Conditions: Head and Neck Squamous Cell Carcinoma Recurrent Head and Neck Carcinoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 81
Healthy volunteers: no

Brief summary:
This randomized phase II trial studies how well cetuximab with or without tivantinib works in treating patients with head and neck cancer that has come back (recurrent), has spread to other places in the body (metastatic), or cannot be removed by surgery. Monoclonal antibodies, such as cetuximab, may interfere with the ability of tumor cells to grow and spread. Tivantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether cetuximab is more effective with or without tivantinib in treating patients with head and neck cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. Response rate (comparing the cetuximab/ARQ 197 \[tivantinib\] combination with cetuximab single agent activity).

SECONDARY OBJECTIVES:

I. Continuous tumor shrinkage. II. Progression-free survival (PFS). III. Overall survival (OS). IV. Objectives I, II, and III above, as well as response rates, will be assessed and compared between treatment arms in the subgroup of patients with high mesenchymal epithelial transition factor (c-MET) expression, and/or high c-MET copy number.

V. Single agent activity for ARQ 197 (tivantinib) in patients who have failed cetuximab.

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

ARM I: Patients receive cetuximab intravenously (IV) over 60-120 minutes on days 1 and 15 and tivantinib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive cetuximab IV over 60-120 minutes on days 1 and 15. Patients who fail cetuximab as a single agent may receive single agent tivantinib PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 5 years.

Arms:
arm 1: Patients receive cetuximab IV over 60-120 minutes on days 1 and 15 and tivantinib PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive cetuximab IV over 60-120 minutes on days 1 and 15. Patients who fail cetuximab as a single agent may receive single agent tivantinib PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Cetuximab intervention 2: Laboratory Biomarker Analysis intervention 3: Tivantinib
Intervention descriptions: intervention 1: Given IV intervention 2: Correlative studies intervention 3: Given PO

Protocol document:
Prot_SAP_000.pdf: 
i 
 
 
SUMMARY OF CHANGES 
For Protocol Amendment #7 to: 
 
NCI Protocol #: 9165 
Local Protocol #: 12-1359 
 
NCI Version Date:   02/01/16 (last NCI approved version)  
Protocol Date:   04/19/16 (current version) 
 
 
# 
Section 
Page 
Change 
1. n/a 
n/a 
Updated  protocol amendment number and protocol version date throughout the 
document 
2. Protocol 
History 
4 
Updated  protocol history 
3. Section 7.1 
37 
Replaced CAPER for ARQ197 (tivantinib) version 2.1, June 17, 2013 with 
version 2.2, February 19, 2016 


1 
 
 
NCI Protocol #:  
9165        Version   04/19/2016 
Local Protocol #:  
12-1359  
 
TITLE:  A randomized phase II trial of ARQ 197 (tivantinib)/cetuximab versus cetuximab in 
patients with recurrent/metastatic head and neck cancer. 
 
 
Coordinating Center: 
 
 
The University of Chicago Consortium 
 
*Principal Investigator: 
Tanguy Seiwert, MD 
 
5841 S. Maryland Ave, MC2115 
 
Chicago, IL60616, USA 
 
773-702-2452 
 
773-702-3002 
 
tseiwert@medicine.bsd.uchicago.edu 
 
Site Investigators: 
University of Chicago Phase II Consortium 
 
Francis Worden M. D. 
University of Michigan  
Comprehensive Cancer Center 
C361 MIB 0848 
1500 E Medical Center Drive 
Ann Arbor, MI  48109-0848 
Ph: (734) 936-0453 
fworden@umich.edu 
 
James L. Wade III, M.D.  
JLWADE3@sbcglobal.net  
Decatur Memorial Hospital 
2300 N. Edward Street, Decatur, IL 62526 
(217) 876-6600  
Krishna Rao, MD, PhD 
krao@siumed.edu  
Southern Illinois University School of Medicine 
315 W. Carpenter Street 
Springfield, IL  62794-9678 
(217) 545-7969  
Bruce Brockstein, M.D. 
bbrockstein@northshore.org  
NorthShore Healthcare 
2650 Ridge Ave.,  
Evanston, IL 60201 
(847) 570-2515 
Sreenivasa Nattam, M.D. 
ledgar@fwmoh.com    
Fort Wayne Oncology/Hematology  
11143 Parkview Plaza Drive, Suite 100., 
Fort Wayne, IN 46815-5099 
(260) 484-8830 
Mark Kozloff, M.D. 
mfkozloff@aol.com  
S. Yalavarthi, M.D. 
sulochana2001@hotmail.com  
Ingalls Hospital  
1 Ingalls Dr. Harvey, 
IL 60430-1144 
(708) 339-4800 
Bethany G. Sleckman, M.D. 
slecbg@stlo.mercy.net  
Mercy Hospital 
607 S. New Ballas Road, Ste 3425,  
St. Louis, MO 63141 
(314) 251-7057 
Sachdev P. Thomas, M.D. 
sthomas@illinoiscancercare.com  
James A. Knost, M.D. 
jknost@illinoiscancercare.com 
Illinois Cancer Care (Peoria) 
8940 N. Wood Sage Road, Peoria, IL  61615-7828 
(309) 243-3605 
Dan P. Zandberg, MD 
Assistant Professor of Medicine 
University of Maryland Greenebaum Cancer Center 


2 
 
 
22 South Greene Street, N9E17, Baltimore, MD 
(410) 328-7904  
E-mail: dzandberg@umm.edu 
 
Dr. Mark Agulnik, M.D. 
Northwestern Memorial Hospital  
676 N. St. Clair, Suite 850  
Chicago, IL 60611  
P: (312) 695-0990 
E-mail: m-agulnik@northwestern.edu 
 
Sara Grethlein, MD  
 sjgrethl@iu.edu 
Indiana University Simon Cancer Center  
535 Barnhill Drive, RT440  
Indianapolis, IN 46202  
P: 317-962-9000 
 
Mayo Phase 2 Consortium 
 
  
Katheriner Price, M.D.  
Mayo Clinic Cancer Center  
200 First Street SW  
Rochester MN 55905  
Telephone: 507-284-2511  
Fax: 507-284-5280  
E-mail: price.katherine@mayo.edu 
  
  
 
Daniel Anderson, MD 
Metro MN CCOP 
3800 Park Nicollet Blvd 
St. Louis Park, MN 55416 
952-993-1517 
952-993-1550 
Daniel.m.anderson@healthpartners.com 
 
Mohammed Milhem, MD 
University of Iowa Hospitals and Clinics 
200 Hawkins Drive 
Iowa City, IA  52242 
P: 319-356-2324 
E-mail: mohammed-milhem@uiowa.edu 
 
  
 
  Kelly Cutis, M.D.  
Mayo Clinic Arizona 
13400 East Shea Boulevard  
  Scottsdale AZ 985259  
 Telephone: 480-301-8296  
Fax: 480-301-8572  
Curtis.kelly1@mayo.edu 
 
Douglas R. Adkins, M.D. 
Washington University 
School of Medicine 
 
Campus Box 8056 
660 South Euclid Avenue 
St. Louis MO  63110 
Telephone: 314-362-5654  
Fax: 314-362-7086  
dadkins@dom.wustl.edu    
 
California Cancer Consortium 
 
David R. Gandara, MD 
University of California Davis Cancer 
4501 X Street, Sacramento CA 95817 
(P) 916-734-3771 
(F) 916-734-7946 
david.gandara@ucdmc.ucdavis.edu 
 
Dean Lim, MD 
City of Hope Comprehensive Cancer Center 
1500 East Duarte Road, Duarte CA 90101 
Phone: (626) 256-HOPE 
Fax: (626) 301-8898 
Dlim@coh.org 
 
 
Chandra P. Belani, MD 


3 
 
 
Barbara Gitlitz, M.D. 
USC/Norris Comprehensive Cancer Center 
1441 Eastlake Avenue 
Los Angeles, CA 90033-0804 
Phone: 323-865-3959 
Fax: (323) 865-0061 
gitlitz@usc.edu 
 
Penn State Milton S. Hershey Medical Center 
Penn State Cancer Institute, H072 
500 University Drive, P.O. Box 850 
Hershey, PA  17033-0850 
Phone: 717-531-1078 
Fax: 717-531-0002 
E-mail: cbelani@psu.edu  
 
 
Julie Bauman, MD 
Department of Hematology/Oncology 
UPMC Cancer Pavilion, 5th Floor 
5150 Centre Avenue 
Pittsburgh, PA 15232 
Ph: 412-648-6589 
baumanje@upmc.edu 
Stephen Koehler, MD 
City of Hope Medical Group, Inc., 
209 Fair Oaks Avenue 
South Pasadena, CA 91030 
626/396-2900 
Skoehler@cohmg.com 
 
Ammar Sukari, MD 
Wayne State University/Karmanos Cancer Institute 
4100 John R Mail code: HW04HO 
Detroit, MI 48201 
Phone: 313 576 8778 
Fax: 313 576 8767 
sukaria@karmanos.org 
 
 
 
U Chicago Research Personnel 
Biostatistician: 
Theodore Karrison. PhD 
University of Chicago 
5841 S. Maryland Ave., MC 2007, Chicago, IL 60637  
(773) 702-9326 
tkarrison@health.bsd.uchicago.edu 
Phase II Regulatory Manager: 
Supriya Perambakam, CCRP 
University of Chicago 
5841 S. Maryland Ave., MC 1140,  
Chicago, IL 60637 
Phone:(773) 702-6793 
Email speramb@bsd.uchicago.edu  
Responsible Research Nurses: 
Talal Ali, RN 
773-834-4848 
tali2@medicine.bsd.uchicago.edu 
 
 
Nicole Hannigan, RN 
773-702-4848 
nhannigan@medicine.bsd.uchicago.edu 
 
University of Chicago Medical Center  
5841 S. Maryland Ave. MC2115  
Chicago, IL 60637  
 
 
Responsible Data Manager/ Study Registrar: 
Phase II CRA 
The University of Chicago 
Section of Hematology/Oncology 
5841 S. Maryland Ave. MC2115 
Chicago, IL 60637 
Phone: 773-834-3095; Fax: 773-702-4889 
 
PhaseIICRA@medicine.bsd.uchicago.edu 
Group Chairman: 
Walter M. Stadler, M.D.  
wstadler@medicine.bsd.uchicago.edu 
University of Chicago 
5841 S. Maryland Ave., MC 2115 
Chicago, IL 60637 
Tel: (773) 702-4150 
Fax: (773)834-0188 
 


4 
 
 
Contract #  
N01-CM-2011-00071 
NCI Supplied Agent: 
ARQ 197 (tivantinib) (NSC 750832 IND 112603 )   
 
Commercial Agents: 
 
Cetuximab (Bristol-Myers/Imclone/Eli Lilly) 
Tumor Type:  
Head and Neck Cancer, NOS; 10025960 
 
Protocol History 
Version Date 
Protocol Type / Version # 
2/17/12 
Version 1.0- Original Submission 
4/24/12 
Changes submitted in response to NCI consensus review. 
5/11/12 
Changes submitted in response to NCI follow-up review. 
09/20/12 
Amendment # 1. Updated Investigators for Mayo and California Consortia and other personnel 
on Face Page. Added new Appendix F: Patient’s Medication Diary 
5/28/13 
Amendment #2. Updated Site Investigators UCP2C, Mayo and California Consortium. 
Clarification eligibility criteria in section 3.1. Provided clarification under general guidelines for 
section 4.2- registration process to indicate that, patients should begin protocol treatment within 
14 days after randomization. Clarification on the duration of follow-up in section 5.4. Updated 
blood processing language, updated key personnel and shipping information in section 9.2- 
under correlative studies. Schema was amended to include baseline evaluations are to be 
conducted within 2 weeks prior to start of protocol therapy and also that EKG will be evaluated 
at baseline and later in section 10.0. Provided clarifications on definitions for “evaluable for 
objective response” and “Evaluable Non-Target Disease Response” in section 11.1. Included 
clarifications on Sample size/accrual rate, stratification factors, reporting/exclusions and on 
randomization in the section statistical considerations.. Updated Appendix C for Tissue/Sample 
collection form. 
9/27/13 
Amendment #3. Updated CTEP IND agent in Section 2.2. Clarification on exclusion criteria in 
section 3.2. Provided clarification under agent administration for cetuximab under Section 5.1. 
Under section 7.1 updated CAPER for ARQ197 with revised CAPER. Updated baseline 
evaluations under study calendar from 2 weeks to 16 days. Included a new reference.  
12/30/13 
Amendment #4. Updated site PI at Indiana University and also updated Chicago research 
personnel. Replaced CAPER for Cetuximab with safety data from FDA-approved package 
insert. Under Route of administration in Section 8.1, was updated to indicate that it is acceptable 
“to crush the tablet (ARQ 197) as long as it is taken orally”. 
04/15/14 
Amendment #5. Provided clarification of how ARQ 197 should be taken under subsection 3.1.9. 
Updated Adverse Event Expedited Reporting System (AdEERS) with CTEP Adverse Event 
Reporting System (CTEP-AERS) throughout the protocol. Provided clarification about 
administration via G-tube under section 8.1. Provided clarification in the study calendar under section 10.0. 
02/01/16 
Amendment #6. Changed the local PI at Indiana University from Wagner to Grethlein. 
04/19/16 
Amendment #7. Updated CAPER for ARQ197 (tivantinib) version 2.2, February 19, 2016 
 
 
 
 
 
 
 
 
 
 
 

















6&+(0$















3OHDVHQRWH3DWLHQWVZKRIDLOFHWX[LPDEDVDVLQJOHDJHQWKDYHWKHRSWLRQWRUHFHLYH$54
WLYDQWLQLEVLQJOHDJHQWDIWHUZDUGV


&7VFDQDVVHVVPHQWRIUHVSRQVH WXPRU PHDVXUHPHQWV5(&,67ZLOOEHHYHU\F\FOHV 
ZHHNVIRUDOOSDWLHQWV

&HWX[LPDE
1 
7LYDQWLQLE
&HWX[LPDE
1 
5
$
1
'
2
0
,
=
(

5HFXUUHQW
PHWDVWDWLF+1&
&HWX[LPDEQDwYH
7LYDQWLQLE
2SWLRQDO
7UHDWXQWLO
3URJUHVVLYH'LVHDVH
1 
3ULPDU\2XWFRPH
5HVSRQVH5DWH5(&,67
6HFRQGDU\2XWFRPHV
D&RQWLQXRXVWXPRUVKULQNDJH
E3)6
F26
G2XWFRPHVDFZLOOEHDQDO\]HGLQWXPRUVZLWKF
0(7FRS\QXPEHU!DQGRUKLJKH[SUHVVLRQ,+&


6 
 
 
 
TABLE OF CONTENTS 
 
 
Page 
SCHEMA ........................................................................................................................................5 
 
1. OBJECTIVES ..........................................................................................................................8 
 
1.1  
Primary Objectives ......................................................................................................8 
 
1.2  
Secondary Objectives ..................................................................................................8 
 
2. BACKGROUND ......................................................................................................................8 
 
2.1  
Study Disease ................................................................................................................8 
 
2.2  
CTEP IND agent ..........................................................................................................9 
 
2.3  
Cetuximab (commercial) ...........................................................................................17 
 
2.4  
Rationale .....................................................................................................................18 
 
2.5 
Correlative Studies Background ..............................................................................20 
 
3. PATIENT SELECTION........................................................................................................21 
 
3.1  
Eligibility Criteria  .....................................................................................................21 
 
3.2  
Exclusion Criteria ......................................................................................................22 
 
3.3  
Inclusion of Women and Minorities .........................................................................24 
 
4. REGISTRATION PROCEDURES ......................................................................................24 
 
4.1 
General Guidelines ....................................................................................................24 
 
4.2 
Registration Process ..................................................................................................25 
 
5. TREATMENT PLAN ............................................................................................................25 
 
5.1  
Agent Administration ................................................................................................26 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines ....................27 
 
5.3  
Duration of Therapy ..................................................................................................29 
 
5.4  
Duration of Follow Up ...............................................................................................30 
5.5 
Criteria for Removal from Study .............................................................................30 
 
6. DOSING DELAYS/DOSE MODIFICATIONS ..................................................................31 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................37 
 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) .................37 
      7.2       Adverse event list(s) for commercial agent………………………………………  39 
 
7.3 
Adverse Event Characteristics..................................................................................39 
 
7.4 
Expedited Adverse Event Reporting ........................................................................40 
 
7.5 
Routine Adverse Event Reporting ............................................................................42 
 
7.6 
Secondary Malignancy ..............................................................................................42 
7.7 
Second Malignancy ....................................................................................................42 
 
8. PHARMACEUTICAL INFORMATION ............................................................................42 
 
8.1  
CTEP IND agent ........................................................................................................42 
 
8.2  
Cetuximab (commercial) ...........................................................................................44 


7 
 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES .........................................46 
9.1 
Biomarker Studies .....................................................................................................46 
9.2 
Laboratory Correlative Studies ................................................................................48 
 
10. STUDY CALENDAR ............................................................................................................50 
 
11. MEASUREMENT OF EFFECT ..........................................................................................51 
11.1 
Antitumor Effect – Solid Tumors ............................................................................51 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS ...........................................58 
 
12.1 
Data Reporting ...........................................................................................................59 
 
12.2 
CTEP Multicenter Guidelines ...................................................................................59 
 
12.3 
Collaborative Agreements Language .......................................................................60 
 
13. STATISTICAL CONSIDERATIONS .................................................................................61 
 
13.1 
Study Design/Endpoints ............................................................................................61 
 
13.2 
Sample Size/Accrual Rate .........................................................................................62 
 
13.3 
Stratification Factors .................................................................................................63 
 
13.4 
Analysis of Secondary Endpoints .............................................................................64 
 
13.5 
Reporting and Exclusions .........................................................................................64 
 
13.6 
Randomization ...........................................................................................................65 
 
REFERENCES .............................................................................................................................65 
 
APPENDICES 
 
APPENDIX A 
Performance Status Criteria ..............................................................................................68 
 
APPENDIX B 
CTEP Multicenter Guidelines ..........................................................................................69 
 
APPENDIX C 
Tissue Sample Collection Form .......................................................................................71 
 
APPENDIX D 
Information on Potential Drug Interactions for patients ..................................................72 
 
APPENDIX E 
Management of Cetuximab induced acneiform rash ........................................................75 
APPENDIX F 
Patient’s Medication Diary ...............................................................................................76 
 
 
 


8 
 
 
 
1. OBJECTIVES 
 
1.1 Primary Objectives 
 
Response Rate  
(We will compare the cetuximab/ARQ 197 (tivantinib) combination with cetuximab 
single agent activity. 
 
1.2. 
Secondary Objectives 
 
a) Continuous tumor shrinkage 
b) PFS  
c) OS 
d) Endpoints a), b), and c) above, as well as response rates, will be assessed and 
compared between treatment arms in the subgroup of patients with high c-MET 
expression (anticipated to be ~84% of patients (Seiwert et al, Cancer Research, 
2009), and/or high c-MET copy number (anticipated >10% and largely overlapping 
with MET IHC (Seiwert et al, Cancer Research, 2009)). 
e) Single agent activity for ARQ 197 (tivantinib) in patients who have failed 
cetuximab 
 
 
2. BACKGROUND 
 
2.1  
Study Disease 
 
Head and Neck squamous cell carcinoma (HNSCC) is the 6th most common cause of 
cancer death worldwide with more than 600,000 cases annual. In the United States, 
approximately 40,500 new HNSCC cases and 11,000 deaths were expected in 2006. 
HNSCC results in significant morbidity because major vital functions such as 
nutrition, respiration and communication are impaired.  
 
Approximately two thirds of patients with HNSCC will present with locoregional 
disease and despite aggressive local therapy, close to than half will succumb to 
recurrent and/or metastatic disease. If untreated, the median survival of patients with 
metastatic disease is dismal and on the order of 4 months (Ang, Berkey et al. 2002).  
 
In patients with recurrent or metastatic HNSCC, the only therapeutic options are 
usually palliative consisting of systemic chemotherapy and the EGFR inhibitor 
cetuximab (Vermorken, Mesia et al. 2008). Median survival is estimated at 10.1 
months using a combination of cisplatin/5-FU/cetuximab. Cytotoxic chemotherapy 


9 
 
 
can have significant toxicities, consisting of bone marrow suppression, 
nausea/vomiting, rash, hand-foot syndrome, and many others. 
 
2.2 CTEP IND Agent 
 
 
2.2.1 ARQ 197 (Tivantinib) 
Receptor tyrosine kinases (RTKs) have emerged as an important class of 
molecular targets for anti-cancer therapy.  The encouraging results from agents 
such as imatinib mesylate (Gleevec) against cancers with the constitutively active 
Bcr-Abl mutation, as well as erlotinib, an inhibitor of mutated and overexpressed 
EGF receptor kinase, have provided important clinical evidence that molecularly 
targeted RTK inhibitors are efficacious and can have a significant and broad 
effect against various cancers.  As more RTKs are implicated in the 
pathophysiology of oncogenesis, the notion has been put forward that the signal 
transduction pathways that are served by these RTKs become dominant in 
initiating and maintaining the pro-proliferative and antiapoptotic phenotype of the 
transformed cell.  Indeed, there is growing evidence that dysregulated RTK 
signaling in cancer cells may result in so-called “oncogene addiction,” providing 
the opportunity to selectively kill cancer cells by ablating RTK signaling 
pharmacologically (Weinstein, 2002).   
The c-Met RTK mediates the signals for a variety of physiological processes that 
have implications for oncogenesis, including migration, invasion, cell 
proliferation, and angiogenesis.  A wide variety of human cancers exhibit 
constitutively dysregulated c-Met activity, either through over-expression of the 
c-Met kinase, activating mutations in c-Met, or increased autocrine or paracrine 
secretion of the c-Met ligand hepatocyte growth factor/scatter factor (HGF/SF).  
These alterations have been strongly implicated in tumor progression and 
metastasis in a variety of cancers, and a high constitutive activation of the c-Met 
RTK has been correlated with poor clinical prognosis (Jiang et al., 1999; 
Birchmeier et al., 2003). 
c-Met can be activated in both a ligand-dependent manner, by the overexpression 
of c-Met and/or its ligand HGF, or a ligand-independent manner as in the case of 
activating mutations of c-Met such as those described in sporadic and hereditary 
papillary renal carcinoma (Birchmeier et al., 2003).  Activation and 
autophosphorylation of c-Met results in the binding and phosphorylation of 
adaptor proteins such as Gab1, Grb2, Shc and c-Cbl, and results in the subsequent 
activation of signaling pathways, including the PI3K/Akt, FAK, STAT and 
Ras/MEK/Erk pathways that play various roles in cell survival, proliferation, 
invasion, and angiogenesis (Furge et al., 2000; Christensen et al., 2003).  In the 
melanocyte lineage, c-Met expression is upregulated by microphthalmia-
associated transcription factor (MITF), which has been implicated in the 
oncogenesis of melanoma and other cancers (Levy et al., 2006; McGill et al., 
2006).  


10 
 
 
The presence of c-Met in most cancers, and its role in controlling multiple signal 
transduction pathways involved in tumor growth render this enzyme a logical 
therapeutic target for human cancer. 
ARQ 197 (tivantinib) is a potent RTK inhibitor with high selectivity for the c-Met 
RTK, as determined by biochemical and cellular assays.  A comprehensive review 
of ARQ 197 (tivantinib) can be found in the ARQ 197 (tivantinib) Investigator’s 
Brochure (2010). 
Tivantinib also appears to have anti-tubulin activity, and may act as a cytototixc. 
Some investigators believe that the anti-tubulin activity contributes more to 
tivantinib’s anti-cancer activity than the anti- c-Met activity (Michieli et al., 2013) 
2.2.2 Nonclinical Pharmacology 
 
       In Vitro Efficacy 
ARQ 197 (tivantinib) selectively inhibits the in vitro biochemical activity of 
recombinant c-Met with a Ki of approximately 355 nM.  The potency of ARQ 197 
(tivantinib) inhibition of c-Met activity was independent of ATP concentration, 
suggesting that the mode of inhibition of ARQ 197 (tivantinib) is of a non-
competitive nature.  While ARQ 197 (tivantinib) inhibits c-Met kinase activity, it 
is not a promiscuous kinase inhibitor.  When ARQ 197 (tivantinib) was profiled 
against 230 protein kinases at a nominal concentration of 5 or 10 mcM, ARQ 197 
(tivantinib) inhibited only four protein kinases greater than 20% under the 
conditions of this assay.  These data suggest that ARQ 197 (tivantinib) is a highly 
selective c-Met kinase inhibitor. 
In cell-based kinase assays, ARQ 197 (tivantinib) inhibited HGF-induced 
activation of c-Met (as gauged by autophosphorylation) with an IC50 between 0.1 
mcM – 0.5 mcM in multiple human cancer cell lines.  This suppression was 
effective for at least eight to twelve hours after withdrawal of ARQ 197 
(tivantinib), demonstrating a sustained durability of c-Met inhibition by ARQ 197 
(tivantinib).  Furthermore, ARQ 197 (tivantinib) decreased phosphorylation of 
most of the c-Met downstream effectors including FAK, STAT-3, Erk-1 and Erk-
2, though not Akt.  This indicates that by inhibiting c-Met, ARQ 197 (tivantinib) 
also induces a decrease in the phosphorylation and activation of many 
downstream targets in the pathways served by this oncogenic kinase.   
ARQ 197 (tivantinib) showed broad-spectrum in vitro anticancer activity against 
human tumor lines, including those derived from breast, pancreas, colon, gastric, 
and lung.  The potency of ARQ 197 (tivantinib) in cancer cells expressing 
detectable c-Met ranges from 0.1 – 0.6 mcM.  By contrast, cells lacking c-Met 
such as NCI-H661 (human non-small cell lung cancer cells) and NCI-H446 
(human small cell lung cancer cells) yielded IC50s approximately 10-fold higher, 
indicating a correlation between the presence of c-Met and the sensitivity of the 
cells towards ARQ 197 (tivantinib). The ability of ARQ 197 (tivantinib) to inhibit 
c-Met phosphorylation correlates with its ability to inhibit growth and induce 
apoptosis in c-Met expressing cancer cells.   


11 
 
 
Overexpression of c-Met correlates with tumor cell migration and invasiveness, 
and invasion assays demonstrated that ARQ 197 (tivantinib) was able to potently 
inhibit invasion in c-Met expressing tumor cell lines (IC50s of approximately 0.3 
to 0.45 mcM), but less so in non-c-Met expressing lines (IC50 = 5.4 mcM).  In a 
wound healing assay, ARQ 197 (tivantinib) also inhibited migration of NCI-H441 
cells (human lung adenocarcinoma) in response to HGF, the ligand for the c-Met 
receptor.  Overall, these results indicate that ARQ 197 (tivantinib) has anticancer 
activity, an effect, which is mediated via its inhibition of c-Met. 
Another study assessed a panel of 64 human cancer cell lines encompassing a 
spectrum of genotypes and tissue origins.  The combination of ARQ 197 
(tivantinib) and sorafenib showed synergistic cytotoxicity in nine cell lines, 
including three NSCLC cell lines, two breast cancer cell lines, a melanoma cell 
line, a renal clear cell carcinoma cell line, a cervical carcinoma cell line, and a 
squamous cell carcinoma cell line.  Additivity was seen with the ARQ 197 
(tivantinib)/sorafenib combination across a wide range of 40 human cancer cell 
lines including, but not limited to, five colon cancer lines, five breast cancer cell 
lines, four additional NSCLC cell lines, and three hepatocellular carcinomas 
(HCC). 
 
In Vivo Efficacy 
When administered via daily oral dosing, ARQ 197 (tivantinib) was shown to be 
efficacious against multiple human cancer xenograft models.  Beginning at a dose 
level of 200 mg/kg, tumor growth inhibition was seen in breast (79%), colon 
(39%), pancreatic (58%), prostate (72%), and gastric (52%) models.  Increasing 
the dose to 300 mg/kg improved tumor inhibition in colon (55%), pancreatic 
(60%), and prostate (77%) models.  ARQ 197 (tivantinib) was well tolerated in 
these studies with no drug related clinical signs or deaths.  There was no 
significant change in body weight at any of the dose levels tested.  Furthermore, 
the antitumor activity of ARQ 197 (tivantinib) is accompanied by the ablation of 
c-Met activity, as assessed by the decreased level of phosphorylated c-Met in the 
dissected xenograft tumor tissue.  This suggests a potential mechanism-based 
clinical biomarker. 
In human tumor xenograft models, results of a study conducted with the NCI-
H522 NSCLC cell line suggest that antitumor effects of ARQ 197 (tivantinib) and 
sorafenib were modestly additive and the combination of the two agents was 
extremely well tolerated, with no body weight gain changes or deaths observed. 
 
2.2.3. Nonclinical Pharmacokinetics 
The pharmacokinetics of ARQ 197 (tivantinib) were evaluated and compared in 
mice, rats, and dogs using different dosing routes, levels, and formulations.  In 
general, exposure to ARQ 197 (tivantinib) increased as the dose was increased. 
Overall, the corresponding increases in AUC0-inf and Cmax were generally not dose 
proportional.  The t1/2 of ARQ 197 (tivantinib) generally ranged from 1 – 4.5 
hours across all studies and all species, though there were a few exceptions.  For 


12 
 
 
instance, rats displayed a highly variable t1/2 (1.48 – 37.8 hours), the reason for 
which is unknown.  Bioavailability after single-dosing was somewhat variable 
between species: 16-35% in rats, 33-60% in dogs, and 21-37% in mice.  After 
multiple dosing in 7-day, 28-day, 8-week, and 26-week studies, there were no 
consistent changes in Cmax and AUC values in rat or dog, indicating that there was 
no marked accumulation of ARQ 197 (tivantinib) after multiple dosing. 
 
Metabolism 
Mass balance and tissue distribution studies indicated that primary route of 
elimination of ARQ 197 (tivantinib) is fecal and that ARQ 197 (tivantinib) 
generally did not accumulate (after 96 hours) in any of the tissues tested.  Data 
from in vitro metabolism studies suggest that ARQ 197 (tivantinib) is relatively 
stable in human liver microsomes with a t1/2 of 29 min.  The t1/2 of ARQ 197 
(tivantinib) in male dog liver microsomes was similar to that of human liver 
microsomes with a t1/2 of 29 min (t1/2 in female dog liver microsomes was 20.5 
min).   
From studies conducted with individual CYP P450 isozymes, ARQ 197 
(tivantinib) was rapidly metabolized by CYP2C19 (t1/2 = 2.83 min) and 
moderately metabolized by CYP 3A4 (t1/2 = 16.3 min).  The t1/2 values for the 
other CYP P450s (1A2, 2C9, 2D6, and 2C8) tested were all greater than 27.4 min.  
Drugs which affect the activity of CYP2C19 or CYP3A4 may markedly alter the 
plasma concentration of ARQ 197 (tivantinib).  The IC50 of ARQ 197 (tivantinib) 
was evaluated for each CYP 450 isoform (1A2, 2C8, 2C9, 2C19, 2E1 and 3A4), 
and all were greater than 10 mcM. 
 
2.2.4 Nonclinical Toxicology 
Preclinical toxicity for ARQ 197 (tivantinib) was assessed in the rat and beagle 
dog in single dose studies as well as repeat dose studies of up to 26 weeks in 
duration.  In 28-day repeat-dose studies, clinical pathology signs typically 
observed at the high dose (45 mg/kg) included lower red cell mass, lower absolute 
reticulocyte count, and lower absolute neutrophil and monocyte counts for males 
and females.  In addition, females had lower absolute lymphocyte and eosinophil 
counts.  Microscopic findings at high doses included depletion of lymphocytes in 
the thymus, femur and sternum bone marrow depletion, and hypertrophy and 
vacuolation in peripherolobular hepatocytes.  Importantly, these clinical and 
anatomic pathology findings were reversed by 2 weeks after cessation of dosing. 
 
Clinical Experience 
The pharmacokinetics, metabolism, safety, and efficacy of ARQ 197 (tivantinib) 
have been investigated in multiple phase 1 and phase 2 clinical trials in cancer 
patients.  Two phase 1 dose escalation trials (ARQ 197-101 and ARQ 197-103) 
have defined the maximum tolerated dose (MTD) and recommended phase 2 dose 
(RP2D) for continuous doses of ARQ 197 (tivantinib) as a single agent.  Another 


13 
 
 
phase 1 study (ARQ 197-111) evaluated the MTD and RP2D of ARQ 197 
(tivantinib) administered in combination with erlotinib on a continuous schedule.  
Additional ongoing phase 1 and phase 1/2 trials evaluating ARQ 197 (tivantinib) 
include ARQ 197-114 (monotherapy in HCC); ARQ 197-116 (combination with 
sorafenib); and ARQ 197-117 (combination with gemcitabine). 
In addition, there have been two completed phase 2 clinical trials.  One trial (ARQ 
197-204) evaluated the efficacy of ARQ 197 (tivantinib) in patients with MITF-
associated tumors, and the other (ARQ 197-209) was a global, randomized, 
placebo controlled, double-blind phase 2 trial comparing treatment with erlotinib 
plus ARQ 197 (tivantinib) versus treatment with erlotinib plus placebo in patients 
with previously treated non-small cell lung cancer (NSCLC).  There is also an 
ongoing phase 2 randomized, placebo-controlled trial (ARQ 197-215) in patients 
with HCC. 
Detailed information for each of these studies, including pharmacokinetic data, 
can be found in the Investigator’s Brochure (2010).  Safety and efficacy results 
are summarized below. 
 
Phase 1 Studies 
Study ARQ 197-101 was a phase 1 dose escalation trial of ARQ 197 (tivantinib) 
in adult patients with locally advanced or metastatic solid tumors.  Thirteen dose 
levels ranged from 10 – 360 mg BID and two dosing schedules (intermittent vs. 
continuous) were explored.  Additional patients were enrolled and treated at the 
360 mg BID continuous dose, which was determined to be the RP2D in another 
Phase 1 clinical trial (ARQ 197-103).  The most common drug-related adverse 
events (AEs; ≥5% and ≥2 events) seen in this study were fatigue (13.9%), nausea 
(13.9%), vomiting (10.1%) and diarrhea (6.3%).  Serious adverse events (SAEs) 
reported at a >3% incidence were disease progression and dehydration (6.3% for 
each) and anemia, nausea, renal failure acute, and vomiting (3.8% for each).  Two 
patients were discontinued from the study due to dyspnea and deep vein 
thrombosis.  No dose-limiting toxicities (DLTs) were reported at doses below 360 
mg BID in this study.  The myelosuppression events of neutropenia, leukopenia 
and thrombocytopenia resolved in 9 days, with treatment continuing thereafter.  
Vomiting and dehydration resolved in 6 days.  A total of 79 patients were 
evaluable for efficacy analysis per the study protocol.  Three (3.8%) of these 
patients achieved partial responses (PR).  Forty (50.6%) patients achieved stable 
disease (SD).   
Study ARQ 197-103 was a phase 1 dose escalation trial of ARQ 197 (tivantinib) 
given twice daily continuously in adult patients with advanced solid tumors.  The 
MTD was found to be 360 mg BID.  A total of 59 patients were enrolled to this 
study.  The most common (≥5% and ≥2 events) drug-related AEs were fatigue 
(15.7%), nausea (13.7%), vomiting (11.8%), anorexia (7.8%), diarrhea (7.8%), 
anemia (5.9%), febrile neutropenia (5.9%), and weight loss (5.9%).  SAEs 
reported at a >5% incidence (more than 1 subject) were febrile neutropenia 


14 
 
 
(5.9%) and disease progression (9.8%).  Among 29 evaluable patients, 17 
demonstrated SD as their best response.   
Study ARQ 197-114 is an ongoing safety study of ARQ 197 (tivantinib) in 
cirrhotic subjects with HCC.  ARQ 197 (tivantinib) is administered continuously 
at a dose level of 360 mg BID.  Thus far, a total of 21 patients have been enrolled 
in this study.  The most common drug-related AEs (>5% and >2 events) are 
asthenia (47.6%), neutropenia (42.9%), anemia (42.9%), leukopenia (38.1%), 
anorexia (38.1%), diarrhea (28.6%), alopecia (19.0%), thrombocytopenia 
(14.3%), vomiting (14.3%), hepatobiliary disorders (14.3%), hyperbilirubinemia 
(14.3%), lymphopenia (9.5%), bradycardia (9.5%), dysgeusia (9.5%), and 
oropharyngeal pain (9.5%).  Drug-related SAEs leading to discontinuation from 
the study include three cases of neutropenia.  Of 16 evaluable patients, six have 
exhibited a decrease in tumor volume by RECIST criteria. 
Study ARQ 197-111 is an ongoing phase 1 dose escalation trial of ARQ 197 
(tivantinib) administered in combination with erlotinib in adult patients with 
advanced solid tumors.  One DLT (neutropenia) was reported in a patient 
receiving an ARQ 197 (tivantinib) dose of 360 mg BID.  Based on these data, a 
dose of 360 mg ARQ 197 (tivantinib) BID in combination with erlotinib 150 mg 
daily has been identified as the RP2D.  The most commonly-reported drug-related 
AE in this study was bradycardia, with 15 episodes reported in four patients; these 
events were generally mild and asymptomatic (grade 1), and 14 of these events 
occurred at the 360 mg BID dose level of ARQ 197 (tivantinib).  One drug-related 
bradycardia event did not resolve.  Other common drug-related AEs (≥5% and ≥2 
events) were fatigue (31.3%), rash (15.6%), diarrhea (21.9%), pruritus (15.6%), 
muscle spasms (15.6%), anemia (12.5%), nausea (12.5%), dermatitis acneiform 
(15.6%), anorexia (6.3%), vomiting (6.3%), flatulence (6.3%), dry skin (12.5%), 
neutropenia (6.3%), and pyrexia (6.3%).  As of July 23, 2010, 32 patients were 
enrolled and evaluable for efficacy.  One subject out of 32 (3.1%) achieved an 
unconfirmed PR.  Fourteen (43.8%) patients achieved SD as their best response 
with a range of follow-up between 8 and 37 weeks. 
 
Phase 2 Studies 
Protocol ARQ 197-204 was a phase 2 study of ARQ 197 (tivantinib) in patients 
with MITF-associated tumors, including translocation-associated renal cell 
carcinoma (t-RCC), alveolar soft-part sarcoma (ASPS), and clear-cell sarcoma 
(CCS).  The initially enrolled patients received 120 mg ARQ 197 (tivantinib) 
BID; patients enrolled after the RP2D was determined (in ARQ 197-103) received 
360 mg ARQ 197 (tivantinib) BID.  Among 47 patients treated in this study, ARQ 
197 (tivantinib) demonstrated a favorable safety profile and was well tolerated at 
both doses.  The most common (≥5% and ≥2 events) drug-related AEs were 
fatigue, pyrexia, nausea, vomiting, diarrhea, retching, anemia, lymphopenia, pain 
in extremity, anorexia, headache, insomnia, dyspnea, cough, neutrophil count 
decreased, decreased white blood cell count, increased alanine aminotransferase 
level, increased aspartate aminotransferase level, decreased hemoglobin level, 


15 
 
 
sinus bradycardia, and rash.  Forty-five patients were evaluable for efficacy.  One 
patient with CCS demonstrated a confirmed PR.  Twenty-seven patients 
demonstrated SD, including 21 with ASPS, three with t-RCC, and three with 
CCS.  Overall, 12 subjects experienced SD for >24 weeks.   
Study ARQ 197-209 was an ongoing global, randomized, placebo-controlled, 
double-blind phase 2 trial comparing treatment with erlotinib plus ARQ 197 
(tivantinib)versus treatment with erlotinib plus placebo in patients with previously 
treated NSCLC.  The most commonly reported AEs related to the ARQ 197 
(tivantinib)-erlotinib combination (≥5% and ≥2 events) were rash (63.1%), 
diarrhea (35.7%), fatigue (33.3%), pruritus (22.6%), and dry skin (20.2%).  
Thirty-seven deaths were reported to occur within 30 days of the last dose of 
study drug.  According to the investigator assessment, there were 7 PRs and 40 
SDs among 73 evaluable patients in the erlotinib plus ARQ 197 (tivantinib) 
treatment group, for an objective response rate (ORR) of 9.6% and a disease 
control rate of 64.4%.  For the erlotinib plus placebo group, there were 5 PRs and 
35 SDs among 72 evaluable subjects, for an ORR of 6.9% and disease control rate 
of 55.6%. 
ARQ 197-215 is an ongoing placebo-controlled study of ARQ 197 (tivantinib) in 
subjects with HCC.  A total of 49 patients have been enrolled in the study.  The 
most common drug-related AEs are neutropenia (16.3%), anemia (12.2%), fatigue 
(8.2%), asthenia (8.2%), vomiting (6.1%), diarrhea (6.1%), and nausea (6.1%).  
SAEs which may or may not be related to the study drug include fatigue (3 
events), anemia (2), neutropenia (2), and sepsis (2).  Two patient deaths (due to 
sepsis and neutropenic sepsis) have been attributed to study drug. 
 
Myelosuppression 
As of July 23, 2010, there were 266 patients enrolled and treated with ARQ 197 
(tivantinib) in six ARQ 197 (tivantinib) monotherapy studies.  A total of 58 events 
of myelosuppression (65 anemia, 29 neutropenia, 17 leukopenia, 13 
thrombocytopenia, 11 lymphopenia, and 4 febrile neutropenia) were reported.  
One grade 5 case of pancytopenia case was reported.  The greatest incidence of 
NCI CTCAE grade 3 or 4 events of myelosuppression (anemia and neutropenia) 
was in subjects with HCC in study ARQ 197-114. 
To reduce the risk of severe myelosuppression events, a complete blood count 
(CBC) should be performed weekly during the first cycle of therapy, and at 
subsequent time points as designated in the protocols.  This testing schedule 
follows hematology recommendations for monitoring in subjects treated with 
CYP2C19 or CYP3A4 inhibitors.  Subjects who have neutropenia are to be 
monitored more closely throughout the study and follow dose modifications or 
delays as specified in the protocols. 
 
Sinus Bradycardia/Bradycardia 


16 
 
 
Bradycardia has been reported in monotherapy and combination therapy clinical 
trials of ARQ 197 (tivantinib).  Bradycardia was also one of the most frequently 
reported AEs in a phase 1 trial of ARQ 197 (tivantinib) in combination with 
erlotinib (Study ARQ 197-111).  The majority of these events have been mild and 
asymptomatic.  Therefore, studies will exclude patients with a history of 
congestive heart failure or other clinically relevant cardiac problems, as defined in 
section 3.2 (“Exclusion Criteria”).  In addition, bradycardic patients with a heart 
rate <50 beats per minute should have an ECG done on day 1 of every cycle, or as 
clinically indicated. 
 
Pharmacokinetics 
Approximately 345 subjects with cancer and over 100 healthy subjects 
participated in phase 1 studies of ARQ 197 (tivantinib).  Clinical PK data are 
available from multiple clinical studies using ARQ 197 (tivantinib) as either the 
amorphous solid or 1 of 2 crystalline forms designated form A or form B.  
Overall, following oral administration ARQ 197 (tivantinib) is moderately 
absorbed with a Tmax ranging from 2 – 6 hours.  In general, ARQ 197 (tivantinib) 
exposure increases with increases in dose; however, exposure is not dose 
proportional.  There is wide intersubject variability in ARQ 197 (tivantinib) PK.  
Based on population pharmacokinetic (PopPK) analysis, this variability is partly 
due to CYP2C19 polymorphism, fed status during ARQ 197 (tivantinib) 
administration, ARQ 197 (tivantinib) form (amorphous versus crystalline A 
versus crystalline B), and also possibly ethnicity differences (Caucasian versus 
Japanese).   
In vitro human liver microsome studies indicate involvement of both CYP2C19 
and cytochrome P450 3A4 (CYP3A4) in ARQ 197 (tivantinib) metabolism.  In 
humans, ARQ 197 (tivantinib) showed a genotype exposure relationship dictated 
mainly by CYP2C19 genotype.  In healthy subjects, CYP2C19 poor metabolizers 
(PMs) had much higher exposure than extensive metabolizers (EMs), as reflected 
by AUC0-48 and Cmax (11-fold and 3-fold higher, respectively) and lower clearance 
(mean of 2.4 L/h versus mean of 33.9 L/h).  However, based on steady state 
exposure data in cancer subjects the PM exposure (AUC0-12) is only 1.4- to 4-fold 
greater than EM exposure.  Hence, differences in CYP2C19 metabolism will 
contribute to variability in PK between subjects.  In a phase 1 dose-escalation 
study, 10 of 43 patients were characterized as PMs.  
Additional studies comparing the PK of the amorphous form of ARQ 197 
(tivantinib) to the crystalline forms A and B of ARQ 197 (tivantinib) showed that 
the amorphous form of ARQ 197 (tivantinib) resulted in higher exposure (Cmax, 
AUC) than either crystalline form A or B.  Specifically, Cmax was approximately 
60% to 70% lower for forms A and B, respectively, compared with the 
amorphous form.  Similarly, AUC was 20% to 30% lower for crystalline forms A 
and B, respectively, relative to the amorphous form.  
When ARQ 197 (tivantinib) was administered immediately after a high-fat meal 
to healthy subjects, the exposure was 3 times greater than the exposure under 


17 
 
 
fasting conditions, when the agent is administered at least 1 hour before and 2 
hours after a meal (fed:  AUC0-last 13356 +5385 ng/hr/mL and AUC0-inf 13558 
+6397 ng/hr/mL; fasting:  AUC0-last 4858 +1793 ng/hr/mL and AUC0-inf 6166 
+2393).  However, when ARQ 197 (tivantinib) crystalline B was administered 
360 mg BID (the phase 3 dose) to cancer subjects (study ARQ 197-117), the 
exposure was similar under fed versus fasting conditions (fed:  12251 ng/hr/mL; 
fasting:  10453 ng/hr/mL), and comparable in both cases to the exposure in 
healthy, fed subjects.  Additionally, when administered under fed conditions, the 
variability in ARQ 197 (tivantinib) exposure is generally lower compared with the 
fasted condition.  
Detailed preliminary pharmacokinetic data can be found in the most recent ARQ 
197 (tivantinib) Investigator’s Brochure (2010). 
 
 
 
2.3 Cetuximab 
 
Cetuximab (Erbitux®, C-225) is a chimerized monoclonal IgG1 subclass antibody with 
binding affinity to the epidermal growth factor receptor (EGFR) that exceeds the 
natural ligand epidermal growth factor (EGF). Cetuximab effectively blocks binding 
of EGF and transforming growth factor alpha (TGF-α) to EGFR and prevents ligand-
induced activation, stimulates EGFR internalization, and effectively removes EGFR 
from the cell surface. Cetuximab is FDA approved for the treatment of head and neck 
cancers in combination with radiation and in the palliative setting typically with 
chemotherapy. 
 
Several clinical studies have demonstrated the safety and efficacy of cetuximab in the 
treatment of HNSCC. Vermorken et al, treated 103 patients with incurable stage 
III/IV, platinum refractory HNSCC with single agent cetuximab (at 400 mg/m2 initial 
dose and 250 mg/m2 weekly subsequently)(Vermorken, Trigo et al. 2007). The 
objective response rate (ORR) in this population was 14%, median time to 
progression was 2.3 months and median overall survival (OS) was 5.9 months. The 
treatment was well tolerated. 
 
In another trial 117 patients with metastatic or recurrent HNSCC were randomized 
between cetuximab plus cisplatin (100 mg/m2 every 28 days) or cisplatin plus 
placebo. The addition of cetuximab to cisplatin improved ORR (26% vs. 10%), 
median PFS (4.2 months vs. 2.7 months), and median OS (9.2 months vs. 8.0 months) 
versus control. Cetuximab therapy was associated with increases in the risk of 
neutropenia, acneform rash, and dyspnea, but the treatment was generally well 
tolerated.  
On the basis of this trial as well as other reports including combinations with 
chemotherapy and radiation in the pre-clinical and clinical setting two pivotal phase 
III studies were started.  The first phase III trial enrolled 424 patients with 
locoregionally advanced HNSCC – randomization between cetuximab + radiotherapy 
(RT) versus radiation alone. Median progression free survival (primary endpoint) in 
the cetuximab/RT arm was 17.1 months, compared to 12.4 months in the RT alone 


18 
 
 
arm (= overall survival of of 49 months versus 29.3 months. Both arm were reported 
to comparable RT related toxicities. The primary observed adverse event in this trial 
attributed to cetuximab was an acneform rash in 17% in the cetuximab/RT group and 
only 1% in the RT alone arm. 
 
In 2008, results from the landmark phase III EXTREME trial (Vermorken, Mesia et 
al. 2008), comparing cetuximab in combination with either cisplatin plus 5-
fluorouracil (5-FU) or carboplatin plus 5-FU with combinations of cisplatin/5-FU or 
carboplatin/5-FU alone were reported. Results indicated a statistically significant 
survival benefit associated with adding cetuximab to these regimens.  
 
Based on trials using cetuximab (420 patients receiving cetuximab monotherapy or 
354 patients receiving cetuximab + chemotherapy (patients with metastatic colorectal 
cancer)) cetuximab was well tolerated.  The most serious adverse reactions 
associated with cetuximab were:  Infusion reaction (3%); Dermatologic toxicity (1%); 
Interstitial lung disease (0.4%); Fever (5%); Sepsis (3%); Kidney failure (2%); 
Pulmonary embolus (1%); Dehydration (5%) in patients receiving cetuximab plus 
irinotecan, 2% in patients receiving cetuximab monotherapy; Diarrhea (6%) in 
patients receiving cetuximab plus irinotecan, 0% in patients receiving cetuximab 
monotherapy. 17 (4%) patients receiving cetuximab monotherapy discontinued 
treatment primarily because of adverse events. The most common adverse events seen 
in 420 patients receiving cetuximab monotherapy were acneform rash (90%), 
asthenia/malaise (48%), nausea (29%), fever (27%), constipation (26%), abdominal 
pain (26%), headache (26%), and diarrhea (25%). The most common adverse events 
seen in 354 patients receiving cetuximab plus irinotecan were acneform rash (88%), 
asthenia/malaise (73%), diarrhea (72%), nausea (55%), abdominal pain (45%), and 
vomiting (41%).  
 
Cetuximab is currently Food and Drug Administration (FDA)- approved for use in 
combination with radiotherapy in the treatment of locally or regionally advanced 
HNSCC, as well as in the recurrent/ metastatic setting as a single agent, or in 
combination with cytotoxic chemotherapy. 
 
 
2.4 
Rationale 
EGFR is expressed at very high levels in >90% of Head and Neck cancers (HNC; 
>NSCLC) and treatment with cetuximab (alone or in combination with chemotherapy 
or radiation) is now considered a standard of care. Nevertheless the response rate to 
EGFR inhibitors (cetuximab response rate = 13%, 40-50% stable disease) and median 
progression free survival of 70 days (Vermorken et al, JCO, 2007) remain 
disappointing. While treatment benefit is generally considered to be comparable to 
cytotoxic therapies with lower toxicity, the potential of EGFR as a therapeutic target 
in this highly EGFR expressing disease has not been fully exploited. Clinically 
treatment for recurrent/metastatic disease is either given in combination with 
chemotherapy (EXTREME) or after initial cytotoxic chemotherapy. 
 
In our translational and preclinical work we demonstrated the following: 


19 
 
 
Eighty-four percent of the HNC samples showed c-MET overexpression (>NSCLC), 
and 18 of 20 HNC cell lines (90%) expressed c-MET. HGF overexpression was 
present in 45% of HNC. c-MET inhibition with SU11274/PF-2341066 abrogated c-
MET signaling, cell viability, motility/migration in vitro, and tumor angiogenesis in 
vivo. Increased c-MET gene copy number was present with >10 copies in 3 of 23 
(13%) tumor tissues. A greater-than-additive inhibition of cell growth was observed 
when combining a c-MET inhibitor with   an EGFR inhibitor and synergy was 
mediated 
via 
erbB3 
signaling. 
Finally 
we 
identified 
single 
nucleotide 
variants/mutations in the semaphorin (T230M/E168D/N375S), juxtamembrane 
(T1010I/R988C), and tyrosine kinase (T1275I/V1333I) domains (incidence: 13.5%) 
although functional contribution of these variants will require further study. 
 
We demonstrated that c-MET is functionally important in HNC with prominent 
overexpression, and increased gene copy number, in the vast majority of HNC. c-
MET 
inhibition 
abrogated 
c-MET 
functions, 
including 
proliferation, 
migration/motility, and angiogenesis. We concluded that c-MET is a promising, novel 
target for HNC and combination approaches with EGFR inhibitors should be 
explored. 
 
The importance of c-MET in general for head and neck cancers and a relationship to 
EGFR signaling is well supported by corroborative literature: Knowles et al 
demonstrated the importance of HGF and c-MET for HNC independently (Knowles, 
et al Clinical Cancer Research 2009). Particular emphasis was put on the tumor 
fibroblast HGF production. Furthermore recent data from the Univ. of Pittsburgh 
(California Consortium) show strong synergy of c-MET with EGFR inhibition, and 
extensive crosstalk between the two receptors (Xu et al, Clinical Cancer Research, 
2011. 
 
Both EGFR and c-MET signal downstream via the common signaling 
adaptor/receptor erbB3, as demonstrated for NSCLC previously and confirmed for 
HNC (Seiwert et al, Cancer Research 2009).  Preclinical co-targeting of EGFR and 
MET revealed strong synergy in HNC (Seiwert et al, 2009, Cancer Research; Xu et 
al, 2011, Clinical Cancer Research). Furthermore two phase II randomized studies in 
NSCLC have yielded positive results suggesting that c-MET inhibition can augment 
the efficacy of EGFR inhibition and improve PFS in biomarker defined patient 
populations. EGFR and MET signaling are overlapping and it is well established that 
one can compensate for the other and joint inhibition provides benefit/synergy. It is 
crucial to identify the correct biologic subgroup/s that benefit most. Our preclinical 
work as well as NSCLC lung cancer data suggest that increased c-MET copy number 
and c-MET expression are the most likely candidate predictive biomarkers also for 
HNC. 
 
 
Based on these preclinical findings we now propose to study the EGFR inhibitor 
cetuximab and the c-MET inhibitor ARQ 197 (tivantinib) in combination.  
 


20 
 
 
 
2.5 
Correlative Studies Background 
See above for preclinical rationale. Clinically the rationale is largely supported by 
prior experiences with ARQ 197 (tivantinib) and the c-MET antibody MetMab. 
 
The phase II randomized study of ARQ 197 (tivantinib) in NSCLC identified c-MET 
copy number as a biomarker of ARQ 197 (tivantinib) benefit (Sequist, Schiller et al, 
ESMO, 2010). 
 
The phase II randomized study of MetMab (antibody fragment against the c-MET 
receptor) demonstrated that benefit of MetMab was limited to tumors with c-MET 
expression using a standardized and centralized IHC methodology (Spigel et al, 
ESMO, 2010). 
 
In this study we will evaluate both c-MET copy number and c-MET expression. 
 
 
 
 


21 
 
 
3. PATIENT SELECTION 
 
 
3.1  
Eligibility Criteria  
 
 
 
 
Inclusion Criteria: 
3.1.1 Histologically / cytologically confirmed diagnosis of squamous cell 
carcinoma of Head and Neck origin not amenable to curative intent therapy. 
Both HPV(+) and HPV(-) are eligible, but status has to be known prior to 
randomization (although not required for consenting). Any type of tissue 
based HPV assessment is acceptable (e.g. p16 IHC or HPV ISH). If local 
HPV testing is not available slides can be sent to the University of Chicago 
for HPV testing. Please note that p16 IHC is generally only considered to be 
accurate for oropharyngeal tumors. 
 
3.1.2 Presence of measurable lesions (as per RECIST 1.1). Generally a ≥10mm 
tumor lesion (in the longest diameter by CT scan) or a Lymph node ≥15mm 
(short axis) is considered measurable disease when evaluated by CT scan 
(with a slice thickness no greater than 5 mm). Please review full RECIST 1.1 
criteria (Eisenhauer EA et al, Eur J Ca, 2009) as well as Section 11 for further 
details. 
3.1.3 Availability of tissue (10 tumor containing FFPE slides/sections) 
 
 
3.1.4 ECOG performance status of 0, 1 (see Appendix A). 
 
3.1.5 Patients who have received cetuximab or another inhibitor of EGFR in the 
curative intent treatment setting (e.g. with radiation or during induction 
chemotherapy (prior to definitive, curative intent therapy)) are eligible for the 
study. 
 
3.1.6 Age >18 years.  
 
Because no dosing or adverse event data are currently available on the use of  
ARQ 197 (tivantinib) in patients <18 years of age, children are excluded from 
this study, but will be eligible for future pediatric trials. 
 
3.1.7 Life expectancy of greater than 8 weeks. 
 
3.1.8 Patients must have normal organ and marrow function as defined below: 
 
 hemoglobin  
 
 
 
 
>9.0 g/dL  
 leukocytes  
 
 
 
 
>3,000/mcL 
 absolute neutrophil count  
>1,500/mcL 
 platelets  
 
 
 
 
 
>100,000/mcL 
 total bilirubin 
 
 
 
 
<1.5 X institutional upper limit of normal  
 AST(SGOT)/ALT(SGPT)  
<2.5 X institutional upper limit of normal 
 serum creatinine  
 
 
 
<1.5 X  institutional upper limit of normal 
 
OR 


22 
 
 
 creatinine clearance  
 
 
>60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal. 
 
3.1.9  
Patients must be able to swallow ARQ 197 (tivantinib) by 
mouth, unless adequate data about administration by G-tube becomes 
available. Tablets may be crushed, but must be taken orally. 
 
3.1.10 HIV-positive patients with normal immune function (CD4 count >200) are 
eligible if there are no drug interactions with ARQ 197 (tivantinib) or 
cetuximab.  
 
 
3.1.11 The effects of ARQ 197 (tivantinib) on the developing human fetus are 
unknown.  For this reason and because tyrosine kinase inhibitors 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 
and for the duration of study participation.  Should a woman become pregnant 
or suspect she is pregnant while she or her partner is participating in this 
study, she should inform her treating physician immediately.  Men treated or 
enrolled on this protocol must also agree to use adequate contraception prior 
to the study, for the duration of study participation, and 4 months after 
completion of ARQ 197 (tivantinib) administration. 
 
3.1.12 Ability to understand and the willingness to sign a written informed consent 
document. 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who have had chemotherapy or radiotherapy within 2 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 2 
weeks earlier. 
 
3.2.2 Nasopharyngeal tumors that show lymphoepithelioma histology 
 
3.2.3 Patients who have received more than 2 prior cytotoxic treatments in the 
palliative treatment setting are ineligible. 
 
3.2.4 Patients who have received prior treatment with an EGFR or MET inhibitor in 
the palliative treatment setting are ineligible 
 
 
3.2.5 Patients with known, active brain metastases should be excluded from this 
clinical trial because of their poor prognosis and because they often develop 
progressive neurologic dysfunction that would confound the evaluation of 


23 
 
 
neurologic and other adverse events. Patients with treated brain metastases 
stable for >=12 weeks are eligible. Use of corticosteroids (for patients with 
brain metastasis and other indications for corticosteroid use) is acceptable on a 
low maintenance or tapering dose schedule. 
 
3.2.6 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to AR 197 (tivantinib) or cetuximab. 
 
3.2.7 Concurrent life-threatening diseases: Patients with diseases which with 
reasonable certainty do not limit life expectancy to 12 months or less are 
eligible. Assessment of such concurrent illnesses should be by the Principal 
Investigator 
 
3.2.8 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. 
 
3.2.9 Pregnant women are excluded from this study because ARQ 197 (tivantinib) 
is a tyrosine kinase inhibitor 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 ARQ 197 
(tivantinib), breastfeeding should be discontinued if the mother is treated with 
ARQ 197 (tivantinib). 
3.2.10 Concurrent use of warfarin (therapeutic use) is allowed, but requires close 
monitoring of PT/INR (See Section 5.2) 
 
3.2.11 ARQ 197 (tivantinib)is metabolized by CYP2C19, and to a lesser extent 
CYP3A4.  The metabolism and consequently overall pharmacokinetics of 
ARQ 197 (tivantinib) could be altered by inhibitors and/or inducers or other 
substrates of CYP2C19 and CYP3A4.  While inhibitors/inducers of these 
cytochrome P450 isoenzymes are not specifically excluded, investigators 
should be aware that ARQ 197 (tivantinib) exposure may be altered by the 
concomitant administration of these drugs.   
 
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.aspx; 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.  
 
3.2.12 History of congestive heart failure defined as Class II to IV per New York 
Heart Association (NYHA) classification; active coronary artery disease 
(CAD); clinically significant bradycardia or other uncontrolled, cardiac 


24 
 
 
arrhythmia defined as ≥ grade 3 according to National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, or 
uncontrolled hypertension; myocardial infarction occurring within 6 months 
prior to study entry (myocardial infarction occurring >6 months prior to study 
entry is permitted). 
 
3.2.13   Patients may not be receiving any other investigational agents 
 
3.3  
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.  Each 
center will be responsible for ensuring that a representative set of patients (as defined 
by the Census Bureau) is enrolled. 
 
 
4.  REGISTRATION PROCEDURES 
 
4.1  
 General Guidelines 
 
Eligible patients will be entered on study centrally at the University of Chicago by the 
Study Registrar. All sites should call the Study Registrar, , at 773-834- 3095 or 
PhaseIICRA@medicine.bsd.uchicago.edu, to verify agent availability. The UC Phase 
II Consortium Affiliate Forms are available on the UC P2C website at: 
 
  
• https://webres.uccrc.org/login/login  
  
 
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. Eligible patients will be entered on study centrally at the University of 
Chicago by the study Registrar. All sites should call the study Registrar at (773) 834 
3095 to verify agent availability.  
 
ARQ 197 (tivantinib) may be requested by submitting an agent order through PMB 
Online Agent Order Processing (OAOP) application. Refer to section Section 8.1.3.1 
for more information. 
 
Following registration, the study registrar at the University of Chicago will randomize 
the patient immediately, and patients should begin protocol treatment within 14 days 
after randomization. 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 
Registrar should be notified of cancellations as soon as possible. 
 
 
 


25 
 
 
 
 
 
4.2   
Registration Process 
 
All patients must be successfully registered and randomized with the University of 
Chicago Registrar, prior to the commencement of treatment. The following 
documents should be completed by the research nurse or data manager and faxed to 
(773) - 702 4889 or emailed PhaseIICRA@medicine.bsd.uchicago.edu to the 
Registrar: 
 Provider of information 
 Treating Physician  
 Patient name and hospital ID number  
 Patient's zip code of residence  
 Date & copy of signed informed consent  
 Race, gender, date of birth of patient  
 Diagnosis and date of initial diagnosis  
 HPV status (can be provided later, but is required for successful randomization) 
 Complete Phase II Consortium Affiliate Clinical Trial Patient Registration 
Form  
 Source documentation for eligibility and pre-study procedures 
The research nurse or data manager at the participating site will then call (773-834-
3095) or e-mail PhaseIICRA@medicine.bsd.uchicago.edu to confirm all selection 
criteria listed in Section 4.0. To complete the registration process, the Coordinator 
will: 
 
Assign a patient study number  
 
Register the patient on the study  
 
Assign patient to treatment arm based on Randomization (see Section 13) 
 
Fax or e-mail the patient study number and dose to the participating site 
 
Provide randomization information regarding treatment arm 
 
Call the research nurse or data manager at the participating site and verbally confirm 
registration. 
 
 
5. TREATMENT PLAN 
 
 
 
 
 
Patients are randomized between two arms (see schema below): 
1. cetuximab 500mg/m2 iv, every two weeks, PLUS  ARQ 197 (tivantinib) 360mg BID, by 
mouth 
2. cetuximab 500mg/m2 iv, every two weeks 






 $JHQW$GPLQLVWUDWLRQ

7UHDWPHQWZLOOEHDGPLQLVWHUHGRQDQRXWSDWLHQWEDVLV5HSRUWHGDGYHUVHHYHQWVDQG
SRWHQWLDOULVNVIRU$54WLYDQWLQLEDQGFHWX[LPDEDUHGHVFULEHGLQ6HFWLRQ
$SSURSULDWH GRVH PRGLILFDWLRQV IRU $54  WLYDQWLQLE DQG FHWX[LPDE DUH
GHVFULEHGLQ6HFWLRQ1RLQYHVWLJDWLRQDORUFRPPHUFLDODJHQWVRUWKHUDSLHVRWKHU
WKDQWKRVHGHVFULEHGEHORZPD\EHDGPLQLVWHUHGZLWKWKHLQWHQWWRWUHDWWKHSDWLHQW
V
PDOLJQDQF\

 $54WLYDQWLQLEDGPLQLVWUDWLRQ


3DWLHQWVUHFHLYH$54WLYDQWLQLERQDQRXWSDWLHQWEDVLV7KHVWDUWLQJGRVH
LVPJE\PRXWKWZLFHGDLO\ 

7KHSDWLHQWZLOOEHUHTXHVWHGWRPDLQWDLQDPHGLFDWLRQGLDU\RIHDFKGRVHRI
PHGLFDWLRQ7KHPHGLFDWLRQGLDU\ZLOOEHUHWXUQHGWRFOLQLFVWDIIDWWKHHQGRI
HDFKF\FOH$VDPSOHPHGLFDWLRQGLDU\FDQEHUHTXHVWHGIURPWKH8QLYHUVLW\RI
&KLFDJRRU FDQEHSURYLGHGE\WKHUHVSHFWLYHWUHDWPHQW FHQWHUXVLQJDORFDO
WHPSODWH

$54  WLYDQWLQLE WDEOHWV VKRXOG EH DGPLQLVWHUHG RUDOO\ ZLWK PHDOV  $
PLVVHG RU YRPLWHG GRVH   QRW WDNHQ ZLWKLQ  KRXUV LH  KRXUV EHIRUH RU
DIWHU WKH VFKHGXOHG WLPH VKRXOG QRW EH UHSODFHG  7KH SDWLHQW VKRXOG EH
LQVWUXFWHGWRWDNHWKHQH[WVFKHGXOHGGRVHDWWKHUHJXODUO\VFKHGXOHGWLPH

 &HWX[LPDEDGPLQLVWUDWLRQ


&HWX[LPDEZLOOEHJLYHQRQDQRXWSDWLHQWEDVLVHYHU\WZRZHHNVLQWUDYHQRXVO\
DWDGRVHRIPJPJLYHQRYHUPLQXWHVWKHILUVWWLPHWKHQRYHU
PLQXWHVVXEVHTXHQWO\DOOLY

,WLVDFFHSWDEOHWRURXQGWKHFHWX[LPDEGRVHWRWKHQHDUHVWKXQGUHGLIWKLVLVWKH
LQVWLWXWLRQDOVWDQGDUGSUDFWLFH

3DWLHQWV ZLOO UHFHLYH FHWX[LPDE LQWUDYHQRXV LQIXVLRQV YLD LQIXVLRQ SXPS RU
JUDYLW\GULS7KHGRVHRIFHWX[LPDELVPJPDQGLVDGPLQLVWHUHGRYHU
RUPLQXWHV7KHGRVHRIFHWX[LPDELVGHSHQGHQWXSRQWKHSDWLHQW¶VEDVHOLQH
ERG\ZHLJKWLQNLORJUDPVPJNJ,IWKHUHLVDFKDQJHLQERG\ZHLJKW
IURP EDVHOLQH WKLV GRVH VKRXOG EH UHFDOFXODWHG 3DWLHQWV VKRXOG EH REVHUYHG
FORVHO\ GXULQJ FHWX[LPDE LQIXVLRQ DQG IRU  PLQXWHV DIWHU WKH LQIXVLRQ
&HWX[LPDE
1 
7LYDQWLQLE
&HWX[LPDE
1 
5
$
1
'
2
0
,
=
(

5HFXUUHQW
PHWDVWDWLF+1&
&HWX[LPDEQDwYH
7LYDQWLQLE
2SWLRQDO
7UHDWXQWLO
3URJUHVVLYH'LVHDVH
1 


27 
 
 
Infusion times may be increased for patients who experience mild allergic 
reactions, but cannot exceed 4 hours. Prior to infusion, the appropriate volume 
of cetuximab will be drawn from the vial with a sterile syringe and cetuximab 
will be transferred from the syringe into a sterile evacuated container. 
Cetuximab will be filtered through a 0.22-μm protein-sparing or low- protein 
binding in-line filter. After infusion, 0.9% normal saline will be used to flush 
the line. 
• 
Premedication with an H1 antagonist (diphenhydramine 25-50 mg I.V. or oral) 
30 minutes prior to infusion should be given for allergic reaction prophylaxis. 
50mg should be administered prior to the first dose of cetuximab in an effort to 
prevent an infusion reaction.  
• 
Four weeks (28 days) constitutes one cycle of treatment. Treatment continues 
until one of the criteria in Section 5.3 applies. 
• 
If a patient develops a hypersensitivity reaction despite diphenhydramine 
pretreatment, the infusion should be stopped and observation for 15 to 60 
minutes (depending upon the reaction severity) instituted.  Infusion reactions to 
cetuximab may be severe and can occur during or after treatment. At the 
physician’s discretion, it may be possible to resume treatment by administering 
an H2 blocker approximately 30 minutes before restarting the infusion.  The 
addition of an H2 blocker such as famotidine 20 mg IV is optional.  If 
famotidine is unavailable, administer ranitidine 50 mg IV (not cimetidine due 
to the risk for drug interactions). Re-attempting infusion at a slower rate, 
possibly over one hour is appropriate.  Additional treatment of severe allergic 
reactions is at the discretion of the treating physician and may include 
corticosteroids as well as other agents. 
• 
As a routine precaution, patients enrolled in this study will be observed closely 
for any potential adverse events by the medical staff for the duration of the 
cetuximab infusion and until at least 1 hour after the end of the initial infusion, 
in an area with resuscitation equipment and other agents (epinephrine, 
prednisone equivalents, etc.) available. A nurse must be present in the 
immediate treatment area throughout the infusion and observation period. A 
physician must be in close proximity to the patient treatment area. Patients 
should be instructed to report any delayed reactions to the investigator 
immediately.  
• 
Details about dose reductions / resumption of therapy on subsequent treatment 
days are provided in Section 6. 
 
 
 
5.2 
 General Concomitant Medication and Supportive Care Guidelines 
 
 
5.2.1 Prohibited Concomitant Medications 
 
Potential for Drug Interactions 
Because there is a potential for interaction of ARQ 197 (tivantinib) with other 
concomitantly administered drugs through the cytochrome P450 system (see Section 


28 
 
 
2.2.1), 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 D presents an information sheet for 
patients to alert them and their caregivers of any medication changes. 
 
Since ARQ 197 (tivantinib) is metabolized by CYP2C19 and CYP3A4, a potential for 
drug-drug interaction exists when ARQ 197 (tivantinib) is co-administered with drugs 
that are CYP2C19 inhibitors/inducers or strong CYP3A4 inhibitors.  Use of such 
drugs is permissible, but investigators should use caution and be aware that ARQ 197 
(tivantinib) exposure may be altered when concomitantly administrating these drugs. 
No additional laboratory tests are required, but it is expected that side effects as listed 
in this protocol for tivantinib could potentially be more pronounced. 
5.2.1.1 Other Investigational Drug Therapies 
Patients may not receive any other investigational drugs while on study drug. 
 
5.2.1.2 Anticancer Therapies 
No other anticancer therapies may be administered to patients while they are on study 
drug.  These include but are not limited to chemotherapy, radiotherapy, hormonal 
therapy (except megestrol acetate as supportive care), immunotherapy, or 
locoregional therapy. 
 
5.2.1.3.Immunosuppressive therapies 
Patients may not receive any immunosuppressive therapies while on study drug.  
 
5.2.2 Permitted Concomitant Medications 
 
Standard therapies 
Standard therapies for concurrent medical conditions are allowed. 
 
5.2.3. Erythropoietin Stimulating Agents (ESA) 
Please follow ASCO or MEDICARE guidelines for the use of ESA in patients 
diagnosed with cancer, drug labels and the Food and Drug Administration (FDA) 
alerts dated March 9, 2007; November 8, 2007; March 12, 2008; July 31, 2008; and 
December 2, 2008.  We generally discourage routine use of ESAs and use should 
be reserved to patients, who are clinically symptomatic. 
 
Hematopoietic growth factors 
ASCO guidelines should be followed for the use of hematopoietic growth factors, 
including filgrastim or other colony-stimulating factors.   
 
Antiemetics 
Prophylactic and supportive antiemetics may be administered according to common 
practice. 
 
5.2.4. Precautions, Warnings, and Other Supportive Care Guidelines 
 


29 
 
 
Myelosuppression 
Myelosuppression (anemia, neutropenia, febrile neutropenia, thrombocytopenia, 
leukopenia, and lymphopenia) has been reported in single agent and combination 
therapy clinical trials of ARQ 197 (tivantinib).  Complete blood count should be 
performed weekly or every other week.  Caution is advised when any CYP2C19 
inhibitors and/or strong CYP3A4 inhibitors are used as concomitant therapy.  More 
frequent hematology testing and prophylactic use of hematopoietic growth factors is 
advised according to ASCO guidelines. The incidence of myelosuppression is higher 
in patients with HCC.  Subjects with HCC or patients who experience neutropenia 
should be monitored more closely throughout the study and follow dose 
modifications or delays as specified in the protocols. 
 
 
Bradycardia 
Bradycardia has been reported in single agent and combination therapy clinical trials 
of ARQ 197 (tivantinib).  In general, these events were mild to moderate in severity 
and asymptomatic, and subjects recovered without additional therapy.  ARQ 197 
(tivantinib)should be used with caution in patients who have or who are at significant 
risk of developing bradycardia.  Pulse will be evaluated on day 1 of the first cycle and 
on subsequent visits.  Additional EKGs should be performed if clinically indicated, 
especially if significant abnormalities of the baseline or subsequent EKGs are present. 
 
Other 
Treatment of emergent toxicities is at the investigator’s discretion. 
 
5.3 
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, 
 
 
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. 
 
 
Pregnancy 
 
Patients treated with cetuximab as a single agent will have the opportunity to 
receive ARQ 197 (tivantinib) after progressive disease (PD) (see schema at 
beginning of protocol).  
 


30 
 
 
5.4  
Duration of Follow Up 
 
Patients will be followed for any medical issues for a minimum of 8 weeks (6 months 
is recommended) after removal from study or until death, whichever occurs first.  
Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event.  In addition patients will be followed 
for survival 5 years post treatment or until death, whichever occurs first. 
Information on progression (as defined in this protocol) or death will be collected 
even if the patient has been removed from the study previously. 
 
 
 
5.5  
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.3 
applies.  The reason for study removal and the date the patient was removed must be 
documented in the Case Report Form. 
 
Patients may be discontinued from trial treatment and assessments at any time, at the 
discretion of the investigator(s). In addition to the above listed criteria additional 
specific reasons for discontinuing a patient from this trial are: 
• 
patient lost to follow-up (i.e., dropouts)  
• 
protocol non-compliance  
 
If the reason for withdrawal from the trial is the death of the patient, the two options 
for categorizing withdrawal are either progressive disease or an adverse event (AE). 
More than one AE may be documented as a reason for withdrawal. Only one event 
will be captured as the cause of death. Note that death is an outcome and not an 
adverse event. 
 
All deaths that occur within the trial period or within 30 days after administration of 
the last dose of trial drug must be reported to NCI primarily for the purposes of 
serious adverse event (SAE) reporting.  However, deaths unequivocally related to 
progression are not SAEs. All subjects who have new or worsening CTC grade 3 / 4 
laboratory values (CTCAE 4.0) at the time of withdrawal must have further tests 
performed and the results recorded appropriately until the lab values have returned to 
CTC grade 1 or 2, unless these values are not likely to improve because of the 
underlying disease. In these cases, the investigators must record their opinions in the 
subject’s medical records. Laboratory abnormalities should not be reported as 
adverse events unless they meet criteria for a SAE, or the laboratory abnormality 
causes the subject to discontinue from the study, or the investigator insists the 
abnormality should be reported as an AE. 
 
At withdrawal all on-going study-related toxicities and SAEs must be followed until 
resolution, unless in the investigator estimates that the condition is unlikely to resolve 
due to the subject’s underlying disease. 
 
After withdrawal from treatment, subjects must be followed up for all existing and 


31 
 
 
new AEs for 30 days after the last dose of ARQ 197 (tivantinib) and/or cetuximab. 
All new AEs occurring during that period must be reported to NCI and all study-
related toxicities and SAEs must be followed up until resolution if possible. 
 
 
6. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
 
Dose Level 
Tivanitinib Dose 
Starting Dose 
360 mg, po, twice a day 
-1 
240 mg, twice a day 
-2 
120 mg, twice a day 
Up to two dose reductions are acceptable. Persistent toxicities in spite of two dose reductions 
will result in discontinuation of therapy. 
Event Name 
Non-hematological toxicities 
Grade of Event 
Management/Next Dose for 
ARQ 197 (tivantinib) 
Management/Next Dose for 
Cetuximab 
≤ Grade 1 
Continue therapy 
Continue therapy. See 6.2 
Grade 2 
Continue therapy 
Continue therapy. See 6.2 
Grade 3* 
If at least possibly related to 
ARQ 197 (tivantinib) and not 
amenable to an established, 
rapidly effective 
treatment**: hold ARQ 197 
(tivantinib) until resolution to 
≤Grade 2  
If at least possibly related to 
cetuximab and not amenable 
to an established, readily 
effective treatment**: hold 
cetuximab until resolution to 
≤Grade 2. See 6.2 
Grade 4* 
If at least possibly related to 
ARQ 197 (tivantinib) and not 
amenable to an established, 
rapidly effective 
treatment**: hold ARQ 197 
(tivantinib) until resolution to 
≤Grade 2 
If at least possibly related to 
cetuximab and not amenable 
to an established, readily 
effective treatment**: hold 
cetuximab until resolution to 
≤Grade 2. See 6.2 
* Treating Physician to assess relatedness and impact on patient health 
** E.g. adverse events that are readily addressed with additional therapy typically 
within 24 hours – e.g. pain medication for increased pain or insulin for increase 
blood glucose level. 
Patients requiring a delay of >2 weeks should go off protocol therapy. 
Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  For vomiting:  antiemetics.  For diarrhea:  
Loperamide antidiarrheal therapy.  Dosage schedule:  4 mg first onset, followed 
by 2 mg with each loose motion until diarrhea-free for 12 hours (maximum 
dosage:  16 mg/24 hours).  Adjunct anti-diarrheal therapy is permitted and 
should be recorded when used. 
 
Event Name 
Hematological Toxicities*** 


32 
 
 
Grade of Event 
Management/Next Dose for 
ARQ 197 (tivantinib) 
Management/Next Dose for 
Cetuximab 
 Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
 ≥ Grade 3 
neutropenia 
recovering within 
5 days 
Withhold ARQ 197 
(tivantinib) 
If ANC recovers to 
≥1.5 × 109/L (≥1500/mm3) 
within 5 days, resume 
treatment with ARQ 197 
(tivantinib) at the same dose 
level.  
For subsequent dose delays 
resume at one dose level 
lower.**   
Continue therapy if deemed 
appropriate by the treating 
physician  
≥ Grade 3 
neutropenia lasting 
>5 days or ≥ Grade 
3 febrile 
neutropenia 
Withhold ARQ 197 
(tivantinib) for up to 
14 days.*  
If ANC recovers to 
≥1.5 × 109/L (≥1500/mm3) 
within 14 days, treatment 
with ARQ 197 (tivantinib) 
should resume at a dose that 
is decreased by one dose 
level for subsequent 
cycles.** 
If ANC does not recover to 
≥1.5 × 109/L (≥1500/mm3) 
within 14 days after 
interrupting ARQ 197 
(tivantinib), discontinue 
administration of ARQ 197 
(tivantinib). 
Continue therapy if deemed 
appropriate by the treating 
physician 
Platelet count 
<50 × 109/L 
(<50,000/mm3) 
Withhold ARQ 197 
(tivantinib) for up to 14 days.  
If platelet count recovers to 
≥100 × 109/L 
(≥100,000/mm3) within 14 
days, resume treatment with 
ARQ 197 (tivantinib) at 
same dose level.* If a second 
dose delay is required for the 
same event, then decrease 
Continue therapy if deemed 
appropriate by the treating 
physician 


33 
 
 
ARQ 197 (tivantinib) dose 
by one dose level for 
subsequent cycles**.   
If platelet count does not 
recover to ≥100 × 109/L   
(≥100,000/mm3) within 
14 days after interrupting 
ARQ 197 (tivantinib), 
discontinue ARQ 197 
(tivantinib) administration.  
Grade 4 
thrombocytopenia 
Discontinue administration 
of ARQ 197 (tivantinib).   
Discontinue treatment 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
***Felt to be at least possibly related to ARQ 197 (tivantinib) treatment 
Growth factor support with e.g. G-CSF is acceptable as indicated 
 
 
 
6.1 
ARQ 197 (tivantinib) 
 
If using the recommended phase 2 dose (RP2D) of ARQ 197 (tivantinib) (360 mg 
BID), the following dose reductions for toxicity are suggested, in order: 240 mg BID, 
and 120 mg BID.  See Table 6-1 for a suggested dose modification plan for common 
toxicities.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


34 
 
 
Table 6-1: 
Recommended dose modification plan for ARQ 197 (tivantinib) for 
toxicity. 
Event Grade  
(NCI CTC V4.02) 
Action 
Grade 1 or 2 
Continue current dose level. 
Grade 3 
nonhematologic 
If at least possibly related to ARQ 197 (tivantinib) and not amenable to an 
established, rapidly effective treatment*/**: discontinue ARQ 197 
(tivantinib) until resolution to ≤Grade 2 
Subsequent administration after discontinuation of ARQ 197 (tivantinib) 
should be at a dose that is decreased by one dose level for subsequent 
cycles, unless a second dose reduction is required.  A maximum of 2 dose 
reductions is permitted per subject. 
Grade 4 
nonhematologic 
If at least possibly related to ARQ 197 (tivantinib) and not amenable to an 
established, rapidly effective treatment*/**: discontinue ARQ 197 
(tivantinib) until resolution to ≤Grade 2 
Subsequent administration after discontinuation of ARQ 197 (tivantinib) 
should be at a dose that is decreased by one dose level for subsequent 
cycles, unless a second dose reduction is required.  A maximum of 2 dose 
reductions is permitted per subject. 
≥ Grade 3 
neutropenia 
recovering within 
5 days 
Withhold ARQ 197 (tivantinib) 
If ANC recovers to ≥1.5 × 109/L (≥1500/mm3) within 5 days, resume 
treatment with ARQ 197 (tivantinib) at the same dose level.* If a second 
dose delay is required for the same event, then decrease ARQ 197 
(tivantinib) dose by one dose level for subsequent cycles.  For a third or 
fourth dose delay, decrease ARQ 197 (tivantinib) dose by one dose level.  
A maximum of 2 dose reductions is permitted per subject. 
≥ Grade 3 
neutropenia lasting 
>5 days or ≥ Grade 
3 febrile 
neutropenia 
Withhold ARQ 197 (tivantinib) for up to 14 days.  
If ANC recovers to ≥1.5 × 109/L (≥1500/mm3) within 14 days, treatment 
with ARQ 197 (tivantinib) should resume at a dose that is decreased by 
one dose level  for subsequent cycles. *** If a second or third dose delay is 
required for the same event, then again decrease ARQ 197 (tivantinib) dose 
from the current dose by one dose level for subsequent cycles.  A 
maximum of 2 dose reductions is permitted per subject.   
If ANC does not recover to ≥1.5 × 109/L (≥1500/mm3) within 14 days after 
interrupting ARQ 197 (tivantinib) , discontinue administration of ARQ 197 
(tivantinib). 
Platelet count 
<50 × 109/L 
(<50,000/mm3) 
Withhold ARQ 197 (tivantinib) for up to 14 days.  
If platelet count recovers to ≥100 × 109/L (≥100,000/mm3) within 14 days, 
resume treatment with ARQ 197 (tivantinib) at same dose level.*  A 
maximum of 2 dose delays is permitted per subject.  If a second dose delay 
is required for the same event, then decrease ARQ 197 (tivantinib) dose by 
one dose level for subsequent cycles.   
If platelet count does not recover to ≥100 × 109/L  
 
(≥100,000/mm3) within 14 days after interrupting ARQ 197 (tivantinib), 
discontinue ARQ 197 (tivantinib) administration. 
Grade 4 
thrombocytopenia 
Discontinue administration of ARQ 197 (tivantinib).   
* Treating Physician to assess relatedness and impact on patient health 
** E.g. adverse events that are readily addressed with additional therapy – e.g. pain medication 
for increased pain, or insulin for elevated blood glucose levels 
***Patients requiring a delay of >2 weeks should go off protocol therapy. 
6.2  
Cetuximab 
 


35 
 
 
Cetuximab related toxicities 
Cetuximab Infusion 
Reaction 
 
Grade 1 (transient flushing or rash, drug fever <38oC): decrease 
the cetuximab infusion rate by 50% and monitor closely for any 
worsening. 
 
Grade 2 (rash, flushing, urticaria, dyspnea, drug fever ≥38oC): 
stop the cetuximab infusion, administer appropriate therapy, and 
then restart the cetuximab infusion with a decrease in the infusion 
rate of 50% and monitor closely for any worsening. 
 
Grade 1 or 2 Infusion Reaction manifesting only as a delayed 
drug fever (starting after the cetuximab infusion): maintain the 
cetuximab dose and infusion rate and consider administering 
acetaminophen or cyclooxygenase-2 inhibitors (at the dose and 
schedule of the investigator’s discretion) prior to the subsequent 
cetuximab infusion, if not otherwise contraindicated in the 
patient. 
 
A grade 3 reaction consists of: symptomatic bronchospasm with 
or without urticaria, requiring parenteral medication(s); allergy-
related edema/angioedema; hypotension. 
 
A grade 4 reaction (anaphylaxis) is a life-threatening event 
characterized by rapid onset (often within minutes) of airway 
obstruction (bronchospasm, stridor, hoarseness), urticaria, and/or 
hypotension. 
 
Treatment of a Grade 3 or 4 Infusion Reaction: Stop the 
cetuximab infusion immediately and disconnect infusion tubing 
from the patient. Administer epinephrine, bronchodilators, 
antihistamines, glucocorticoids, intravenous fluids, vasopressor 
agents, oxygen, etc, as medically indicated. 
 
Following a grade 3 or 4 infusion reaction, the patient is to 
receive no further cetuximab treatment. In the event of a grade 1 
or 2 infusion reaction, the cetuximab infusion rate should be 
permanently reduced by 50%. 
 
Severe infusion reactions require the immediate interruption of 
cetuximab therapy and permanent discontinuation from further 
therapy.  Appropriate medical therapies include epinephrine, 
corticosteroids, intravenous antihistamines, bronchodilators, and 
oxygen .  Patients should be carefully observed until the complete 
resolution of all signs and symptoms. 
Hypomagnesemia 
The incidence of hypomagnesemia (both overall and severe [NCI 
CTC grades 3  & 4])  is increased in patients receiving 
chemotherapy and cetuximab as compared with those receiving 
chemotherapy alone based on controlled clinical trials.  Patients 
receiving cetuximab therapy should be monitored for 
hypomagnesemia. Magnesium repletion may be necessary based 
on clinical judgment. 
 
Drug Fever 
In the event of isolated drug fever, the investigator must use clinical 
judgment to determine if the fever is related to the study drug or 
to an infectious etiology. 
If a patient experiences isolated drug fever, for the next dose, pre treat 
with acetaminophen or non-steroidal anti-inflammatory agent 
(investigator discretion), repeat antipyretic dose 6 and 12 hours 


36 
 
 
after cetuximab infusion.  The infusion rate will remain 
unchanged for future doses. 
If a patient experiences recurrent isolated drug fever following pre-
medication and post-dosing with an appropriate antipyretic, the 
infusion rate for subsequent dosing should be 50% of previous 
rate.  If fever recurs following infusion rate change, the 
investigator should assess the patient’s level of discomfort with 
the event and use clinical judgment to determine if the patient 
should receive further cetuximab. 
Skin toxicities 
Patients developing dermatologic toxicities while receiving 
cetuximab should be monitored for the development of 
inflammatory or infectious sequelae, and appropriate treatment of 
these symptoms initiated.  Dose modifications of any future 
cetuximab infusions should be instituted in case of severe (grade 
3) acneform rash.  Treatment with topical and/or oral antibiotics 
should be considered; topical corticosteroids are not 
recommended. 
If a patient experiences severe acneform rash, cetuximab treatment 
adjustments should be made according to the following table.  In 
patients with mild and moderate skin toxicity, treatment should 
continue without dose modification. 
Management guidelines for treatment of skin toxicities are well 
established including antibiotics and topical therapies. An 
overview is provided in Appendix E. 
 
Dose levels for cetuximab are as follows. Dose modifications are typically a result of skin 
toxicities, but at the discretion of the principal investigator other grade III/IV toxicities may also 
lead to a dose reduction if felt to be appropriate: 
Cetuximab Dose Levels 
 
Every other week cetuximab dose 
Starting dose 
500 mg/m2 
Dose Level -1 
400 mg/m2 
Dose Level -2 
250 mg/m2 
There will be no dose level reductions below a dose of 250 mg/m2 every other week.  An 
exception can be made if weekly (rather than every other week) dosing is felt to be beneficial, 
and may be attempted. 
 
 
Management of Dermatologic Toxicity 
Grade 
3 
Acneform Rash 
Cetuximab 
Outcome 
Cetuximab 
Dose 
Modification 
1st occurrence 
Delay next infusion 1 to 2 
weeks (per treating MD) 
Improvement 
Continue at 250 mg/m2 


37 
 
 
No Improvement 
Discontinue cetuximab 
2nd occurrence 
Delay next infusion 1 to 2 
weeks (per treating MD)  
Improvement 
Reduce Dose Level -1 
No Improvement 
Discontinue cetuximab 
3rd occurrence 
Delay next infusion 1 to 2 
weeks (per treating MD) 
Improvement 
Reduce to Dose Level -2 
No Improvement 
Discontinue cetuximab 
4th occurrence 
Discontinue cetuximab 
 
 
 
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 List(s) (CAEPRs) 
 
7.1.1 CAEPRs for ARQ 197 (tivantinib) and Cetuximab 
 
7.1.1.1 CAEPR for ARQ 197 (tivantinib, NSC 750832) 
 
 
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/adverse_events.htm for 
further clarification. Frequency is provided based on 756 patients. Below is the CAEPR for ARQ 197 
(tivantinib). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
Version 2.2, February 19, 20161 
 
 Adverse Events with Possible  
 Relationship to ARQ 197 (tivantinib) 
 (CTCAE 4.0 Term) 
[n= 756] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting  
(SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
CARDIAC DISORDERS 
  


38 
 
 
 
 Adverse Events with Possible  
 Relationship to ARQ 197 (tivantinib) 
 (CTCAE 4.0 Term) 
[n= 756] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting  
(SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Sinus bradycardia 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Diarrhea 
 
 Diarrhea (Gr 2) 
 
Nausea 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
INVESTIGATIONS 
  
 
Lymphocyte count decreased 
 
  
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 4) 
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
 
 
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. 
 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
 
 Adverse events reported on ARQ 197 (tivantinib) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that ARQ 197 (tivantinib) caused the 
adverse event: 
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia; Lymph node pain 
CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation; Cardiac arrest; Conduction 
disorder; Myocardial infarction; Paroxysmal atrial tachycardia 
EYE DISORDERS - Dry eye; Eye disorders - Other (blindness unilateral) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Abdominal pain; Ascites; Constipation; Dry 
mouth; Duodenal ulcer; Dyspepsia; Flatulence; Gastrointestinal disorders - Other (eructation [belching]); 
Gastrointestinal disorders - Other (peritoneal hemorrhage); Mucositis oral; Oral pain; Small intestinal 
obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Fever; Flu 
like symptoms; Gait disturbance; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Bile duct stenosis; Hepatic failure; Portal vein thrombosis 
INFECTIONS AND INFESTATIONS - Infection2 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Fracture 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; Aspartate 
aminotransferase increased; Blood bilirubin increased; Electrocardiogram QT corrected interval 
prolonged; GGT increased; INR increased; Investigations - Other (pancytopenia); Platelet count 
decreased; Weight loss 


39 
 
 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperkalemia; 
Hyperuricemia; Hypoalbuminemia; Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Flank pain; 
Generalized muscle weakness; Musculoskeletal and connective tissue disorder - Other (muscle spasms); 
Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Treatment 
related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysgeusia; Headache; Intracranial hemorrhage; Nervous 
system disorders - Other (spinal cord compression); Peripheral motor neuropathy; Seizure; Stroke; 
Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other 
(hydronephrosis); Urinary retention; Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Bronchopulmonary 
hemorrhage; Bronchospasm; Cough; Dyspnea; Hypoxia; Pleural effusion; Pneumonitis; Pneumothorax; 
Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (oropharyngeal pain) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Nail loss; Pruritus; Rash 
acneiform; Skin and subcutaneous tissue disorders - Other (skin fissures); Skin hyperpigmentation 
VASCULAR DISORDERS - Hypertension; Hypotension; Thromboembolic event 
 
 
Note: ARQ 197 (tivantinib) 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 list(s) for commercial agent (Cetuximab)  
 
 
Please also refer to the package insert form the comprehensive list of adverse events. 
 
  Common, very likely (> 10 %) 
 
Acneform rash, asthenia/malaise, fever, nausea, constipation, diarrhea. 
 
 Less likely (2 to 10 %) 
 
Infusion reaction, kidney failure, sepsis, dehydration.  
 
 
 Rare (1% or less) 
 
Dermatology toxicity, interstitial lung disease, pulmonary embolus  
 
 
7.3 
Adverse Event Characteristics  
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0.  A copy of the 


40 
 
 
CTCAE version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 above) 
for expedited reporting purposes only.  ‘Expected’ AEs (the ASAEL) are bold 
and italicized in the CAEPR (Section 7.1.1). 
 
 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
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. 
 
7.4  
Expedited Adverse Event Reporting 
For protocols with CAEPRs not including a “SPEER” category, protocol-specific 
exceptions to the CTEP-AERS reporting table can be found in the CAEPR’s 
“ASAEL” category instead.  This protocol-specific exception is limited to Grade 1 
and Grade 2 ASAEL events, i.e. Grade 3 through Grade 5 ASAEL-listed events are 
NOT exceptions to CTEP-AERS reporting. 
 
 
7.4.1 Expedited AE reporting for this study must use CTEP-AERS (Adverse Event 
Expedited 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 tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour 
notification is to be made to CTEP by telephone at 301-897-7497.  Once 
Internet connectivity is restored, the 24-hour notification phoned in must be 
entered electronically into CTEP-AERS by the original submitter at the site. 
 
7.4.2 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.  
 
7.4.3 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 


41 
 
 
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 “Neoplasms 
benign, malignant and unspecified (incl. cysts and polyps) - Other 
(Progressive Disease)” under the system organ class (SOC) of the same name.  
Evidence that the death was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or progression: clinical 
deterioration associated with a disease process) should be submitted.  
 
 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 


42 
 
 
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 
 
 
 
 
7.5 
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. 
 
7.6 
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.  
 
7.7 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy).  Second malignancies require ONLY 
routine reporting via CDUS unless otherwise specified.  
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents 


43 
 
 
administered in this study can be found in Section 7.1. 
 
 
 
8.1  
CTEP IND Agent 
 
8.1.1 ARQ 197 (tivantinib) (NSC 750832) 
 
Chemical Name:  
(-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-
yl)pyrrolidine-2,5-dione 
 
Other Names:  DS-5178, Tivantinib 
 
Classification:  c-Met inhibitor 
 
CAS Registry Number:  905854-02-06 
 
Molecular Formula:  C23H19N3O2 
 
 
M.W.: 369.43 
 
Mode of Action:  c-Met inhibitor ARQ 197 (tivantinib) binds to the c-Met protein 
and disrupts c-Met signal transduction pathways, which may induce apoptosis in 
tumor cells overexpressing c-Met protein or expressing constitutively activated c-
Met protein. 
 
Description:  White/off-white to yellow microcrystalline powder. 
 
How Supplied:  Daiichi Sankyo supplies and CTEP’s Pharmaceutical Management 
Branch distributes ARQ 197 in 120 mg tablets in 50 mL high-density polyethylene 
bottles with polypropylene caps. ARQ 197 tablets are red orange film coated and 
round with a diameter of 9.2 mm. Inert ingredients include lactose monohydrate, 
croscarmellose sodium, hydroxypropyl cellulose, purified water, and magnesium 
stearate.  The film coating contains purified water, hypromellose, titanium dioxide, 
talc and ferric oxide.   Each bottle contains 100 tablets. 
 
 
Storage:  Store at controlled room temperature (20-25oC) with excursions allowable 
to 15-30oC). 
 
Stability:  Shelf-life surveillance of the intact bottles is ongoing. 
 
Route(s) of Administration:  Oral.  Administer ARQ 197 (tivantinib) tablets with 
food, and advise patients to take tablets with water and swallow them by mouth. It is 
acceptable per the manufacturer (Daiichi Sankyo) to crush the tablet as long as it is 
taken orally. The tablets are to be crushed and mixed with water immediately prior 
to taking the dose.  
Information about administration via G-tube may become available, but at the time 
of this protocol version has not been approved by the manufacturer (Daiichi 


44 
 
 
Sankyo). A note will be sent out should administration per G-tube or other changes 
to the administration become available, and no protocol amendment will be made.    
 
Method of Administration:  tablet  
 
Potential Drug Interactions:  ARQ 197 (tivantinib) is metabolized via a drug 
metabolizing enzyme system associated with cytochrome P450 (CYP2C19 and 
CYP3A4). Interactions with drugs metabolized via the same enzyme system are 
possible. Drugs which inhibit CYP2C19 may markedly increase the plasma 
concentration of ARQ 197 (tivantinib) .  Drugs and substances which inhibit 
CYP3A4 may increase the plasma concentrations of ARQ 197 (tivantinib). (Refer 
to:  
http://medicine.iupui.edu/flockhart/table.htm) 
 
Availability 
 
ARQ 197 (tivantinib) is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
ARQ 197 (tivantinib) is provided to the NCI under a Collaborative Agreement 
between the Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
 
8.1.2 
ARQ 197 (tivantinib) Ordering and Agent Accountability 
 
8.1.2.1 
NCI-supplied agents may be requested by the Principal Investigator (or 
their authorized designee) at each participating institution.  Pharmaceutical 
Management Branch (PMB) policy requires that agent be shipped directly 
to the institution where the patient is to be treated.  PMB does not permit 
the transfer of agents between institutions (unless prior approval from 
PMB is obtained).  The CTEP-assigned protocol number must be used 
for ordering all CTEP-supplied investigational agents.  The responsible 
investigator at each participating institution must be registered with 
CTEP, DCTD through an annual submission of FDA form 1572 
(Statement 
of 
Investigator), 
Curriculum 
Vitae, 
Supplemental 
Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If 
there are several participating investigators at one institution, CTEP-
supplied investigational agents for the study should be ordered under the 
name of one lead investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated 
shipping designees and ordering designees can submit agent requests 
through the PMB Online Agent Order Processing (OAOP) application 
(https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to 
OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and 
the maintenance of an “active” account status and a “current” password..  


45 
 
 
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. 
 
8.1.2.2 Agent Inventory Records – The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of the 
inventory and disposition of all agents received from DCTD using the NCI 
Drug Accountability Record Form (DARF).  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.) 
 
8.2 Cetuximab (commercial) 
 
Other names: Erbitux, C225 
Mode of action: inhibitor of EGFR tyrosine kinase. 
 
Cetuximab is an FDA approved commercially available drug for head and neck 
cancer. Cetuximab is an anti-EGFR human-to-murine chimeric antibody. Cetuximab 
is expressed in SP2/0 myeloma cell line, grown in large scale cell culture bioreactors 
and purified to a high level purity using several purification steps including protein A 
chromatography, ion exchange chromatography, low pH treatment and nanofiltration. 
Cetuximab is not known to be a vesicant. 
 
Supplier/How Supplied 
The product is a sterile, clear, colorless liquid of pH 7.0 to 7.4, which may contain a 
small amount of easily visible, white, amorphous cetuximab particulates. Each single-
use 50-mL vial contains 100 mg of cetuximab at a concentration of 2 mg/mL and is 
formulated in a preservative-free solution containing 8.48 mg/mL sodium chloride, 
1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.42mg/mL sodium phosphate 
monobasic monohydrate, and Water for injection, USP. 
 
Cetuximab will be obtained commercially and supplied via the respective 
pharmacy/established channel for each participating center. 
 
Packaging and Labeling 
Cetuximab for injection will be obtained commercially in single-use, ready-to-use 50-
mL vials containing 2 mg/mL of product. 
 
Handling and Dispensing of Cetuximab 
Cetuximab must be dispensed by authorized personnel according to local regulations. 
Cetuximab should be stored in a secure area according to local regulations. 
 
Storage Requirement/Stability 
Store vials under refrigeration at 2° C to 8° C (36° F to 46° F). DO NOT FREEZE. 
Increased particulate formation may occur at temperatures at or below 0°C. This 
product contains no preservatives. Preparations of cetuximab in infusion containers 
are chemically and physically stable for up to 12 hours at 2° C to 8° C (36° F to 46° 
F) or up to 8 hours at controlled room temperature (20° C to 25° C; 68° F to 77° F). 


46 
 
 
Discard any remaining solution in the infusion container after 8 hours at controlled 
room temperature or after 12 hours at 2° to 8° C. Discard any unused portion of the 
vial. 
 
Preparation and Administration 
Cetuximab must not be administered as an IV push or bolus. Cetuximab must be 
administered with the use of a low protein binding 0.22- micrometer in-line filter. 
Cetuximab is supplied as a 50-mL, single-use vial containing 100 mg of cetuximab at 
a concentration of 2 mg/mL in phosphate buffered saline. The solution should be 
clear and colorless and may contain a small amount of easily visible white amorphous 
cetuximab particulates. DO NOT SHAKE OR DILUTE. Cetuximab can be 
administered via infusion pump or syringe pump. 
 
Infusion Pump: 
• Draw up the volume of a vial using a sterile syringe attached to an appropriate 
needle (a vented spike or other appropriate transfer device may be used). 
•Fill cetuximab into a sterile evacuated container or bag such as glass containers, 
polyolefin bags (eg, Baxter Intravia), ethylene vinyl acetate bags (eg, Baxter Clintec), 
DEHP plasticized PVC bags (eg, Abbott Lifecare), or PVC bags. 
•Repeat procedure until the calculated volume has been put in to the container. Use a 
new needle for each vial. 
•Administer through a low protein binding 0.22-micrometer in-line filter (placed as 
proximal to the patient as practical). 
•Affix the infusion line and prime it with cetuximab before starting the infusion. 
• •Use 0.9% saline solution to flush line at the end of infusion. 
 
Syringe Pump: 
•Draw up the volume of a vial using a sterile syringe attached to an appropriate 
needle (a vented spike may be used). 
•Place the syringe into the syringe driver of a syringe pump and set the rate. 
•Administer through a low protein binding 0.22-micrometer in-line filter rated for 
syringe pump use (placed as proximal to the patient as practical). 
•Connect up the infusion line and start the infusion after priming the line with 
cetuximab. 
•Repeat procedure until the calculated volume has been infused.  
•Use a new needle and filter for each vial.  
•  
•Use 0.9% saline solution to flush line at the end of infusion. 
 
Cetuximab should be piggybacked to the patient’s infusion line. Following the 
cetuximab infusion, a 1-hour observation period is recommended. 
 
Safety Precautions 
Appropriate mask, protective clothing, eye protection, gloves, and Class II vertical- 
laminar-airflow safety cabinets are recommended during preparation and handling. 
Opened vials must be disposed of at the investigational center as chemotherapy or 
biohazardous waste provided documented procedures for destruction are in place. 


47 
 
 
Otherwise, opened vials must be returned to BMS for disposal. For questions 
regarding cetuximab destruction please contact BMS at 866 339-4267 or 203 677- 
7017. 
Cetuximab therapy should be used with caution in patients with known 
hypersensitivity to cetuximab, murine proteins, or any component of this product. It is 
recommended that patients wear sunscreen and hats and limit sun exposure while 
receiving cetuximab as sunlight can exacerbate any skin reactions that may occur. 
 
 For additional information please refer to the FDA approved package 
labeling for cetuximab. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 Biomarker Studies: c-MET copy number / c-MET expression (IHC) 
 
1. Prior experience with c-MET related biomarkers 
The phase II randomized study of ARQ 197 (tivantinib) in NSCLC identified c-MET 
copy number as a strong biomarker of ARQ 197 (tivantinib)  benefit (Sequist, Schiller 
et al, ESMO, 2010). 
The phase II randomized study of MetMab (antibody fragment against the c-MET 
receptor) demonstrated that benefit of MetMab was limited to tumors with c-MET 
expression using a standardized and centralized IHC methodology (Spigel et al, 
ESMO, 2010). 
 
2. Hypothesis 
Targeted agents typically only show activity/benefit in a subgroup of patients. 
Identification of a predictive biomarker greatly improves the effect size for a 
subsequent trial and increasingly is consider a requirement for drug approval.  
 
c-MET genetic changes correlate with responsiveness in preclinical models (namely 
amplification, Smolen et al, PNAS 2006)). 
 
Furthermore protein expression (IHC) may be a valid marker and was shown in a 
clinical trial in lung cancer to correlate with benefit (Spigel et al, ESMO 2010). High 
expression levels are hypothesized to indicate a dependence of the tumor on the 
respective receptor. 
 
 
3. Intended use within the proposed study 
We intended to retrospectively validate the biomarkers outlined below including 
those suggested in the above two NSCLC studies in our patient population of HNC 
patients. 
1. c-MET immunohistochemistry 
2. c-MET copy number 
3. evaluation for c-MET SNPs/mutations * 
4. evaluation of copy number or mutations in c-MET related molecules 
including those hypothesized to cause resistance to c-MET inhibition* 


48 
 
 
5. evaluation of signatures of c-MET sensitivity/resistance using DNA and 
or RNA and or protein* 
6. Blood will be used to extract DNA (from white cells). This DNA will be 
used to compare identified mutations/copy number changes 
 
*Items 3.-5. are optional - pending additional funding from a pending 
grant submission 
 
 
4. Assay method’s validity and appropriateness for the study 
 
Candidate Biomarker 1: c-MET IHC 
Immunohistochemistry has been shown to have predictive potential in a study of 
MetMab in NSCLC patients (Spigel et al. ESMO 2009). We have extensive 
experience with c-MET IHC methodology and implement the test using identical 
methodology (antibody and conditions) to allow comparable results. Briefly we will 
employ the Ventana CONFIRM c-MET antibody (Catalog Number: 790-4430) using 
conditions as described in (Tretiakova et al, J Environ Pathol Toxicol Oncol 2011) 
 
Candidate Biomarker 2: c-MET copy number 
For copy number assessment we will extract tumor DNA from areas of tumor with 
≥60% tumor content and evaluate MET copy number by quantitative PCR. We may 
consider c-MET FISH as an alternative and have experience with both 
methodologies, which in our experience provide comparable results for higher copy 
number changes (Seiwert et al, Cancer Research 2009). 
 
Hypothesis forming additional biomarker analyses: 
In addition we will analyze in an exploratory fashion focusing on treatment 
responders 
c-MET 
sequence 
variations 
(mutations/SNPs) 
in 
the 
kinase/semaphorin/juxtamembrane domain of the c-MET gene, sequence or copy 
number variations in c-MET related genes/proteins, expression profiles or signatures 
e.g. expression of the sole ligand of c-MET (hepatocyte growth factor/HGF), and 
erbB family members (e.g. amphiregulin, heregulin) (Seiwert et al, Cancer Research 
2009).. These analyses will be descriptive in nature and hypothesis forming. Normal 
DNA will be obtained from blood in order to assess somatic versus germline changes. 
Appropriate controls from non-responders may be selected. Analyses of these 
additional biomarkers as well as the parts of the specific methodologies are depending 
on additional funding from a pending grant application. 
 
 
 
 
9.2 
Laboratory Correlative Studies 
 
9.1.1 Tissue and Blood collection 
9.1.1.1 Collection of Specimen 
Previously obtained cancer tissue from biopsies or resections will be used or 
alternatively a new biopsy of the tumor may be performed if clinically justified. 


49 
 
 
Tissue will be used for c-MET IHC staining. A minimum of 10 slides is required per 
patient (14 recommended).  
Each participating site is to ascertain availability of 17-20 five to ten micrometer 
thickness unstained slides that can be used for immunohistochemistry. Availability of 
tumor containing slides is required for participation in the trial. If fewer than 10 slides 
are available an exception can be considered per the the PI (T.Seiwert); please contact 
him for approval (tseiwert@medicine.bsd.uchicago.edu).  
 
9.1.1.2 Handling of Specimens(s) 
- 10-14 slides 5 m thick, cut with a clean blade (use new blade if possible or clean 
vigorously to avoid RNA/DNA, RNase contamination) 
Slides should be usable for immunohisto-chemistry and/or DNA/RNA extraction. 
Review for presence of tumor is required prior to shipment at the local center. 
 
9.1.1.3  Blood: 
9.1.1.3.1 DNA Samples: 
DNA Samples (pharmacogenomic sample) need to be drawn in plastic purple top 
vacutainers and will be used for isolation of normal DNA for validation and 
comparison of tumor related findings. 
-> Two 7-10cc EDTA purple top tubes (plastic), BD#366643 (K2) (use of 
comparable tubes from the local institution is acceptable) 
 
9.1.1.3.2 Serum Samples (pharmacogenomic sample) need to be drawn in plastic 
purple top vacutainers and blood for isolation of normal DNA in SST gold tops using 
the order numbers listed below. Use of other types of tubes needs to be confirmed 
with the PI/Mary Jo Fekete (see contact info below)  
- Two 10cc EDTA purple top tubes (plastic), BD#366643 (K2) (serum) 
- One 7.5cc SST gold top (BD#367987) tube (blood). 
 
 
1. The SST tube(s) must remain at room temperature for 30-60 minutes to clot, 
please invert tube 5x during this time 
2. Spin tube at 1300g for 10 minutes at Room Temperature 
3. Aliquot the serum evenly into cryovials (~0.5ml each) 
4. Samples should be labeled with institution, protocol number (NCI 9165), 
patient initials, patient study ID number, and date of draw 
5. Store Cryovials at -80C until shipping on dry ice at a later date 
 
 
Use of other types of vacutainers needs to be confirmed with the PI/ Mary Jo Fekete 
(see contact info below). Use of red top vacutainers is acceptable in place of gold top 
vacutainers. 
 
Blood samples can be collected in batches, stored frozen at -80C, and subsequently 
shipped in batches. 
 
9.1.1.4 Shipping of Specimen(s) 
Slides: 


50 
 
 
Slides are to be packaged in a slide box with appropriate padding and are to be 
shipped out per courier service (FedEx, UPS, or comparable) to the shipping address 
below: 
 
Bood (Blood): 
DNA Samples (pharmacogenomic sample) need to be drawn in SST/gold top 
vacutainers / serum sample need to be drawn in purple top vacutainer. Both sample 
types need to be shipped on dry ice (EDTA/SST tops will not be supplied by 
University of Chicago and the following order numbers should be used: BD # 366643 
EDTA (K2) purple top (serum samples), BD # 367987 SST 7.5 mL). The samples 
may be batched at institution and shipped to the address below. These samples should 
be shipped on Monday, Tuesday, or Wednesday and cannot be shipped on Friday. 
The shipping address is: 
 
 
University of Chicago 
HTRC, Room P-616 
5835 S. Cottage Grove 
Chicago, IL 60637 
Phone: 773-834-8391 
E-mail: tissuebank@bsd.uchicago.edu 
 
Cost of packaging and shipment cost, as well as procurement of shipping materials 
and courier service shipping supplies are the responsibility of each center and 
appropriate internal budgeting is mandatory for participation in this trial. A reference 
sheet outlining summarizing appropriate shipping procedures will be provided to each 
center. 
 
 
A sample collection form is provided in Appendix C. 
 
On arrival, each sample will be assigned a Study Number. All subsequent handling 
of the tissue samples will be blinded to the investigators performing various tests, 
except for the clinical pathologists. Only biopsy samples determined by the 
pathologist to contain tumour will be subjected to immunohistochemical analysis. For 
all immunohistochemical studies, samples will only be marked with an assigned study 
number. Patient name, diagnosis and other information will be unknown to the 
laboratory/clinical investigators involved and will be revealed only after studies are 
completed for further data analysis and statistics. 
 
 
9.1.1.5 Site(s) Performing Correlative Study: The University of Chicago 
 
10. 
STUDY CALENDAR 
 
Schedules shown in the Study Calendar below are provided as an example and should be 
modified as appropriate. 
 


51 
 
 
Baseline evaluations are to be conducted within   16 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 48 hours 
prior to initiation of the next cycle of therapy. 
 
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 and 
every 2 
weeks 
thereafter 
W
k 
1
2 
Off Studyc 
ARQ 197 (tivantinib) 
 
A-----------------------------(given twice daily) ------------------------------------------A 
 
Cetuximab 
 
B 
 
B 
 
B 
 
B 
 
B 
 
B 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------X 
 
Physical exam 
X 
X 
 
X 
 
X 
 
 
 
X 
 
every 4 
wks 
 
X 
Vital signs 
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 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reseach Blood draw 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistrya 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EKG (at baseline then as 
indicated) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X---------------------------------------------------------------------------------------------X 
X 
Tumor measurements 
X 
Tumor measurements are repeated every 8 weeks.  Documentation (radiologic) 
must be provided for patients removed from study for progressive disease. 
X 
Radiologic evaluation 
X 
Radiologic measurements should be performed every 8 weeks. 
X 
B-HCG 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unstained slides of tumor 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
A: 
ARQ 197 (tivantinib):  Dose as assigned; po twice daily 
B: 
Cetuximab:  Dose as assigned; every two weeks 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium, magnesium 
b: 
Serum pregnancy test (women of childbearing potential). 
c: 
Off-study evaluation. 
Starting week 5 – MD visits are only required every 4 weeks, unless more frequent visits are medically indicated.   
 
11. 
MEASUREMENT OF EFFECT 
 
 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be reevaluated for response every 8   
weeks.  In addition to a baseline scan, confirmatory scans should also be obtained 4-6   


52 
 
 
weeks following initial documentation of objective response. In the case of SD, 
follow-up measurements must have met the SD criteria at least once after study entry 
at a minimum interval of 12 weeks 
 
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) (Eisenhauer EA et al, Eur J Ca, 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. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment with ARQ 197 (tivantinib)/ cetuximab. 
 
Evaluable for objective response.  Only those patients who have measurable 
disease present at baseline, and have received any study drug, 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 (see 
13.5.2).  (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 any study drug, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on 
the presence, absence, or unequivocal progression of the lesions.  
 
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as 
>20 mm by chest x-ray, as >10 mm with CT scan, or >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. If such lesions show evidence of tumor 
progression / have known disease they should be included and measurement 
attempted. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and 
measurable, a lymph node must be >15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed. 


53 
 
 
 
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.  
 
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 4 weeks before the beginning of 
the treatment. 
 
The same method of assessment and the same technique should be used to 


54 
 
 
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 
if it is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not 


55 
 
 
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. 
 
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 
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 


56 
 
 
to represent fibrosis or scarring.  The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and 
supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false 
positive 
CR 
due 
to 
limitations 
of 
FDG-PET 
and 
biopsy 
resolution/sensitivity. 
  
 Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation 
corrected image. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or 
non-target) must have reduction in short axis 
to <10 mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as 
reference the baseline sum diameters. 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as 
reference the smallest sum on study (this 
includes the baseline sum if that is the 
smallest on study).  In addition to the 
relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 
5 mm.  (Note:  the appearance of one or 
more new lesions is also considered 
progressions). 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for 
PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum 
diameters while on study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All 
lymph nodes must be non-pathological in 
size (<10 mm short axis). 
 


57 
 
 
Note:  If tumor markers are initially above 
the upper normal limit, they must normalize 
for a patient to be considered in complete 
clinical response. 
 
 
Non-CR/Non-PD:  
Persistence of one or more non-target 
lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): 
Appearance of one or more new lesions 
and/or unequivocal progression of existing 
non-target 
lesions. 
 
Unequivocal 
progression should not normally trump 
target 
lesion 
status. 
 
It 
must 
be 
representative of overall disease status 
change, not a single lesion increase.     
Although a clear progression of “non-target” lesions only is exceptional, 
the opinion of the treating physician should prevail in such circumstances, 
and the progression status should be confirmed at a later time by the 
review panel (or Principal Investigator). 
 
 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the 
treatment started).  The patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 
    
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-
Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. 
Confirmation** 
CR 
Non-
CR/Non-
PD 
No 
PR 
>4 wks. 
Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
No 
PR 


58 
 
 
CR/Non-
PD/not 
evaluated 
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. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is not 
advised 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 


59 
 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started, including the baseline 
measurements.  
 
11.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of 
progression or death of any cause. 
 
 
 
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 CDUS data will be submitted quarterly to CTEP by electronic 
means.  Reports are due January 31, April 30, July 31, and October 31.  Instructions 
for submitting data using the CDUS can be found on the CTEP web site 
(http://ctep.cancer.gov).  Note:  All adverse events that have occurred on the study, 
including those reported through CTEP-AERS, must 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. 
 
The Coordinating Center is responsible for compiling and submitting CDUS data 
to CTEP for all participants and for providing the data to the Principal 
Investigator for review.   


60 
 
 
 
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-
Party Data”): 
 
a.  NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 


61 
 
 
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 
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: 


62 
 
 
 
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 
 
We are targeting two patient populations based on distinct clinical needs: 
 
This trial will enroll patients who are cetuximab naïve (palliative setting). Typically 
patients will have been treated with cytotoxic chemotherapy in the first line setting 
and would be considered for cetuximab single agent therapy. Such patients will be 
randomized between cetuximab and the combination of ARQ 197 (tivantinib) 
/cetuximab. This patient population would be analogous to the patient population that 
was used in the two c-MET inhibitor NSCLC studies that met their primary endpoints 
(ARQ 197 (tivantinib)  (Sequist et al)/ MetMab (Spigel et al). 
 
Patients who have failed treatment with cetuximab as part of the control arm have the 
option to receive tivantinib as a single agent. This patient population generally has a 
very poor prognosis and effective therapies are lacking. Patients who have failed 
EGFR based therapy (in the recurrent / metastatic setting) typically have a 
progression-free survival of only 1.8 months (based on data from a historical phase II 
network study cohort – DeSouza et al, Clinical Cancer Research, 2012). Such patients 
have either primary or secondary (acquired) EGFR resistance. We hypothesize based 
on pre-clinical evidence that c-MET signaling (analogous to data for NSCLC) serves 
as an “exit” pathway and is a key component in mediating EGFR resistance. 
 
Primary Endpoint: Response Rate  
We will compare in the cetuximab/ ARQ 197 (tivantinib)  combination with single 
agent activity of cetuximab..  
Secondary Endpoints/Analyses: 
a) Continuous tumor shrinkage 
b) PFS  
c) OS 
d) Endpoints a), b), and c) above, as well as response rates, will be assessed and 
compared between treatment arms in the subgroup of patients with high c-MET 
expression (anticipated to be ~84% of patients (Seiwert et al, Cancer Research, 


63 
 
 
2009), and/or high c-MET copy number (anticipated >10% and largely overlapping 
with MET IHC (Seiwert et al, Cancer Research, 2009)). 
e) Single agent activity of ARQ 197 (tivantinib) after failure of cetuximab 
(descriptive) 
 
 
13.2  Sample Size/Accrual Rate 
 
We expect to jointly enroll 3-6 patients per month for a total of 76 response evaluable 
patients (38 patients in each arm) over a period of 18-24 months. Patients will then be 
followed for at least 6 months.  
 
Comparison of combination arm with single agent cetuximab:  Response rates in the 
two arms will be compared using a continuity-corrected chisquare test.  A sample size 
of n=38 patients per arm will provide 80% power to detect a difference of 12% vs. 
35% between the cetuximab and combination treatment arms, using a one-sided test 
at the alpha=0.10 significance level. 
 
Effect Size: We are assuming a comparably large effect size based on the following 
rationale:  
 
Preclinical data suggests high expression levels of MET and EGFR (higher than 
e.g. for NSCLC) as well as strong synergy for combined inhibition (see above). 
 
The relatively poor response rate for cetuximab alone (10-13%) masks that many 
more patients (40%) experience SD and oftentimes experience minor tumor 
shrinkage.  By improving inhibition of an EGFR parallel pathway and achieving 
synergistic tumor inhibition we expect a substantial proportion of SD assessments 
to convert to responses.  
 
The response rates for cytotoxic chemotherapies are generally in this range and it 
is appropriate that an effective targeted therapy (with most head and neck SCCs 
expressing both relevant targets) would be similarly effective.  
 
As a secondary outcome measure we will evaluate continuous tumor shrinkage, 
which will increase power and allow us to detect a smaller difference. 
 
Furthermore as a secondary outcome we will evaluate PFS. We are not adequately 
powered to use PFS as a primary outcome given the sample size limitation. 
Nevertheless a PFS trend/signal comparable to NSCLC data would provide 
support to consider further evaluation in a follow-up study and the design would 
be straightforward given the data from this study to pick the optimal treatment 
and clinical setting. 
Early evaluation for toxicity: For safety evaluation we have scheduled an interim 
safety evaluation after treatment of 3 and 6 patients with the combination of ARQ 197 
(tivantinib) /cetuximab.    If less than 2 of 6 patients experience severe toxicities / 
“DLTs”, the trial will continue, although we will continue to monitor adverse events 
per standard AE evaluation and reporting guidelines. 


64 
 
 
 
Early evaluation for futility: 
An interim look for futility will be performed at the time when half of the patients (14 
per arm) have been randomized and evaluated for response.  If the observed response 
rate in the combination arm is no higher than in the single agent group, early 
termination will be considered.  This will result in a small power loss of < 2% 
(Weiand and Therneau, Cont Clin Trials, 1987). 
 
 
13.3 
Stratification Factors 
 
Patients will be stratified based on HPV status. Any commonly used HPV test is 
acceptable (e.g. p16 IHC, HPV ISH, etc). If HPV status is not available, slides can be 
sent to the University of Chicago and HPV testing will be performed. No interim 
monitoring or efficacy analysis will be done based on this stratification. The goal is 
primarily to ascertain comparability between the two treatment arms. Please note that 
p16 IHC is generally only considered accurate if performed in oropharyngeal tumors 
and retesting in other anatomic sites may be necessary. 
 
13.4 
Analysis of Secondary Endpoints 
 
Secondary endpoints will include change in tumor burden (sum of longest diameters 
of target lesions) from baseline to 8 weeks, PFS, and OS.  Early change in tumor 
burden will be compared between groups using two-sample t-tests.  Waterfall plots 
will be constructed for graphical comparison.  In the event that early deaths within 8 
weeks or dropouts occur, nonparametric Wilcoxon rank-sum tests will be performed 
in place of t-tests, with such patients assigned the worst ranking (Karrison et al, 
JNCI, 2007).   Kaplan-Meier curves will be generated for PFS and OS and the 
treatment arms compared via logrank tests.  We will also fit logistic and Cox (JRSS, 
1972) proportional hazards regression models to examine the effects of laboratory 
correlates on response, PFS, and OS.   
Finally, each of the primary and secondary endpoints will be compared between 
treatment arms among the subgroup of patients with high c-MET expression and/or 
high c-MET copy number in an exploratory fashion.   
 
 
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 ARQ 197 (tivantinib)/ Cetuximab. (also see 
11.1.1). 
 
 
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 unless they are not evaluable as defined under 11.1.1.  


65 
 
 
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).  [Note:  
By arbitrary convention, category 9 usually designates the “unknown” status of 
any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of 
those who received no study medication (see 11.1.1)) should 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.  Precise definitions for categories 4-9 will be 
protocol specific.  
 
All conclusions should be based on all eligible, response evaluable patients (see 
11.1.1)..  Subanalyses may then be performed on the basis of a subset of 
patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of 
treatment, major protocol violations, etc.).  However, these subanalyses may not 
serve as the basis for drawing conclusions concerning treatment efficacy, and 
the reasons for excluding patients from the analysis should be clearly reported.  
The 95% confidence intervals should also be provided.  
 
13.6 
Randomization 
 
Patients will be randomized after eligibility and stratification status are known 
between the two treatment arms (TC and C arms). Randomization is not blinded. 
Randomization will use the method of permuted blocks, stratified by HPV status. 
Randomization will be done at the University of Chicago and investigators are to 
contact 773-834-3095 or e-mail jzavala@medicine.bsd.uchicago.edu 
 to find out treatment arm assignment. The trial will randomize sufficient patients in order to 
obtain 76 evaluable patients. 
 
REFERENCES 
 
Birchmeier, C., W. Birchmeier, E. Gherardi, and G.F. Vande Woude.  (2003).  Met, metastasis, 
motility and more.  Nat Rev Mol Cell Biol.  4:915-925. 
 
Christensen, J.G., et al.  (2003).  A selective small molecule inhibitor of c-Met kinase inhibits c-
Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo.  Cancer 
Res.  63:7345-7355. 
 
DeSouza J. et al (2012). A Phase II study of Lapatinib in Recurrent/Metastatic Squamous Cell 
Carcinoma of the Head and Neck. Clinical Cancer Research (in press) 
 
Eisenhauer E.A. et al. (2009) New response evaluation criteria in solid tumorus: Revised REIST 


66 
 
 
guideline (version 1.1)  Eur J Ca 45:228-247, 2009 
 
Furge, K.A., Y.W. Zhang, and G.F. Vande Woude.  (2000).  Met receptor tyrosine kinase: 
enhanced signaling through adapter proteins.  Oncogene.  19:5582-5589. 
 
Investigator’s Brochure.  (2010)  Investigator’s Brochure: ARQ 197 (Version 5.0, October 6, 
2010).  Daiichi Sankyo Pharma Development, Edison, NJ.  
 
Jiang, W.G., S.E. Hiscox, C. Parr, et al.  (1999).  Antagonistic effect of NK4, a novel hepatocyte 
growth factor variant, on in vitro angiogenesis of human vascular endothelial cells.  Clin Cancer 
Res.  5:3695-3703. 
 
Karrison T. et al. (2007). Design of phase II cancer trials using a continuous endpoint of change 
in tumor size: application to a study of sorafenib and erlotinib in non small-cell lung cancer. J 
Natl Cancer Institute, 99 (19), 1455-61 
 
Knowles L.M. et al (2009). HGF and c-Met Participate in Paracrine Tumorigenic Pathways in 
Head and Neck Squamous Cell Cancer. Clinical Cancer Research 15(11), 3740-3750 
 
Levy C., M. Khaled, and D.E. Fisher.  (2006).  MITF: master regulator of melanocyte 
development and melanoma oncogene.  Trends Mol Med.  12:406-414. 
 
McGill, G.G., R. Haq, E.K. Nishimura, and D.E. Fisher.  (2006).  c-Met expression is regulated 
by Mitf in the melanocyte lineage.  J Biol Chem.  281:10365-10373. 
 
Michieli P, Di Nicolantonio F. (2013). Targeted therapies: Tivantinib—a cytotoxic drug in MET 
inhibitor’s clothes? Nat Rev Clin Oncol. 10:372-4. 
 
Seiwert T.Y. et al. (2009). The MET receptor tyrosine kinase is a potential novel therapeutic 
taget for head and neck squamous cell carcinoma. Cancer Research 69(7), 3021-31 
 
Smolen G.A. et al. (2006). Amplification of MET may identify a subset of cancers with extreme 
sensitivity to the selective tyrosine kinase inhibitor PHA-665752. PNAS 103(7), 2316-21 
 
Spigel D. et al. (2011). Final efficacy results from a randomized phase II study (OAM4558g) 
evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC. World Lung 
Cancer Conference O19.03 
 
Sequist L.V. et al. (2011). Randomized phase II study of erlotinib plus tivantinib versus erlotinib 
plus placebo in previously treated non small-cell lung cancer. Journal of Clinical Oncology 
29(24), 3307-15 
 
Tretiakova M. et al (2011). MET and phosphorylated MET as potential biomarkers in lung 
cancer. J Environ Pathol Toxicol Oncol. 30(4), 341-54 
 
Vemorken J.B. et al. (2008). Platinumb-Based Chemotherapy plus Cetuximab in Head and Neck 
Cancer. N Eng. J Med 359(11), 1116-27 


67 
 
 
 
Vermorken J.B. et al. (2007). Open-Label, Uncontrolled, Multicenter Phase II Study to Evaluate 
the Efficacy and Toxicity of Cetuximab As a Single Agent in Patient with recurrent and/or 
metastatic Squamous Cell Carcinoma of the Head and Neck who failed to respond to Platinum-
based therapy.  Journal of Clinical Oncology, 25(16), 2171-77 
 
Wieand S. and Therneau T., (1987). A two-stage design for randomized trials with binary 
outcomes. Cont Clin Trials 8(1), 20-28 
 
Weinstein, I.B.  (2002). Cancer. Addiction to oncogenes--the Achilles heal of cancer.  Science.  
297:63-6 
 
Xu H., et al. (2011). Dual blockade of EGFR and c-Met abrogates redundant signaling and 
proliferation in head and neck carcinoma cells. Clinical Cancer Research 17(13), 4425-38 


68 
 
 
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. 
  
 
 


69 
 
 
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. 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 


70 
 
 
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. 
 
 


71 
 
 
APPENDIX C 
Tissue Sample Collection Form 
NCI 9165: ARQ 197 (tivantinib)/Cetuximab -- HNC 
Clinician/Research Nurse: Please Fill Out 
Tissue Samples 
Patient Name: ___________________  
 MRN# (if applicable): _______________ 
Patient Protocol ID #: ______________  
Date Tissue Obtained: _________________ 
Institution: ______________________________         Attending Physician: __________________ 
Site of Biopsy: ___________________________ 
Site of Primary Tumor: _______________ 
 
Did Surgical Pathology review tissue for presence of tumor (please circle)?  Yes   No 
Number of unstained slides (10-14 slides (5 m thick),) 
 
Number of 5 m slides:_______________ 
 
 
Blood collection (please check):  
 
Two EDTA tubes (purple top, serum), 2x10ml: ___    One SST tube 7.5ml  (gold top):_________  
(e.g. BD#366643 EDTA (K2)) or similar                                    (e.g BD#: 367987 SST, 7.5ml) or similar_ 
                                                                                     (If volume is <7.5ml provide additional tube/s)__ 
 
Date of blood draw: ________________      Time of blood draw:_____________ 
 
Contact Person’s Phone Number and email Address at Affiliate: 
Shipment Address: 
University of Chicago 
HTRC, Room P-616 
5835 S. Cottage Grove 
Chicago, IL 60637 
Phone: 773-834-8391 
E-mail: tissuebank@bsd.uchicago.edu 
 
Please notify Mary Jo Fekete with the tracking number once the sample was shipped: 
Email: mfekete@bsd.uchicago.edu 
Tel: 773-834-4593 
 
 
Disclaimer: Cost of packaging and shipment cost, as well as procurement of shipping materials 
and courier service shipping supplies are the responsibility of each center and appropriate 
internal budgeting is mandatory for participation in this trial. A reference sheet outlining 
summarizing appropriate shipping procedures will be provided to each center. 
 


72 
 
 
APPENDIX D: 
 
INFORMATION ON POSSIBLE INTERACTIONS WITH OTHER AGENTS FOR 
PATIENTS AND THEIR CAREGIVERS AND NON-STUDY HEALTH CARE TEAM 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental agent ARQ 197 (also known as tivantinib).  This clinical trial is sponsored by the 
National Cancer Institute.  This form is addressed to the patient, but includes important 
information for others who care for this patient.  
 
ARQ 197 (tivantinib) interacts with many drugs that are processed by your liver.  Because of 
this, it is very important to tell your study doctors about all of your medicine before you start this 
study.  It is also very important to tell them if you stop taking any regular medicine, or if you 
start taking a new medicine while you take part in this study.  When you talk about your 
medicine with your study doctor, include medicine you buy without a prescription at the drug 
store (over-the-counter remedy), or herbal supplements such as St. John’s wort.  
 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These are 
the things that you and they need to know:  
 
ARQ 197 (tivantinib) interacts with (a) certain specific enzyme(s) in your liver.  
 The enzyme(s) in question is/are Cytocrhome P450 CYP 2C19 and to a lesser degree CYP 
3A4, and ARQ 197 (tivantinib)  is broken down by this enzyme in order to be cleared 
from your system.  
 ARQ 197 (tivantinib) must be used very carefully with other medicines that need these 
liver enzymes to be effective or to be cleared from your system.   
 Other medicines may also affect the activity of the enzyme.   
o Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of the drug, while substances that decrease the enzyme’s activity 
(“inhibitors”) could result in high levels of the active drug, increasing the chance 
of harmful side effects. 
 You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category.  
 Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered “strong inducers/inhibitors or substrates of 
Cytochrome P450, CYP 2C19 
 Your prescribers should look at this web site 
http://medicine.iupui.edu/clinpharm/ddis/table.asp or consult a medical reference to see if 
any medicine they want to prescribe is on a list of drugs to avoid.   
 Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye.  They also have a generic name—it’s usually small and 
located above or below the brand name, and printed in the ingredient list.  Find the 
generic name and determine, with the pharmacist’s help, whether there could be an 
adverse interaction.   
 


73 
 
 
 
Other medicines can be a problem with your study drugs.  
 
 You should check with your doctor or pharmacist whenever you need to 
use an over-the-counter medicine or herbal supplement.  
 
 Your regular prescriber should check a medical reference or call your 
study doctor before prescribing any new medicine for you.  Your study 
doctor’s name is  
 
 
_____________________________________  
 
and he or she can be contacted at  
 
 
_____________________________________.  
 
 


74 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent 
__________________.  This clinical trial is sponsored by the NCI.  
__________________ interacts with drugs that are processed by your 
liver.  Because of this, it is very important to: 
 Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
 Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
__________________ interacts with a specific liver enzyme called 
CYP______, and must be used very carefully with other medicines that 
interact with this enzyme.  
 Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered “strong 
inducers/inhibitors or substrates of CYP______.” 
 Before prescribing new medicines, your regular prescribers should go 
to http://medicine.iupui.edu/clinpharm/ddis/table.asp for a list of 
drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is ______________ and can be contacted at 
______________.  


75 
 
 
 
APPENDIX E 
 
Management of Cetuximab induced acneiform rash 
 
Patients developing dermatologic toxicities while receiving cetuximab should be monitored for 
the development of inflammatory or infectious complications. 
 
Treatment of acneiform rash should be initiated early starting with grade 2. Dose modifications 
of any future cetuximab infusions are listed in the protocol and should be considered for severe 
(grade 3/4) acneform rash.  
 
Rash can be managed by a variety of treatment options to relieve symptoms and improve rash. 
The recommendations for management are as follows: 
Grade 1 rash: Mild, Grade 1 rash may not need treatment, but close monitoring is to be 
initiated to .  
Grade ≥2 rash: May be treated with any of the following: 
 
-  
Minocycline/doxycycline  
 
-  
Diphenhydramine  
 
- 
topical retinoid  
 
- 
topical clindamycin 
 
- 
topical silver sulfadiazine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


76 
 
 
 
 
 
 
 
APPENDIX F 
PATIENT’S MEDICATION DIARY 
Agent: ARQ 197 (Tivantinib) 
Today’s date _________________________  
          
 
 
 
  
 Patient Name_________________________ (initials acceptable)  
                Patient Study ID_____________ 
_____________________________________ 
1. Complete one form for each cycle of treatment. 
2. ARQ 197 (Tivantinib) should be stored at room temperature. 
3. ARQ 197 (Tivantinib) tablets should be administered orally with meals. A missed or vomited dose should not be replaced, thus 
should take the next scheduled dose at the regularly scheduled time. 
4. Record the date, the time, and the number of ARQ 197 (Tivantinib) capsules taken per day (2 administrations/day). 
5. If you have any comments or notice any side effects, please record them in the Comments column.   
6. Please bring this form and your bottles of ARQ 197 (Tivantinib) when you return for each appointment.   
 
Day 
 
Date 
Time of 
First 
Dose 
Dose taken 
Time of 
Second 
 Dose 
Dose taken 
Comments 
# of capsule taken 
 
# of capsule taken 
 
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 
 
 
 
 
 
 
 
 
Patient’s Signature:__________________________________  
Cycle:__________________ 
Date:__________________   
 
 
CTEP-assigned Protocol #___________ 
 
Local Protocol # ___________________ 


77 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physician’s Office will complete this section: 
1. Date patient started protocol treatment_________________________________________________________________________ 
2. Date patient was removed from study__________________________________________________________________________ 
3. Patient’s planned total daily dose______________________________________________________________________________ 
4. Total number of capsules taken this Month ______________________________________________________________________ 
5. Cycle Number_____________________________________________________________________________________________ 
6. Physician/Nurse/Data Manager’s Signature ______________________________________________________________________