mostly in combination with other agents. 
 
 
Adverse events reported on sorafenib (BAY 43-9006; Nexavar) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that sorafenib (BAY 
43-9006, Nexavar) caused the adverse event:   
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (Thrombotic microangiopathy (e.g., TTP or HUS)); Febrile neutropenia6 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Palpitations; 
Pericardial effusion; Pericarditis; Right ventricular dysfunction; Sinus bradycardia; Sinus 
tachycardia; Supraventricular tachycardia; Ventricular arrhythmia; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Tinnitus 
ENDOCRINE DISORDERS - Adrenal insufficiency; Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Extraocular muscle paresis; Eye 
disorders - Other (color vision deficits); Eye disorders - Other (light to dark adaptation); Eye 
disorders - Other (retinal vein occlusion, bilat); Eye disorders - Other (retinal hemorrhage); Eye 
disorders - Other (visual field distortion); Flashing lights; Keratitis; Photophobia; Retinal 
detachment 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal fistula; Anal mucositis; 
Anal pain; Anal ulcer; Cheilitis; Colitis; Colonic obstruction; Colonic ulcer; Dry mouth; 
Duodenal ulcer; Dyspepsia; Dysphagia; Enterocolitis; Esophageal pain; Esophagitis; Flatulence; 
Gastric ulcer; Gastritis; Gastroesophageal reflux disease; Gastrointestinal disorders - Other 
(diverticulitis); Gastrointestinal disorders - Other (small bowel NOS fistula); Gastrointestinal 


 
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fistula; Hemorrhoids; Ileal fistula; Ileus; Oral pain; Pancreatitis; Proctitis; Rectal fistula; Rectal 
mucositis; Rectal obstruction; Rectal pain; Small intestinal obstruction; Stomach pain; Visceral 
arterial ischemia 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema 
face; Facial pain; Flu like symptoms; Localized edema; Multi-organ failure; Non-cardiac chest 
pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic hemorrhage; Hepatobiliary 
disorders - Other (biliary obstruction secondary to multiple biliary stones) 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Cytokine release syndrome; Immune 
system disorders - Other (systemic inflammatory response syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; Fall; 
Fracture; Hip fracture; Vascular access complication; Wound dehiscence 
INVESTIGATIONS - CPK increased; Cardiac troponin I increased; Cardiac troponin T 
increased; Cholesterol high; Ejection fraction decreased; Fibrinogen decreased; Investigations - 
Other (blood urea nitrogen high) 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Alkalosis; Dehydration; 
Hypermagnesemia; Hypertriglyceridemia; Hyperuricemia; Hypomagnesemia; Tumor lysis 
syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Chest wall 
pain; Generalized muscle weakness; Joint range of motion decreased; Muscle weakness lower 
limb; Muscle weakness upper limb; Musculoskeletal and connective tissue disorder - Other 
(cramping); Myositis; Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Leukemia secondary to oncology chemotherapy; Myelodysplastic syndrome; Tumor 
hemorrhage; Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Depressed level of 
consciousness; Dysgeusia; Dysphasia; Encephalopathy; Extrapyramidal disorder; 
Hydrocephalus; Ischemia cerebrovascular; Lethargy; Leukoencephalopathy; Memory 
impairment; Muscle weakness left-sided; Muscle weakness right-sided; Neuralgia; Peripheral 
motor neuropathy; Peripheral sensory neuropathy; Seizure; Stroke; Syncope; Tremor; Vasovagal 
reaction 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Libido decreased; 
Personality change; Psychosis 
RENAL AND URINARY DISORDERS - Chronic kidney disease; Hematuria; Nephrotic 
syndrome; Proteinuria; Renal and urinary disorders - Other (focal segmental glomerulosclerosis); 
Renal and urinary disorders - Other (right ureter rupture); Renal calculi; Renal hemorrhage; 
Urinary frequency; Urinary incontinence; Urinary retention; Urinary tract obstruction; Urine 
discoloration 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction; 
Gynecomastia; Hematosalpinx; Menorrhagia; Ovarian hemorrhage; Prostatic hemorrhage; 
Spermatic cord hemorrhage; Testicular hemorrhage; Uterine hemorrhage; Vaginal fistula; 
Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory 
distress syndrome; Allergic rhinitis; Bronchospasm; Hiccups; Hoarseness; Hypoxia; Laryngeal 
mucositis; Pharyngeal mucositis; Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; 
Pneumothorax; Pulmonary edema; Pulmonary fibrosis; Respiratory, thoracic and mediastinal 


 
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disorders - Other (nasal septal perforation); Tracheal mucositis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythroderma; Hyperhidrosis; Nail 
loss; Pain of skin; Purpura; Rash acneiform; Scalp pain; Skin and subcutaneous tissue disorders - 
Other (non-life threatening squamous cell carcinoma of skin: keratocanthomas type); Skin 
hyperpigmentation; Skin hypopigmentation; Skin ulceration; Urticaria 
VASCULAR DISORDERS - Flushing; Hematoma; Hot flashes; Hypotension; Phlebitis; 
Vascular disorders - Other (ruptured aortic aneurysm); Vasculitis 
 
 
Note: Sorafenib (BAY 43-9006; Nexavar) 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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7.1.2.4 Sunitinib 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
For Sunitinib Malate (SU011248 L-malate, NSC 736511) 
 
The Comprehensive Adverse Events 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. 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 7115 patients. Below is the CAEPR for 
Sunitinib malate (SU011248 L-malate). 
CTEP-AERS 


 
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   Version 2.14, February 15, 20191 
 
 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 5.0 Term) 
[n= 7115] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia 
 
 
 
 
Hemolytic uremic 
syndrome 
 
 
 
Thrombotic 
thrombocytopenic 
purpura 
 
CARDIAC DISORDERS 
 
 
 
Cardiac disorders - 
Other 
(cardiomyopathy) 
 
 
 
Heart failure 
 
 
 
Left ventricular systolic 
dysfunction 
 
 
 
Myocardial infarction  
ENDOCRINE DISORDERS 
 
 
 
Endocrine disorders - 
Other (thyroiditis) 
 
 
 
Hyperthyroidism 
 
 
Hypothyroidism 
 
 
EYE DISORDERS 
 
 
 
Eye disorders - Other 
(macular edema) 
 
 
 Papilledema 
  
 
 
 
 Vision decreased 
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal distension 
 
 
Abdominal pain 
 
 
 
Anal mucositis 
 
 
 
Constipation 
 
 
 
Diarrhea 
 
 
 
 
Dry mouth 
 
 
Dyspepsia 
 
 
 
 
 
Esophagitis 
 


 
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 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 5.0 Term) 
[n= 7115] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
Flatulence 
 
 
 
 Gastritis 
 
 
 
 Gastroesophageal reflux 
disease 
  
 
 
 
 Gastrointestinal 
perforation2 
 
Mucositis oral 
 
 
 
Nausea 
 
 
 
 
Oral pain 
 
 
 
 
Pancreatitis 
 
Rectal mucositis 
 
 
 
Small intestinal 
mucositis 
 
 
 
Vomiting 
 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS  
 
Chills 
 
 
 
Edema limbs 
 
 
Fatigue 
 
 
 
 
Fever 
 
 
 
Flu like symptoms 
 
 
 
Non-cardiac chest pain 
 
 
HEPATOBILIARY DISORDERS 
 
 
 
Cholecystitis 
 
 
 
Hepatic failure 
 
IMMUNE SYSTEM DISORDERS 
 
 
 
Allergic reaction3 
 
INFECTIONS AND INFESTATIONS 
 
 
 
Infections and 
infestations - Other 
(necrotizing fasciitis) 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
 
 
Wound complication 
 
INVESTIGATIONS 
 
 
Alanine aminotransferase 
increased 
 
 
 
Alkaline phosphatase 
 
 


 
PhII-122, NCI# 9048 
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 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 5.0 Term) 
[n= 7115] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
increased 
 
Aspartate aminotransferase 
increased 
 
 
 
Blood bilirubin increased 
 
 
 
CPK increased 
 
 
 
Creatinine increased 
 
 
 
 
Electrocardiogram QT 
corrected interval 
prolonged 
 
 
Lipase increased 
 
 
 
Lymphocyte count 
decreased 
 
 
 
Neutrophil count decreased  
 
 
Platelet count decreased 
 
 
 
Serum amylase increased 
 
 
 
Weight loss 
 
 
 
White blood cell decreased  
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 
 
 
Dehydration 
 
 
 
Hyperuricemia 
 
 
 
Hypoalbuminemia 
 
 
 
Hypocalcemia 
 
 
 
 
Hypoglycemia 
 
 
Hypophosphatemia 
 
 
 
 
Tumor lysis syndrome  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
 
Arthralgia 
 
 
 
Back pain 
 
 
 
 
Musculoskeletal and 
connective tissue 
disorder - Other (fistula 
formation) 
 
 
Myalgia 
 
 
 
 
Osteonecrosis of jaw 
 
 
Pain in extremity 
 
 


 
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 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 5.0 Term) 
[n= 7115] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
 
Rhabdomyolysis 
 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL 
CYSTS AND POLYPS) 
 
 
 
Leukemia secondary to 
oncology 
chemotherapy 
 
 
 
Myelodysplastic 
syndrome 
 
NERVOUS SYSTEM DISORDERS 
 
 
Dizziness 
 
 
Dysgeusia 
 
 
 
 
Headache 
 
 
 
 
Leukoencephalopathy  
 
 
Nervous system 
disorders - Other 
(cerebral infarction) 
 
 
Paresthesia 
 
 
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
 
 
 
Transient ischemic 
attacks 
 
PSYCHIATRIC DISORDERS 
 
 
Depression 
 
 
 
Insomnia 
 
 
RENAL AND URINARY DISORDERS 
 
 
 
Acute kidney injury 
 
 
 
Nephrotic syndrome 
 
 
 
Proteinuria 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 
Cough 
 
 
 
Dyspnea 
 
 
 
Epistaxis 
 
 
Laryngeal mucositis 
 
 
 
Pharyngeal mucositis  
 
 
Tracheal mucositis 
 
 
 


 
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 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 5.0 Term) 
[n= 7115] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Alopecia 
 
 
 
Dry skin 
 
 
 
 
Erythema multiforme  
 
 Hair color changes 
 
 
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
 
 
 
Pruritus 
 
 
 
Rash maculo-papular 
 
 
 
 
Skin and subcutaneous 
tissue disorders - Other 
(pyoderma 
gangrenosum) 
 
 
Skin hypopigmentation 
 
 
 
 
Stevens-Johnson 
syndrome 
 
 
 
Toxic epidermal 
necrolysis 
 
VASCULAR DISORDERS 
 
 
Hypertension 
 
 
 
 
Thromboembolic event  
 
Vascular disorders - Other 
(hemorrhage)4 
 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed 
to all Principal Investigators at the time of revision.  The current version can be obtained by 
contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and 
the agent should be included in the e-mail. 
 
2Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small 
intestinal perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
3Allergic reactions observed include anaphylaxis and angioedema. 
 
4The majority of hemorrhage events were mild.  Major events, defined as symptomatic bleeding in a 
critical area or organ (e.g., eye, GI tract, GU system, respiratory tract, nervous system [including fatal 


 
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intracranial hemorrhage, and cerebrovascular accident], and tumor site) have been reported. 
 
Adverse events reported on Sunitinib malate (SU011248 L-malate) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that Sunitinib malate 
(SU011248 L-malate) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Pericardial effusion 
GASTROINTESTINAL DISORDERS - Ascites; Dysphagia; Gastrointestinal disorders - Other 
(enteritis); Hemorrhoids; Ileus; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Pain 
INVESTIGATIONS - GGT increased; INR increased 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypokalemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain 
NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Peripheral sensory neuropathy; 
Seizure; Spinal cord compression; Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Confusion 
RENAL AND URINARY DISORDERS - Hematuria; Urinary retention 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Hematosalpinx 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Pharyngolaryngeal pain; 
Pleural effusion; Pneumothorax 
VASCULAR DISORDERS - Flushing; Hypotension 
 
Note: Sunitinib malate (SU011248 L-malate) 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. 
 
7.2. 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 until March 31, 2018 for AE 
reporting.  CTCAE version 5.0 will be utilized for AE reporting beginning 
April 1, 2018.  All appropriate treatment areas should have access to a copy of 
the CTCAE version 5.0.  A copy of the CTCAE version 5.0 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. 
 
• 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 


 
PhII-122, NCI# 9048 
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- 
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. 
 
7.3. Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse 
Event Reporting 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 table 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:  A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below.  Attribution to treatment 
or other cause must be provided. 
Death due to progressive disease should be reported as Grade 5 “Disease 
Progression” under the system organ class (SOC) “General disorders and 
administration site conditions.”  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.  
 
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 


 
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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 
 
7.4. 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. 
 


 
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7.5. 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.  
 
7.6. 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. 
 
7.7. Pregnancy 
 
Patients who become pregnant on study risk intrauterine exposure of the fetus to 
agents which may be teratogenic.  For this reason, pregnancy occurring on study or 
within 6 months following the last dose of study therapy should be reported in an 
expedited manner via CTEP-AERS as “pregnancy, puerperium and perinatal 
conditions - Other (Pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC and reported as Grade 3. 
 
When submitting the CTEP-AERS report for pregnancy, the “Pregnancy Information 
Form” should be completed and faxed along with any additional medical information 
to (301) 230-0159 (see Appendix D).  The potential risk of exposure of the fetus to 
the investigational agent(s) or chemotherapy agent(s) should be documented in the 
Description of Event section of the CTEP-AERS report. 
 
Pregnancy should be followed up until the outcome of the pregnancy is known at 
intervals deemed appropriate by her physician(s).  The “Pregnancy Information 
Form” should be used for all follow-ups.  If the baby is born with a birth defect or 
other anomaly, then a second CTEP-AERS report is required.  


 
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8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 7.1. 
 
8.1. AMG 386 (NSC 751173) 
 
Chemical Name:  N/A 
 
Other Name:  -trebananib 
 
Classification:  Anti-angiopoietin peptibody 
 
M.W.:  63.5 kD 
 
Approximate Solubility:  N/A 
 
Mode of Action:  AMG 386 selectively inhibits angiopoietins, thereby blocking 
the interaction between Ang1 and Ang2 with their receptor Tie-2.  By inhibiting 
Ang1 and Ang2 from binding to Tie2 receptors, AMG 386 results in an anti-
tumor effect.  In nonclinical studies, AMG 386 reduced proliferation of tumor 
endothelial cells and inhibited the growth of human xenograft tumors in mice, 
while having minimal effects on normal tissues. 
 
Description:  A non-glycosylated homodimer consisting of IgG1 Fc domain with 
4 copies of an anti-Ang2 peptide.  Each monomeric unit contains 10 cysteine 
residues that are involved in 4 intrachain disulfide bonds and 2 interchain 
disulfide bonds.  AMG 386 contains 287 amino acids. 
 
How Supplied:  Amgen, Inc., supplies and CTEP/DCTD distributes AMG 386 as 
a 150 mg, 240 mg, and 600 mg lyophilized powder for Injection vials packaged in 
20 mL, 20 mL, and 50 mL vial sizes, respectively.  AMG 386 is a single-use vial, 
sterile, preservative-free, and contains 10 mM histidine, 4% (w/v) mannitol, 2% 
(w/v) sucrose, 10 mM arginine hydrochloride, and 0.01% (w/v) polysorbate 20 to 
a pH of 7.1. 
 
Currently, the 240 mg vials are being used in all CTEP sponsored protocols.  
Once the NCI has depleted the 240 mg supply, stop using the dosing tables that 
are currently available in the protocol.  All calculated dose in Dose Levels 
10mg/kg, 15 mg/kg, and 30 mg/kg will be rounded to the nearest vial size using 
150 mg or/and 600 mg vials.  Please refer to Appendix H for dose rounding 
guidelines that use the 150 mg and 600 mg vials. 
 
AMG 386 (mg) per vial 
Volume SWFI for reconstitution (mL) 
150 
5 
240 
8 


 
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600 
20 
 
Preparation:  Take the vial(s) out of the refrigerator only when ready to prepare the 
drug for patients. 
 
Note: Amgen Inc. does not classified AMG 386 as cytotoxic; however, if and only if 
your site requires the use of vial adaptors, a 0.2 µm PES (polyethersulfone) in-line 
filter must be used during the IV administration to reduce the risk of stopper 
particles in the IV solution. 
 
Step 1:  Make 30 mg/mL stock solution: 
1. Reconstitute vial within 3 hours once removed from the refrigerator. If it is 
not reconstituted within 3 hours, discard the drug.  
2. Inject the required volume of sterile Water for Injection as indicated in the 
table above into the drug vial with the needle directed toward the side of the 
vial to avoid foaming.  This results in a             30 mg/mL solution.  Do not 
use bacteriostatic water.  
3. Swirl gently until all lyophilized powder is dissolved.  Dissolution usually 
takes 2 minutes or less.  The diluted solution is clear, colorless to slightly 
yellow.  
4. Do not shake. 
5. This stock solution is stable up to 1 hour when stored at ambient temperature 
and up to 24 hours when refrigerated at 20 to 80C, protected from light. 
 
Step 2:  Reconstitute the final IV product: 
Withdraw the calculated amount of the drug from the stock solution (30 mg/mL) and 
further dilute it in 0.9% Sodium Chloride Injection, USP to a final concentration 
between 1.2 mg/mL – 30 mg/mL.  The prepared IV bag can be stored at ambient 
temperature, protected from light for up to 6 hours (i.e., from the time the drug is 
diluted in 0.9% NS to the time it is ready to be administered).  The final IV bag must 
be protected from light if not used immediately. 
 
Storage:  Refrigerate the intact vials at 2˚ to 8˚ C upon receipt.  Protect the vials 
from light.  Do not freeze. 
 
The prepared IV bag can be stored at ambient temperature, protected from light 
for up to 6 hours (this does not include the 1 hour preparation of the stock 
solution) before administration. 
 
Stability:  Shelf-life studies of AMG 386 are ongoing.  The stock solution (30 
mg/mL) is stable up to 1 hour at ambient temperature and up to 24 hours 
refrigerated at 2˚ to 8˚ C, protected from light.  The final IV solution is stable up to 
6 hours at ambient temperature, and must be protected from light if not used 
immediately.. 
 
Route(s) of Administration:  Intravenous. 


 
PhII-122, NCI# 9048 
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Method of Administration:  Infuse over 60 minutes via an infusion pump.  If 
well tolerated, subsequent infusions can be given over 30 minutes.  Flush the IV 
line with 0.9% NS (minimum volume is 5 mL) before and after the each IV 
infusion. 
Note: the IV bag does not need to be protected from light during the IV 
infusion). 
 
Potential Drug Interactions:  Coadministration of VEGF inhibitors (motesanib, 
sorafenib, sunitinib, and bevacizumab) and/or chemotherapeutic agents 
(FOLFOX, FOLFIRI, paclitaxel, docetaxel, carboplatin, cisplatin, PLD, 
topotecan, and capecitabine) has not been demonstrated to alter the 
pharmacokinetics (Cmax or AUC) of AMG 386. 
 
Patient Care Implications:  If extravasation occurs follow your institutional 
guidelines for treatment.  Mild to moderate edema, usually in the upper and/or 
lower extremities, has occurred when AMG 386 is given concomitantly with other 
drugs.  Co-administration of AMG 386 with sorafenib may result in retinal artery 
thrombosis, which can result in permanent impairment of vision or vision loss. 
 
Availability 
 
AMG 386 is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI.  AMG 386 is provided to the 
NCI under a Collaborative Agreement between the Pharmaceutical Collaborator 
and the DCTD, NCI (see Section 12.3). 
 
8.1.1 Agent Ordering and Agent Accountability 
 
8.1.1.1 
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. 
 
Submit all agent requests electronically to PMB.  Active CTEP-
registered investigators and investigator-designated shipping designees 


 
PhII-122, NCI# 9048 
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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) 276-6575 
Monday through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
 
8.1.1.2 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.) 
 
8.2. Commercial Agents 
 
 
 
8.2.1 Bevacizumab (Avastin®) 
 
Product description:  Bevacizumab 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.  Bevacizumab 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 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 (Avastin®) is commercially available. 
 
Solution preparation:  Please refer to the package insert for preparation instructions.   
 
Route of administration:  Administer bevacizumab only as an intravenous (IV) 
infusion. Do not administer as an intravenous push or bolus.  
• First infusion: Administer infusion over 90 minutes. 


 
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• Subsequent infusions: Administer second infusion over 60 minutes if first infusion 
is tolerated; administer all subsequent infusions over 30 minutes if infusion over 60 
minutes is tolerated. 
 
 
 
8.2.2 Pazopanib (VotrientTM) 
 
Product description:  Pazopanib is a tyrosine kinase inhibitor (TKI). Pazopanib is 
presented as the hydrochloride salt, with the chemical name 5-[[4-[(2,3-dimethyl-2H-
indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide 
monohydrochloride. It has the molecular formula C21H23N7O2S•HCl and a 
molecular weight of 473.99. Pazopanib hydrochloride has the following chemical 
structure: 
 
 
 
Pazopanib hydrochloride is a white to slightly yellow solid. It is very slightly soluble 
at pH 1 and practically insoluble above pH 4 in aqueous media. 
 
Each 200 mg tablet of pazopanib contains 216.7 mg of pazopanib hydrochloride, 
equivalent to 200 mg of pazopanib free base. 
 
The inactive ingredients of pazopanib are: Tablet Core: Magnesium stearate, 
microcrystalline cellulose, povidone, sodium starch glycolate. Coating: Gray film-
coat: Hypromellose, iron oxide black, macrogol/polyethylene glycol 400 (PEG 400), 
polysorbate 80, titanium dioxide. 
 
Pazopanib (VotrientTM) is commercially available. 
 
Route of administration:  Pazopanib tablets are for oral administration.  
 
Please consult the package insert for the drug administration guidelines and other 
clinical information. 
 
 
 
8.2.3 Sorafenib (Nexavar®) 
 
Product description:  Nexavar®, a kinase inhibitor, is the tosylate salt of sorafenib.  
Sorafenib tosylate has the chemical name 4-(4-(3-[4-Chloro-3-
(trifluoromethyl)phenyl]ureido)phenoxy)N2-methylpyridine-2-carboxamide 4-
methylbenzenesulfonate and its structural formula is: 
 


 
PhII-122, NCI# 9048 
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Sorafenib tosylate is a white to yellowish or brownish solid with a molecular formula 
of C21H16ClF3N4O3 x C7H8O3S and a molecular weight of 637.0 g/mole. 
Sorafenib tosylate is practically insoluble in aqueous media, slightly soluble in 
ethanol and soluble in PEG 400. 
 
Each red, round Nexavar® film-coated tablet contains sorafenib tosylate (274 mg) 
equivalent to 200 mg of sorafenib and the following inactive ingredients: 
croscarmellose sodium, microcrystalline cellulose, hypromellose, sodium lauryl 
sulphate, magnesium stearate, polyethylene glycol, titanium dioxide and ferric oxide 
red. 
 
Sorafenib (Nexavar®) is commercially available. 
 
Route of administration:  Sorafenib tablets are for oral administration. 
 
Please consult the package insert for the drug administration guidelines and other 
clinical information. 
 
 
 
8.2.4 Sunitinib (Sutent®) 
 
Product description:  Sunitinib (Sutent®), an oral multi-kinase inhibitor, is the 
malate salt of sunitinib. Sunitinib malate is described chemically as Butanedioic acid, 
hydroxy-, (2S)-, compound with N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-
dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide 
(1:1). The molecular formula is C22H27FN4O2 x C4H6O5 and the molecular weight 
is 532.6 Daltons. The chemical structure of sunitinib malate is: 
 
 
 


 
PhII-122, NCI# 9048 
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Sunitinib malate is a yellow to orange powder with a pKa of 8.95. The solubility of 
sunitinib malate in aqueous media over the range pH 1.2 to pH 6.8 is in excess of 25 
mg/mL. The log of the distribution coefficient (octanol/water) at pH 7 is 5.2. 
 
Sunitinib malate capsules are supplied as printed hard shell capsules containing 
sunitinib malate equivalent to 12.5 mg, 25 mg or 50 mg of sunitinib together with 
mannitol, croscarmellose sodium, povidone (K-25) and magnesium stearate as 
inactive ingredients. 
 
The orange gelatin capsule shells contain titanium dioxide, and red iron oxide. The 
caramel gelatin capsule shells contain titanium dioxide, red iron oxide, yellow iron 
oxide and black iron oxide. The white printing ink contains shellac, propylene glycol, 
sodium hydroxide, povidone and titanium dioxide. 
 
Sunitinib (Sutent®) is commercially available.   
 
Route of administration:  Sunitinib capsules are for oral administration. 
 
Please consult the package insert for the drug administration guidelines and other 
clinical information. 


 
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9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1. Tumor Tissue-Based Correlative Studies 
 
 
 
9.1.1 Pre-Treatment Biopsy 
 
Assent to performing a fresh tumor biopsy is a requirement of this trial.  Refer to 
Section 5.1 for details regarding the timing and performance of this biopsy.  Paraffin 
blocks will be made and processed according to standard institutional protocols. 
Paraffin-embedded tissue blocks containing formalin-fixed tumor must be submitted 
for evaluation of expression of relevant molecular targets.   
 
 
9.1.2 Archival Specimen 
 
Submission of an archival tumor specimen is a requirement for participation on this 
trial.  An unstained tumor block from the original resection is preferred.  Where an 
archival block cannot be released by the governing pathology department, 5 x 6μm re-
cuts on 10-12 slides is requested. 
 
 
 
9.1.3 Specimen Handling and Shipping 
 
Biopsy specimens will be collected in formalin and embedded in paraffin by the local 
pathology department.  See Appendix F for shipping instructions. 
 
 
 
9.1.4 
Methodology 
 
Gene expression profiling will be performed in a CLIA-certified laboratory 
(Response Genetics Inc.).  Each block will be reviewed for quality and tumor content 
by a board-certified pathologist.  Ten µm-thick sections will be prepared from 
identified areas with the highest tumor concentration.  Manual micro-dissection using 
a light microscope will be performed on all tumor samples to ensure >80% tumor 
cells is dissected. RNA isolation from paraffin-embedded samples will be performed 
according to a proprietary procedure defined by Response Genetics. After RNA 
isolation, cDNA will be prepared from each sample. Quantitation of the genes of 
interest and an internal reference (β-actin) cDNA will be performed using a 
fluorescence-based real-time detection method (ABI PRISM 7900HT Sequence 
detection System [TaqMan®] Applied Biosystems, Foster City, CA). The polymerase 
chain reaction mixture consists of primer, probe, AmpliTaq Gold Polymerase, the 
dNTP mixture and the TaqMan Buffer.  A reference dye is added to a final reaction 
volume which is 20 μL (all reagents from Applied Biosystems, Foster City, CA). 
 
All samples will be amplified in triplicate for each gene.  For each sample, parallel 
TaqMan polymerase chain reactions will be performed for the gene of interest and the 
β-actin reference gene to normalize the gene expression. The obtained ratio between 
the values provides relative gene expression levels for each gene of interest.  Markers 


 
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will be prioritized in the following order in the absence of sufficient tissue to perform 
all of the markers on a given specimen: 
 
 
 
Markers of angiopoietin-Tie2 mediated angiogenesis 
• Ang1 
• Ang2 
• Tie2 
 
 Markers of VEGF-pathway mediated angiogenesis 
• VEGF 
• VEGFR1 
• VEGFR2 
• NRP-1   
 
 
 
 
 
Markers of alternative pro-angiogenic pathways 
• IL-8 
• VCAM-1 
• bFGF  
 
9.2. Pharmacodynamic Correlative Studies 
 
 9.2.1 
Plasma Collection 
 
 One purple top blood tube (EDTA), ~10 mL, will be collected at baseline (prior to 
cycle 1), prior to cycle 2, prior to cycle 3, and at progression.  It is important that 
blood is collected at all timepoints and that the specimens are consistently 
processed according to protocol instructions. 
 
 
9.2.2 
Specimen Handling and Shipping 
 
The EDTA tube should be spun in a standard laboratory centrifuge to separate 
plasma, buffy coat cells, and red blood cells (see Appendix F for blood handling 
protocol). All tubes should be frozen as rapidly as possible, and then stored in a -
70° C freezer until shipped.  See Appendix F for shipping instructions. 
 
 
 
 
 
9.2.3 
Methodology 
 
Biomarker levels will be multiplexed where possible using multiplex bead 
suspension arrays and analyzed using the Luminex xMAP® system (Luminex 
Corporation, Austin, Tx).  Individual Enzyme-linked Immunosorbent Assays 
(ELISAs) will be performed for the remaining markers and where Fc depletion is 
required.  Analyses will be performed by the laboratory of Dr. Philip Mack.  The 
following markers will be measured (listed in order of priority if sample is 
insufficient to perform all markers): 
 
 
 
 
Markers angiopoietin-Tie2 pathway activity 


 
PhII-122, NCI# 9048 
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• Ang2  
• soluble Tie2 
 
 
Markers of VEGF pathway activity 
• VEGF-A 
• soluble VEGFR2 
 
 
 
 
 
 
 
Markers of alternative pro-angiogenic pathways 
• IL-8 
• ICAM-1 
• VCAM-1 
• bFGF  
• PDGF 
• PlGF  
 
9.3. Pharmacogenetic Correlative Studies 
 
 
9.3.1 
Specimen Collection 
 
 Genomic DNA will be collected from peripheral blood mononuclear cells will be 
collected at baseline (prior to cycle 1). 
 
 
9.3.2 
Specimen Handling and Shipping 
 
A separate sample is not required for pharmacogenetic analysis.  White blood 
cells containing genomic DNA will be isolated from the buffy coat layer as 
described in section 9.2.2.   
 
 
9.3.3 
Methodology 
 
Polymorphisms in these genes will be analyzed by polymerase chain reaction-
restriction length polymorphism (PCR-RFLP) as previously described (Schneider 
et al. 2008).  Pharmacogenetic analysis will be performed in the laboratory of Dr. 
Heinz Lenz.  Polymorphisms in the following genes will be analyzed: 
 
 
VEGF- pathway  
• VEGF-A 
• VEGFR2 
• PlGF 
 
 
 
 
Angiopoietin-Tie2 pathway 
• Ang1 
• Ang2  
• Tie2 
 


 
PhII-122, NCI# 9048 
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Alternative pro-angiogenic pathways  
• IL-8 
• ICAM-1 
• VCAM-1 
• FGFR4   
 


 
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10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy.  
Scans and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the 
patient’s condition is deteriorating, laboratory evaluations should be repeated within 72 hours 
prior to initiation of the next cycle of therapy.  Cycle length is defined as 6 weeks.  Unless 
otherwise specified, assessments may be performed within a 72 hour window of the indicated 
timepoint. 
 
Pre- 
Study 
Wk 
-1 
Wk 
1j 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13+ 
Off 
Studyk 
AMG386 
 
 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
 
Bevacizumab 
 
 
B 
 
B 
 
B 
 
B 
 
B 
 
B 
 
B 
 
Pazopanib 
 
 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
 
Sorafenib 
 
 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
 
Sunitinib 
 
 
E 
E 
E 
E 
 
 
E 
E 
E 
E 
 
 
E 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
 
X------------------------------------------------------------------------------------------------X 
 
Physical exam 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Vital signs (including BP) 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Performance status 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
CBC w/diff, pltsa 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Serum chemistrya,b  
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Serum Liver Tests (for 
patients on Pazopanib only)1 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
Coagulationc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH, free T4d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urine dipstick 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
EKG (as indicated) 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Echo/MUGA (as indicated)f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
 
X------------------------------------------------------------------------------------------------X 
X 
Tumor measurements 
X 
 
Tumor measurements are repeated every 12 weeks (+/- 7 days).  Documentation 
(radiologic) must be provided for patients removed from study for progressive 
disease. 
X 
Radiologic evaluation 
X 
 
Radiologic measurements should be performed every 12 weeks (+/- 7 days). 
X 
B-HCG 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Tumor Biopsyh 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival Tumor Specimen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
PhII-122, NCI# 9048 
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Correlative Collectioni 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
A: 
AMG386:  15 mg/kg IV weekly  (D1, 8, 15, 22, 29, and 36) 
B: 
Bevacizumab: 10 mg/kg IV every 2 weeks (D1, 15, and 29) 
C: 
Pazopanib: Dose as assigned.  Once daily orally. 
D:  Sorafenib: Dose as assigned.  Twice daily orally.  
E:  
Sunitinib: Dose as assigned.  Once daily for 4 weeks, followed by 2 week rest period. 
a: 
Laboratory tests will be done within 14 days prior to registration.  Laboratory tests will also be repeated within 72 hours of treatment 
on week 1, week 2, week 4 and then every 3 weeks (twice per cycle) 
b:  
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
c:  
Prothrombin time / INR, activated partial thromboplastin time 
d: 
TSH, free T4 performed once every other cycle.  Required only for patients on pazopanib, sunitinib, or sorafenib. 
e:  
Urine dipstick will be performed at baseline once per cycle.  See section 6.6. 
f: 
LVEF assessment ≤4 weeks prior to registration: required for patients with history or symptoms of congestive heart failure. 
g:  
Serum pregnancy test (women of childbearing potential). 
h:  
To be performed within 1 week after registration.  See Section 5.1.   
i:  
Blood for correlatives will be collected at baseline, prior to cycle 2, prior to cycle 3, and at progression.   
j:  
Treatment should begin between 3 and 5 working days after completion of tumor biopsy and after complete recovery from the biopsy 
procedure. 
k:  
Off-study evaluation.   
1:      Serum liver tests should be monitored before initiation of treatment with pazopanib and at weeks 3, 5, 7, and 9.  Thereafter, 
monitoring should occur at months 3 and 4, and as clinically indicated.  Periodic monitoring should continue after month 4. 


 
PhII-122, NCI# 9048 
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11. MEASUREMENT OF EFFECT 
 
11.1. Antitumor Effect – Solid Tumors 
 
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 at 
least 4 weeks following initial documentation of objective response. 
 
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. 
 
11.2. Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment with AMG 386. 
 
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.  
 
11.2.1 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) 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 might or 
might 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 


 
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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 pathological 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. 
 
‘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.  
 
11.2.2 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. 


 
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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 
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 


 
PhII-122, NCI# 9048 
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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 
relapse in trials where recurrence following complete response (CR) or surgical 
resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If 
markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.  Specific guidelines for 
both CA-125 response (in recurrent ovarian cancer) and PSA response (in 
recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin 
Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which 
are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between 
partial responses (PR) and complete responses (CR) in rare cases (e.g., residual 
lesions in tumor types, such as germ cell tumors, where known residual benign 
tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or stable 
disease (an effusion may be a side effect of the treatment) and progressive 
disease. 
 
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 


 
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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. 
 
11.3. Response Criteria 
 
 
 
11.3.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions.  Any 
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 


 
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PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum 
diameters while on study. 
 
 
11.3.2 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. 
 
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. 
 
Non-CR/Non-PD:  
Persistence of one or more non-target 
lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
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). 
 
 
 
11.3.3 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. 
    
 
 
 
 
 


 
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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 
>4 wks. 
Confirmation** 
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. 
** 
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. 
 
 
 
 
 
 
 
 


 
PhII-122, NCI# 9048 
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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 
 
11.4. 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.  
 
11.5. Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of 
progression or death, whichever occurs first. 
  
12. 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). 
 
12.1. 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 


 
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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).  
 
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse 
events (both routine and expedited) that have occurred on the study and meet the 
mandatory CDUS reporting guidelines must be reported via the monitoring 
method identified above.  If your study has been assigned to CDUS-Abbreviated 
reporting, no adverse event reporting (routine or expedited) is required to be 
reported via CDUS. 
 
12.1.2 Responsibility for Data Submission 
 
Study participants are responsible for submitting CDUS data and/or data forms to 
either the Coordinating Center or to the Lead Organization on the study quarterly.  
The date for submission to the Coordinating Center or to the Lead Organization 
will be set by them.  CDUS does not accept data submissions from the 
participants on the study.  When setting the dates, allow time for Coordinating 
Center compilation, Principal Investigator review, and timely submission to 
CTEP by the quarterly deadlines (see Section 12.1.1).  For trials monitored by 
CTMS, a quarterly report of data will be provided by Theradex to the 
Coordinating Center. 
 
Either the Coordinating Center or the Lead Organization is responsible for 
compiling and submitting CDUS data to CTEP for all participants and for 
providing the data to the Principal Investigator for review.   
 
 
 
12.1.3. Data Collection Forms and Submission Schedule 
 
 
 
 
All data will be collected using COH data collection forms via an electronic data 
capture system. Any original data collection forms will reside at the originating 
institutions in secure location. 
 
ELIGIBILITY CHECKLIST: The data manager at the registering site will have 
completed and faxed this form at the time of registration. 
ON-STUDY FORM (FORM OS): Completed on-study forms due within two 
weeks of registration. 
TREATMENT FORM (FORM RX): Completed treatment forms are due within 
four weeks of completion of a cycle. 
ADVERSE EVENT COLLECTION: Completed adverse events collection form 
due within four weeks of completion of a cycle. 
FLOW SHEETS: Protocol specific flow sheets are to be submitted along with 
each treatment form. 
RESPONSE/OFF-STUDY/FOLLOW-UP: Form F/U is to be submitted each 
time a patient is evaluated for response and/or new follow-up information is 


 
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obtained. 
SUPPLEMENTAL DATA FORM: The timeline for submission of the 
supplemental data form will be protocol specific, if applicable. 
12.2. CTEP Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the CTEP Multicenter 
Guidelines.  The specific responsibilities of the Principal Investigator and the 
Coordinating Center (Study Coordinator) and the procedures for auditing are 
presented in Appendix B. 
• The Principal Investigator/Coordinating Center is responsible for distributing all 
IND Action Letters or Safety Reports received from CTEP to all participating 
institutions for submission to their individual IRBs for action as required. 
 
• 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. 
 
12.3. 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 
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-


 
PhII-122, NCI# 9048 
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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 
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 


 
PhII-122, NCI# 9048 
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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. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1. Study Design/Endpoints 
 
 
 
 
Design:  This is a randomized phase II study in patients with advanced renal cell 
carcinoma.  Patients will be randomized to treatment with AMG 386 monotherapy 
(arm A) or AMG 386 plus bevacizumab, pazopanib, sorafenib, or sunitinib (arm B).  
This phase II trial is designed to assess efficacy of each arm.  
 
 
 
 
Primary Endpoint: The primary endpoint of this trial is treatment efficacy evaluated 
by overall tumor response rate (ORR) using RECIST v1.1 criteria in each treatment 
arm.  The overall tumor response rate is defined as the total number of efficacy-
evaluable patients who achieve a complete or partial response by RECIST 1.1 criteria.     
 
 
 
 
In this study we will define as efficacy-evaluable, any eligible patient who began 
therapy (and received any amount of the first dose of AMG 386). 
 
13.2. Sample Size/Accrual Rate 
 
 
 
 
For assessment of clinical outcome, both arms will be evaluated separately using a 
Simon Optimum design with as maximum of 39 patients, an interim evaluation after 
17 patients, and with alpha=0.10 (when the response rate is ≤ 3%) and beta=0.10 
(when the response rate is 15%).  If AMG 386 is ineffective (alone or in the presence 
of an anti-VEGF agent), then we would expect to see no objective responses (by 
RECIST v1.1), while a 15% response rate would be taken as interesting enough to 
encourage future study.  Thus, if 0/17 or < 2/39 patients experience an objective 
response within each arm, this will be taken as evidence that the response rate in that 
arm is less than 15%.  Conversely, if 3 or more patients out of 39 experience an 
objective response, that will be taken as evidence that the true response rate is greater 
than 3%.  Based on prior accrual, the accrual rate is anticipated to be 4 patients per 
month.   
 
13.3. Analysis of Secondary Endpoints 
 


 
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Secondary Endpoints: 
 
 
 
1) To evaluate progression free survival in each arm. 
 
 
 
2) To evaluate the tolerance and toxicity of AMG 386 alone and in combination with 
continuation of the prior VEGF targeted regimen. 
 
Progression free survival (PFS):  Progression free survival, defined as the duration 
of time from start of treatment to time of progression or death, whichever occurs first, 
will be analyzed in the efficacy-evaluable population. 
 
 
 
 
Monitoring Safety/Toxicity: Safety and toxicity will be reviewed monthly at the 
CCCP Data Coordinating Meetings, in which all toxicities (especially Grade 3+) are 
assembled and reviewed.  The first 6 patients treated with the combination of each 
anti-VEGF agent and AMG 386 will be specifically monitored during these calls.  In 
addition, safety boundaries (using a modified sequential probability ratio test) will be 
used to flag excessive, unacceptable toxicities.  Additionally, because there is limited 
experience with AMG 386 at 15 mg/kg in combination with anti-VEGF agents and 
due to a mandate for tumor biopsy in the RCC cohort, there will be separate dedicated 
monthly conference calls for this trial monitoring toxicity events and the safety of the 
mandatory research biopsy. 
 
Rules for Monitoring Safety:  In this trial, unacceptable toxicity (TOX) will be 
defined as any toxicity due to treatment, that results in a death.  Patients who 
complete the first course of treatment (i.e. receive 80% of the total planned amount of 
AMG 386 (accounting for dose reductions as specified in the protocol), or who fail to 
complete the first course for reasons of toxicity or side effects, will be considered at 
risk for TOX (for purposes of applying these toxicity monitoring boundaries).  
 
Criteria for flagging an excessive number of patients with TOX are based on the 
sequential probability ratio test with =0.10, =0.05, po=0.03 and pa=0.15. Every 
time a patient is classified as having had a TOX, the cumulative number of patients 
(X) who have experienced a TOX will be compared to the number of patients (N) 
who are at risk.  If the number of patients, N, is greater than NX, the number given in 
the bottom row of the Table below, then the boundary has not been crossed. If N is 
less than or equal to NX, then the boundary has been crossed and a careful review of 
all the toxicities and tolerability will be initiated. 
 
Table:  Boundary for Monitoring Toxicity  
X: # pts who experienced a TOX 
2 
3 
4  
5 
Nx:  Boundary crossed if # pts. At risk (N) is  Nx 
9 
22 
35 
39 
 
These rules were selected to ensure a reasonable chance that the boundary would not 
be crossed if the true chance of TOX were less than 3-5% and a reasonable chance 
that the boundary would be crossed if the true chance were 15-20%. The Table below 
summarizes these probabilities. The values in the table below are based on 10,000 
simulations and are accurate to 0.01 (based on a 95% confidence interval). 
 
 
 


 
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Table: Probability that the Toxicity Monitoring Boundary is Crossed Because Too Many 
Patients Experienced a TOX  
True Chance of an Unacceptable Toxicity (TOX) 
3% 
5% 
10% 
15% 
20% 
Probability of Suspending Accrual 
to Review Toxicities   
N=17 
0.03 
0.10 
0.32 
0.56 
0.74 
N=39 
0.05 
0.17 
0.56 
0.85 
0.96 
 
 
 
 
Summary of Clinical Endpoints:  All patients who begin treatment with AMG 386 
will be accounted for, in each of the 2 arms separately; number of prior chemotherapy 
regimens, prior treatment with an mTOR inhibitor, number of courses begun, number 
of courses completed, reason off treatment, reason off study, total drug(s) received, 
toxicities (grade, type, cycle, and attribution) experienced, best response, and time to 
progression will be listed for each patient and summarized using standard descriptive 
methods – point estimates and associated confidence intervals.  Kaplan-Meier plots 
will be used to display the PFS in each arm.    
 
13.4. Analysis of Correlative Endpoints 
 
 
 
 
Correlative Endpoints: 
1) To evaluate the association between pretreatment tumor gene expression levels and 
response to AMG 386 in combination with continuation of the prior VEGF targeted 
agent.  
 
 
 
2) To evaluate the association between SNPs in angiogenic genes and response to 
AMG 386 in combination with continuation of the prior VEGF targeted agent.  
 
 
 
3) To compare changes in circulating angiogenic factors in RCC patients treated with 
AMG 386 monotherapy to those treated with AMG 386 in combination with VEGF-
targeted therapy. 
 
 
 
4) To compare expression of angiogenic genes in RCC tumors from archival 
specimens to the expression in biopsy specimens performed after progression on anti-
VEGF therapy. 
 
The long-range goal should AMG 386, alone or with VEGF-targeted therapy, prove 
to be effective in the treatment of RCC, would be to identify subsets of patients who 
are more likely (or who are very unlikely) to benefit from treatment with AMG 386 – 
using baseline archival or biopsy tumor specimens.  The first step in identifying 
predictive markers is simply to establish an association with outcome.  Follow-up 
studies will be needed, to better quantify the relationships and to accurately estimate 
the sensitivity and specificity of individual markers, or a panel of markers, for 
predicting response to AMG 386. 
 
 
 
 
The analyses and descriptions below assume that we will be using objective response 
(CR+PR vs. SD+PD) as the clinical outcome variable to evaluate the potential 
predictive biomarkers.  However, in addition, we will repeat the analyses using (1) 
progression-free-survival (PFS) (with Kaplan-Meier plots, the logrank test and the 
Cox proportional hazards model, instead of scatterplots, t-tests, contingency tables 


 
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and associated chi-square tests and logistic regression) and (2) using the percent 
change in tumor burden by RECIST v1.1 (with scatterplots, correlations, and linear 
regressions) to assess whether biomarker patterns have the potential for identifying 
patients who are more or less likely to benefit from treatment with AMG 386.   These 
additional analyses will serve two purposes:  (1) if there are strong patterns, we would 
expect to observe them using other metrics of anti-tumor activity, and (2) in an 
exploratory fashion, they may reveal patterns that are not apparent with the 
dichotomous response rate.   
 
 
 
 
The levels of the circulating angiogenic factors will be analyzed as continuous 
variables (most likely after transformation). The gene expression results from the 
pretreatment tumor biopsies are expressed as ratios between that of the gene of 
interest and the internal reference gene β-actin and can be analyzed as continuous 
variables – generally after log transformation.  Polymorphisms are categorical; 
generally the wildtype homozygous genotype is compared to the genotypes 
containing the less frequent allele.   
 
 
 
 
The initial analysis of tumor gene expression will be performed on pre-treatment 
tumor biopsies.  At a minimum, there will be study specimens for 17 patients who 
receive AMG 386 alone and 17 patients who receive AMG 386 with an anti-VEGF 
agent; if AMG 386 demonstrates anti-tumor activity in RCC, then we will have 
specimens for 39 patients in arm A and arm B respectively.   
 
 
 
 
(1) The expression of angiopoietin-, VEGF-, and anti-angiogenic therapy resistance-
related markers will be compared between archival specimens and the research 
biopsy specimens.  Both archival and biopsy specimens will be sought for all patients.  
Assuming specimens are available for 90% of patients, we anticipate that there will 
be 30 (90% of 17+17) or 50 (90% of 17+39) or 70 (90% of 39+39) paired specimens 
allowing the comparison of the gene expression levels in archival specimens (before 
anti-VEGF therapy) with levels in biopsy specimens (after anti-VEGF therapy).  In 
addition to comparing the mean levels and patient-to-patient variability based on the 
two sets of specimens, we will be especially interested in whether the two types of 
specimens result in the same ranking of patients according to each of the gene 
expression levels; thus, the Spearman correlation coefficient, and associated 95% 
confidence interval will be calculated. The table below provides the 95% confidence 
intervals for a selection of possible observed correlation coefficients.  The observed 
correlation coefficients will be used to better understand whether the archival 
specimens convey the same information as the biopsy specimens. 
 
Table:  Example of 95% Confidence Intervals for Possible Observed Spearman 
Correlation between Gene Expression Levels Determined in Archival Specimens and 
Determined in Biopsy Specimens 
Observed 
Correlation 
95% Confidence Interval with 
30 Pairs of Specimens  
(90% of 17+17) 
95% Confidence Interval with 
50 Pairs of Specimens  
(90% of 17+39) 
0.60 
(0.31, 0.79) 
(0.39, 0.75) 
0.65 
(0.38, 0.82) 
(0.45, 0.79) 
0.70 
(0.46, 0.85) 
(0.52, 0.82) 


 
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0.75 
(0.54, 0.87) 
(0.60, 0.85) 
0.80 
(0.62, 0.90) 
(0.67, 0.88) 
0.85 
(0.71, 0.93) 
(0.75, 0.91) 
0.90 
(0.80, 0.95) 
(0.83, 0.94) 
 
 
 
 
(2) The observed clinical activity of AMG 386 (+/- anti-VEGF therapy) will 
determine how the biomarker data will be examined and used.  To illustrate this, 
two possible scenarios are described:  (a) If AMG 386 +/- anti-VEGF therapy is 
inactive and no responders are observed in any of the 2x17=34 patients, and (b) the 
drug combination AMG 386 (+ anti-VEGF therapy) has demonstrated activity and 
there are at least 3 patients with objective responses in 39 patients (if 15% of patients 
have an objective response, we can expect about 5-6 responders). 
 
 
 
 
(a) If AMG 386 + anti-VEGF therapy demonstrates no (or very little) activity, tumor 
gene expression levels, the polymorphisms and the baseline circulating angiogenic 
factors will be summarized – overall and by disease.  The changes, at the 2nd and 3rd 
cycles, in the circulating levels will also be summarized (using standard descriptive 
statistics); t-tests for each marker (and possibly the multivariate Hotelling’s T2) will 
be used to evaluate whether there were any changes at all (overall) and whether the 
changes were in the hypothesized favorable direction – if necessary, adjusting for 
disease.  These patterns – baseline and changes, or lack of changes – may help to 
explain why AMG 386 + anti-VEGF therapy was inactive.  That is, these analyses 
can be used to understand whether the expected biological (PD) effects were observed 
and thus this trial will provide important information even in the absence of clinical 
activity.  In this setting, the use of PFS or percent change in tumor burden may reveal 
signals or patterns that are not apparent with the dichotomous response rate.     
  
 
 
 
(b) If AMG 386 + anti-VEGF therapy is shown to be active, then scatterplots, means, 
and confidence intervals will be used to display the differences between the 
responders and non-responders, in terms of each of the continuous biomarkers – at 
baseline and the changes.  The two groups will be compared in terms of 
polymorphisms, using methods for categorical data.   Of particular interest is the 
possibility that this agent is reasonably effective in a subset of patients and essentially 
ineffective in the remaining patients – and that this subset can be defined by one 
correctly identified biomarker.  These proposed descriptive analyses will identify 
very strong patterns should they exist (e.g. if there are 4 or 5 responders and all 4 or 5 
have expression levels for a marker that are all above or all below the median).   The 
purpose of these exploratory analyses is to revise and refine hypotheses regarding the 
role of AMG 386 in the treatment of RCC – with the understanding that these new 
hypotheses will require testing.   
 
 
 
 
No formal adjustment will be made to account for the number of comparisons; if 
warranted, resampling will be used to assess the robustness (internal validity) of the 
identified differences and patterns.  The goal of these analyses – in addition to better 
understanding why tumors did or did not respond – is to identify a subset of 
biomarkers which can be further studied should this agent undergo additional testing. 
 


 
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13.5. Reporting and Exclusions 
 
13.5.1 Evaluation of toxicity – All patients will be evaluable for toxicity from the time 
of their first treatment with AMG 386, bevacizumab, pazopanib, sorafenib, or 
sunitinib. 
 
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 (with the exception of those 
who received no study medication) – i.e. those who are efficacy-evaluable will 
be included in the main analysis of the response rate.  Patients in response 
categories 4-9 should 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.   
 
14. CCCP POLICIES FOR MONITORING CONSORTIUM TRIALS 
 
 The protocol principal investigator (PI) is responsible for monitoring the conduct and 
progress of this Phase II 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 (see Section 7) 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 Data 
Coordinating Center 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 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: 
 
 (a)  
for Phase I trials, all dose limiting toxicities and decisions regarding dose 
escalation, expansion, as well as decisions to terminate escalation, and 
 
 
(b)  
for Phase II trials, the toxicities and therapeutic endpoints referred to in the 
statistical plan. 
 
 
 


 
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 The Data Coordinating Committee meets monthly to review data management and data 
quality issues – completeness of data submissions as well as accuracy in terms of built-in, 
computerized logic checks. Any issues identified and the corrective plans are presented to 
the Internal Committee and at the next CCCP teleconference meeting for review and 
approval.  
 
 
 
Oversight 
 
 
Oversight of the conduct of CCCP trials occurs at several levels: 
 
1.  
The Data Coordinating Center 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 Data 
Coordinating Center. At the monthly teleconferences, the accrual of each open 
protocol is reviewed. 
 
 
 
2.  
CTEP specifics the monitoring method for NCI-sponsored protocols coordinated 
by the CCCP.  For trials monitored by the NCI-designated clinical trials 
monitoring service (CTMS), CTMS will audit patients’ records on each protocol – 
at each participating institution; these audits are initiated by CTEP. For all other 
CCCP trials, patient records at each institution are audited in accord with 
institutional cancer center policies. 
 
 
 
3.  
An independent CCCP DSMC will review CCCP trials every 6 months. This 
DSMC will consist of 5 voting members (3 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. 
 
 a.  DSMC meetings will take place twice a year. Additional meetings will be 
convened if necessary. 
 b.  This DSMC will review each CCCP trial in terms of accrual, toxicity/safety, 
and adherence to trial design, audit results, and likelihood of successful 
completion. 
c.   The DSMC will report to the CCCP leadership.


 
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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. 
 
 
 
 
 
 
 
 
 
 


 
PhII-122, NCI# 9048 
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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. 
 
 
 


 
PhII-122, NCI# 9048 
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• Audits may be accomplished in one of two ways:  (1) source documents and research 
records for selected patients are brought from participating sites to the Coordinating 
Center for audit, or (2) selected patient records may be audited on-site at participating 
sites.  If the NCI chooses to have an audit at the Coordinating Center, then the 
Coordinating Center is responsible for having all source documents, research records, all 
IRB approval documents, NCI Drug Accountability Record forms, patient registration 
lists, response assessments scans, x-rays, etc. available for the audit. 
 
Inclusion of Multicenter Guidelines in the Protocol 
• The protocol must include the following minimum information:  
➢ The title page must include the name and address of each participating institution and 
the name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
➢ The Coordinating Center must be designated on the title page. 
➢ Central registration of patients is required.  The procedures for registration must be 
stated in the protocol. 
➢ Data collection forms should be of a common format.  Sample forms should be 
submitted with the protocol.  The frequency and timing of data submission forms to 
the Coordinating Center should be stated. 
➢ Describe how AEs will be reported from the participating institutions, either directly 
to CTEP or through the Coordinating Center. 
➢ Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions. 
 
Agent Ordering 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied 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.  
 
 
 
 
 


 
PhII-122, NCI# 9048 
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APPENDIX C - List of drugs that may have potential CYP3A4 interactions 
 
CYP3A4 Substrates 
Albuterol 
Alfentanil 
Alprazolam 
Amiodarone 
Amlodipine 
Amprenavir 
Aprepitant 
Aripiprazole 
Atazanavir 
Atorvastatin 
Benzphetamine 
Bisoprolol 
Bortezomib 
Bosentan 
Bromazepam 
Bromocriptine 
Budesonide 
Buprenorphine 
Buspirone 
Busulfan 
Carbamazepine 
Cerivastatin 
Chlordiazepoxide 
Chloroquine 
Chlorpheniramine 
Cilostazol 
Cisapride 
Citalopram 
Clarithromycin 
Clobazam 
Clonazepam 
Clorazepate 
Cocaine 
Colchicine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Dantrolene 
Dapsone 
Delavirdine 
Diazepam 
Dihydroergotamine  
Diltiazem  
Disopyramide  
Docetaxel 
Doxepin 
Doxorubicin 
Doxycycline 
Efavirenz 
Eletriptan 
Enalapril 
Eplerenone 
Ergoloid mesylates 
Ergonovine 
Ergotamine 
Erythromycin 
Escitalopram 
Estradiol 
Estrogens, conj., synthetic 
Estrogens, conj., equine 
Estrogens, conj., esterified 
Estrone 
Estropipate 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemestane 
Felbamate 
Felodipine 
Fentanyl 
Flurazepam 
Flutamide 
Fluticasone 
Fosamprenavir 
Gefitinib 
Haloperidol 
Ifosfamide 
Imatinib 
Indinavir 
Irinotecan 
Isosorbide 
Isosorbide dinitrate 
Isosorbide mononitrate 
Isradipine  
Itraconazole 
Ketamine  
Ketoconazole 
Lansoprazole 
Letrozole 
Levonorgestrel 
Lidocaine 
Losartan 
Lovastatin 
Medroxyprogesterone 
Mefloquine 
Mestranol 
Methadone 
Methylergonovine 
Methysergide 
Miconazole 
Midazolam 
Miglustat 
Mirtazapine 
Modafinil 
Montelukast 
Moricizine 
Nateglinide 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nimodipine 
Nisoldipine 
Norethindrone 
Norgestrel 
Ondansetron 
Paclitaxel 
Pergolide 
Phencyclidine 
Pimozide 
Pipotiazine 
Primaquine 
Progesterone 
Quetiapine 
Quinidine 
Rabeprazole  
Ranolazine 
Repaglinide 
Rifabutin 
Ritonavir 
Salmeterol 
Saquinavir 
Sibutramine 
Sildenafil 
Simvastatin 
Sirolimus 
Spiramycin 
Sufentanil 
Sunitinib 
Tacrolimus 
Tamoxifen 
Tamsulosin 
Telithromycin 
Teniposide 
Tetracycline 
Theophylline 
Tiagabine 
Ticlopidine 
Tipranavir 
Tolterodine 
Toremifene 
Trazodone 
Triazolam 
Trimethoprim 
Trimipramine 
Troleandomycin 
Vardenafil 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Zolpidem 
Zonisamide 
Zopiclone 
 
 


 
PhII-122, NCI# 9048 
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CYP3A4 Inhibitors 
Acetominophen 
Acetazolamide 
Amiodarone 
Amlodipine 
Amprenavir 
Anastrozole 
Aprepitant 
Atazanavir 
Atorvastatin 
Azelastine 
Azithromycin 
Betamethasone 
Bortezomib 
Bromocriptine 
Caffeine 
Cerivastatin 
Chloramphenicol 
Chlorzoxazone 
Cimetidine 
Ciprofloxacin 
Cisapride 
Clarithromycin 
Clemastine 
Clofazimine 
Clotrimazole 
Clozapine 
Cocaine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Danazol 
Dasatinib (1) 
Delavirdine 
Desipramine 
Dexmedetomidine 
Diazepam 
Diclofenac 
Dihydroergotamine 
Diltiazem 
Disulfiram 
Docetaxel 
Doxorubicin 
Doxycycline 
Drospirenone 
Efavirenz 
Enoxacin 
Entacapone 
Ergotamine 
Erythromycin 
Ethinyl estradiol 
Etoposide 
Felodipine 
Fentanyl 
Fluconazole 
Fluoxetine 
Fluvastatin 
Fluvoxamine 
Fosamprenavir 
Glyburide 
Grapefruit juice (1) 
Haloperidol 
Hydralazine 
Ifosfamide 
Imatinib 
Indinavir 
Irbesartan 
Isoniazid 
Isradipine 
Itraconazole 
Ketoconazole 
Lansoprazole 
Lidocaine 
Lomustine 
Losartan  
Lovastatin 
Mefloquine 
Mestranol 
Methadone 
Methimazole 
Methoxsalen 
Methylprednisolone 
Metronidazole 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine 
Mitoxantrone 
Modafinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nisoldipine 
Nizatidine 
Norfloxacin 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxybutynin 
Paroxetine 
Pentamidine 
Pergolide 
Phencyclidine 
Pilocarpine 
Pimozide 
Pravastatin 
Prednisolone 
Primaquine 
Progesterone 
Propofol  
Propoxyphene 
Quinidine 
Quinine 
Quinupristin 
Rabeprazole 
Ranolazine 
Risperidone 
Ritonavir 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sirolimus 
Sulconazole 
Tacrolimus 
Tamoxifen 
Telithromycin 
Teniposide 
Testosterone 
Tetracycline 
Ticlopidine 
Tranylcypromine 
Trazodone 
Troleandomycin 
Valproic acid 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Voriconazole 
Zafirlukast 
Ziprasidone 
 
CYP3A4 Inducers 
Aminoglutethimide 
Carbamazepine 
Fosphenytoin 
Nafcillin  
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital  
Phenytoin 
Primidone 
Rifabutin 
Rifampin  
Rifapentine 
St. John’s wort (2) 
When drugs classified as ‘substrates’ are co-administered with pazopanib, sorafenib or sunitinib, there is the potential for higher concentrations 
of the ‘substrate’. When pazopanib, sorafenib or sunitinib are co-administered with compounds classified as ‘inhibitors’, increased plasma 
concentrations of pazopanib, sorafenib or sunitinib is the potential outcome. The co-administration of ‘inducers’ would potentially lower 
plasma pazopanib, sorafenib or sunitinib concentrations. 
 
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF, Armstrong LL, Goldman MP, Lance LL eds. 
Drug Information Handbook 15TH ed. Hudson, OH; LexiComp Inc. 2007: 1899-1912.   
Only major substrates and effective inducers are listed.   
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at http://medicine.iupui.edu/flockhart/. 
 
(1)  Malhotra et al. (2001). Clin Pharmacol Ther. 69:14-23. 
 
(2)  Mathijssen et al. (2002). J Natl Cancer Inst. 94:1247-1249. 
      Frye et al. (2004). Clin Pharmacol Ther. 76:323-329. 
 
 
 
 
 
 
 
 
Updated on May 1, 2007 
 
 


 
PhII-122, NCI# 9048 
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APPENDIX D – Pregnancy Information Form 
 
 
The following form must be submitted as described in Section 7.7. 


 
PhII-122, NCI# 9048 
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CTEP Protocol #9048 
Local Protocol #PhII-122 
PhII-122, NCI# 9048 
8.26.20v 
133 
APPENDIX E – Pill Diaries 
Today’s date _____________________  
 
 
Agent: Pazopanib 
Patient Name_____________________(initials acceptable)  Patient Study ID __________________________ 
Instructions to Patients: You will receive pazopanib in 200mg tablets.  Your doctor will tell you how many 
tablets to take each day.  Pazopanib should be ingested with a glass of water at least 1 hour before food or at least 2 
hours a meal.  You should try and take your daily dose of dovitinib at approximately the same time each day.  Do 
not crush pazopanib tablets.   
Day 
Date 
Time of Dose 
# of tablets taken 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
29 
 
 
 
 
30 
 
 
 
 
31 
 
 
 
 
32 
 
 
 
 
33 
 
 
 
 
34 
 
 
 
 
35 
 
 
 
 
36 
 
 
 
 
37 
 
 
 
 
38 
 
 
 
 
39 
 
 
 
 
40 
 
 
 
 
41 
 
 
 
 
42 
 
 
 
 
Patient’s signature _________________________________________________________________________ 
 
 
Physician’s Office will complete this section: 
1. Patient’s planned total daily dose ___________________________________________________ 
2. Total number of tablets taken this month _____________________________________________ 
3. Physician/Nurse/Data Manager’s Signature ___________________________________________ 


CTEP Protocol #9048 
Local Protocol #PhII-122 
PhII-122, NCI# 9048 
8.26.20v 
134 
Today’s date _____________________  
 
 
Agent: Sorafenib 
Patient Name_____________________(initials acceptable)  Patient Study ID __________________________ 
Instructions to Patients: You will receive sorafenib in 200mg tablets.  Your doctor will tell you how many tablets 
to take each day.  You will take sorafenib twice each day.  Sorafenib should be ingested with a glass of water at least 
1 hour before food or at least 2 hours a meal.   
Day 
Date 
Time of 
Dose 
# of tablets 
taken AM 
# of tablets 
taken PM 
Comments 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 
29 
 
 
 
 
 
30 
 
 
 
 
 
31 
 
 
 
 
 
32 
 
 
 
 
 
33 
 
 
 
 
 
34 
 
 
 
 
 
35 
 
 
 
 
 
36 
 
 
 
 
 
37 
 
 
 
 
 
38 
 
 
 
 
 
39 
 
 
 
 
 
40 
 
 
 
 
 
41 
 
 
 
 
 
42 
 
 
 
 
 
 
Patient’s signature _________________________________________________________________________ 
 
 
Physician’s Office will complete this section: 
1. Patient’s planned total daily dose ___________________________________________________ 
2. Total number of tablets taken this month _____________________________________________ 
3. Physician/Nurse/Data Manager’s Signature ___________________________________________ 


CTEP Protocol #9048 
Local Protocol #PhII-122 
PhII-122, NCI# 9048 
8.26.20v 
135 
Today’s date _____________________  
 
 
Agent: Sunitinib 
Patient Name_____________________(initials acceptable)  Patient Study ID __________________________ 
Instructions to Patients: You will receive sunitinib in 50 mg, 25 mg, or 12.5 mg tablets.  Your doctor will tell you 
how many tablets to take each day.  Sunitinib can be taken with or without food.  You should try and take your daily 
dose of sunitinib at approximately the same time each day.   
Day 
Date 
Time of Dose 
# of tablets taken 
Comments 
50mg 
25mg 
12.5mg 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
29 
 
 
 
 
30 
 
 
 
 
31 
 
 
 
 
32 
 
 
 
 
33 
 
 
 
 
34 
Do Not Take Sunitinib Days 29-42. 
 
35 
 
 
 
 
36 
 
 
 
 
37 
 
 
 
 
38 
 
 
 
 
39 
 
 
 
 
40 
 
 
 
 
41 
 
 
 
 
42 
 
 
 
 
 
Patient’s signature _________________________________________________________________________ 
 
 
 
Physician’s Office will complete this section: 
1. Patient’s planned total daily dose ___________________________________________________ 
2. Total number of tablets taken this month _____________________________________________ 
3. Physician/Nurse/Data Manager’s Signature ___________________________________________ 


 
PhII-122, NCI# 9048 
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APPENDIX F - Specimen Shipment Guidelines 
 
1.  Tumor Biopsy Specimens 
 
Archived and protocol specific biopsy specimens will be collected in formalin and processed by 
the local pathology department.  Processed specimens will then be submitted to the laboratory of 
Dr. Philip Mack. Institutions should notify the recipient by either phone or fax prior to shipping 
specimens. This will allow the recipient to track the package in the event that there are any 
problems in delivery.  All archival paraffin block/slide specimens should be sent at ambient 
temperature.  Specimens should be shipped to the following address: 
 
Philip C. Mack, PhD 
UC Davis Cancer Center 
4501 X Street, Suite 3016 
Sacramento, CA 95817 
Laboratory Phone: 916-734-3734 
Fax: 916-734-2361 
Email: philip.mack@ucdmc.ucdavis.edu 
 
2.  Blood Specimens 
 
Cryovials (1.5 – 2 mL size) must be labeled with the protocol number (PhII-122), Consortium 
patient ID, patient’s initials, date of specimen collection, and specimen type. 
 
• Collect ~10 mL whole blood in a purple top (EDTA) tube. 
 
• Immediately invert tube (gently) 8 – 10 times. This reduces the possibility of clot 
formation. 
 
• Place tube on wet ice or refrigerate until centrifugation. 
 
• Within 2 hours of blood draw, centrifuge sample at 800 x G for 10 minutes. 
 
• Immediately after centrifuging, transfer plasma to a new, sterile 15 mL conical centrifuge 
tube.  
o Pipette slowly to avoid disturbing the buffy coat layer. 
o Leave a small amount of plasma (~ .5 cm) above the buffy coat layer. 
 
o Centrifuge plasma at 1500 x G for 10 minutes to pellet any remaining platelets.  
After the second spin, transfer the plasma in 1 mL aliquots to 4 labeled cryovials, 
taking care to avoid the pellet at the bottom of the tube.  
 
• While plasma is being centrifuged for the second time, transfer buffy coat from the 
original EDTA tube to 1 labeled cryovial. 
o The buffy layer is the off-white layer between the plasma and the red blood cells. 
o Pipette slowly in a circular motion to obtain as many buffy coat cells as possible. 


 
PhII-122, NCI# 9048 
8.26.20v 
137 
o Contamination of the buffy coat with red blood cells is expected and not a 
concern. There is no need to further purify the white blood cells with a Ficol 
separation. 
 
• Snap-freeze cryovials in liquid nitrogen (if available). 
 
• Store cryovials in a -70° C freezer until shipped. 
 
Shipping Instructions 
 
Prior to shipping, the Specimen Submission Form (please email cccp@coh.org for a copy of the 
form) should be faxed to the Statistical Center at the City of Hope AND the Mack lab (916-734-
2361).  There must be a completed specimen collection form for each time point collected. 
 
The frozen specimens (along with completed Specimen Submission Forms) should be shipped on 
dry ice by overnight courier Monday through Wednesday to: 
 
Philip C. Mack, Ph.D. 
Division of Hematology/Oncology 
University of California, Davis Cancer Center 
4501 X Street, Suite 3016 
Sacramento, CA 95817 
 
Contact: 
Leslie J. Snyder or Philip C. Mack 
Phone: 916/734-3734 
E-mail: leslie.snyder@ucdmc.ucdavis.edu 
 
The Federal Guidelines for Shipment are as follows: 
• The specimen must be wrapped in an adsorbent material; 
• The specimen must be placed in an AIRTIGHT container (resealable bag); 
• Pack the resealable bag and specimen in an Styrofoam shipping container along with 
enough dry ice to last for 2 days; 
• Pack the Styrofoam shipping container in a cardboard box; 
• The cardboard box must be labeled with a Hazardous Materials label for the Dry Ice. 
 
 
 
 
 
 


 
PhII-122, NCI# 9048 
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APPENDIX G - 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
PhII-122, NCI# 9048 
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139 
APPENDIX H – AMG 386 Dose Rounding Guideline Tables 
 
 
Table 1.0  
Dose Level: 15 mg/kg 
Subject’s Actual 
Weight 
AMG 386  
Weight in 
kilograms (kg) 
AMG 386 dose in 
milligrams (mg) 
Number of Vials to Dispense 
150 mg 
600 mg 
Total 
number of 
vials to 
dispense 
25 to 34.9 
450 
3 
0 
3 
35 to 44.9 
600 
0 
1 
1 
45 to 54.9 
750 
1 
1 
2 
55 to 64.9 
900 
2 
1 
3 
65 to 74.9 
1050 
3 
1 
4 
75 to 84.9 
1200 
0 
2 
2 
85 to 94.9 
1350 
1 
2 
3 
95 to 104.9 
1500 
2 
2 
4 
105 to 114.9 
1650 
3 
2 
5 
115 to 124.9 
1800 
0 
3 
3 
125 to 134.9 
1950 
1 
3 
4 
135 to 144.9 
2100 
2 
3 
5 
145 to 154.9 
2250 
3 
3 
6 
155 to 164.9 
2400 
0 
4 
4 
165 to 174.9 
2550 
1 
4 
5 
175 to 184.9 
2700 
2 
4 
6 
185 to 194.9 
2850 
3 
4 
7 
195 to 204.9 
3000 
0 
5 
5