Conditions: Recurrent Renal Cell Carcinoma Stage III Renal Cell Cancer Stage IV Renal Cell Cancer Type 1 Papillary Renal Cell Carcinoma Type 2 Papillary Renal Cell Carcinoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 55
Healthy volunteers: no

Brief summary:
This randomized phase II trial studies how well tivantinib with or without erlotinib hydrochloride works in treating patients with metastatic or locally advanced kidney cancer that cannot be removed by surgery. Tivantinib and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the response rate (confirmed complete and partial response) of patients with locally advanced or metastatic papillary renal cell carcinoma treated with either ARQ 197 (tivantinib) or ARQ 197 combined with erlotinib (erlotinib hydrochloride).

SECONDARY OBJECTIVES:

I. To assess the progression free survival (PFS) of patients with locally advanced or metastatic papillary renal cell carcinoma treated with either ARQ 197 or ARQ 197 combined with erlotinib.

II. To assess the safety and tolerability of ARQ 197 therapy and ARQ 197 combined with erlotinib.

III. To descriptively assess the role of prior treatment on outcome.

TERTIARY OBJECTIVES:

I. To bank tissue specimens for future use and once funding is obtained to evaluate the expression of tissue correlative biomarkers such as hepatocyte growth factor receptor (c-MET) and epidermal growth factor receptor (EGFR), and to perform exploratory correlation with clinical outcomes.

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

ARM I: Patients receive tivantinib orally (PO) twice daily (BID) on days 1-28.

ARM II: Patients receive tivantinib PO BID and erlotinib hydrochloride PO once daily (QD) on days 1-28.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for up to 2 years.

Arms:
arm 1: Patients receive tivantinib PO BID on days 1-28. arm 2: Patients receive tivantinib PO BID and erlotinib hydrochloride PO QD on days 1-28.

Interventions: intervention 1: Erlotinib Hydrochloride intervention 2: Laboratory Biomarker Analysis intervention 3: Tivantinib
Intervention descriptions: intervention 1: 150 mg (1 tablet) by mouth on days 1-28, once daily, until disease progression intervention 2: Correlative studies intervention 3: 360 mg (3 tablets) by mouth, Twice daily (720 mg total daily dose) on days 1-28, until disease progression

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
Distribution Date:   
TBD 
CTEP Submission Date:   
May 10, 2016 
 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
FROM: 
William Nava, Protocol Coordinator (E-mail:  wnava@swog.org) 
 
RE: 
S1107, "Parallel (Randomized) Phase II Evaluation of ARQ 197 and 
ARQ 197 in Combination with Erlotinib in Papillary Renal Cell 
Carcinoma.” Study Chairs: Drs. P.W. Twardowski and P.N. Lara, Jr. 
 
REVISION #4 
 
Study Chair:  Przemyslaw W. Twardowski, M.D. 
Phone number:  626/256-4673 ext. 68218 
E-mail:  ptwardowski@coh.org 
 
IRB Review Requirements 
(   ) 
Full board review required    
( √ ) Expedited review allowed 
(   ) 
No review required  
 
Status Change 
 
(   )  IRB Review only 
 
(   )  Activation 
(   )  Closure  
(   )  Reactivation 
  
Protocol changes 
(   )  Eligibility changes  
(   )  Treatment / Dose Modification / Study Calendar changes  
( √ )  Informed Consent changes 
( √ )  Patient notification not required 
(   ) 
Patient notification required  
(   )  Scientific / Statistical Consideration changes 
(   )  Specimen Submission changes 
(   )  Data Submission / Forms changes  
(   )  Editorial / Administrative changes 
(   )  Other: 
 
 
 
REVISION #4 
 
The revision has been prepared in response to the Request for Rapid Amendments 
(RRA) for ARQ 197 (tivantinib) received on April 11, 2016 from Dr. John Wright 
(wright@ctep.nci.nhi.gov), Dr. James Zwiebel (zwiebelj@ctep.nci.nih.gov), and Dr. 
Meg Mooney (mooneym@ctep.nci.nhi.gov).  
 
 
 
 


 
 
 
Revision #2 (contd.) 
 
Page 2 
 
 
The above-referenced study has been updated as follows: 
 
1. 
The Version Date of the protocol has been updated. 
 
2. 
Page 10-11, Section 3.1b:  The ARQ 197 adverse effects section has been replaced with a 
CTEP modified risk information Comprehensive Adverse Events and Potential Risks (CAEPR) 
Version 2.2, February 19, 2016.  This section has been updated as follows: 
 
• The SPEER grades have been updated. 
 
• Added New Risk: 
• Reported but With Insufficient Evidence for Attribution: Acute coronary syndrome; Allergic 
rhinitis; Atrial fibrillation; Conduction disorder; Fall; Hypomagnesemia; Hypophosphatemia; 
Hypoxia; Intracranial hemorrhage; Myocardial infarction; Paroxysmal atrial tachycardia; 
Pneumonitis; Pneumothorax; Portal vein thrombosis 
 
• Increase in Risk Attribution: 
• Changed to Likely from Less Likely: Fatigue 
• Change to Less Likely from Reported but With Insufficient Evidence for Attribution: Alopecia 
 
The model consent form has been revised as follows: 
 
1. 
The Version Date has been updated. 
 
2. 
Page 6, Risk Section:   
 
• 
A new section for ‘Common, Some may be serious’ has been added to include Tiredness. 
• 
Hair loss has been added to the ‘Occasional, Some May Be Serious’ section. 
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
 
 
 


 
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PRIVILEGED COMMUNICATION 
Activated August 20, 2012 
FOR INVESTIGATIONAL USE ONLY 
 
 
 
SWOG 
 
PARALLEL (RANDOMIZED) PHASE II EVALUATION OF ARQ 197 AND ARQ 197 IN COMBINATION 
WITH ERLOTINIB IN PAPILLARY RENAL CELL CARCINOMA 
 
NCT #01688973 
 
 
STUDY CHAIRS: 
AGENTS: 
 
Przemyslaw W. Twardowski, M.D. (Medical Oncology) 
Supplied by CTEP: 
City of Hope National Medical Center 
 
Dept of Medical Oncology & Therapeutics Research 
ARQ 197 (Tivantinib) (NSC-750832) (IND-112603) 
1500 East Duarte Rd 
Erlotinib (OSI-774, Tarceva)  
Duarte, CA 91010 
 
(NSC-718781) (IND-63383) 
Phone:  626/256-4673 ext. 68218 
 
FAX:  626/301-8898 
 
E-mail: ptwardowski@coh.org 
BIOSTATISTICIANS: 
 
 
Primo N. Lara, Jr., M.D. (Medical Oncology) 
Cathy M. Tangen, Dr.P.H. (Biostatistics) 
UC Davis Cancer Center 
Hongli Li, M.S. 
4501 X Street 
SWOG Statistical Center 
Sacramento, CA  95817 
Fred Hutchinson Cancer Research Center 
Phone:  916/734-3771 
1100 Fairview Avenue North, M3-C102 
FAX:  916/734-7946 
P.O. Box 19024 
E-mail: primo.lara@ucdmc.ucdavis.edu  
Seattle, WA  98109-1024 
 
Phone:  206/667-4623 
ECOG-ACRIN STUDY CHAIR: 
FAX:  206/667-4408 
 
E-mail: ctangen@fhcrc.org 
Elizabeth R. Plimack, M.D. 
E-mail: hongli@fhcrc.org  
Fox Chase Cancer Center 
 
E-mail:  elizabeth.plimack@fccc.edu 
 
 
PARTICIPANTS 
 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
SWOG/SWOG 
 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
 
NCIC-CTG/NCIC Clinical Trials Group 
 
NRG/NRG Oncology 
 
 
 
 
 
 


 
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TABLE OF CONTENTS 
 
 
Page 
PARTICIPANTS ......................................................................................................................... 1 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ..... 4 
SCHEMA .................................................................................................................................... 5 
1.0 
OBJECTIVES................................................................................................................ 6 
1.1 
Primary Objective .......................................................................................................... 6 
1.2 
Secondary Objectives ................................................................................................... 6 
1.3 
Translational Medicine Objectives ................................................................................ 6 
2.0 
BACKGROUND ............................................................................................................ 6 
3.0 
DRUG INFORMATION ................................................................................................. 8 
3.1 
ARQ 197 (DS-5178) (NSC-750832) (IND-112603) ....................................................... 9 
3.2 
Erlotinib (NSC-718781; IND-63383) .............................................................................. 13 
4.0 
STAGING CRITERIA .................................................................................................... 19 
5.0 
ELIGIBILITY CRITERIA ............................................................................................... 20 
5.1 
Disease Related Criteria ............................................................................................... 20 
5.2 
Prior Therapy Criteria .................................................................................................... 20 
5.3 
Clinical/Laboratory Criteria ............................................................................................ 21 
5.4 
Specimen Submission Criteria ...................................................................................... 22 
5.5 
Regulatory Criteria ........................................................................................................ 22 
6.0 
STRATIFICATION FACTORS ...................................................................................... 23 
7.0 
TREATMENT PLAN ..................................................................................................... 23 
7.1 
Treatment Schedule ...................................................................................................... 23 
7.2 
Administration through G-tube ...................................................................................... 23 
7.3 
Concomitant Medications .............................................................................................. 24 
7.4 
Drug Compliance .......................................................................................................... 24 
7.5 
Reporting Cycle-Specific Toxicity and Dose Information .............................................. 24 
7.6 
Criteria for Removal from Protocol Treatment .............................................................. 24 
7.7 
Discontinuation of Treatment ........................................................................................ 24 
7.8 
Follow Up Period ........................................................................................................... 24 
8.0 
DOSAGE MODIFICATIONS ......................................................................................... 24 
8.1 
NCI Common Terminology Criteria for Adverse Events ............................................... 24 
8.2 
General Considerations................................................................................................. 24 
8.3 
Patient Evaluations ........................................................................................................ 25 
8.4 
Radiation Therapy for Palliation .................................................................................... 25 
8.5 
ARQ 197 Dose Modification .......................................................................................... 25 
8.6 
Erlotinib Dose Modificationa .......................................................................................... 27 
8.7 
Suggested management of toxicities ............................................................................ 28 
8.8 
Dose Modification Contacts .......................................................................................... 29 
8.9 
Adverse Event Reporting .............................................................................................. 29 
9.0 
STUDY CALENDAR ..................................................................................................... 30 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS ................................ 32 
10.1 
Measurability of lesions ................................................................................................. 32 
10.2 
Objective status at each disease evaluation ................................................................. 33 
10.3 
Best Response .............................................................................................................. 34 
10.4 
Performance Status ...................................................................................................... 35 
10.5 
Time to Death ................................................................................................................ 35 
10.6 
Progression-Free Survival ............................................................................................. 35 
11.0 
STATISTICAL CONSIDERATIONS ............................................................................. 36 
11.1 
Accrual Goal .................................................................................................................. 36 
11.2 
Analysis of Primary Endpoint ........................................................................................ 36 
11.3 
Analysis of Secondary Endpoints .................................................................................. 36 
11.4 
Analysis of Translational Medicine Endpoints ............................................................... 37 
11.5 
Data and Safety Monitoring Committee Oversight ........................................................ 37 


 
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12.0 
DISCIPLINE REVIEW ................................................................................................... 37 
13.0 
REGISTRATION GUIDELINES .................................................................................... 37 
13.1 
Registration Timing ....................................................................................................... 37 
13.2 
Investigator/Site Registration ........................................................................................ 37 
13.3 
OPEN Registration Requirements ................................................................................ 38 
13.4 
Registration procedures ................................................................................................ 39 
13.5 
Exceptions to SWOG registration policies will not be permitted. .................................. 40 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................ 40 
14.1 
Data Submission Requirement ..................................................................................... 40 
14.2 
Master Forms ................................................................................................................ 40 
14.3 
Data Submission Procedures ........................................................................................ 40 
14.4 
Data Submission Overview and Timepoints ................................................................. 41 
15.0 
SPECIAL INSTRUCTIONS ........................................................................................... 42 
15.1 
Specimen Banking ........................................................................................................ 42 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS .................................................. 42 
16.1 
Adverse Event Reporting Requirements ....................................................................... 44 
17.0 
BIBLIOGRAPHY ........................................................................................................... 49 
18.0 
APPENDIX .................................................................................................................... 50 
18.1 
Determination of Expedited Adverse Event Reporting Requirements .......................... 51 
18.2 
S1107 Intake Calendar.................................................................................................. 53 
 


 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
 
To submit site registration 
documents: 
For patient 
enrollments: 
Submit study data 
directly to the Lead 
Cooperative Group 
unless otherwise 
specified in the protocol: 
 
CTSU Regulatory Office 
1818 Market Street, 
Suite 1100 
Philadelphia, PA19103 
 
Fax: 215-569-0206 
 
Email:  
 
CTSURegulatory@ctsu.coccg.org 
 
For more information, call the 
CTSU Help Desk at 888-823-
5923 or the Regulatory Help Desk 
at 866-651-CTSU. 
 
 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which 
can be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
 
 
 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave.  Please 
see the data submission 
section of the protocol for 
further instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password.  
For patient eligibility questions contact the SWOG Data Operations Center by phone or email: 
 
Phone:  206/652-2267 
E-mail:  guquestion@crab.org 
 
For treatment or toxicity related questions contact the Study PI of the Coordinating Group (Dr. 
Przemyslaw W. Twardowski at 626/256-4673 ext. 68213).   
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help 
Desk by phone or e-mail: 
 
CTSU General Information Line:  888-823-5923 
E-mail:  ctsucontact@westat.com 
 
All calls and correspondence will be triaged to the appropriate CTSU representative. 
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website: 
 
https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU Regulatory 
and Monitoring Policy 
The CTSU website is located at https://www.ctsu.org 
 
 


 
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SCHEMA 
 
 
 
Locally Advanced Or Metastatic 
Papillary Renal Cell Carcinoma 
(One Prior Therapy For Advanced Disease Allowed) 
 
 
 
 
 
 
 
 
RANDOMIZATION 
 
 
 
 
 
 
 
 
 
 
Arm 1 
Arm 2 
 
ARQ 197                                          
ARQ 197 
                                                                                                               
and Erlotinib 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Progression 
 
 
 
 
 
 
 
Follow Up 
3 Years 


 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
The primary objective of this study is to assess the response rate (confirmed complete 
and partial response) of patients with locally advanced or metastatic papillary renal cell 
carcinoma treated with either ARQ 197 or ARQ 197 combined with erlotinib. 
 
1.2 
Secondary Objectives 
 
a. 
To assess the progression free survival (PFS) of patients with locally advanced or 
metastatic papillary renal cell carcinoma treated with either ARQ 197 or ARQ 197 
combined with erlotinib. 
 
b. 
To assess the safety and tolerability of ARQ 197 therapy and ARQ 197 combined 
with erlotinib. 
 
c. 
To descriptively assess the role of prior treatment on outcome. 
 
1.3 
Translational Medicine Objectives 
 
To bank tissue specimens for future use and once funding is obtained to evaluate the 
expression of tissue correlative biomarkers such as c-MET and EGFR, and to perform 
exploratory correlation with clinical outcomes. 
 
 
2.0 
BACKGROUND 
 
Clinical trials for advanced kidney cancer have focused primarily on the most common histologic 
type - clear cell carcinoma (cRCC) which on the molecular level is characterized by derangements 
of VHL-HIF-VEGF pathway.  Papillary carcinoma (pRCC) is the second most common histologic 
subset of kidney cancer and accounts for 15% of cases.  Among non-clear cell histology pRCC 
constitutes about 50% of cases.  pRCC is associated with different molecular characteristics than 
cRCC. C-Met proto-oncogene mutations have been identified in patients with familial and sporadic 
cases of pRCC and implicated in its pathophysiology. (1, 2) In preclinical models c-Met inhibitors 
showed activity against several hereditary papillary renal cell carcinoma-related mutations and 
tumor xenografts.  (3)  While the treatment of advanced cRCC has undergone dramatic changes 
with the introduction of receptor tyrosine kinase (rTKI) and m-TOR inhibitors, management of 
pRCC and other non-clear cell histologies remains undefined.  There have been no published 
clinical trials specifically evaluating the effects of these new compounds in pRCC, but the analysis 
of clinical trials that allowed treatment of various RCC histologies provides some insight into their 
efficacy in pRCC. In an expanded access trial of sunitinib in RCC, 276 patients (11.8% of total) 
with non-clear cell histologies were identified.  A majority of them had prior cytokine therapy. 
Unfortunately this trial did not differentiate between the different non-clear cell subtypes, but 
based on prevalence it is likely that pRCC constituted a significant fraction of these patients.  A 
response rate of 5.4% and median PFS of 6.7 months were noted.  (4)  A small Phase II trial of 
sunitinib in patients with non-clear cell RCC enrolled 26 patients (including 13 patients with 
pRCC).  There were no objective responses and median PFS was 48 days. (5)  Choueiri reported 
on the efficacy of sunitinib and sorafenib in metastatic non-clear cell RCC.  (6)  This retrospective 
analysis identified 53 patients who had been treated with either sunitinib or sorafenib at five 
different cancer centers in the USA and France.  The number of patients with pRCC was 41, of 
which 23 had received prior systemic therapy (non-VEGF targeted).  Of the 41 patients with 
pRCC, 13 were treated with sunitinib.  Response rate was 15% and median PFS was 7.6 months.  
In a subset analysis patients with pRCC treated with sunitinib had the longest median PFS of 11.9 
months (compared to 5.1 months if treated with sorafenib p<0.001). The m-TOR inhibitor 
temsirolimus was evaluated in previously untreated patients with metastatic RCC who had  


 
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unfavorable clinical characteristics. (7) This study included a significant number of patients with 
non-clear cell histology. In a subset analysis that included 55 patients withpRCC, median PFS was 
7 months.  These outcomes in patients with non-clear RCC compare with the RR of 39% and 
median PFS of 11 months reported in a pivotal Phase III trial of patients with cRCC treated with 
sunitinib.  (8)  Dual c-MET/VEGFR-2 inhibitor foretinib demonstrated 13.5% response rate and 
median PFS of 9.3 months.  Responses were significantly more common in patients with germline 
mutations. (9) Overall the analysis of available data suggests that clinical benefit of targeted 
agents, although present in pRCC, is inferior to the one observed in clear cell histology. 
 
Preclinical data indicates that absence of VHL mutations (VHL mutations are typically not seen in 
pRCC) is associated with greater activity of epidermal growth factor receptor (EGFR) inhibitors in 
RCC.  (10)  Based on that observation, the oral EGFR inhibitor erlotinib has been evaluated in a 
Phase II trial of patients with metastatic pRCC in SWOG.  (11)  Patients with histologically 
confirmed advanced or metastatic pRCC received erlotinib at 150 mg po q day until disease 
progression.  Thirty nine patients were evaluable for response.  With a median follow-up of 12.8 
months; four patients had confirmed PR for RR of 10%.  Median overall survival was 26.9 months.   
Probability of freedom from treatment failure at 6 months was 29%.  There was one Grade 5 
adverse event (AE) of pneumonitis and one Grade 4 thrombotic event. As expected only two 
patients (2/35) demonstrated mutations in vHL gene confirming that pRCC is typically associated 
with wild-type vHL.  All but one specimen stained positive for EGFR (17/18) but no association 
was observed between EGFR score or staining intensity with clinical outcome. This suggests that 
mutational status, receptor amplification or differential intracellular signaling mechanisms may 
play a more significant role in predicting clinical benefit from EGFR-directed therapies. These 
findings were consistent with those of EGFR therapy in other diseases.  Overall results of this 
study demonstrated activity of erlotinib in patients with pRCC and in the absence of an obvious 
superior alternative support further evaluation of erlotinib either alone or in combination with 
therapies targeting other relevant pathways in patients with pRCC.   
 
ARQ 197 is a selective inhibitor of the c-Met receptor tyrosine kinase.  ARQ 197 has been 
evaluated in a Phase I study in patients with advanced solid tumors who failed standard therapy.  
(12)  Thirty eight patients were enrolled.  The most frequent treatment-related side effects were 
fatigue (24%), diarrhea (21%) and constipation (21%).  Grade 3 or greater events possibly or 
probably related to ARQ 197 included elevations of ALP (3%), ALT (3%), AST (3%).  No DLT was 
observed.  Two patients achieved partial response and 19 had stable disease.  Recent evidence 
suggests that c-Met signaling promotes resistance to EGFR inhibition by stimulating ERBB3 
(HER3)-dependent PI3K activation and dual EGFR and c-Met inhibition has been proposed as a 
strategy to overcome resistance to EGFR-inhibition.   A Phase I dose escalation trial of ARQ 197 
and erlotinib in patients with advanced solid tumors has been conducted.  Erlotinib was given at 
150 mg daily and ARQ 197 was escalated from 120 mg BID to 360 mg BID.  Twenty-five patients 
were treated and minor tumor regressions were seen in four out of ten evaluable patients.  
Pharmacokinetic data revealed no evidence of drug-drug interaction.  Two patients experienced 
serious adverse events including neutropenia and sinus bradycardia but no DLTs were reported.  
Continuous therapy with erlotinib and ARQ 197 appeared to be well tolerated and a Phase II 
combination dose (RP2D) of ARQ 197 of 360 mg BID and erlotinib of 150 mg daily was 
recommended. (13) 
 
The combination of two tyrosine kinase inhibitors (TKIs), erlotinib and ARQ-197, which respectively 
target EGFR and MET was tested in the ACHN renal papillary cancer cell line. This cell line 
harbors a base substitution in the MET gene at T1010I, which appears to confer a growth 
advantage compared to wild-type expression.  Dose response curves were conducted to 
determine the activity of each agent.  The ACHN cell line expresses high protein levels of both 
EGFR and MET, which are both active under normal culturing conditions.  ACHN cells were 
responsive to either agent individually, particularly to ARQ-197 with a 50% inhibitory concentration 
(IC50) of ~0.8uM.  Median Effect analysis was conducted to determine the interaction of the 
agents.  At all dose levels tested, the combined treatment outperformed either individual agent, 
and was additive to synergistic at the effective doses tested.  Erlotinib treatment  


 
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of ACHN cells at a 2uM dose (24h) resulted in reduced phosphorylation of EGFR, concomitant 
with increase a small in MET activity.  At this dose, erlotinib had negligible impact on 
phosphorylation of downstream signal transduction factors AKT and ERK.  ARQ-197 resulted in 
diminished activity and protein levels of MET accompanied by reduction of both AKT and ERK 
phosphorylation.  Additionally, ARQ-197 ablated p-EGFR, although not to the extent observed by 
erlotinib.  The combination of the two agents further reduced both pAKT and pERK compared to 
ARQ-197 alone, and synergized with erlotinib to inhibit EGFR phosphorylation. (Personal Written 
Communication, January 201, PC Mack, Ph.D., PN Lara, Jr., M.D., UC Davis Cancer Center) 
 
Based on erlotinib activity data in pRCC and preclinical studies indicating activity of c-Met 
inhibitors in pRCC and important interplay between EGFR and c-Met pathways we propose to 
conduct a randomized Phase II trial of ARQ 197 alone and in combination with erlotinib.  (3, 14)  
Specifically, ARQ 197 represents a new compound that warrants testing in pRCC.  If promising, 
this compound would have enhanced activity when combined with other active and theoretically 
synergistic compounds such as erlotinib, and if ARQ 197 proves inactive as a single agent, it 
could help potentiate erlotinib.  As the combination study would be of interest regardless of the 
outcome of the single agent ARQ 197 study, these studies will be run in parallel.  This has the 
effect of accelerating our understanding of the role of ARQ 197 in pRCC.  The hypothesis is that 
both ARQ 197 and the combination of ARQ 197 and erlotinib will demonstrate promising activity 
against pRCC with an acceptable toxicity profile. 
 
Inclusion of Minorities: 
 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  The anticipated accrual in the ethnicity/race and sex 
categories is shown in the table below. 
 
 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
3 
6 
9 
Not Hispanic or Latino 
24 
45 
69 
Total Ethnic 
27 
51 
78 
Racial Category 
American Indian or Alaskan Native 
0 
1 
1 
Asian 
1 
1 
2 
Black or African American 
4 
7 
11 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
22 
42 
64 
Racial Category: Total of all Subjects* 
27 
51 
78 
 
 
3.0 
DRUG INFORMATION 
 
Investigator's Brochures:   
 
For information regarding Investigator's Brochures, please refer to SWOG Policy #15. 
 
For this study, ARQ 197 and erlotinib are being provided under an IND held by the National 
Cancer Institute.  The Investigator's Brochures may be obtained by contacting the NCI's 
Pharmaceutical Management Branch (PMB) at 240/276-6575. 
 


 
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3.1 
ARQ 197 (DS-5178) (NSC-750832) (IND-112603) 
 
a. 
DESCRIPTION 
 
Chemical Name or Amino Acid Sequence:  (3R,4R)-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 
 
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 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. 
 
b. 
TOXICOLOGY 
 
Comprehensive Adverse Events and Potential Risks list (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/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 579 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. 
 


 
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Version 2.2, February 19, 20161 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 This 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. 
2 Infection 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 
 
 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 
  
 
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) 


 
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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 
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. 
 
Potential Drug Interactions:  ARQ 197 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 and CYP3A4 may markedly increase the plasma 
concentration of ARQ 197.   
 


 
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c. 
PHARMACOLOGY 
 
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 and Stability:  Refer to the label for specific storage conditions.  Shelf-life 
surveillance of the intact bottles is on-going. 
 
Administration:  Oral.  Administer ARQ 197 tablets with food, and advise patients to 
take tablets with water and swallow them whole.   
 
d. 
SUPPLIER 
 
ARQ 197 is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI.  ARQ 197 is provided to the NCI 
under a Collaborative Agreement between ArQule, Inc., Daiichi Sankyo, Inc. and 
the DCTD, NCI. 
 
Drug Ordering:  NCI supplied agents may be requested by the Principal 
Investigator (or their authorized designee) at each participating institution. 
Pharmaceutical Management Branch (PMB) policy requires that agent be shipped 
directly to the institution where the patient is to be treated.  PMB does not permit 
the transfer of agents between institutions (unless prior approval from PMB is 
obtained).  The CTEP assigned protocol number must be used for ordering all 
CTEP supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form 
(FDF). If there are several participating investigators at one institution, CTEP 
supplied investigational agents for the study should be ordered under the name of 
one lead investigator at that institution.   
 
Drug may be requested by submitting agent requests through the PMB Online 
Agent Ordering 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. 
 
Drug Returns:  All unused drug supplies should be returned to the PMB.  When it 
is necessary to return study drug (e.g. sealed vials remaining when expired vials 
are recalled by the PMB), investigators should return the study drug to the PMB 
using the NCI Return Agent Form available on the NCI home page 
(http://ctep.cancer.gov).  
 
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition and return 
of all drugs received from the PMB using the Drug Accountability Record Form 
available on the NCI home page (http://ctep.cancer.gov). 
 


 
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Questions about drug orders, transfers, returns or accountability should be 
addressed to the PMB by calling 240/276-6575 Monday through Friday between 
8:30 a.m. and 4:30 p.m. Eastern time by emailing PMBAfterHours@mail.nih.gov 
anytime.  
 
3.2 
Erlotinib (NSC-718781; IND-63383) 
 
a. 
DESCRIPTION 
 
Chemical Name: 
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-
quinazolinamine, monohydrochloride 
 
Other Names: 
Erlotinib hydrochloride, Tarceva™, OSI-774 
 
Classification: 
Tyrosine kinase Inhibitor (EGFR) 
 
Molecular Formula: 
C22H23N3O4 
M.W.: 393.4 (free base) 
 
 
429.9 (hydrochloride salt) 
 
Mode of Action: 
Direct inhibition of EGFR tyrosine kinase 
 
b. 
TOXICOLOGY 
 
Reported Adverse Events and Potential Risks: 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for OSI-
774 (erlotinib, NSC 718781) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited, 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI via CTEP-AERS (except as 
noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification.  Frequency is provided based on 3,622 patients.  Below is 
the CAEPR for OSI-774 (erlotinib). 
 
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. 
 


 
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Version 2.4, July 24, 20131 
 
Adverse Events with Possible  
Relationship to OSI-774 (erlotinib) 
 (CTCAE 4.0 Term) 
[n= 3622] 
 
 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
 
(formerly known as 
ASAEL) 
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
 
EYE DISORDERS 
  
 
Conjunctivitis 
 
 Conjunctivitis (Gr 2) 
 
Dry eye 
 
 Dry eye (Gr 2) 
 
Eye disorders - Other 
(eyelash in-growth 
and/or thickening) 
 
  
 
 
Eye disorders - 
Other (corneal 
perforation) 
  
 
 
Keratitis 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Gastrointestinal 
hemorrhage2 
 
  
 
 
Gastrointestinal 
perforation3 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
 
Nausea 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INFECTIONS AND INFESTATIONS 
  
 
Skin infection4 
 
 Skin infection4 (Gr 2) 
INVESTIGATIONS 
  
 
Alanine 
aminotransferase 
increased 
 
 Alanine 
aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase 
increased 
 
  
 
Aspartate 
aminotransferase 
increased 
 
 Aspartate 
aminotransferase 
increased (Gr 3) 
 
Blood bilirubin 
increased 
 
 Blood bilirubin 
increased (Gr 3) 


 
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Adverse Events with Possible  
Relationship to OSI-774 (erlotinib) 
 (CTCAE 4.0 Term) 
[n= 3622] 
 
 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
 
(formerly known as 
ASAEL) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
 
 
Intracranial 
hemorrhage 
  
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Epistaxis 
 
  
 
Pneumonitis 
 
 Pneumonitis (Gr 3) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
 
Erythema 
multiforme 
  
 
Nail loss 
 
 Nail loss (Gr 2) 
 
 
Palmar-plantar 
erythrodysesthesia 
syndrome 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash acneiform 
 
 Rash acneiform (Gr 2) 
Rash maculo-
papular 
 
 
 Rash maculo-papular 
(Gr 3) 
1 This 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. 
2 Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, 
Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, 
Esophageal 
varices 
hemorrhage, 
Gastric 
hemorrhage, 
Hemorrhoidal 
hemorrhage, 
Ileal 
hemorrhage, 
Intra-abdominal 
hemorrhage, 
Jejunal 
hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic 
hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper 
gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS 
SOC. 
3 Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, 
Esophageal 
perforation, 
Gastric 
perforation, 
Ileal 
perforation, 
Jejunal 
perforation, Rectal perforation, and Small intestinal perforation under the 
GASTROINTESTINAL DISORDERS SOC. 
4 Includes infection of the skin (folliculitis or cellulitis) as complications of rash. 


 
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Also reported on OSI-774 (erlotinib) trials but with the relationship to OSI-
774 (erlotinib) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated intravascular 
coagulation 
EYE DISORDERS - Blurred vision; Eye disorders - Other (orbital cellulitis); 
Uveitis; Watering eyes 
GASTROINTESTINAL DISORDERS - Colitis; Constipation; Duodenal ulcer; 
Dysphagia; Esophagitis; Gastric ulcer; Gastritis; Gastrointestinal disorders - Other 
(pneumatosis intestinalis); Pancreatitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema 
limbs 
HEPATOBILIARY DISORDERS - Cholecystitis 
INVESTIGATIONS - Creatinine increased; INR increased (in patients taking 
Coumadin); Lymphocyte count decreased; Platelet count decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; 
Hypocalcemia; 
Hypokalemia; 
Hypomagnesemia; 
Hyponatremia; 
Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized 
muscle weakness 
NERVOUS SYSTEM DISORDERS - Dizziness; Ischemia cerebrovascular; 
Peripheral sensory neuropathy 
PSYCHIATRIC DISORDERS - Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult 
respiratory distress syndrome; Pharyngolaryngeal pain 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Urticaria 
VASCULAR DISORDERS - Thromboembolic event 
 
Note: OSI-774 (erlotinib) 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. 
 
Note:  OSI-774 (erlotinib)-induced diarrhea and/or vomiting has been associated 
with dehydration, hyperkalemia; hypocalcemia; hypokalemia; hypomagnesemia; 
hyponatremia; hypophosphatemia, increased creatinine, and renal failure. 
 
Note:  Cases of hepatic failure and hepatorenal syndrome (including fatalities) 
have been reported during use of OSI-774 (erlotinib) in patients with baseline 
hepatic impairment.   
 
Warning:  Treatment with erlotinib should be used with extra caution in 
patients with total bilirubin > 3 x ULN.  Patients with hepatic impairment 
(total bilirubin > ULN or Child-Pugh A, B and C) should be closely 
monitored during therapy with erlotinib.  Erlotinib dosing should be 
interrupted or discontinued if changes in liver function are severe such as 
doubling of total bilirubin and/or tripling of transaminases in the setting of 
pretreatment values outside normal range. 
 
Warning:  Cases of hepatic failure and hepatorenal syndrome (including 
fatalities) have been reported during use of erlotinib, particularly in patients 
with baseline hepatic impairment.  Therefore, periodic liver function testing 
(transaminases, bilirubin, and alkaline phosphatase) is recommended.  In 
the setting of worsening liver function tests, dose interruption and/or dose  


 
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reduction with frequent liver function test monitoring should be 
considered.  Erlotinib dosing should be interrupted or discontinued if total 
bilirubin is > 3 x ULN and/or transaminases are > 5 x ULN in the setting of 
normal pretreatment values.  
 
Warning:  Cases of hepatorenal syndrome, acute renal failure (including 
fatalities), and renal insufficiency have been reported.  Some were 
secondary to baseline hepatic impairment while others were associated 
with severe dehydration due to diarrhea, vomiting, and/or anorexia or 
concurrent chemotherapy use.  In the event of dehydration, particularly in 
patients with contributing risk factors for renal failure (e.g., pre-existing 
renal disease, medical conditions or medications that may lead to renal 
disease, or other predisposing conditions including advanced age), 
erlotinib therapy should be interrupted and appropriate measures should 
be taken to intensively rehydrate the patient.  Periodic monitoring of renal 
function and serum electrolytes is recommended in patients at risk of 
dehydration. 
 
Gastrointestinal Perforation: Patients receiving erlotinib are at increased risk of 
developing gastrointestinal perforation, which was observed uncommonly. Some 
cases had a fatal outcome.  Patients receiving concomitant anti-angiogenic 
agents, corticosteroids, NSAIDs, and/or taxane based chemotherapy, or who 
have prior history of peptic ulceration or diverticular disease, are at increased risk. 
Erlotinib should be permanently discontinued in patients who develop 
gastrointestinal perforation. 
 
Bullous and Exfoliative Skin Disorders: Bullous, blistering and exfoliative skin 
conditions have been reported, including very rare cases suggestive of Stevens-
Johnson syndrome/Toxic epidermal necrolysis, which in some cases were fatal. 
Erlotinib treatment should be interrupted or discontinued if the patient develops 
severe bullous, blistering, or exfoliating conditions. 
 
Ocular Disorders: Very rare cases of corneal perforation or ulceration have been 
reported during use of erlotinib. Other ocular disorders including abnormal 
eyelash growth, keratoconjunctivitis sicca or keratitis have been observed with 
erlotinib treatment and are known risk factors for corneal perforation/ulceration. 
Erlotinib therapy should be interrupted or discontinued if patients present with 
acute/worsening ocular disorders such as eye pain. 
 
Potential Drug Interactions:  Erlotinib is both protein bound (92% to 95%) and 
metabolized by CYP3A4.  Therefore, a potential for drug-drug interactions exists 
when erlotinib is co-administered with drugs that are highly protein-bound or 
CYP3A4 inhibitors or inducers.  
 
There is a potential interaction between erlotinib and warfarin. Patients have 
experienced elevated INRs and bleeding with this combination of drugs. Patients 
on warfarin and erlotinib should have more frequent INR/PT determinations (e.g., 
weekly for the first month and weekly for a minimum of 2 weeks following 
discontinuation erlotinib). 
 
Proton Pump Inhibitor:  Erlotinib's solubility decreases as the pH increases. Co-
administration of omeprazole with erlotinib will decrease the AUC and Cmax by 46% 
and 61%, respectively.  
 


 
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H2-antagonist: Avoid concomitant use of erlotinib with gastric acid reducing agents 
if possible.  When ranitidine 300 mg is given with erlotinib, erlotinib AUC and Cmax  
decrease by 33% and 54%, respectively.  Increasing the dose of erlotinib will not 
compensate the loss of exposure.  However, if an H2-antagonist receptor is 
needed, take erlotinib at least 2 hours before or 10 hours following the H2-
antagonist administration.  Dosing such, erlotinib loss of exposure is minimized to 
AUC of 15% and Cmax of 17%. 
 
Patient Care Implications:  If the patient vomits after taking the tablets, the dose is 
replaced only if the tablets can actually be seen and counted. 
 
Patients should wear sun screen protection, hat, and long sleeves to avoid sun as 
it can exacerbate skin rash. 
 
Patients should be advised to stop smoking while taking erlotinib.  Smoking 
induces CYP1A2 enzymes and alters erlotinib exposure by 64% 
 
Pregnancy and Lactation:  No information on pregnancy and lactation in humans 
is available yet. 
 
c. 
PHARMACOLOGY 
 
Total clearance of erlotinib is similar to hepatic blood flow in dogs and rats.  At 
intravenous doses > 1 mg/kg the clearance decreases and the plasma drug 
exposure increases supra-proportionately in rats and dogs.  In vitro, the agent is 
slowly oxidized by liver microsomes.  Erlotinib is extensively metabolized in rats 
and dogs with only a small amount excreted unchanged in urine, bile and feces.  
In a rat model designed to study pulmonary first pass extraction, erlotinib had a 
pulmonary extraction of approximately 48%.  In vitro studies have shown that the 
agent is metabolized by CYP1A1, which is expressed in lung tissue.  Several 
circulating metabolites have been identified in mouse, rat and dog and 
subsequently synthesized and demonstrated to be potent as EGFR inhibitors.  
Only one, OSI-420, a hydroxylated metabolite, was a major metabolite in 
systemic circulation with a metabolite: parent ratio of 1:4 in plasma from rats or 
dogs given oral doses.  This compound is as potent as erlotinib in the in vivo 
tumor xenograft model. 
 
The enzymes responsible for formation of the major metabolite in humans were 
identified as cytochromes P450 3A4 and 3A5 (expressed in liver) and 1A1 
(expressed in lung). Studies on the inhibition potential of erlotinib and its major 
metabolite, OSI-420, on the main human cytochrome P450 isoenzymes revealed 
a relatively strong inhibition of CYP 3A4 by erlotinib (Ki 8 µM) and a weak 
inhibition of CYPs 1A2 and 3A4 by OSI-420 (Ki 20 µM). Further studies to 
evaluate the mechanism of inhibition are ongoing. 
 
Oral bio-availability was found to be 77% in rats and 88% in dogs.  Plasma 
protein binding is 92 - 95% in humans, rats, monkeys and mice, and was 85% in 
dogs. 
 
How Supplied:  Erlotinib is supplied as 25 mg, 100 mg, and 150 mg white film-
coated tablets.  In addition to the active ingredient, erlotinib, the tablets contain 
lactose, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, 
and magnesium stearate.  Tablets are unmarked and unscored.  The 25 mg 
tablets [1/4 inch diameter, 3 mm deep (formerly non-film coated)], 100 mg tablets 
(11/32 inch diameter, 5 mm deep), and 150 mg tablets (13/32 inch diameter, 5.1 
mm deep) are supplied 30 tablets/bottle. 


 
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Storage and Stability:  Store in accordance with the package labeling.  Shelf life 
surveillance studies of the intact bottle are on-going.  Current data indicates 
erlotinib is stable for at least 3 years at room temperature. 
 
Administration:  Erlotinib is administered orally.  Tablets should be taken once 
daily preferably in the morning with up to 200 mL of water one hour before or two 
hours after food. 
 
d. 
SUPPLIER 
 
Erlotinib is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI.  Erlotinib is provided to the NCI 
under a Clinical Trails Agreement between OSI Pharmaceuticals and the NCI 
Division of Cancer Treatment and Diagnosis (DCTD).   
 
Drug Ordering:  NCI supplied agents may be requested by the Principal 
Investigator (or their authorized designee) at each participating institution. 
Pharmaceutical Management Branch (PMB) policy requires that agent be shipped 
directly to the institution where the patient is to be treated.  PMB does not permit 
the transfer of agents between institutions (unless prior approval from PMB is 
obtained).  The CTEP assigned protocol number must be used for ordering all 
CTEP supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form 
(FDF). If there are several participating investigators at one institution, CTEP 
supplied investigational agents for the study should be ordered under the name of 
one lead investigator at that institution.   
 
Drug may be requested by submitting agent requests through the PMB Online 
Agent Ordering 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. 
 
Drug Returns:  All unused drug supplies should be returned to the PMB.  When it 
is necessary to return study drug (e.g. sealed vials remaining when expired vials 
are recalled by the PMB), investigators should return the study drug to the PMB 
using the NCI Return Agent Form available on the NCI home page 
(http://ctep.cancer.gov).  
 
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition and return 
of all drugs received from the PMB using the Drug Accountability Record Form 
available on the NCI home page (http://ctep.cancer.gov). 
 
Questions about drug orders, transfers, returns or accountability should be 
addressed to the PMB by calling 240/276-6575 Monday through Friday between 
8:30 a.m. and 4:30 p.m. Eastern time by emailing PMBAfterHours@mail.nih.gov 
anytime.  
 
 
4.0 
STAGING CRITERIA 
 
This section is not applicable to this study.  


 
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5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered eligible for 
registration.  Use the spaces provided to confirm a patient's eligibility.  For each criterion requiring test 
results and dates, please record this information on the S1107 Prestudy Form and submit via MediData 
Rave® (see Section 14.0).  Any potential eligibility issues should be addressed to the Data Operations 
Center in Seattle at 206/652-2267 prior to registration. 
 
In calculating days of tests and measurements, the day a test or measurement is done is considered Day 
0.  Therefore, if a test is done on a Monday, the Monday 2 weeks later would be considered Day 14.  This 
allows for efficient patient scheduling without exceeding the guidelines.  If Day 14, 21, 28, 42 or 56 falls on 
a weekend or holiday, the limit may be extended to the next working day. 
 
SWOG Patient No.  
 
 
Patient’s Initial (L,F,M).  
 
 
5.1 
Disease Related Criteria 
 
a. 
Patients must have histologically or cytologically confirmed papillary histology 
renal cell carcinoma which is metastatic, or locally advanced and unresectable.  
Mixed histologies will be allowed provided that they contain ≥ 50% of the papillary 
component. 
 
b. 
Patients must have measurable disease, defined as at least one lesion that can 
be accurately measured in at least one dimension (see Section 10.0).  X-rays, 
scans or physical examinations used for tumor measurement must have been 
completed within 28 days prior to registration.  X-rays, scans or physical 
examinations for non-measurable disease must have been completed within 42 
days prior to registration.  All disease must be assessed and documented on the 
Baseline Tumor Assessment Form. 
 
c. 
Patients with metastatic disease who have a resectable primary tumor and are 
deemed a surgical candidate may have undergone resection.  At least 28 days 
must have elapsed since surgery and patient must have recovered from any 
adverse effects of surgery. 
 
d. 
Patients with a history of brain metastases who are asymptomatic and have not 
received steroid therapy in the 14 days prior to registration are eligible. Anti-
seizure medications are allowed provided they are non-enzyme inducing (e.g. 
topiramate, levatiracetam, gabapentin). 
 
5.2 
Prior Therapy Criteria 
 
a. 
Patients may have received up to one prior systemic therapy for advanced or 
metastatic renal cell carcinoma. Patients must not have received a MET inhibitor 
or erlotinib as prior therapy. At least 21 days must have elapsed since completion 
of prior systemic therapy, 42 days for nitrosoureas or mitomycin C.  Patients must 
have recovered from all associated toxicities at the time of registration. 
 
b. 
Patients may have received prior radiation therapy, but must have measurable 
disease outside the radiation port.  At least 21 days must have elapsed since 
completion of prior radiation therapy. Patients must have recovered from all 
associated toxicities at the time of registration. 
 
c. 
Patients must not be receiving or planning to receive any other investigational 
agents. 


 
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SWOG Patient No.  
 
 
Patient’s Initial (L,F,M).  
 
 
5.3 
Clinical/Laboratory Criteria 
 
a. 
Patients must have a complete physical examination and medical history within 
28 days prior to registration. 
 
b. 
Patients must have a Zubrod performance status of 0 - 2 (see Section 10.4). 
 
c. 
Patients must have adequate hematologic function as documented by a WBC ≥ 
2,000/mcL, an ANC ≥ 1,000/mcL, and a platelet count ≥ 75,000/mcL.  These 
tests must be obtained within 14 days prior to registration. 
 
d. 
Patients must have adequate hepatic function as evidenced by serum bilirubin ≤ 
1.5 x institutional upper limits of normal (ULN).  Serum transaminase (SGOT/AST 
and SGPT/ALT) must be ≤ 1.5 x the institutional ULN unless the liver is involved 
with the tumor, in which case serum transaminase (SGOT/SGPT) must be ≤ 5 x 
the institutional ULN.  These tests must be obtained within 14 days prior to 
registration. 
 
e. 
Serum creatinine must be ≤ 2 x the institutional ULN and obtained within 14 days 
prior to registration. 
 
f. 
Sodium, potassium and calcium must be obtained within 14 days prior to 
registration. 
 
g. 
Patients with a known history of the following corneal diseases are not eligible:  
dry eye syndrome, Sjogren's syndrome, keratoconjunctivitis sicca, exposure 
keratopathy, Fuch's dystrophy or other active disorders of cornea. 
 
h. 
Patients known to be HIV-positive and receiving combination anti-retroviral 
therapy are not eligible due to possible pharmacokinetic interactions with erlotinib 
and ARQ 197. 
 
i. 
Patients must be able to take oral medications.  Patients must not have 
gastrointestinal tract disease resulting in an inability to take oral medication or a 
requirement for IV alimentation, prior surgical procedures affecting absorption, or 
active peptic ulcer disease.  Patients with intractable nausea or vomiting are not 
eligible. 
 
j. 
Patients must not be pregnant or nursing because ARQ 197 and erlotinib have 
the potential for teratogenic or abortifacient effects. There is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the 
mother with ARQ 197 or erlotinib. Women/men of reproductive potential must 
have agreed to use an effective contraceptive method. A woman is considered to 
be of "reproductive potential" if she has had menses at any time in the preceding 
12 consecutive months.  In addition to routine contraceptive methods, "effective 
contraception" also includes heterosexual celibacy and surgery intended to 
prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a 
hysterectomy, bilateral oophorectomy or bilateral tubal ligation.  However, if at any 
point a previously celibate patient chooses to become heterosexually active 
during the time period for use of contraceptive measures outlined in the protocol, 
he/she is responsible for beginning contraceptive measures. 


 
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SWOG Patient No.  
 
 
Patient’s Initial (L,F,M).  
 
 
5.3 
Clinical/Laboratory Criteria (contd.) 
 
k. 
No other prior malignancy is allowed except for the following: adequately treated 
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately 
treated Stage I or II cancer from which the patient is currently in complete 
remission, or any other cancer from which the patient has been disease-free for 5 
years. 
 
5.4 
Specimen Submission Criteria 
 
a. 
Patients must be offered the opportunity to participate in specimen banking for 
future translational medicine studies (see Section 15.0). 
 
5.5 
Regulatory Criteria 
 
a. 
All patients must be informed of the investigational nature of this study and must 
sign and give written informed consent in accordance with institutional and federal 
guidelines. 
 
b. 
As a part of the OPEN registration process (see Section 13.4 for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that the 
current (within 365 days) date of institutional review board approval for this study 
has been entered in the system. 
 


 
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6.0 
STRATIFICATION FACTORS 
 
Patients will be randomized using a dynamic balancing algorithm (15) with stratification based on:  
 
Prior systemic therapy for advanced or metastatic disease (none vs 1). 
 
 
7.0 
TREATMENT PLAN 
 
For treatment or dose modification related questions, please contact Dr. Przemyslaw Twardowski 
at 626/256-4673 ext. 68218 or Dr. Primo N. Lara, Jr. at 916/734-3771.  For dosing principles or 
questions, please consult the SWOG Policy #38 "Dosing Principles for Patients on Clinical Trials" 
at http://swog.org (then click on "Policies and Manuals" under the "Visitors" menu and choose 
Policy #38)  
 
7.1 
Treatment Schedule 
 
Patients will be randomized to either Arm 1: ARQ 197 or Arm 2:  ARQ 197 and erlotinib. 
 
a. 
Treatment schedule for Arm 1: ARQ 197 
 
AGENT 
DOSE 
ROUTE 
DAYS 
INTERVAL 
DURATION 
 
ARQ 197* 
360 mg 
By mouth 
1-28     Twice daily   
Until disease 
 
(3 tablets) 
 
 
(about 12 hours 
progression 
 
720 mg total  
 
apart) 
 
 daily dose 
 
b. 
Treatment schedule for Arm 2: ARQ 197+ erlotinib 
 
 
AGENT 
DOSE 
ROUTE 
DAYS   INTERVAL 
DURATION 
 
ARQ 197*          360 mg        By mouth 
1-28        Twice daily 
Until disease 
 
(3 tablets) 
 
 
(about 12 hours 
progression 
 
720 mg total  
 
apart) 
 
daily dose 
 
Erlotinib**         150 mg        By mouth 
1-28        Daily 
Until disease 
 
(1 tablet) 
 
 
 
progression 
 
* ARQ-197 is supplied as tablets for oral administration.  Patients should take ARQ 197 
twice daily (about 12 hours apart), with food. 
** Erlotinib tablets should be taken in the morning with up to 200 mL of water on an 
empty stomach (one hour before or two hours after eating). 
 
NOTE:  A cycle of therapy is defined as twenty-eight days.  There will be no pause 
between cycles.  Patients will be evaluated for response/progression every two 
treatment cycles and will continue on therapy until progression or other reason for 
removal from treatment (see Section 7.6). 
 
7.2 
Administration through G-tube 
 
Administration of the study medications through a G-tube is not allowed. 
 


 
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7.3 
Concomitant Medications 
 
The use of supportive care medications is allowed according to institutional standards. 
 
7.4 
Drug Compliance 
 
Drug compliance will be recorded by patients on the Intake Calendar (see Appendix 18.2). 
Institutional CRAs will review and ascertain patient adherence with protocol therapy at the 
end of treatment for each cycle.  Calendar should be kept in the patient's clinic chart.  
Note that the Intake Calendar is provided only as a tool for tracking compliance.  Sites 
may utilize institutional pill diaries or other source documentation in place of the Intake 
Calendar at the discretion of the treating physician. 
 
7.5 
Reporting Cycle-Specific Toxicity and Dose Information 
 
Because this study contains an investigational drug for which CTEP holds the IND, it falls 
under CTEP requirement for full reporting.  This involves required submission of cycle-
specific toxicity and dose information (see Section 14.4c, the S1107 Treatment Form, and 
the S1107 Adverse Event Form).  A cycle is defined as 28 days. 
 
7.6 
Criteria for Removal from Protocol Treatment 
 
a. 
Progression of disease or symptomatic deterioration (as defined in Section 10.2). 
 
b. 
Unacceptable toxicity. 
 
c. 
All protocol treatment is held for any reason > 3 weeks. 
 
d. 
The patient may withdraw from the study at any time for any reason. 
 
e. 
Physician discretion. 
 
7.7 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice. 
 
7.8 
Follow Up Period 
 
All patients will be followed for a maximum of three years. 
 
 
8.0 
DOSAGE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 4.0 for toxicity and Serious Adverse Event reporting.  A copy of the CTCAE 
Version 4.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov).  All 
appropriate treatment areas should have access to a copy of the CTCAE Version 4.0. 
 
8.2 
General Considerations 
 
a. 
Missed doses are to be omitted rather than made up. 
 
b. 
If multiple toxicities are seen for any given single agent, administer dose based 
on greatest reduction required for any single toxicity observed. 


 
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c. 
Reductions apply to the treatment given in the preceding cycle and are based on 
toxicities observed since the prior dose. 
 
d. 
Once dose is reduced, patients will continue at new dose.  No dose re-
escalations are allowed. 
 
e. 
If the patient vomits after taking the tablets, the dose is replaced only if the tablets 
can actually be seen and counted. 
 
f. 
Use of G-CSF and erythropoietin for patients being treated on this study is at the 
discretion of the treating physician.  If used, it must be documented in the "Notes" 
section of the S1107 Treatment Form. 
 
8.3 
Patient Evaluations 
 
Patients will be evaluated every two weeks for the first eight weeks and then once every 
four weeks to determine toxicities and the appropriate dose modification (decrease, hold, 
or discontinue).  If all protocol treatment is delayed more than three weeks, patients will 
be removed from protocol treatment. 
 
8.4 
Radiation Therapy for Palliation  
 
If patients require radiation therapy for palliation in the absence of progressive disease 
please contact the primary Study Chair, Dr. Przemyslaw Twardowski M.D. 626-256-4673 
ext 68218. 
 
8.5 
ARQ 197 Dose Modification 
 
If ARQ 197 is held, erlotinib will also be held for patients on Arm 2 and resumed at the 
same time treatment with ARQ 197 is resumed.  There will be no dose reduction of 
erlotinib if the toxicity was thought to be related to ARQ 197. 
 
a. 
Hematologic toxicities: 
 
 
 
 
 
 
 
 
* Treatment may be held up to 21 days and can be resumed at the next lower 
dose level once ANC is ≥ 1000x106/L and platelet count is ≥ 75,000 x106/L. 
Patients who cannot tolerate ARQ 197 at 120 mg BID will be removed from 
the protocol. No dose re-escalation is allowed. 
 
Absolute neutrophil 
count (ANC) (x106/L) 
Platelets 
(x106/L) 
ARQ 197 
          ≥ 1,000       and 
≥ 75,000 
100% dose 
          < 1,000      or 
< 75,000 
*Hold until ANC ≥ 1,000 and 
platelets ≥ 75,000 and reduce 
to the next lower dose  level     


 
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b. 
Non-hematologic toxicities: 
 
The following modifications should be followed in the event of ARQ 197 related-
non-hematologic toxicity.  
 
Toxicity Grade(NCI CTCAE v4.0) 
Percent of full dose of ARQ 197l 
0-2 
100% 
3 
Hold* 
4 
Hold* 
 
* Treatment may be held up to 21 days Any patient who experiences Grade 3 or 
greater non-hematologic toxicity which resolves to Grade 0 or 1 may be 
treated at a next lower dose level of  ARQ 197 for subsequent doses. Patients 
who cannot tolerate ARQ 197 at 120 mg BID will be removed from the 
protocol. No dose re-escalation is allowed. 
 
c. 
ARQ 197 Dose Level Reductions 
 
Starting Dose 
First Reduction 
Second Reduction 
360 mg BID 
240 mg BID 
120 mg BID 
 
NOTE:  Any patient who fails to tolerate treatment of 120 mg BID will be 
withdrawn from protocol treatment.  If a treatment is delayed more than 21 days 
for the resolution of ARQ 197-related toxicities to Grade 0 or 1 patient will be 
removed from the protocol. 
 


 
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8.6 
Erlotinib Dose Modificationa  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(a) Doses that have been reduced should not be re-escalated.  Any patient who fails to 
tolerate treatment at 50 mg/day will discontinue erlotinib and continue on single agent 
ARQ 197. 
(b) If the event does not resolve to Grade 0 or 1 within 21 days, erlotinib will be 
discontinued and patient will continue on a single agent ARQ 197 
(c) Only if ≥ 2 Grade level change from baseline 
 
Erlotinib Dose Level Reductions 
 
 
Starting Dose 
First Reduction 
Second Reduction 
 
 
 
 
 
 
150 mg/day 
100 mg/day 
50 mg/day 
 
 
 
NOTE: Any patient who fails to tolerate erlotinib at 50 mg/day will continue on single agent 
ARQ 197. If a treatment is delayed more than 21 days for the resolution of erlotinib-
related toxicities to Grade 0 or 1, discontinue erlotinib and continue ARQ 197 alone. 
 
Toxicity 
(NCI CTCAE v4.0) 
Dose Modification 
Diarrhea 
Grade 1  
None.  Initiate therapy with loperamide.(8.7a) 
Grade 2 
Hold erlotinib.  Initiate loperamide until resolution to Grade 0-1.  
Resume therapy at the same dose. 
Grade 3b or 4b 
Hold erlotinib.  Initiate therapy with loperamide and appropriate 
supportive care until resolution to Grade 0 or 1 and then restart 
at 1 dose level lower 
Rash 
Grade 1 
None 
Grade 2 
None. Initiate treatment (8.7b).  If rash persists and is 
intolerable or worsens over 10 – 14 days, then reduce by 1 
dose level.  
Grade 3 
Reduce by 1 dose level.  If rash persists or worsens over 10 – 
14 days, then interrupt erlotinib until resolution to Grade 0, 1 or 
2 and then restart 1 dose level lower. 
Grade 4 
Permanently discontinue erlotinib. 
Interstitial Lung Disease 
Any Grade 
If ILD is suspected, erlotinib should be interrupted immediately 
pending diagnostic evaluation.  If ILD is diagnosed, erlotinib 
should be discontinued permanently and appropriate treatment 
instituted as necessary. 
Other Toxicities Attributable to Erlotinib  
Grade 1 or 2 
None 
Grade 3 or 4 b, c 
Interrupt erlotinib until resolution to Grade 0 or 1 and then restart 
1 dose level lower. 
Other Toxicities (hematologic and non-hematologic) attributable to ARQ 197 
Grade 1 or 2 
None 
Grade 3 or 4  
Hold erlotinib until ARQ 197 is resumed. If toxicity was deemed 
related to ARQ 197 no dose reduction of erlotinib is indicated  


 
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8.7 
Suggested management of toxicities  
 
a. 
Diarrhea. The recommended dose of loperamide is 4 mg at first onset, followed 
by 2 mg every 2 to 4 hours until diarrhea resolves for 12 hours In the event of 
severe or persistent diarrhea, nausea, anorexia, or vomiting associated with 
dehydration, erlotinib therapy should be interrupted and appropriate measures 
should be taken to intensively treat the dehydration.  Since there have been rare 
reports of hypokalemia and/or acute renal failure (including fatalities), secondary 
to severe dehydration, renal function and serum electrolytes (including 
potassium) should be monitored in this setting. 
 
b. 
Rash/skin toxicity. Patients should be informed that skin toxicity is to be expected 
during treatment with erlotinib.  Skin toxicity may take the form of dry skin, rash, 
acneiform eruption, or hair or nail changes.  Prophylactic treatment of the skin 
may prevent or reduce skin toxicity.  The patient should be encouraged to use an 
alcohol-free, emollient cream applied twice a day to the entire body as soon as 
the patient starts therapy with erlotinib.  Creams and ointments are recommended 
because they have a greater ability to retain moisture than lotions.  Examples of 
suitable emollient creams include:  Neutrogena® Norwegian formula, SARNA® 
Ultra, Vanicream™, Aveeno® (fragrance-free formulation), and Eucerin® cream.  
Other over-the-counter aqueous creams or emulsifying ointments may also 
provide symptomatic benefit.  Lotions should be avoided because they often 
contain alcohol, which will dry the skin.  Patients should also be encouraged to 
use a titanium dioxide or zinc oxide-based sunscreen product applied to sun-
exposed areas twice per day. 
 
Patients who develop skin toxicity and are symptomatic should be treated with 
topical therapy such as hydrocortisone cream or clindamycin gel.  If needed, oral 
minocycline or oral doxycycline may be combined with the topical therapy.  A 
topical immodulating cream such as Elidel could also be considered.  For more 
severe rash, oral corticosteroids may be beneficial.  Patients who fail to respond 
to these measures may have the dose of erlotinib interrupted or reduced.   
 
Minocycline is known to interfere with anticoagulants and oral contraceptives.  
Patients treated with minocycline who are taking anticoagulants and/or oral 
contraceptives should be monitored accordingly. 
 
Bullous, blistering and exfoliative skin conditions have been reported, including 
cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, 
which in some cases were fatal.  Interrupt or discontinue erlotinib treatment if the 
patient develops severe bullous, blistering, or exfoliating conditions.   
 
c. 
Ocular Disorders.  Corneal perforation or ulceration has been reported during use 
of erlotinib.  Other ocular disorders including abnormal eyelash growth, 
keratoconjunctivitis sicca or keratitis have been observed with erlotinib treatment 
and are known risk factors for corneal ulceration/perforation.  Interrupt or 
discontinue erlotinib therapy if patients present with acute/worsening ocular 
disorders such as eye pain. 
 


 
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8.8 
Dose Modification Contacts 
 
For treatment or dose modification related questions, please contact Dr. Przemyslaw 
Twardowski at 626/256-4673 ext. 68218 or Dr. Primo N. Lara, Jr. at 916/734-3771.   
 
8.9 
Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Chair, the NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
 


 
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9.0 
STUDY CALENDAR 
Ω 
√ 
 
 
Cycle 1 
Cycle 2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Cycle 
7 
 
REQUIRED STUDIES 
PRE 
STUDY 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Follow-
Up 
1 
3 
5 
7 
9 
13 
17 
21 
25 
PHYSICAL 
History & Physical Exam 
X * 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight and Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease Assessment ≠ 
X 
X 
X 
X 
Toxicity Notation 
X 
X 
X 
X 
X 
X 
X 
X 
S1107 Baseline Abnormalities Form 
X 
LABORATORY 
CBC/Differential/Platelets 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bilirubin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SGOT & SGPT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Creatinine 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrolytes (see Section 5.3f)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test (if applicable) 
X 
TISSUE SAMPLES 
Archived tissue sample (see Section 15.0) 
X 
X-RAYS AND SCANS 
X-rays/Scans as needed for disease 
measurement  ≠ 
X 
 
 
 
 
X 
 
X 
 
X 
X 
TREATMENT ∆ 
ARM 1 
ARQ 197 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ARM 2 
ARQ 197 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Erlotinib 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Click here for FOOTNOTES 
 


 
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NOTE:  Forms are found on the protocol abstract page on the SWOG website (www.swog.org).  Forms submission guidelines 
are found in Section 14.0. 
 
FOOTNOTES 
 
* Physical exam and medical history must be completed within 28 days prior to registration (see Section 5.3a). 
∆  Continuous oral daily dosing (see Section 7.1). 
Ω Protocol treatment and parameters will continue at these intervals until off protocol treatment per Section 7.6.  While on protocol 
treatment, disease assessments will continue every 8 weeks until progression.  If patient is removed from protocol treatment prior to 
disease progression, assessments will be continued on this schedule until disease progression. 
√  After disease progression, follow-up will occur (with lab tests and scans performed at the discretion of the treating investigator) every 3 
months for the first year and then every 6 months thereafter for up to three years after registration or until death. 
≠ Tumor assessment will be done after every second cycle by the same method used at baseline. REMEMBER, RESPONSE SHOULD BE 
CONFIRMED BY A SECOND DETERMINATION AT LEAST 4 WEEKS AFTER A COMPLETE OR PARTIAL RESPONSE HAS BEEN 
NOTED. 
 
 
 


 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
10.1 
Measurability of lesions 
 
a. 
Measurable disease: Measurable disease is defined differently for lymph nodes 
compared with other disease and will be addressed in a separate section below. 
 
1. 
Lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 2.0 cm  by chest x-ray, by ≥ 1.0 
cm  with CT or MRI scans, or ≥ 1.0 cm with calipers by clinical exam. All 
tumor measurements must be recorded in decimal fractions of 
centimeters (or millimeters). 
 
The defined measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 0.5 cm or less.  If CT scans have 
slice thickness greater than 0.5 cm, the minimum size for a measurable 
lesion should be twice the slice thickness.   
 
2. 
Malignant lymph nodes are to be considered pathologically enlarged and 
measurable if it measures ≥ 1.5 cm in SHORT AXIS (greatest diameter 
perpendicular to the long axis of the lymph node) when assessed by scan 
(CT scan slice recommended being no greater than 0.5 cm). 
 
b. 
Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter < 1.0 cm or pathologic lymph nodes with ≥ 1.0 cm to < 
1.5 cm 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 non-measurable as are previously 
radiated lesions that have not progressed. 
 
c. 
Notes on measurability 
 
1. 
For CT and MRIs, 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 by performed with breath-hold scanning 
techniques, if possible.  
 
2. 
PET-CT:  At present, the low dose or attenuation correction CT portion of 
a 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, then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with 
conventional CT. 
 
3. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. 
 
4. 
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. 
 
5. 
If a target lesion becomes very small some radiologists indicate that it is 
too small to measure.  If the lesion is actually still present, a default 
measurement of 0.5 cm should be applied.  If the radiologist believes the 
lesion has gone, a default measurement of 0.0cm should be recorded. 


 
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10.2 
Objective status at each disease evaluation   
 
Objective Status is to be recorded at each evaluation. All measurable lesions up to a 
maximum of 2 lesions per organ 5 lesions in total, representative of all involved organs, 
should be identified as target lesions at baseline. 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.  Measurements must be provided for target measurable lesions, 
while presence or absence must be noted for non-target measurable and non-
measurable disease.   
 
For studies that use disease progression as an endpoint, whole body scanning at specific 
intervals is necessary to determine that progression is NOT present outside of the “target” 
areas. Therefore, in these studies it is not acceptable to image only the “target” areas of 
the body in follow-up scans. For study-specific imaging requirements, see the Study 
Calendar in Section 9.0.   
 
a. 
Complete Response (CR):  Complete disappearance of all target and non-target 
lesions (with the exception of lymph nodes mentioned below).  No new lesions.  
No disease related symptoms.   Any lymph nodes (whether target or non-target) 
must have reduction in short axis to < 1.0 cm.  All disease must be assessed 
using the same technique as baseline. 
 
b. 
Partial Response (PR): Applies only to patients with at least one measurable 
lesion. Greater than or equal to 30% decrease under baseline of the sum of 
appropriate diameters of all target measurable lesions.  No unequivocal 
progression of non-measurable disease.  No new lesions.  All target measurable 
lesions must be assessed using the same techniques as baseline. 
 
c. 
Stable: Does not qualify for CR, PR, Progression or Symptomatic Deterioration.  
All target measurable lesions must be assessed using the same techniques as 
baseline. 
 
d. 
Progression: One or more of the following must occur:  20% increase in the sum 
of appropriate diameters of target measurable lesions over smallest sum 
observed (over baseline if no decrease during therapy) using the same 
techniques as baseline, as well as an absolute increase of at least 0.5 cm.  
Unequivocal progression of non-measurable disease in the opinion of the treating 
physician (an explanation must be provided).   Appearance of any new lesion/site.  
Death due to disease without prior documentation of progression and without 
symptomatic deterioration (see Section 10.2e). 
 
 
Notes regarding new lesions:  FDG-PET imaging can complement regular scans 
in identifying new lesions according to the following algorithm.  
 
1. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of progression based on a new lesion. 
 
2. 
No FDG-PET at baseline and a positive FDG-PET at follow-up 
corresponding to a potential new site of disease must have a 
confirmation by anatomical assessment (e.g. CT, MRI, x-ray) as new site 
of disease to be considered progressive disease.  In such a case, the 
date of progressive disease will be the date of the initial abnormal FDG-
PET.   


 
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e. 
Symptomatic deterioration:  Global deterioration of health status requiring 
discontinuation of treatment without objective evidence of progression.  Efforts 
should be made to obtain objective evidence of progression after discontinuation. 
 
f. 
Assessment inadequate, objective status unknown.  Progression or 
symptomatic deterioration has not been documented, and one or more target 
measurable lesions have not been assessed or inconsistent assessment 
methods were used. 
 
g. 
Objective status notes: 
 
1. 
Non-measurable and non-target measurable disease do not affect 
Objective Status  in determination of CR (must be absent--a patient who 
otherwise has a CR, but who has non-measurable or non-target 
measurable disease present or not assessed, will be classified as having 
a PR). However, non-measurable and non-target lesions are included in 
determination of progression (if new sites of disease develop or if 
unequivocal progression occurs in the opinion of the treating physician).  
 
2. 
An objective status of PR or stable cannot follow one of CR.  Stable can 
follow PR only in the rare case that tumor increases too little to qualify as 
progression, but enough that a previously documented 30% decrease no 
longer holds. 
 
3. 
In cases for which initial flare reaction is possible (hypercalcemia, 
increased bone pain, erythema of skin lesions), objective status is not 
progression unless either symptoms persist beyond 4 weeks or there is 
additional evidence of progression.   
 
4. 
Lesions that appear to increase in size due to presence of necrotic tissue 
will not be considered to have progressed.  
 
5. 
For bone disease documented on bone scan only, increased uptake does 
not constitute unequivocal progression. However, increase in the soft 
tissue component of a lesion as measured by CT or MRI would constitute 
progression. 
 
6. 
Appearance of new pleural effusions does not constitute unequivocal 
progression unless cytologically proven of neoplastic origin, since some 
effusions are a toxicity related to therapy or other medical conditions. 
Increase in the size of an existing effusion does not constitute 
unequivocal progression, since the fluid status of the patient could alter 
the size of the effusion.  
 
7. 
If CR determination depends on a lesion for which the status is unclear 
by the required tests, it is recommended the residual lesion be 
investigated with biopsy or fine needle aspirate.   
 
10.3 
Best Response 
 
This is calculated from the sequence of objective statuses. 
 
a. 
CR:  Two or more objective statuses of CR a minimum of four weeks apart 
documented before progression or symptomatic deterioration. 


 
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b. 
PR: Two or more objective statuses of PR or better a minimum of four weeks 
apart documented before progression or symptomatic deterioration, but not 
qualifying as CR. 
 
c. 
Unconfirmed CR:  One objective status of CR documented before progression or 
symptomatic deterioration but not qualifying as CR or PR. 
 
d. 
Unconfirmed PR:  One objective status of PR documented before progression or 
symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR. 
 
e. 
Stable/no response:  At least one objective status of stable/no response 
documented at least 6 weeks after registration and before progression or 
symptomatic deterioration, but not qualifying as anything else above. 
 
f. 
Increasing disease:  Objective status of progression within 12 weeks of 
registration, not qualifying as anything else above.   
 
g. 
Symptomatic deterioration: Objective status of symptomatic deterioration within 
12 weeks of registration, not qualifying as anything else above.   
 
Inadequate assessment, response unknown:  Progression or symptomatic deterioration 
greater than 12 weeks after registration and no other response category applies. 
 
10.4 
Performance Status 
 
Patients will be graded according to the Zubrod Performance Status Scale. 
 
POINT 
DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, e.g., light 
housework, office work.   
 
2 
Ambulatory and capable of self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours.   
 
3 
Capable of limited self-care, confined to bed or chair more than 
50% of waking hours.   
 
4 
Completely disabled; cannot carry on any self-care; totally 
confined to bed or chair.   
 
10.5 
Time to Death   
 
From date of registration to date of death due to any cause.  Patients last known to be 
alive are censored at date of last contact. 
 
10.6 
Progression-Free Survival 
 
From date of registration to date of first documentation of progression or symptomatic 
deterioration (as defined above), or death due to any cause.  Patients last known to be 
alive without report of progression are censored at date of last contact. 
 
 


 
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11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Accrual Goal 
 
A parallel (randomized) two-stage design will be used for patient accrual. When 
conducting both studies in parallel, each study acts independently.  Eligible patients with 
advanced pRCC will be enrolled according to two strata: Strata 1 = 1st line therapy, Strata 
2 = 2nd Line therapy. Patients will be randomized to either Arm 1 (single agent ARQ 197) 
or Arm 2 (ARQ 197+ erlotinib), as long as both arms are open as per stopping rules and 
toxicity considerations. Each arm will be conducted as an independent clinical trial. The 
primary endpoint, RECIST response (confirmed CR and PR) will be evaluated every two 
cycles.  There will be no crossover from the single agent arm to the double agent arm. 
 
11.2 
Analysis of Primary Endpoint 
 
Arm 1: ARQ 197 as a single agent (35 patients):   
 
With no activity of ARQ 197 as a single agent in pRCC, we would expect a response rate 
of 10%. We would consider ARQ 197 promising for further investigation if the response 
rate were ≥ 30%.  Initially, 20 eligible patients will be accrued to this arm of the study. If 0-
1 patients are responders, this would constitute lack of evidence of sufficient activity, and 
this arm would be closed to accrual. We would expect this to occur 1% of the time if the 
true probability of response was 30%.  If this arm shows adequate activity in the first 
stage, and toxicity and safety considerations permit, accrual will continue until a total of 35 
eligible patients are accrued. If the total number of patients out of 35 who respond is 8+, 
we would consider this agent promising and worthy of further investigation in pRCC if 
toxicity and PFS data are also supportive. In this arm, the design has a significance level 
(probability of falsely declaring that an agent with a 10% response probability is worthy of 
further investigation) of 2%, and a power (probability of correctly declaring that an agent 
with a response rate of 30% is worthy of further investigation) of 87%. Thirty five eligible 
patients are sufficient to estimate the confirmed response to within ±17% (95% 
confidence interval). 
 
Arm 2: ARQ 197 plus erlotinib (35 patients): 
 
For ARQ 197 as a combination with erlotinib, we have specified the study with the same 
two-stage design. While the criteria might be considered slightly higher considering the 
S0317 data on erlotinib showing responses and prolonged stable disease, raising the bar 
is considered unwarranted in this case for two main  reasons: 1) this study permits pre-
treated patients; 2) S0317, with only previously untreated patients had 5/52 patients with 
responses, including unconfirmed responses, and only 29% free from treatment failure at 
6 months, suggesting a reasonable probability that erlotinib alone would not pass the first 
stage in this study. As a result, the same design considerations for Arm 1 apply. The 
operating characteristics of these rules were described above. 
 
11.3 
Analysis of Secondary Endpoints 
 
Safety and Tolerability will be summarized by arm by examining the frequency and 
severity of toxicities grade by the CTCAE v4.0 (Common Terminology Criteria for Adverse 
Events), the frequency and extent of required dose modifications, and the frequency and 
cause of patient withdrawal for reasons other than progression. 
 
Thirty five eligible patients are sufficient to estimate the probability of an adverse event 
within ±17% (95% confidence interval). Any adverse event occurring with at least a 5% 
probability is likely to be seen at least once (83% chance). 
 
Assuming an ineligibility rate of approximately 10%, total accrual (eligible + ineligible) to 
this study is expected to be 78 patients. 


 
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Progression-free survival will be estimated by arm. Thirty five eligible patients are 
sufficient to estimate the 4 month progression-free survival within ±17% (95% confidence 
interval). 
 
11.4 
Analysis of Translational Medicine Endpoints 
 
Correlative analysis will be exploratory in the context of this Phase II trial. There are 
several different statistical analyses that will be performed on the correlates: 
 
The role of c-MET and EGFR, when available, will be explored through the use of Cox 
regression, categorical analysis (responders/non-responders versus high expressors, 
etc.), and graphical presentations. 
 
11.5 
Data and Safety Monitoring Committee Oversight 
 
There is no formal data and safety monitoring committee for Phase II studies.  Toxicity 
and accrual monitoring are done routinely by the Study Chair, study Statistician and the 
Disease Committee Chair.  Endpoint monitoring is done by the study Statistician and 
Study Chair.  Accrual reports are generated weekly and formal toxicity reports are 
generated every 6 months.  In addition, the Statistical Center, Adverse Event Coordinator 
at the Operations Office, SAE Physician Reviewer, and Study Chair monitor toxicities on 
an ongoing basis. 
 
 
12.0 
DISCIPLINE REVIEW 
 
There will be no formal discipline review done in conjunction with this study. 
 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Patients must be registered prior to initiation of treatment (no more than five working days 
prior to planned start of treatment).     
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a patient for this study, investigators must be registered 
members of a Cooperative Group.  Each investigator must have an NCI investigator 
number and must maintain an “active” investigator registration status through the annual 
submission of a complete investigator registration packet (FDA Form 1572 with original 
signature, current CV, Supplemental Investigator Data Form with signature and Financial 
Disclosure Form with original signature) to the Pharmaceutical Management Branch, 
CTEP, DCTD, NCI.  These forms are available on the CTSU Web site (enter credentials 
at https://www.ctsu.org; then click on the Register tab) or by calling the PMB at 240/276-
6575  Monday through Friday between 8:30 a.m. and 4:30 p.m. Eastern time. 
 
Each investigator or group of investigators at a clinic site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory 
Office before they can enroll patients.  Study centers can check the status of their 
registration packets by querying the Regulatory Support System (RSS) site registration 
status 
page 
of 
the 
CTSU 
member 
web 
site 
by 
entering 
credentials 
at 
https://www.ctsu.org.  
 


 
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Requirements for site registration: 
 
• 
CTSU IRB Certification 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet 
 
13.3 
OPEN Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 
 
Oncology Patient Enrollment Network (OPEN) will also ask additional questions that are 
not present on the SWOG Registration Worksheet.  The individual registering the patient 
must be prepared to provide answers to the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Cooperative Group Credit 
 
f. 
Credit Investigator 
 
g. 
Patient Initials 
 
h. 
Patient’s Date of Birth 
 
i. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
j. 
Country of Residence 
 
k. 
ZIP Code 
 
l. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 
 
m. 
Ethnicity (select one): 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
n. 
Method of Payment (select one): 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 
• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self Pay (No Insurance) 


 
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• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 
o. 
Race (select all that apply): 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 
• 
Native Hawaiian or other Pacific Islander 
• 
White 
• 
Unknown 
 
13.4 
Registration procedures 
 
a. 
All site staff (SWOG and CTSU Sites) will use OPEN to enroll patients to this 
study.  OPEN is a web-based application and can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org, or from the OPEN Patient Registration link on the 
SWOG CRA Workbench.  
 
b. 
Prior to accessing OPEN site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes, 
and the affirmation of eligibility on the Registration Worksheet has been 
signed 
by 
the 
registering 
investigator 
or 
another 
investigator 
designate. Site staff should refer to Section 5.0 to verify eligibility. 
 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
 
• 
The study site is listed as “approved” in the CTSU RSS. 
 
c. 
Access requirements for OPEN: 
  
• 
Site staff will need to be registered with CTEP and have a valid and 
active CTEP-IAM account. This is the same account (user ID and 
password) used for the CTSU members' web site.  
 
• 
To perform registrations, the site user must have been assigned the 
'Registrar' role on the SWOG or CTSU roster:  
 
1. If you are a SWOG member, to perform registrations on SWOG 
protocols you must have an equivalent 'Registrar' role on the SWOG 
roster.  Role assignments are handled through SWOG.  
 
2. If you are not a SWOG member, to perform registrations on SWOG 
protocols you must have the role of Registrar on the CTSU roster. 
Site and/or Data Administrators can manage CTSU roster roles via 
the new Site Roles maintenance feature under RSS on the CTSU 
members' web site. This will allow them to assign staff the "Registrar" 
role.  
 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.   Please print this confirmation for your 
records.   
 


 
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d. 
Further instructional information is provided on the OPEN tab of the CTSU 
members’ 
side 
of 
the 
CTSU 
website 
at 
https://www.ctsu.org 
or 
at 
https://open.ctsu.org.  For any additional questions contact the CTSU Help Desk 
at 1-888-823-5923 or ctsucontact@westat.com. 
 
13.5 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirement 
 
Data must be submitted according to the protocol requirements for ALL patients 
registered, whether or not assigned treatment is administered, including patients deemed 
to be ineligible.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible. 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the SWOG web site 
(www.swog.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see Section 14.3a for details.  
Exceptions to online data submission are patient-completed (e.g. Quality of Life) forms 
and source documents (e.g. pathology/operative/lab reports). 
 
If you need to submit data that are not available for online data submission, these should 
be submitted via facsimile to 800/892-4007 or 206/342-1680 locally.  Please do not use 
cover sheet for faxed data.  Please make sure that each page of all faxed data include the 
SWOG patient number, study ID and patient initials. 
 
14.3 
Data Submission Procedures  
 
a. 
SWOG institutions must submit data electronically via the Web using Medidata 
Rave® at the following url: 
 
https://login.imedidata.com/selectlogin 
 
1. 
If prompted, select the ‘CTEP-IAM IdP’ link. 
2. 
Enter your valid and active CTEP-IAM userid and password.  This is the 
same account used for the CTSU members’ web site and OPEN. 
 
b. 
You may also access Rave® via the SWOG CRA Workbench.  Go to the SWOG 
web site (http://swog.org) and logon to the Members Area using your SWOG 
Roster ID Number and password. After you have logged on, click on 
Workbenches, then CRA Workbench to access the home page for the CRA 
Workbench and follow the link to Rave® provided in the left-hand navigation 
panel. 
 


 
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To access the CRA Workbench the following must be done (in order): 
 
1. 
You are entered into the SWOG Roster and issued a SWOG Roster ID 
Number, 
 
2. 
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed,  
 
3. 
Your Web User Administrator has added you as a web user and has 
given you the appropriate system permissions to view data for that 
institution. 
 
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  
For point 3, contact your local Web User Administrator (refer to the "Who is my 
Web User Administrator?" function on the swog.org Members logon page).  
 
For difficulties with the CRA Workbench, please email 
technicalquestion@crab.org. 
 
c. 
Institutions participating through the Cancer Trials Support Unit (CTSU), please 
refer to the CTSU Participation Table. 
 
14.4 
Data Submission Overview and Timepoints 
 
a. 
WITHIN 7 DAYS OF REGISTRATION:   
 
Submit the following: 
 
S1107 Advanced Renal Carcinoma Onstudy Form  
 
Baseline Tumor Assessment Form  
 
S1107 Baseline Abnormalities Form  
 
Radiology reports from all scans performed to assess disease at baseline 
 
Pathology Report 
 
b. 
WITHIN 28 DAYS OF REGISTRATION:   
 
Submit materials outlined in Section 15.0 to Lab #201. 
 
c. 
WITHIN 7 DAYS OF COMPLETION OF EACH CYCLE WHILE ON PROTOCOL 
TREATMENT: 
 
Submit the S1107 Treatment Form and S1107 Adverse Event Form documenting 
required parameters as specified on the Study Calendar. 
 
d. 
WITHIN 14 DAYS AFTER EVERY DISEASE ASSESSMENT, AFTER EVERY 
SECOND CYCLE WHILE ON PROTOCOL TREATMENT; IF PATIENT HAS 
NOT PROGRESSED ONCE OFF PROTOCOL TREATMENT THEN CONTINUE 
TO SUBMIT EVERY 8 WEEKS UNTIL PROGRESSION: 
 
Submit the Follow-Up Tumor Assessment Form and all Radiology Reports until 
documented disease progression per Section 10.2d or removal from protocol 
treatment. 


 
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e. 
WITHIN 14 DAYS OF DISCONTINUATION OF TREATMENT: 
 
Submit the Off Treatment Notice and final S1107 Treatment Form and S1107 
Adverse Event Form. 
 
f. 
AFTER OFF TREATMENT, EVERY 3 MONTHS FOR THE FIRST YEAR AND 
THEN EVERY 6 MONTHS UNTIL DEATH OR FOR A MAXIMUM OF 3 YEARS: 
 
Submit the Follow-Up Form. 
 
g. 
WITHIN 14 DAYS OF PROGRESSION/RELAPSE: 
 
Submit a Follow Up Tumor Assessment Form, Radiology Report, S1107 
Treatment Form and S1107 Adverse Event Form (if the patient was still on 
protocol treatment) or Follow-Up Form (if the patient was off protocol treatment) 
documenting date, site and method for determining progression/relapse. 
 
h. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH: 
 
Submit the Notice of Death and final S1107 Treatment Form, S1107 Adverse 
Event Form (if the patient was still on protocol treatment) or Follow-Up Form  (if 
the patient was off protocol treatment) documenting death information. 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Specimen Banking 
 
Specimens for banking for future use for translational medicine studies are optional for 
the patient. 
 
a. 
With patient’s consent an archival tumor paraffin block or sixteen 5 micron 
unstained slides must be submitted prestudy (see Section 9.0): 
 
b. 
Specimen collection and submission instructions can be accessed on the SWOG 
Specimen Submission webpage: 
 
(http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp), or via the 
link on the S1107 protocol abstract page on the SWOG website (www.swog.org). 
 
c. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 


 
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Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) 
and the Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code 
of Federal Regulations 45 CFR 46). 
 
Drug Accountability 
 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312. 
 
Publication and Industry Contact 
 
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 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. 
 


 
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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: 
 
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. 
 
Monitoring 
 
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. 
 
Confidentiality 
 
Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained. 
 
16.1 
Adverse Event Reporting Requirements  
 
a. 
Purpose 
 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as 
well as those who will enroll in future studies using similar agents. Adverse events 
are reported in a routine manner at scheduled times during a trial. (Directions for  


 
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routine reporting are provided in Section 14.0.) Additionally, certain adverse 
events must be reported in an expedited manner to allow for more timely 
monitoring of patient safety and care. The following guidelines prescribe 
expedited adverse event reporting for this protocol. See also Appendix 18.1 for 
general and background information about expedited reporting. 
 
b. 
Reporting method 
 
This study requires that expedited adverse events be reported using the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS).  
CTEP's guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted to the SWOG Operations Office 
electronically via the CTEP-AERS web-based application located at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_eve
nts.htm. 
 
c. 
When to report an event in an expedited manner 
 
Some adverse events require 24-hour notification (refer to Table 16.1) via CTEP-
AERS.  
 
When the adverse event requires expedited reporting, submit the report within the 
number of calendar days of learning of the event, as specified in Table 16.1.  
 
In the rare event when internet connectivity is disrupted a 24-hour notification is 
made to NCI by telephone at 301-897-7497.  An electronic report MUST be 
submitted immediately upon re-establishment of internet connection.  
 
Any supporting documentation requested by CTEP should be submitted in 
accordance with instructions provided by the CTEP-AERS system. 
 
d. 
Other recipients of adverse event reports 
 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local policy 
and procedures. 
 
e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the patient has received at least one dose of the 
investigational agent(s) as part of the trial. Reporting requirements are provided in 
Table 16.1. The investigational agents used in Arms 1 and 2 of this study are 
ARQ 197 and erlotinib. If there is any question about the reportability of an 
adverse event or if on-line CTEP-AERS cannot be used, please telephone or 
email the SAE Specialist at the SWOG Operations Office, 210/614-8808 or 
adr@swog.org, before preparing the report. 
 
 


 
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Table 16.1: 
 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under a CTEP IND within 30 Days of the Last Administration of the 
Investigational Agent ARQ 197 or erlotinib in this study 
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 or Section 16.1f.   
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 
24 hours of learning of the AE, followed by a complete expedited report within 5 
calendar days of the initial 24-hour report. 
 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 
10 calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite 
require reporting as follows:  
 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
 
May 5, 2011 
 


 
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f. 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Late Phase 2 and Phase 3 Studies Utilizing an Agent under a 
CTEP IND: 
 
1) 
Group-specific instructions 
 
Submission of the on-line CTEP-AERS report plus any necessary 
amendments generally completes the reporting requirements.  In 
addition, you may be asked to submit supporting clinical data to the 
Operations Offices in order to complete the evaluation of the event.  If 
requested, the supporting data should be sent within 5 calendar days by 
fax to 210-614-0006.  Supporting clinical data submitted should include: 
• 
Printed copy of the first page of the CTEP-AERS Report. 
• 
Copies of clinical sourced documentation of the event. 
• 
If applicable, and they have not yet been submitted to the 
SWOG Data Operations Center copies of Off Treatment 
Notice and/or Notice of Death. 
 
g.   
Reporting Secondary Malignancy, including AML/ALL/MDS 
 
1. 
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 to 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. 
 
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. 
 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf  
 
2. 
Supporting documentation should be submitted to CTEP in accordance 
with instructions provided by the CTEP-AERS system.  A copy of the 
report and the following supporting documentation must also be 
submitted to SWOG Operations Office within 30 days by fax to 210/614-
0006 or mail to the address below: 
 
• 
a copy of the pathology report confirming the AML/ALL /MDS 
diagnosis 
• 
(if available) a copy of the cytogenetics report   


 
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SWOG 
ATTN: SAE Program 
4201 Medical Drive, Suite 250 
San Antonio, Texas 78229 
 
NOTE: If a patient has been enrolled in more than one NCI-sponsored 
study, the report must be submitted for the most recent trial. 
 
 
h.  
Reporting Pregnancy, Fetal Death, and Death Neonatal 
 
1. 
Pregnancy Study participants who become pregnant while on study; that 
pregnancy should be reported in an expedited manner via CTEP-AERS 
as Grade 3 “Pregnancy, puerperium and perinatal conditions – 
Other (pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC.   
 
Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report. 
 
2. 
Fetal Death Fetal Death defined in CTCAE as “A disorder characterized 
by death in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation” should be 
reported expeditiously as Grade 4 “pregnancy, puerperium and 
perinatal 
conditions 
– 
Other (pregnancy loss)” under the 
Pregnancy, puerperium and perinatal conditions SOC.   
 
3. 
Death Neonatal  Neonatal death, defined in CTCAE as “A disorder 
characterized by cessation of life occurring during the first 28 days of life” 
that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention should be reported expeditiously.   
 
A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration – Other (neonatal loss)” under the 
General disorders and administration SOC. 
 
Fetal death and neonatal death should NOT be reported as a Grade 5 event.  If 
reported as such, the CTEP-AERS interprets this as a death of the patient being 
treated. 
 
NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should also be completed 
and faxed with any additional medical information to 301-230-0159.  The potential 
risk of exposure of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” section of the 
CTEP-AERS report. 
 
The Pregnancy Information Form is available at:  
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm   
 
 
 


 
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17.0 
BIBLIOGRAPHY 
 
1. 
Schmidt L. et al. Novel Mutations of the Met proto-oncogene in papillary renal carcinomas. 
Oncogene 18: 2343 -2350, 1999. 
 
2. 
Yang X et al. A Molecular Classification of papillary renal cell carcinoma. Cancer Res 2005; 65 
(13) July 1, 5628-37, 2005.  
 
3. 
Bellon SF, et al. c-Met Inhibitors with novel binding mode show activity against several hereditary 
papillary renal cell carcinoma-related mutations. J Biol Chem; 283(5):2675-83, 2008. 
 
4. 
Oudard S, Szczylik C, Porta C, Bracarda S, Hawkins R, Bjarnason G, Lee SH, Carteni G, 
Eberhardt W, Gore M. Safety and efficacy of sunitinib in an expanded-access trial of metastatic 
renal cell carcinoma :updated results and subpopulation analysis. European Urology Supplements 
Volume 7, Issue 3, p246, March 2008. 
 
5. 
Plimack ER, Jonasch E, Bekele BN, Smith LA, Araujo JC, Tannir NM. Sunitinib in non-clear cell 
renal cell carcinoma: A Phase II study J.Clin. Oncol. 26 (Suppl.) Abstract 5112, 2008. 
 
6. 
Choueiri T, et al. Efficacy of Sunitinib and Sorafenib in Metastatic Papillary and Chromophobe 
renal cell carcinoma. JCO. Vol 26 (1):127-13, 2008. 
 
7. 
Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa or both for advanced renal 
cell carcinoma. N Engl J Med 2007; 356 (22): 2271-2281. 
 
8. 
Motzer RJ, Hutson TE, Tomczak P, et al. Phase III randomized trial of sunitinib malate (SU11248) 
versus interferon-alfa as first-line systemic therapy for patients with metastatic renal cell 
carcinoma. N Engl J Med 2007 Jan 11; 356: 115-124. 
 
9. 
Perera AD, Kleymenova ED, Walker CL. Requirement for the Hippel-Lindau tumor suppressor 
gene for functional epidermal growth factor blockade by monoclonal antibody C225 in renal cell 
carcinoma. Clin Can Res 6:1518, 2000. 
 
10. 
Pan C, Hussey M, Lara P, Mack PC, Nagle RB, Dutcher J, Samlowski W, Clark J, Crawford ED, 
Gordon MS. A Phase II trial of the EGFR inhibitor Erlotinib in Patients with Advanced Papillary 
Renal Cell Carcinoma – SWOG S0317.  Proceeding of ASCO 2007, Abstract # 15516. 
 
11. 
Garcia A, Rosen L, Cunningham CC, Nemunaitis J, Li C., Rulewski N, Dovholuk A, Savage R, 
Chan T, Bukowski R, Mekhail T. Phase 1 Study of ARQ 197, a selective inhibitor of the c-Met 
RTK in patients with metastatic solid tumors reaches recommended phase 2 dose. JCO, 2007 
ASCO Annual Meeting Proceedings Part I.Vol25, No 18S; 3525, 2007. 
 
12. 
Laux I, Goldman J, Just R, Brady K, Li J, Schwartz B, Savage R, Garmey E, Rosen L. Phase I 
dose escalation trial (ARQ 197-111) evaluating combination of selective c-Met inhibitor ARQ 197 
and erlotinib. Proceedings of ASCO 2009. Accepted. 
 
13. 
Jo M, Stolz DB, Esplen JE, et al. Cross-talk between epidermal growth factor receptor and c-Met 
signal pathways in transformed cells. J Biol Chem 275:8806-8811, 2000. 
 
14. 
Green SJ, Dahlberg S. Planned versus attained design in phase II clinical trials. Stat Med 11, pp. 
853–862), 1992. 
 
15. 
Pocock SJ, Simon R.  Sequential treatment assignment with balancing for prognostic factors in 
controlled clinical trials.  Biometrics 31:103-115, 1975. 


 
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18.0 
APPENDIX 
 
18.1 
Determination of Expedited Adverse Event Reporting Requirements 
 
18.2 
Intake Calendar 
 


 
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18.1 
Determination of Expedited Adverse Event Reporting Requirements 
 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during a trial. (Directions for routine reporting are provided in 
Section 14.0.) Additionally, certain adverse events must be reported in an expedited 
manner to allow for more timely monitoring of patient safety and care. Expedited adverse 
event reporting principles and general guidelines follow; specific guidelines for expedited 
adverse event reporting on this protocol are found in Section 16.1. 
 
All serious adverse events determined to be reportable to the Institutional Review Board 
responsible for the oversight of the patient must be reported according to local policy and 
procedures.  Documentation of this reporting should be maintained for possible inspection 
during quality assurance audits. 
 
Steps to determine if an adverse event is to be reported in an expedited manner (This 
includes all events that occur while on treatment or within 30 days of the last dose of 
protocol treatment.) 
 
Step 1: Determine whether the patient has received an investigational agent, commercial 
agent, or a combination of investigational and commercial agents. 
 
An investigational agent is a protocol drug administered under an Investigational New 
Drug Submission (IND). In some instances, the investigational agent may be available 
commercially, but is actually being tested for indications not included in the approved 
package label.  
 
Commercial agents are those agents not provided under an IND but obtained instead 
from a commercial source. The NCI, rather than a commercial distributor, may on some 
occasions distribute commercial agents for a trial. 
 
When a study includes both investigational and commercial agents, the following rules 
apply.   
 
Concurrent administration: When an investigational agent(s) is used in combination with a 
commercial agent(s), the combination is considered to be investigational and expedited 
reporting of adverse events would follow the guidelines for investigational agents. 
 
Sequential administration:   When a study includes an investigational agent(s) and a 
commercial agent(s) on the same study arm with sequential administration all expedited 
reporting of adverse events should follow the guidelines for the type of agent being given.  
For example, if the patient begins the study on the investigational agent(s), then all 
expedited reporting of adverse events should follow guidelines for the investigational 
agent(s).  Once the patient begins receiving the commercial agent(s) then all expedited 
reporting of adverse events should follow the guidelines for commercial agent(s).   
 
Step 2: Identify the type of event using the NCI Common Terminology Criteria for Adverse 
Events (CTCAE). The CTCAE provides descriptive terminology and a grading scale for 
each adverse event listed. A copy of the CTCAE can be downloaded from the CTEP 
home page (http://ctep.cancer.gov). Additionally, if assistance is needed, the NCI has an 
Index to the CTCAE that provides help for classifying and locating terms.  
 
Step 3:  Grade the event using the NCI CTCAE version specified in the protocol for 
reporting serious adverse events. 
 


 
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Step 4: Determine if the adverse event is Expected or an Exception to Expedited 
Reporting.  Expected events are those that have been previously identified as resulting 
from administration of the agent and are listed in one of the following:   
 
• 
The current NCI SPEER (Specific Protocol Exceptions to Expedited Reporting) 
for treatments using agents provided under an NCI-held IND, or an equivalent 
listing for treatments using agents provided under a Non-CTEP-held IND; located 
in Section 3.0 of the protocol. 
• 
For treatments using commercial agents, the current CAEPR (Comprehensive 
Adverse Event and Potential Risks), ASAEL (Agent Specific Adverse Event List), 
or other list of expected toxicities located in Section 3.0 of the protocol, or the 
drug package insert.   
• 
Exception to Expedited reporting located in Section 16.1 f of the protocol. 
 
An adverse event is considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in one of the areas outlined 
above. 
 
Step 5:  Determine whether the adverse event involved hospitalization or a prolongation 
of hospitalization (≥ 24 hours). 
 
Step 6:  Additionally, for commercial drugs, determine whether the adverse event is 
related to the protocol therapy. Attribution categories are as follows: Unrelated, Unlikely, 
Possible, Probable, and Definite.  Consult the appropriate table for expedited reporting 
criteria for commercial agent(s). 
 
NOTE:   Any event that occurs more than 30 days after the last dose of study agent and 
is attributed (possible, probable, or definite) to the study agent(s) must be reported 
according to the instructions above and as outlined in the appropriate table in Section 
16.1. 
 


 
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18.2 
S1107 Intake Calendar 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Signature: 
 
SWOG Patient ID________  Patient Initials (L, F, M) ________ SWOG Study #__________
 
 
 
Institution/Affiliate _______________________  Physician _____________________________ 
Instructions for the participant: 
This is a monthly calendar on which you are to record the number of tablets/pills/capsules you 
take each day.  Be sure you have enough calendars to last until your next appointment.  If you 
develop any side effects from the tablets/pills/capsules, mark this on the calendar on the day you 
note the effect.  Bring your calendars with you each time you have an appointment. 
 
If you have questions contact: ____________________ Telephone: _____________________ 
 
Your next appointment is: _______________________ 
Special instructions: 
 
Month: 
 
Year: