Conditions: Colorectal Cancer
Keywords: BRAF Mutant Metastatic
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 106
Healthy volunteers: no

Brief summary:
This randomized phase II trial studies how well irinotecan hydrochloride and cetuximab with or without vemurafenib works in treating patients with colorectal cancer that has spread to nearby tissue or lymph nodes, that has spread to other places in the body, or cannot be removed by surgery. Irinotecan hydrochloride and vemurafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, may block the ability of tumor cells to grow and spread. It is not yet known whether irinotecan hydrochloride and cetuximab are more effective with or without vemurafenib in treating colorectal cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the progression-free survival (PFS) of v-raf murine sarcoma viral oncogene homolog B (BRAF) mutant metastatic colorectal cancer patients treated with irinotecan (irinotecan hydrochloride), cetuximab, and vemurafenib, compared to a control arm of irinotecan and cetuximab.

SECONDARY OBJECTIVES:

I. To evaluate the frequency and severity of toxicity associated with each of the treatment arms in this patient population.

TERTIARY OBJECTIVES:

I. To evaluate overall survival (OS) in treatment Arms 1 and 2. II. To evaluate the overall response rate (ORR), including confirmed and unconfirmed, complete and partial response, in treatment Arms 1 and 2 in the subset of patients with measurable disease.

III. To estimate rates of OS, ORR, and PFS in patients who register to Arm 3 after disease progression on Arm 1.

IV. To evaluate low-frequency Kirsten rat sarcoma viral oncogene homolog (KRAS) or neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) mutations as detected by high-depth sequencing as predictive biomarkers of efficacy.

V. To evaluate phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) pathway activation through PIK3CA mutations or phosphatase and tensin homolog (PTEN) protein loss as a predictive biomarker of innate resistance to this regimen.

VI. To evaluate gene expression signatures from screened patients with v-raf murine sarcoma viral oncogene homolog B wild type (BRAFWT) and BRAFV600E tumors.

VII. To provide validation of BRAF immunohistochemistry (IHC) using complementary sequencing methodology from screened patients with BRAFWT and BRAFV600E tumors.

VIII. To confirm the estimated sensitivity of detectable BRAF V600E circulating cell-free deoxyribonucleic acid (DNA) as a non-invasive biomarker for BRAF V600E mutation as detected by IHC in the primary tumor.

IX. To correlate radiographic tumor response with change in quantification of BRAFV600E alleles in circulating cell-free DNA.

X. To monitor for known mechanism of acquired resistance to epidermal growth factor receptor (EGFR) inhibition in circulating cell-free DNA (KRAS, NRAS mutations).

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

ARM I: Patients receive cetuximab intravenously (IV) and irinotecan hydrochloride IV on days 1 and 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may cross over to Arm II.

ARM II: Patients receive cetuximab and irinotecan hydrochloride as in Arm I and vemurafenib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2-6 months for 3 years.

Arms:
arm 1: Patients receive cetuximab IV and irinotecan hydrochloride IV on days 1 and 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may cross over to Arm II. arm 2: Patients receive cetuximab and irinotecan hydrochloride as in Arm I and vemurafenib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: cetuximab intervention 2: irinotecan hydrochloride intervention 3: vemurafenib
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given PO

Protocol document:
Prot_SAP_ICF_000.pdf: 
 
 
 
 
 
 
 
 
 
Distribution Date: 
July 1, 2017 
E-mailed Date: 
June 28, 2017 
 
 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
 
FROM: 
Danae Campos, Protocol Coordinator (E-mail: dcampos@swog.org) 
 
 
RE: 
S1406, “Randomized Phase II Study of Irinotecan and Cetuximab 
with or without Vemurafenib in BRAF Mutant Metastatic Colorectal 
Cancer.”  Study Chairs: S. Kopetz, H-J. Lenz, and A. Magliocco. 
 
MEMORANDUM 
 
Study Chair:  Scott Kopetz, M.D., Ph.D. 
Phone number: 713/792-2828 
E-mail: skopetz@mdanderson.org 
 
IRB Review Requirements 
(  ) No review required 
 
 
 
MEMORANDUM 
 
This memorandum serves as notification to sites as an update on the safety of 
vemurafenib. New risks have been associated with the study drug as noted in 
the attached letter. A revision with these new risks is forthcoming. 
 
Please inform patients and exercise caution as outlined in the attached letter 
and according to guidance from your IRB. 
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
 
cc:  
PROTOCOL & INFORMATION OFFICE 
Elliott Lee - Biologics Inc. 
NCI Coop Coverage - Genentech 






 
 
 
 
 
 
March 15, 2017 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Vemurafenib 
 
MEMORANDUM 
 
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: 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug vemurafenib. Please access these safety reports 
via the study’s abstract page or the safety report link on the SWOG website  
(https://swog.org/safetyreports/safetyreports.asp). 
 
These safety reports pertain to 
the following study: 
 
 
S1406 Gastrointestinal 
Reports:
 
 
Jan. 05, 2017 
AER1425062 
Jan. 10, 2017 
AER1871130 
Jan. 23, 2017 
AER1882493 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 


IND Safety Reports for Vemurafenib 
Page 2 
 
 
 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Elliott Lee – Biologics 
NCI Coop Coverage – Genentech 
 


 
 
 
 
 
 
 
 
 
Distribution Date: March 1, 2017 
E-mail Date 
February 16, 2017 
 
 
 
TO:  
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
 
FROM:  
SWOG Operations Office 
 
 
RE:  
Change in e-mail address for Biologics, Inc. 
 
MEMORANDUM 
 
IRB Review Requirements 
(   ) 
Full board review required    
(   ) 
Expedited review allowed 
(  ) No review required  
 
 
MEMORANDUM 
 
The purpose of this memorandum is to alert sites to a change in email address for 
Biologics, Inc., the drug distributor for the following studies: 
 
S1014 
S1216 
S1304 
S1313 
S1403 
S1406 
S1602 
 
Beginning February 20th, 2017, the email address clinicaltrials@biologicsinc.com will no 
longer be valid and clinicalresearchservices@biologicsinc.com will no longer be 
accepting drug order submissions. 
  
Please ensure all clinical trial drug order submissions that are emailed are being 
addressed to CRSorders@biologicsinc.com; all other communication outside of drug 
order 
submissions 
may 
continue 
to 
be 
addressed 
to 
clinicalresearchservices@biologicsinc.com.     
  
Please note CRSorders@biologicsinc.com will only allow for inbound submission. If you 
require a response to an inquiry regarding an order please ensure it is addressed to 
clinicalresearchservices@biologicsinc.com. 
  
Drug orders submitted via fax to 919-256-0794 will still be processed as usual. 
 
cc: PROTOCOL & INFORMATION OFFICE 
 


 
 
 
 
 
 
 
February 1, 2017 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
FROM: 
Danae Campos, Protocol Coordinator (E-mail: dcampos@swog.org) 
 
RE: 
S1406, “Randomized Phase II Study of Irinotecan and Cetuximab with 
or without Vemurafenib in BRAF Mutant Metastatic Colorectal Cancer.”  
Study Chairs: S. Kopetz, H-J. Lenz, and A. Magliocco. 
 
MEMORANDUM 
 
Study Chair:  Scott Kopetz, M.D., Ph.D. 
Phone number: 713/792-2828 
E-mail: skopetz@mdanderson.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:  
 
 
MEMORANDUM 
 
The purpose of this memorandum is to document that the drug Vemurafenib 
distributed under lots M1074 and M1076 will expire at the end of February 2017. 
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
 
cc:  
PROTOCOL & INFORMATION OFFICE 
Elliott Lee - Biologics Inc. 
NCI Coop Coverage - Genentech 


 
 
 
 
 
 
December 15, 2016 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
FROM: 
SWOG Operations Office 
 
RE: 
S1406, “Randomized Phase II Study of Irinotecan and Cetuximab with 
or without Vemurafenib in BRAF Mutant Metastatic Colorectal Cancer.”  
Study Chairs: S. Kopetz, H-J. Lenz, and A. Magliocco. 
 
STATUS NOTICE 
 
Study Chair:  Scott Kopetz, M.D., Ph.D. 
Phone number: 713/792-2828 
E-mail: skopetz@mdanderson.org 
 
IRB Review Requirements 
(   ) 
Full board review required 
(  ) Expedited review allowed  
(   ) 
No review required 
 
Status Change 
(   )  IRB Review only 
(   )  Activation 
( X )  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:  
 
 
PERMANENT CLOSURE OF REGISTRATION STEP 2  
AND REGISTRATION STEP 3 
 
The purpose of this memorandum is to document that Registration Step 2 was 
effectively permanently closed on April 22, 2016, subsequent to the permanent 
closure of Registration Step 1 on April 1, 2016 (distributed on March 15, 2016), 
however a notice was never distributed.  
 
Registration Step 3 will also be permanently closed, effective December 29, 
2016 at 11:59pm PT. 
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
 
cc:  
PROTOCOL & INFORMATION OFFICE 
 
Elliott Lee - Biologics Inc. 
NCI Coop Coverage - Genentech 


 
 
 
 
 
 
December 15, 2016 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Vemurafenib 
 
MEMORANDUM 
 
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: 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug vemurafenib. Please access these safety reports 
via the study’s abstract page or the safety report link on the SWOG website  
(https://swog.org/safetyreports/safetyreports.asp). 
 
These safety reports pertain to 
the following study: 
 
 
S1406 Gastrointestinal 
Reports:
 
 
Nov. 28, 2016 Mfr Rpt #1610430 FU 
Nov. 30, 2016 Mfr Rpt #1840684 FU 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 


IND Safety Reports for Vemurafenib 
Page 2 
 
 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Elliott Lee – Biologics 
NCI Coop Coverage – Genentech 
 


 
 
 
 
 
 
December 1, 2016 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Vemurafenib 
 
MEMORANDUM 
 
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: 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug vemurafenib. Please access these safety reports 
via the study’s abstract page or the safety report link on the SWOG website  
(https://swog.org/safetyreports/safetyreports.asp). 
 
These safety reports pertain to 
the following study: 
 
 
S1406 Gastrointestinal 
Reports:
 
 
Jul.   15, 2016 Mfr Rpt #1781618 
Jul.   26, 2016 Mfr Rpt #1793468 
Sep. 26, 2016 Mfr Rpt #1170815 FU 
Oct.  13, 2016
Mfr Rpt #1840684 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 


IND Safety Reports for Vemurafenib 
Page 2 
 
 
 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Elliott Lee – Biologics 
NCI Coop Coverage – Genentech 
 


 
 
 
 
 
 
Distribution Date: 
December 1, 2016 
CTEP Submission Date: 
November 10, 2016 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
FROM: 
SWOG Operations Office 
 
RE: 
S1406, “Randomized Phase II Study of Irinotecan and Cetuximab with 
or without Vemurafenib in BRAF Mutant Metastatic Colorectal Cancer.”  
Study Chairs: S. Kopetz, H-J. Lenz, and A. Magliocco. 
 
REVISION #4 
 
Study Chair:  Scott Kopetz, M.D., Ph.D. 
Phone number: 713/792-2828 
E-mail: skopetz@mdanderson.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 
 
Updates for the translational medicine component of the above-noted study have 
been made as follows: 
 
1. 
Title Page, Page 1:  The version date of the protocol and model consent 
form have been updated.  
 
2. 
Section 1.4g, Page 7: The text in the parentheses “(KRAS, NRAS 
mutations)” was removed. 
 
3. 
Section 11.5f, Page 47: A sentence was added to indicate that analysis of 
plasma samples at baseline, during therapy, and at the time of progression 
will be done across all arms (including Arm 3).  Subsequent points were 
renumbered. 


 
S1406 
 
Revision #4 (contd.) 
 
Page 2 
 
 
 
 
4. 
Section 11.5g, Page 47:  A sentence was added to indicate that analysis of plasma 
samples at baseline and at the time of progression will be done on all arms (including 
progression on Arm 3).  Subsequent points were renumbered. 
 
5. 
Section 18.2b.4, Page 77:  Paragraph one was revised to indicate that Foundation 
Medicine will perform the gene sequencing. 
 
Paragraph 2, first sentence:  The number of FFPE slides to be used for DNA analysis was 
changed from 3 to 6 and “300 ng DNA” was changed to “600 ng DNA”. 
 
Paragraph 2, second sentence:  The text “might be examined” was changed to “will be 
examined”, MSI status and mutation load was added and “FoundationOne® Next 
Generation” referenced as the sequencing panel to be used. 
 
Paragraph 2, third sentence: The sentence outlining potential plans regarding genes that 
will be examined and technologies to be used was deleted. 
 
Paragraph 3:  The sentence referring to retrospective Cobas version 2.0 testing to validate 
IHC was deleted. 
 
Paragraph 5, first sentence: The sentence was updated to reflect “NGS assay” will be 
used instead of “BEAMing assay”, digital droplet PCR will be performed and MD Anderson 
and Guardant Health listed as potential labs to conduct the plasma analysis. 
 
6. 
Section 18.2c, Page 77: The following changes were made in the first paragraph: 
Second bullet:  “hMLH1” was added prior to “IHC”. 
Third bullet: 
Guardant Health (Redwood City, CA) was added as a potential lab to 
perform circulating cell-free DNA analysis. 
Fourth bullet: 
FoundationOne® NGS multigene panel” replaces “Cobas sequencing” and 
“Foundation Medicine” replaces “Genentech/Roche Molecular Diagnostics”. 
 
Second paragraph:  Number of slides and amount of DNA needed for various studies was 
updated. 
 
Third paragraph:  “Cobas 2.0 analysis” was removed from list of tests to be conducted. 
 
Model Informed Consent 
 
The screening and accrual goals referenced in the consent form for Step 1 and Step 2 were 
inadvertently not updated when Section 11.1 was changed (see Revision #3, distributed 1/15/16). 
Therefore, the consent forms are being updated at this time. 
 
Consent Form – Step 1, page 3:  Under, “Why is this study being done?”, the second paragraph 
was changed from “We expect that about 440 patients will get this screening for this study and 
expect that about 78 patients will go on to the treatment part of the study” was changed to “We 
expect that about 163 patients will get this screening for this study and expect that about 105 
patients will go on to the treatment part of the study.” 
 
Consent Form – Step 2, page 11:  Under, “Why is this study being done?”, the last sentence of the 
first paragraph was changed from “There will be about 78 people taking part in this study” to “There 
will be about 105 people taking part in this study.” 
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
 
cc:  
PROTOCOL & INFORMATION OFFICE 
Elliott Lee - Biologics Inc. 
NCI Coop Coverage - Genentech 


 
 
 
 
 
 
August 1, 2016 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Vemurafenib 
 
MEMORANDUM 
 
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: 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug vemurafenib. Please access these safety reports 
via the study’s abstract page or the safety report link on the SWOG website  
(https://swog.org/safetyreports/safetyreports.asp). 
 
These safety reports pertain to 
the following study: 
 
 
S1406 Gastrointestinal 
Reports:
 
 
Mar. 29, 2012 Mfr Rpt #802100 
Jun. 03, 2016 
Mfr Rpt #1523326 FU 
Jun. 13,2016  
Mfr Rpt #1444937 FU 
Jun. 29, 2016 
Mfr Rpt #1610430 FU 
Jun. 29, 2016 
Mfr Rpt #1611016 FU 
Jul.  04, 2016
Mfr Rpt #1730135 FU 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 


IND Safety Reports for Vemurafenib 
Page 2 
 
 
 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Elliott Lee – Biologics 
NCI Coop Coverage – Genentech 
 


 
 
 
 
 
 
 
 
July 1, 2016 
 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
FROM: 
Kimberly F. Kaberle, Protocol Coordinator (E-mail:  kkaberle@swog.org) 
 
RE: 
S1406, “Randomized Phase II Study of Irinotecan and Cetuximab with or 
without Vemurafenib in BRAF Mutant Metastatic Colorectal Cancer.”  Study 
Chairs: S. Kopetz, H-J. Lenz, and A. Magliocco. 
 
MEMORANDUM 
 
Study Chair:  Scott Kopetz, M.D., Ph.D. 
Phone number: 713/792-2828 
E-mail: skopetz@mdanderson.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: 
 
 
MEMORANDUM 
 
The purpose of this memorandum is to inform sites that the shelf life of vemurafenib 
batch M1076 has been extended. Please see attached notice for additional information. 
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
 
cc:  
PROTOCOL & INFORMATION OFFICE 
Elliott Lee - Biologics Inc. 
NCI Coop Coverage - Genentech 




 
 
 
 
 
 
June 15, 2016 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Vemurafenib 
 
MEMORANDUM 
 
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: 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug vemurafenib. Please access these safety reports 
via the study’s abstract page or the safety report link on the SWOG website  
(https://swog.org/safetyreports/safetyreports.asp). 
 
These safety reports pertain to 
the following study: 
 
 
S1406 Gastrointestinal 
Reports:
 
 
Mar. 28, 2016 Mfr Rpt #1730135 
May 04, 2016 
Mfr Rpt #1546842 
May 18, 2016
Mfr Rpt #1697226 FU 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 


 
IND Safety Reports for Vemurafenib 
Page 2 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
cc: 
PROTOCOL & INFORMATION OFFICE 
Elliott Lee – Biologics 
NCI Coop Coverage – Genentech 


 
 
 
 
 
May 15, 2016 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Vemurafenib 
 
MEMORANDUM 
 
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: 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug vemurafenib. Please access these safety reports 
via the study’s abstract page or the safety report link on the SWOG website 
(https://swog.org/safetyreports/safetyreports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S1406 Gastrointestinal 
Reports: 
 
 
Jan. 06, 2016 
Mfr Rpt #1468479 FU 
Jan. 12, 2016 
Mfr Rpt #1655508 FU 
Jan. 13, 2016 
Mfr Rpt #1683112 
Jan. 14, 2016 
Mfr Rpt #1689416 
Feb. 03, 2016 Mfr Rpt #1683112 FU 
Feb. 05, 2016 Mfr Rpt #1485799 FU 
Feb. 17, 2016 Mfr Rpt #1697226 
Feb. 22, 2016 Mfr Rpt #1426019 FU 


S1406 
IND Safety Reports for Vemurafenib 
Page 2 
 
 
Feb. 23, 2016 Mfr Rpt #1709035 
Mar. 01, 2016 Mfr Rpt #1605498 FU 
Mar. 16, 2016 Mfr Rpt #1697226 FU 
Mar. 18, 2016 Mfr Rpt #1560245 FU 
Mar. 18, 2016 Mfr Rpt #1709035 FU 
 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Elliott Lee – Biologics 
NCI Coop Coverage – Genentech 


 
 
 
 
 
 
 
 
April 1, 2016 
 
 
 
 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
 
FROM: 
Kimberly F. Kaberle, Protocol Coordinator (E-mail:  kkaberle@swog.org) 
 
 
RE: 
S1406, “Randomized Phase II Study of Irinotecan and Cetuximab with or 
without Vemurafenib in BRAF Mutant Metastatic Colorectal Cancer.”  Study 
Chairs: S. Kopetz, H-J. Lenz, and A. Magliocco. 
 
MEMORANDUM 
 
Study Chair:  Scott Kopetz, M.D., Ph.D. 
Phone number: 713/792-2828 
E-mail: skopetz@mdanderson.org 
 
IRB Review Requirements 
 
(   ) 
Full board review required.  Reason: 
(   ) 
Initial activation (should your institution choose to participate) 
(   ) 
Increased risk to patient 
(   ) 
Complete study redesign 
(   ) 
Addition of tissue banking requirements 
(   ) 
Study closure due to new risk information 
 
(    ) Expedited review allowed 
 
( √ ) No review required 
 
 
MEMORANDUM 
 
The purpose of this memorandum is to inform sites that the shelf life of vemurafenib 
batch M1074 has been extended. Please see attached notice for additional information. 
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
 
cc:  
PROTOCOL & INFORMATION OFFICE 
Elliott Lee - Biologics Inc. 
NCI Coop Coverage - Genentech 




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7


 
 
S1406 
 
Page 1 
 
Version Date 11/10/16 
 
 
 
PRIVILEGED COMMUNICATION 
Distributed for IRB Review Only 9/24/14 
FOR INVESTIGATIONAL USE ONLY 
Activated November 13, 2014 
 
 
SWOG 
 
RANDOMIZED PHASE II STUDY OF IRINOTECAN AND CETUXIMAB WITH OR WITHOUT 
VEMURAFENIB IN BRAF MUTANT METASTATIC COLORECTAL CANCER 
 
 
NCT #02164916 
 
STUDY CHAIRS: 
AGENTS: 
 
Scott Kopetz, M.D., Ph.D. (Medical Oncology) 
IND-Exempt Agents: 
UT MD Anderson Cancer Center 
Cetuximab (NSC-714692) 
1515 Holcombe Blvd 
Irinotecan (Camptosar®)(NSC-616348) 
Department of GI Med Onc, Unit 426 
 
Houston, TX 77030 
SWOG-Held IND Agents: 
Phone: 713/792-2828 
Vemurafenib (NSC-761431) (IND-122167) 
FAX: 713/745-1163 
E-mail: skopetz@mdanderson.org   
 
Heinz-Josef Lenz, M.D. (Translational Medicine) 
NCTN INVESTIGATORS: 
University of Southern California 
Norris Comprehensive Cancer Center 
Luis Diaz, M.D. (ECOG-ACRIN) 
1441 Eastlake Avenue 
Ludwig Center for Genetics and Therapeutics 
Los Angeles, CA 90033 
1650 Orleans St., Rm 590 
Phone: 323/865-3955 
Baltimore, MD 21231 
FAX: 323/865-0061 
Phone: 410/95-8878 
E-mail: lenz@usc.edu  
FAX: 410/955-0548 
 
E-mail: ldiaz1@jhmi.edu  
Anthony Magliocco (Translational Medicine) 
H Lee Moffitt Cancer Center 
Chloe Atreya (ALLIANCE) 
Department of Pathology 
UC San Francisco 
12902 Magnolia Dr. 
1600 Divisadero St, 4th Floor 
Tampa, FL 33612 
San Francisco, CA 94115 
Phone: 813/745-3980 
Phone: 415/353-9888 
FAX: 813/745-2689 
FAX: 415/353-9636 
E-mail: anthony.magliocco@moffitt.org 
E-mail: chloe.atreya@ucsf.edu  
 
 
BIOSTATISTICIANS: 
Carmen Allegra (NRG) 
 
University of Florida, Cancer Pavilion 
Shannon McDonough, M.S. 
2000 SW Archer Rd. 
Katherine A. Guthrie, Ph.D. 
Gainesville, FL 32608 
SWOG Statistical Center 
Phone: 352/265-0725 
Fred Hutchinson Cancer Research Center 
FAX: 352/273-5006 
1100 Fairview Avenue N, M3-C102 
E-mail: carmen.allegra@medicine.ufl.edu  
P.O. Box 19024 
Phone: 206/667-4623 
FAX: 206/667-4408 
E-mail: smcdonou@fhcrc.org  
E-mail: kguthrie@fhcrc.org 
 
 


 
S1406 
 
Page 2 
 
Version Date 11/10/16 
 
 
 
 
 
 
PARTICIPANTS 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
 
NRG/NRG Oncology 
 
SWOG/SWOG 
 
 
 
 


 
S1406 
 
Page 3 
 
Version Date 11/10/16 
 
 
 
TABLE OF CONTENTS 
 
PARTICIPANTS ............................................................................................................................................ 2 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 5 
SCHEMA ....................................................................................................................................................... 6 
1.0 
OBJECTIVES .................................................................................................................................. 7 
1.1 
Primary Objective ............................................................................................................................. 7 
1.2 
Secondary Objectives ...................................................................................................................... 7 
1.3 
Other Objectives .............................................................................................................................. 7 
1.4 
Translational Objectives ................................................................................................................... 7 
2.0 
BACKGROUND ............................................................................................................................... 8 
3.0 
DRUG INFORMATION .................................................................................................................. 11 
3.1 
Cetuximab (IMC-C225, Erbitux®) (NSC-714692) ........................................................................... 11 
3.2 
Irinotecan (Camptosar ®) (NSC616348) ....................................................................................... 14 
3.3 
Vemurafenib (Zelboraf®) (NSC-761431) (IND-122167) ................................................................. 15 
4.0 
STAGING CRITERIA ..................................................................................................................... 20 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 21 
5.1 
Step 1 Initial Registration: BRAFV600E Testing ............................................................................... 21 
5.2 
Step 2 Randomization .................................................................................................................... 23 
5.3 
Step 3 Crossover Registration ....................................................................................................... 25 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 26 
6.1 
Stratification Factors ...................................................................................................................... 26 
6.2 
Randomization ............................................................................................................................... 26 
7.0 
TREATMENT PLAN ...................................................................................................................... 26 
7.1 
Pre-Medication * ............................................................................................................................. 26 
7.2 
Treatment – Arm 1 ......................................................................................................................... 26 
7.3 
Treatment – Arm 2 ......................................................................................................................... 27 
7.4 
Drug Compliance Documentation .................................................................................................. 27 
7.5 
Crossover following disease progression on Arm 1 ....................................................................... 27 
7.6 
Criteria for Removal from Protocol Treatment ............................................................................... 28 
7.7 
Discontinuation of Treatment ......................................................................................................... 28 
7.8 
Follow-Up Period ............................................................................................................................ 28 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS .............................................. 28 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 28 
8.2 
General Considerations ................................................................................................................. 29 
8.3 
Dose Modifications ......................................................................................................................... 29 
8.4 
Dose Modifications Contacts ......................................................................................................... 35 
8.5 
Adverse Event Reporting ............................................................................................................... 35 
9.0 
STUDY CALENDAR ...................................................................................................................... 35 
9.1  
Arm 1: Cetuximab + Irinotecan ...................................................................................................... 36 
9.2  
Arm 2: Cetuximab + Irinotecan + Vemurafenib .............................................................................. 37 
9.3  
Arm 3: Cetuximab + Irinotecan + Vemurafenib .............................................................................. 38 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ..................................................... 40 
10.1  
Measurability of Lesions................................................................................................................. 40 
10.2  
Objective Status at Each Disease Evaluation ................................................................................ 41 
10.3  
Best Response ............................................................................................................................... 42 
10.4 
Performance Status: ...................................................................................................................... 43 
10.5 
Progression-Free Survival.............................................................................................................. 43 
10.6 
Time to Death ................................................................................................................................. 44 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 44 
11.1 
Accrual Goals ................................................................................................................................. 44 
11.2 
Primary Analysis and Power Justification ...................................................................................... 44 
11.3 
Other Analyses ............................................................................................................................... 45 
11.4 
Data and Safety Monitoring ........................................................................................................... 45 
11.5 
Translational Medicine ................................................................................................................... 45 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 48 


 
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13.0 
REGISTRATION GUIDELINES ..................................................................................................... 48 
13.1 
Registration Timing ........................................................................................................................ 48 
13.2 
Investigator/Site Registration ......................................................................................................... 49 
13.3 
OPEN Registration Requirements ................................................................................................. 49 
13.4 
Registration Procedures................................................................................................................. 50 
13.5 
Exceptions to SWOG registration policies will not be permitted .................................................... 51 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 52 
14.1 
Data Submission Requirement ...................................................................................................... 52 
14.2 
Master Forms ................................................................................................................................. 52 
14.3 
Data Submission Procedures ........................................................................................................ 52 
14.4 
Data Submission Overview and Timepoints .................................................................................. 53 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 56 
15.1 
SWOG Specimen Tracking System (STS) .................................................................................... 57 
15.2  
Specimens for BRAF V600 testing (required for patients) ............................................................. 57 
15.3  
Specimens for translational medicine and correlative studies (required for patients) ................... 58 
15.4 
Specimens for Translational Medicine: Co-Clinical PDX Model Trial (optional for patients) ......... 59 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 61 
16.1 
Adverse Event Reporting Requirements........................................................................................ 61 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 68 
18.0 
APPENDIX ..................................................................................................................................... 72 
18.1 
Determination of Expedited Adverse Event Reporting Requirements ........................................... 73 
18.2 
Translational Medicine ................................................................................................................... 75 
18.3  
Inhibitors/Inducers of CYP3A4 & CYP1A2 and QTc Prolonging Medications ............................... 78 
 
 
 
 
 


 
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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 for 
instructions on 
using the OPEN 
system. 
 
Online Data Submission:  This protocol will 
use Medidata Rave® for electronic data 
submission.  Access Rave® using your active 
CTEP-IAM userid and password at the 
following url: 
 
https://login.imedidata.com/selectlogin 
 
Other Tools and Reports:  Institutions 
participating through the CTSU continue to 
have access to other tools and reports 
available on the SWOG Workbench.  Access 
this by using your active CTEP-IAM userid 
and password at the following url: 
 
https://crawb.crab.org/TXWB/ctsulogon.aspx 
 
The study protocol and all related forms and documents must be downloaded from the protocol-
specific Web page of the CTSU Member Web site located at https://www.ctsu.org. Sites must use the 
current form version and adhere to the instructions and submission schedule outlined in the protocol. 
 
CTSU sites should follow procedures outlined in the protocol for Site registration, Patient Enrollment, 
Adverse Event Reporting, Data Submission (including ancillary studies), and Drug Procurement. 
 
For patient eligibility questions contact the SWOG Data Operations Center by phone or email: 
 
206-652-2267 
giquestion@crab.org 
 
For treatment or toxicity related questions contact the Study PI of the Coordinating Group. 
 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help 
Desk by phone or e-mail: 
 
888-823-5923 
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 
 
The CTSU Web site is located at https://www.ctsu.org 
 
 


 
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SCHEMA 
 
Metastatic adenocarcinoma of the colon or rectum 
 
 
 
Patient needs BRAF  
 
 
BRAF results available 
testing for V600E mutation 
and patient has V600E mutation* 
 
 
 
STEP 1 INITIAL REGISTRATION 
STEP 1 INITIAL REGISTRATION 
 
  and submission of specimen   
 
 
 
 
  for V600E mutation in BRAF per Section 15.1 
 
 
 
 
 
       BRAF V600E mutant 
 
 
 
 
No 
 
 
Yes 
 
 
      
 
     No follow-up 
 
 
STEP 2 RANDOMIZATION 
 
 
 
Arm 1: Cetuximab + Irinotecan  
 
Arm 2: Vemurafenib + Cetuximab + Irinotecan 
 
 
  
PROGRESSION 
ANY OTHER 
PROGRESSION, SYMPTOMATIC 
REASON** 
DETERIORATION, ANY OTHER 
 
REASON**, DEATH 
 
 
 
 (Optional) 
STEP 3 CROSSOVER 
     REGISTRATION:  
OFF TREATMENT 
OFF TREATMENT 
  Arm 3:  Vemurafenib  
+Cetuximab + Irinotecan 
 
 
 
PROGRESSION, SYMPTOMATIC  
 DETERIORATION, ANY OTHER 
*NOTE: If patient has BRAF results available from CLIA- 
          REASON**, DEATH 
certified laboratory, Step 1 Initial Registration and Step 2  
 
Randomization occur at the same time. BRAF results  
 
must be submitted to SWOG.  
          OFF TREATMENT 
 
 
** See Section 7.6. 
 


 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
To evaluate the progression-free survival (PFS) of BRAF mutant metastatic colorectal 
cancer patients treated with irinotecan, cetuximab, and vemurafenib, compared to a 
control arm of irinotecan and cetuximab. 
 
1.2 
Secondary Objectives 
 
a. 
To evaluate the frequency and severity of toxicity associated with each of the 
treatment arms in this patient population. 
 
1.3 
Other Objectives 
 
a. 
To evaluate overall survival (OS) in treatment Arms 1 and 2. 
 
b. 
To evaluate the overall response rate (ORR), including confirmed and 
unconfirmed, complete and partial response, in treatment Arms 1 and 2 in the 
subset of patients with measurable disease. 
 
c. 
To estimate rates of OS, ORR, and PFS in patients who register to Arm 3 after 
disease progression on Arm 1.  
 
1.4 
Translational Objectives 
 
a. 
To evaluate genetic alterations, including low-frequency KRAS or NRAS 
mutations (definitive list of genes to be finalized after completion of enrollment 
based on latest scientific knowledge) as detected by high-depth sequencing as 
predictive biomarkers of efficacy. 
 
b. 
To evaluate PIK3CA pathway activation through PIK3CA mutations or PTEN 
protein loss as a predictive biomarker of innate resistance to this regimen.  
 
c. 
To evaluate gene expression signatures from screened patients with BRAFWT 
and BRAFV600E tumors. 
 
d. 
To provide validation of BRAF IHC using complementary sequencing 
methodology from screened patients with BRAFWT and BRAFV600E tumors. 
 
e. 
To confirm the estimated sensitivity of detectable BRAF V600E circulating cell-
free DNA as a non-invasive biomarker for BRAF V600E mutation as detected by 
IHC in the primary tumor. 
 
f. 
To correlate radiographic tumor response with change in quantification of BRAF 
V600E alleles in circulating cell-free DNA. 
 
g. 
To monitor for known mechanism of acquired resistance to EGFR inhibition in 
circulating cell-free DNA. 
 
h. 
To assess the correlation of treatment efficacy between the patients and the 
matched patient-derived xenograft (PDX) models. 
 
i. 
To assess the correlation between PDX mechanisms for resistance and 
circulating free DNA (cfDNA) in plasma samples of matched patients following 
progression of disease. 


 
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2.0 
BACKGROUND 
 
BRAF-mutations in metastatic colorectal cancer: Mutations in the BRAF oncogene are 
present in 5-10% of all human cancers and occur most frequently in melanoma (approximately 
50%), colorectal cancer (7-10%), papillary thyroid cancer (45-50%), non-small cell lung cancer 
(3%), and serous ovarian cancers (30%). (1-8)  Throughout all tumor types, the BRAF mutation 
manifests itself in over approximately 90% of cases as a valine-to-glutamic acid substitution in 
amino acid 600 of the kinase (V600E), which leads to a BRAF kinase domain ten-times more 
active than its BRAF wild-type counterpart and promotes tumor formation and growth via 
constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway. (1) 
Colorectal cancer remains the second leading cause of cancer mortality in the United States, with 
over 50,000 estimated deaths in 2012. (9)  As stated above, BRAF mutations occur in fewer than 
10% of all these tumors.  These mutations are typically associated with older age at the time of 
diagnosis, female gender, right-sided primary location, gene hypermethylation, and microsatellite 
instability. (10,11)  Additionally, the presence of a BRAF mutation is widely accepted as a poor 
prognostic marker in patients with metastatic colorectal cancer. (12-16) Multiple retrospective 
reviews have reported that, for patients with Stage II and III BRAF-mutated tumors, recurrence-
free survival and overall survival following surgical resection are historically worse than for their 
BRAF wild-type counterparts. (17,18) One retrospective study reported a median overall survival 
of 10 months for patients with Stage IV disease with BRAF-mutated tumors, significantly worse 
than the 34.7 months for patients with metastatic, BRAF wild-type colorectal cancer. (19)  
 
Inefficacy of BRAF inhibitors as monotherapy in BRAF-mutated colorectal cancer: 
Vemurafenib is a selective kinase inhibitor of the mutated V600E BRAF kinase that has no 
activity against the wild-type BRAF kinase domain. In a Phase I trial of patients with BRAF-
mutated metastatic colorectal cancer, a partial response was noted in a single patient among 21 
patients treated with the BRAF inhibitor (response rate < 5%). (20) Therefore, there is a dire need 
to introduce novel, effective treatment options for patients with BRAF-mutated metastatic 
colorectal cancer. 
 
Blockade of BRAF and EGFR as a novel approach in BRAF-mutated colorectal cancer: Two 
papers have provided important insight into the mechanisms driving innate resistance to 
vemurafenib in BRAF-mutated metastatic colorectal cancer.  Prahallad and colleagues used short 
hairpin RNA (shRNA) sequences on a kinase library screen in BRAF-mutated colorectal cancer 
cell lines treated with vemurafenib and found that the shRNA vectors targeting the epidermal 
growth factor receptor (EGFR) resulted in a synergistic inhibition of cell growth. (21)  Based on 
these findings, the group next treated three different BRAF-mutated colorectal cell lines with a 
combination of vemurafenib and one of two classes of available anti-EGFR therapies – 
cetuximab, a monoclonal antibody against EGFR, or gefitinib, a small molecule tyrosine kinase 
inhibitor of EGFR – and found a strong synergistic interaction between the two therapies.  Of 
note, a low response was seen when either vemurafenib or anti-EGFR therapy (cetuximab or 
gefitinib) was used as a single-agent therapy.  Interestingly, a drastic increase in expression of 
phosphorylated EGFR was detected when cells were treated with vemurafenib alone, a finding 
which generated the hypothesis that treatment with a BRAF inhibitor may induce a reflexive 
activation of EGFR needed to maintain activity of the MAPK signaling cascade and hinder 
cytotoxicity from vemurafenib monotherapy.  Concomitant BRAF inhibition and EGFR blockade 
resulted in a more complete suppression of Akt, MEK, and ERK phosphorylation relative to 
vemurafenib alone.   
 
In a second study, levels of phosphorylated ERK, a downstream kinase in the MAPK pathway, 
were initially decreased in BRAF-mutated colorectal cancer cell lines when treated with 
vemurafenib, but that re-expression of phospho-ERK could be detected within 24 hours of 
treatment with vemurafenib. (22)  Levels of phosphorylated CRAF also increased within 24 hours 
of BRAF inhibition, a finding suggesting that activated CRAF may bypass the blockade of BRAF 
by vemurafenib to maintain MAPK activity needed to perpetuate cell growth in vitro.  Treating  


 
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different BRAF-mutated colorectal cell lines with vemurafenib and gefitinib suppressed 
expression not only of phospho-EGFR but also of phospho-CRAF.  As phospho-EGFR was also 
expressed after treatment with vemurafenib alone, these experiments corroborate the idea that 
BRAF-mutated colorectal cells harbor resistance to vemurafenib by immediate upregulation of the 
MAPK pathway by activating EGFR. 
 
It has been shown that resistance to single-agent vemurafenib is associated with activated 
receptor tyrosine kinases, including EGFR, which may be responsible for initial resistance. In 
addition, exposing colon cancer cell lines to increasing and prolonged BRAF inhibition leads to 
acquired EGFR overexpression and acquired high level.  Murine studies that included BRAF + 
EGFR inhibition demonstrated that the combination of BRAF + EGFR inhibition led to tumor 
regression in 5 of 10 mice. (23) The addition of irinotecan to the combination resulted in tumor 
regression in 10 of 10 mice, compared to no regression (0/10 mice) with irinotecan and EGFR 
inhibition without BRAF inhibition.  Collectively, this data supports a combination approach of 
irinotecan with BRAF plus EGFR inhibition in colorectal cancer. 
 
In this study, the control arm of irinotecan plus cetuximab is utilized as a standard subsequent 
therapy for patients previously treated with a 5-FU combination of FOLFOX/XELOX, FOLFOXIRI, 
or FOLFIRI, commonly administered with bevacizumab.  Despite prior cohort studies suggesting 
lack of benefit of EGFR monoclonal antibodies in patients with BRAF mutant tumors, subsequent 
randomized studies demonstrated the poor prognosis of this cohort, but suggested maintained 
incremental benefit from EGFR inhibition. (24,25) These and other studies have also shown that 
addition of anti-EGFR therapies to standard chemotherapy regimens does not improve survival in 
patients with BRAF-mutated metastatic colorectal cancer, and thus this biomarker is not 
predictive for a survival benefit. (26,27)  
 
A Phase I trial is currently underway in which patients with advanced BRAF-mutated solid tumors 
are being treated with the combination of vemurafenib, cetuximab, and irinotecan.  As of 
1/31/2014, ten patients had been enrolled.  Nine of these patients had a diagnosis of colorectal 
cancer (the other with appendiceal adenocarcinoma and no neuroendocrine features).  Seven 
patients had been treated at dose level 1 (vemurafenib 480 mg by mouth twice daily, cetuximab 
500 mg/m2 every 14 days, and irinotecan 180 mg/m2 every 14 days), and three at dose level 2 
(vemurafenib increased to 720 mg by mouth twice daily).  At dose level 1, only one Grade 3 
adverse event has been observed (arthralgia) and resolved with dose reduction.  Of the five 
patients with metastatic CRC who have thus far been evaluated, responses have been detected 
in 4, with a reduction of tumor size of -44% (range 0-70%) as the median best response.  The 
durations of response in these patients have been 5, 5+, 8+, 12+, and 14+ cycles (data 
unpublished).  These results, although early, suggest that the combination of vemurafenib with 
irinotecan and cetuximab is well tolerated and may cause a biological response in patients with 
these tumors. 
 
In summary, patients with BRAF-mutated metastatic colorectal cancer have poor prognoses and 
demonstrate poor responses both to traditional chemotherapy combinations for colorectal cancer 
and to BRAF inhibitors which have demonstrated efficacy in other malignancies driven by BRAF 
mutations.  In vitro work has suggested that upregulation of EGFR in the presence of BRAF 
inhibition may generate a bypass mechanism through which these tumors may continue to 
survive and proliferate.  The addition of cetuximab in order to block EGFR has been shown in cell 
lines and in mice models to overcome EGFR activation and restore sensitivity to vemurafenib.  
Furthermore, adding the cytotoxic chemotherapeutic agent irinotecan generates added 
cytotoxicity with this combination, as seen with in vivo models.  Very preliminary Phase I results 
of the vemurafenib, cetuximab, and irinotecan combination intimate that these three drugs are 
safe for patients and may lead to promising results not seen before in this cohort of patients with 
colorectal cancer. 


 
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Patient-derived xenografts (PDXs) as improved models for studying human malignancy: 
PDXs serve as biologically relevant models for studying metastatic cancer which utilize 
immunosuppressed mice that are subcutaneously implanted with biopsied human tumor 
specimens. (40,41) This model maintains a higher degree of intratumoral heterogeneity and 
incorporates 
human 
stroma 
from 
the 
implanted 
tumor 
that 
recapitulates 
a 
tumor 
microenvironment.  In contrast, these attributes are not provided by tumor cells in culture or 
through homogenous cell-line derived xenografts.  Additionally, the PDX platform also maintains 
slower doubling times for tumor growth and higher number of available molecular subtypes.  
These properties enable the use of PDXs as more realistic models to investigate novel therapies 
and resistance mechanisms for other types of malignancies.  Prior work employing a PDX model 
of mCRC in a mock clinical trial comparing cetuximab with placebo showed similar outcomes to 
clinical trials in humans which had been run in an unmatched set of patients. (42-45) In addition, 
other retrospective series, in colorectal cancer and in other solid malignancies, have reported 
similarities in outcomes between patient responses to chemotherapy and tumor shrinkage in 
tumor xenografts. (46-48) However, the number of patients whose tumors were utilized was small 
and limits definitive conclusions to be made.  
 
While these examples hint that the PDX model retrospectively may be promising to recapitulate 
responses in humans across various types of malignancies, thus far correlations in outcomes 
between the PDX model and the matched patient are poorly understood in prospective analyses. 
If a correlation between patient response on this study and a response in the matched PDX 
model is observed, then these findings may serve as the initial rationale for the design of future 
clinical trials for patients.  
 
Inclusion of Women and 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.  
 
Note: We estimate that approximately 440 patients will be screened for BRAF V600E mutation in 
order to enroll the 78 patients necessary for the study. This table represents only the patients with 
the BRAF mutation who register to Step 2 (randomization). 
 


 
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Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
3 
3 
6 
Not Hispanic or Latino 
44 
55 
99 
Total Ethnic 
47 
58 
105 
Racial Category 
American Indian or Alaskan Native 
1 
1 
2 
Asian 
2 
2 
4 
Black or African American 
4 
4 
8 
Native Hawaiian or other Pacific Islander 
1 
1 
2 
White 
39 
50 
89 
Racial Category: Total of all Subjects 
47 
58 
105 
 
 
3.0 
DRUG INFORMATION 
 
Investigator’s Brochures  
 
For information regarding Investigator’s Brochures, please refer to SWOG Policy 15. 
 
For this study, cetuximab and irinotecan are commercially available; therefore, Investigator 
Brochures are not applicable to these drugs.  Information about commercial drugs is publicly 
available in the Physician’s Desk Reference (PDR), prescribing information and other resources. 
 
For this study, vemurafenib is investigational and is being provided under an IND held by SWOG. 
For INDs filed by SWOG, the protocol serves as the Investigator Brochure for the performance of 
the protocol. In such instances submission of the protocol to the IRB should suffice for providing 
the IRB with information about the drug. However, in cases where the IRB insists on having the 
official Investigator Brochure from the company, further information may be requested by 
contacting the SWOG Operations Office at 210/614-8808. 
 
3.1 
Cetuximab (IMC-C225, Erbitux®) (NSC-714692) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Cetuximab, a chimerized antibody of the IgG1 subclass, 
was originally derived from a mouse myeloma cell line.  Cetuximab was 
genetically engineered by cloning the heavy and light chains of cetuximab and 
adapting them for expression together with the constant regions of the human 
kappa light chain and human gamma 1 heavy chain.  The chimerization resulted 
in an antibody with binding affinity to epidermal growth factor receptors (EGFR) 
greater than the natural ligand epidermal growth factor (EGF).  Cetuximab blocks 
binding of EGF and transforming growth factor alpha (TGFα) to EGFR and 
inhibits ligand-induced activation of this tyrosine kinase receptor.  Cetuximab also 
stimulates EGFR internalization, effectively removing the receptor from the cell 
surface for interaction with ligand. 


 
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b. 
PHARMACOKINETICS 
 
1. 
Absorption: When cetuximab was administered as monotherapy or in 
combination with chemotherapy or radiation therapy it exhibited 
nonlinear pharmacokinetics.  The area under the concentration time 
curve (AUC) increased in a greater than dose proportional manner while 
the clearance decreased from 0.08 to 0.02 L/h/m2 as the dose increased 
from 20 to 200 mg/m2.  The clearance seemed to plateau at doses 
greater than 200 mg/m2. 
 
2. 
Distribution: The volume of distribution of cetuximab is independent of 
the dose and is approximately the plasma volume (2 to 3 L/m2).  When 
administered at the recommended dose regimen of 400 mg/m2 initial 
dose followed by 250 mg/m2 weekly dose, the concentration of 
cetuximab reached steady-state levels by the third weekly infusion with 
mean peak and trough concentrations in the range of 168 to 235 and 41 
to 85 mcg/mL, respectively. 
 
3. 
Metabolism: 
Cetuximab 
is 
eliminated 
via 
the 
EGFR 
binding/ 
internalization on hepatocytes and skin in a saturable manner. 
 
4. 
Elimination:  At the recommended dose regimen, the mean half-life of 
cetuximab was approximately 112 hours (range 63–230 hours). 
 
c. 
ADVERSE EFFECTS  
 
1. 
Possible Side Effects of Cetuximab 
 
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. 
 
Adverse effects reported in > 20% to 100% of subjects treated with 
cetuximab include: nail changes, radiation recall, rash, itching, dry skin, 
acne, dehydration, weight loss, anorexia, mucositis, constipation, 
diarrhea, vomiting, nausea, insomnia, headache, fatigue, pain, fever, 
infection, cough, and dyspnea. 
 
Adverse effects reported in 4% to 20% of subjects include: allergic 
reaction/hypersensitivity which may cause rash, hypotension, wheezing, 
shortness of breath, and swelling of the face or throat, confusion, 
depression, anxiety, syncope, sepsis, and pulmonary embolism. 
Adverse effects that are rare and serious that occurred in 3% or less of 
subjects 
include: 
interstitial 
lung 
disease, 
renal 
failure, 
and 
cardiopulmonary arrest and/or sudden death.  
 
Note: Cetuximab in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the 
other agent, or the combination may result in events never previously 
associated with either agent. 
 


 
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Additional information on common, serious, or severe reactions includes: 
 
Infusion Reactions:  In clinical trials, severe, potentially fatal infusion 
reactions were reported.  These events included the rapid onset of 
airway 
obstruction 
(bronchospasm, 
stridor, 
and 
hoarseness), 
hypotension, shock, loss of consciousness, myocardial infarction, and/or 
cardiac arrest.  Approximately 90% of severe infusion reactions occurred 
with the first infusion despite premedication with antihistamines. 
 
Dermatologic Toxicity:  In clinical studies of cetuximab, dermatologic 
toxicities, including acneiform rash, skin drying and fissuring, and 
inflammatory and infectious sequelae (e.g. blepharitis, conjunctivitis, 
keratitis, cheilitis, cellulitis, cyst), and hypertrichosis were reported. In 
patients with advanced colorectal cancer, acneiform rash was reported in 
88% (560/633) of all treated patients, and was severe (Grade 3 or 4) in 
12% (79/633) of these patients. Subsequent to the development of 
severe dermatologic toxicities, complications including S. aureus sepsis 
and abscesses requiring incision and drainage were reported. 
 
Non-suppurative 
acneiform 
rash 
described 
as 
“acne”, 
“rash”, 
“maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative 
dermatitis” was observed in patients receiving cetuximab plus irinotecan 
or cetuximab monotherapy. One or more of the dermatological adverse 
events were reported in 88% (14% Grade 3) of patients receiving 
cetuximab plus irinotecan and in 90% (10% Grade 3) of patients 
receiving cetuximab monotherapy. Acneiform rash most commonly 
occurred on the face, upper chest, and back, but could extend to the 
extremities and was characterized by multiple follicular- or pustular-
appearing lesions. Skin drying and fissuring were common in some 
instances, and were associated with inflammatory and infectious 
sequelae (e.g. blepharitis, cellulitis, cyst).  Two cases of S. aureus sepsis 
were reported.  The onset of acneiform rash was generally within the first 
two weeks of therapy. Although in a majority of the patients the event 
resolved following cessation of treatment, in nearly half of the cases, the 
event continued beyond 28 days. 
 
A related nail disorder, occurring in 14% of patients (0.3% Grade 3), was 
characterized as a paronychial inflammation with associated swelling of 
the lateral nail folds of the toes and fingers, with the great toes and 
thumbs as the most commonly affected digits. 
 
Hypomagnesaemia:  In patients treated with cetuximab during clinical 
trials, hypomagnesemia occurred in 55% of 365 patients with colorectal 
cancer and head and neck cancer, and was severe (NCI CTC Grades 3 
and 4) in 6–17%.  The addition of cetuximab to cisplatin and 5-fluoruracil 
resulted in an increased incidence of hypomagnesemia (14% vs. 6%) 
and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin 
and 5-fluorouracil alone.  The onset of hypomagnesemia and 
accompanying electrolyte abnormalities occurred days to months after 
initiation of cetuximab. 
 
2. 
Pregnancy and Lactation: Pregnancy Category C.  There are no 
adequate and well-controlled studies of cetuximab in pregnant women.  
Based on animal studies, EGFR has been involved in the control of 
prenatal development and may be essential for normal organogenesis,  


 
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proliferation, and differentiation in the developing embryo.  Human IgG is 
known to cross the placental barrier; therefore, if administered to a 
pregnancy woman, cetuximab may be transmitted from the mother to the 
developing fetus and has the potential to cause fetal harm  
 
It is not known whether cetuximab is secreted in human milk.  IgG 
antibodies, such as cetuximab, can be excreted in human milk and has 
the potential to cause serious adverse reactions in the nursing infant.  
Based on the mean half-life of cetuximab, nursing should not resume for 
at least 60 days following the last dose of cetuximab. 
 
3. 
Drug Interactions: There are no reports of drug interactions with 
cetuximab. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan  
 
e. 
HOW SUPPLIED  
 
Cetuximab is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert. 
 
f. 
STORAGE, PREPARATION & STABILITY 
 
Refer to the current FDA-approved package insert. 
 
3.2 
Irinotecan (Camptosar ®) (NSC616348) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Irinotecan and its metabolite SN-38 inhibit topoisomerase 
I. Topoisomerase I relieves torsional strain in the DNA helix during replication 
and RNA transcription by inducing single-strand breaks. By binding with the 
topoisomerase I—DNA complex, irinotecan or SN-38 prevents the religation of 
the single-strand breaks. Irreversible DNA damage occurs when a DNA 
replication fork encounters the irinotecan or SN-38/topoisomerase I complexes 
resulting in double-strand DNA breaks. Camptothecins are highly S-phase 
specific in their activity due the requirement of DNA synthesis. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: N/A 
 
2. 
Distribution: Protein binding of irinotecan is 30-70%, whereas SN-38 
shows a higher protein binding of 95%. Both irinotecan and SN-38 are 
primarily bound to albumin. Volume of distribution of irinotecan is 
approximately 110-234 L/m2. 
 
3. 
Metabolism: Irinotecan is metabolized primarily in the liver by 
carboxylesterase to SN-38, and via hepatic cytochrome P450 (CYP) 3A4 
to aminopentane carboxylic acid (APC). SN-38 is conjugated to form a 
glucuronide metabolite by the enzyme UDP-glucuronosyl transferase 
1A1 (UGT1A1). Genetic polymorphisms exist in the enzyme UGT1A1, 
leading to different levels of exposure and toxicity among patients.  In 
addition, both irinotecan and SN-38 undergo plasma hydrolysis between 
their active (lactone) and inactive forms (carboxylate). Finally, a small 
amount 
of 
irinotecan 
is 
metabolized 
by 
the 
intestinal 
wall. 


 
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4. 
Elimination: Approximately 10-25% of irinotecan is recovered unchanged 
in urine whereas only small amounts of SN-38 have been found. 
Clearance is approximately 13.5 L/hr/m2. In addition, irinotecan has 
approximately 25% biliary excretion. 
 
c. 
ADVERSE EFFECTS  
 
1. 
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. 
 
Adverse effects reported in > 20% to 100% of subjects treated with 
irinotecan include: diarrhea and cholinergic reaction (may be severe), 
constipation, 
nausea, 
vomiting, 
asthenia, 
infection, 
leukopenia, 
neutropenia, alopecia, anorexia, weight loss, anemia, fatigue,  fever, 
pain, dizziness, cough, dyspnea, mucositis, rash, thrombocytopenia. 
Adverse effects reported in 4% to 20% of subjects include: 
gastrointestinal perforation, hypersensitivity reaction, cardiovascular 
events, thromboembolic events, interstitial lung disease. 
 
2. 
Pregnancy and Lactation: Pregnancy Category D. It is not known 
whether irinotecan or its derivatives are excreted in human milk. 
 
3. 
Drug Interactions: Irinotecan and its active metabolite SN-38 may be 
substrates 
for 
CYP3A4, 
CYP2B6, 
OATP1B1/SCLO1B1, 
P-
glycoprotein/ABCB1 and UGT1A1. Inducers or inhibitors may affect 
serum concentrations of irinotecan. Drugs of strong CYP3A4 inducers 
should be discontinued for at least 2 weeks before starting irinotecan 
therapy.  Drugs of strong CYP3A4 inhibitors should be discontinued at 
least 1 week before starting irinotecan therapy.  St. John Wort and 
Ketoconazole are contraindicated during irinotecan therapy.  Due to 
potential drug interactions, a complete patient medication list, including 
irinotecan, should be screened prior to initiation of and during treatment 
with irinotecan. Refer to the current FDA-approved package insert. See 
Section 8.0 Toxicities to be Monitored and Dosage Modifications. 
 
d. 
DOSING & ADMINISTRATION 
 
Dosing – See Section 7.0 Treatment Plan  
 
e. 
HOW SUPPLIED  
 
Irinotecan is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert for additional information. 
 
f. 
STORAGE, PREPARATION & STABILITY 
 
Refer to the current FDA-approved package insert for storage, stability and 
special handling information. 
 
3.3 
Vemurafenib (Zelboraf®) (NSC-761431) (IND-122167) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Inhibitor of mutated forms of the BRAF serine-threonine 
kinase enzyme, including BRAF V600E, exhibiting anti-tumor effects in 
melanomas with mutated BRAF V600E. BRAF gene mutations may lead to cell 
proliferation in the absence of growth factors. 
 


 
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b. 
PHARMACOKINETICS 
 
1. 
Absorption: Time to peak ~3 hours 
 
2. 
Distribution: Vd ~106L, >99% protein binding 
 
3. 
Metabolism: Not appreciably metabolized in humans, however CYP3A4 
was the primary enzyme responsible for the metabolism of vemurafenib.  
Unchanged vemurafenib was the major component detected in plasma 
samples following oral administration. 
 
4. 
Elimination: Feces (94%) & urine (1%), half life elimination 57 hours (30-
120 hour range) 
 
c. 
ADVERSE EFFECTS  
 
1. 
Adverse Effects: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events with Possible Relationship to Vemurafenib 
Likely (>20%) 
Less Likely (4 – ≤20%) 
Rare but Serious (≤3%) 
CARDIAC DISORDERS 
 
Peripheral Edema 
Atrial fibrillation 
Hypotension 
Prolonged QT interval 
Retinal vein occlusion 
Vasculitis 
EYE DISORDERS 
 
 
Photosensitivity 
Photophobia 
Blurred vision 
Uveitis 
GASTROINTESTINAL DISORDERS 
Nausea 
Diarrhea 
Vomiting 
Decreased appetite 
Constipation 
Dysgeusia 
Colonic polyps 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fatigue 
Headache 
 
 
HEPATOBILIARY DISORDERS 
 
Increased gamma-glutamyl 
transferase 
Increased serum alkaline 
phosphatase 
Increased serum ALT 
Increased serum AST 
Increased serum bilirubin 
IMMUNE SYSTEM DISORDERS 
 
Allergic Reaction 
Anaphylaxis 
Hypersensitivity Reactions 
METABOLISM AND NUTRITION DISORDERS 
 
 
Weight loss 
MUSCULOSKELETAL AND CONNECTIVE TISSURE DISORDERS 
Arthralgia 
Myalgia 
Limb pain 
Back pain 
Musculoskeletal pain 
weakness 
Arthritis 


 
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QT Prolongation: Vemurafenib has been shown to increase the QT 
interval, leading to ventricular arrhythmias including Torsade de Pointes.  
Use with caution in patients who are taking concurrent QT prolonging 
medications or products. 
 
2. 
Pregnancy and Lactation: Pregnancy Category D. Vemurafenib may 
cause fetal harm. Adequate contraception methods should be 
implemented during and at least two months after treatment.  Excretion 
in breast milk is not known. 
 
3. 
Drug Interactions: In vitro studies have demonstrated that vemurafenib is 
a substrate of CYP3A4 (major). Use vemurafenib with caution when 
administered concurrently with potent CYP3A4 inhibitors or inducers, 
due to possible increased or decreased plasma concentrations of 
vemurafenib, respectively. Concomitant use of vemurafenib with drugs of 
narrow therapeutic windows that are metabolized by CYP3A4, CYP1A2, 
or CYP2D6 are not recommended.  If coadministration cannot be 
avoided, use caution and consider a dose reduction of CYP1A2 or 
CYP2D6 substrates.  Use caution and monitor INR when vemurafenib is 
given with warfarin. 
 
Use vemurafenib with caution with QT prolonging medications (e.g. 
antiarrhythmics, antipsychotic agents that prolong the QT interval, HIV 
protease inhibitors, moxifloxacin).  Consider therapy modification. 
 
Due to potential drug interactions, a complete patient medication list, 
including vemurafenib, should be screened prior to initiation of and 
during treatment with vemurafenib. See Section 8.0 Toxicities to be 
Monitored and Dosage Modifications. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan 
 
e. 
HOW SUPPLIED 
 
1. 
Vemurafenib is available as a 240 mg oral tablet in a bottle of 120 
tablets. 
 
NERVOUS SYSTEM DISORDERS 
 
 
Cranial nerve palsy (facial) 
Dizziness 
Peripheral neuropathy 
RENAL AND URINARY DISORDERS 
 
 
Increased serum creatinine 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Alopecia 
Pruritus 
Skin photosensitivity 
Rash 
Hyperkeratosis 
Skin neoplasm 
Squamous cell carcinoma of 
skin 
Maculopapular rash 
Xeroderma 
Sunburn 
Erythema 
Papular rash 
Malignant melanoma(new 
primary) 
Stevens-Johnson syndrome 
Toxic Epidermal Necrosis 


 
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2. 
Biologics Inc. from Genentech will supply commercial grade product 
labeled for investigational use vemurafenib. 
 
f. 
STORAGE, PREPARATION & STABILITY 
 
1. 
Tablets should be stored at room temperature (20o-25oC or 68o-77oF).  
Store in the original container with the lid tightly closed.  
 
2. 
Sites and subjects are advised to keep vemurafenib in its original 
container when feasible. If a container must be opened, repackage in a 
secure container, dispense a sufficient supply and store the remaining 
product in its original container.  Labeling should be done in accordance 
to the law and contain the statement “CAUTION: NEW DRUG – LIMITED 
BY FEDERAL LAW TO INVESTIGATIONAL USE.” 
 
3. 
Storage excursions are permitted to 15o-30oC or 59o-86oF.   
 
g. 
DRUG ORDERING & ACCOUNTABILITY 
 
1. 
Drug ordering:  
 
a. 
Vemurafenib may be requested by the Principal Investigator (or 
their authorized designee) by completing and faxing the 
Biologics Drug Request form for S1406.  The form should be 
faxed to the number listed on the order form.  Authorized and 
completed orders will be processed and shipped “same day” of 
receipt if received before 2:00 pm EST Monday through Friday. 
Authorized and completed orders received after 2:00 pm EST 
Monday through Friday will be processed and shipped the next 
business morning.  Packages are tracked until confirmed 
delivered and delivery exceptions are managed with the highest 
level of urgency to ensure therapy start date adherence.  
Packing slips with the shipment tracking number included will be 
faxed to the designated site coordinator for all shipments.  
Biologics will be closed for the following holidays: New Year’s 
Day, 
Memorial 
Day, 
Independence 
Day, 
Labor 
Day, 
Thanksgiving Day, Thanksgiving Friday, Christmas Eve, and 
Christmas Day.  
 
b. 
Once a patient is registered, the site will fax a completed Drug 
Request form to Biologics at 919/256-0794.  Upon receipt of 
faxed Drug Request form, Biologics will:  
 
1. 
Place a call or email to the site confirming the Drug 
Request form was received, while providing the estimated 
day and time of arrival of the study drug. 
 
2. 
Biologics will ship the requested quantity of bottles for 
the patient to complete their cycles of vemurafenib.  
During Month 5 and Month 11, biologics will place a call 
to the study site to arrange for the next shipment of 
study drug for the subsequent cycle.  


 
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3. 
All study drug will be shipped in original manufacturers 
packaging with a patient-specific label adhered to the 
outer packaging.  Biologics will place the manufacturer’s 
packaging in a resealable bag.  Each shipment includes 
a protocol  label on the resealable bag with the following 
information: 
 
• 
The Study Number (i.e., SWOG S1406); 
• 
SWOG Patient ID# 
• 
IND caution statement and/or local regulatory 
statements 
• 
Drug identification   
• 
Lot number and Expiration date 
• 
Dosing instructions (i.e., “Administer as directed per 
Protocol SWOG S1406”) 
• 
Storage instructions  
• 
Emergency contact instructions 
 
4. 
Once study drug is received at the clinical trial site, the 
designated site coordinator validates the contents of 
package and matches the information provided on 
packing slip, signs off on the packing slip, and faxes 
completed form to Biologics to validate shipment has 
been received and is accurate. 
 
NOTE:  The vemurafenib shipped is labeled either 
RO5185426 or PLX4032.  The vemurafenib Investigator 
Brochure indicates that it is also known as RO5185426 
and/or PLX4032. For editorial simplicity, the compound 
is referred to as vemurafenib in the Investigator 
Brochure.  Labeling may also include reference to 
Brafistus, which is an acronym for BRAF, IST 
(investigator sponsored trial), US. 
 
c. 
All drug orders are shipped via FedEx for Priority Overnight 
delivery for shipments to US sites. 
 
The Biologics distribution team monitors packages throughout 
duration of transit via Fed Ex website and FedEx One Call 
Solution (live support). Real-time monitoring enables the 
Biologics distribution team to mitigate potential delivery delays 
(e.g. misrouted packages).  
 
In the event a package cannot be delivered within the 24 hour 
time period (e.g., due to severe weather), Biologics’ distribution 
team works proactively with Fed Ex One-Call, confirming the 
exact location of the package and providing instruction to Fed-Ex 
to return the package to Biologics. Upon notification of a delayed 
shipment, a replacement shipment will be sent to the site, as 
authorized. Sites are also alerted “same day” to any delays in 
delivery and provided estimated time for arrival of replacement 
package.  The process for delayed deliveries including recovery 
strategies, are detailed in a Biologics SOP that may be provided 
upon approval of this proposal. All delivery exceptions will be 
reported via Accountability Reporting. 


 
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2. 
Drug Handling and Accountability (NCI logs or other) 
 
a. 
Drug Accountability: The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of 
the receipt, disposition, and return or disposal of all drugs 
received from the supplier using the 
NCI 
Oral Drug 
Accountability Record Form (NCI Oral DARF) available at 
http://ctep.cancer.gov.  
 
Questions about drug orders, transfers, returns, or accountability 
should be addressed to the Clinical Research Services at 
Biologics, Inc. at 800-693-4906 or  
Clinicalresearchservices@biologicsinc.com.  
 
b. 
Electronic logs are allowed as long as a print version of the log 
process is the exact same appearance as the current NCI Oral 
DARF.  
 
3. 
Drug return and/or disposition instruction  
 
a. 
Drug Return: At the conclusion of the study, remaining inventory 
is documented in the accountability records and unused drug will 
be destroyed per local institutional guidelines.. 
 
b. 
Drug expiration: If packaging does not have expiration date, 
check with drug ordering designee and/or PI to confirm receipt of 
ongoing stability testing letter. If packaging has an expiration 
date, indicate drug expiration date on the DARF and use the 
drug lots with shorter expiration date first. 
 
4. 
Questions about drug orders, transfers, returns, or accountability should 
be addressed to the Clinical Research Services at Biologics, Inc. at 800-
693-4906 or Clinicalresearchservices@biologicsinc.com. 
 
 
4.0 
STAGING CRITERIA 
 
Staging criteria are 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 Onstudy 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 4 weeks later would be considered Day 28.  This 
allows for efficient patient scheduling without exceeding the guidelines.  If Day 7 or 28 falls on a 
weekend or holiday, the limit may be extended to the next working day. 
 
SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
5.1 
Step 1 Initial Registration: BRAFV600E Testing 
 
 
If patient has already had BRAF testing, he or she must satisfy these eligibility criteria 
before being considered for Step 2 Randomization.  
 
 
a. 
Disease Related Criteria 
 
1. 
Patients 
must 
have 
histologically 
or 
cytologically 
documented 
adenocarcinoma of the colon or rectum that is either metastatic, or 
locally advanced and unresectable. NOTE:  In the event that both cecal 
and appendiceal primaries are considered, patient is eligible if it is 
concluded by the treating oncologist to most likely be cecal based on 
pathological, surgical, and clinical interpretation.  Clinical diagnosis must 
be clearly documented in the “Comments” section on the S1406 Onstudy 
Form. 
 
2. 
Patients must have BRAFV600E mutant status documented by a CLIA 
certified laboratory on a pathology report prior to Step 2 registration. Use 
of an FDA-approved test is preferred although other BRAF tests at a 
CLIA-certified laboratory will also be accepted.  
 
If a BRAFV600E mutation is known, then the patient must be registered to 
Step 2 Randomization immediately following Step 1 Initial Registration.  
 
If testing has not been performed locally, BRAFV600E testing must be 
completed by the central lab (see Section 15.1) prior to Step 2 
Randomization. If the specimen does not have a BRAFV600E mutation, the 
patient is ineligible for Step 2 Randomization. 
 
3. 
Brain metastases are allowed if they have been adequately treated with 
radiotherapy or surgery and stable for at least 90 days prior to Step 1 
Initial 
Registration. 
Eligible 
patients 
should 
be 
neurologically 
asymptomatic and without corticosteroid treatment for at least 7 days 
prior to Step 1 Initial Registration.  
 
4. 
Patients must have had one or two prior regimens of systemic 
chemotherapy for metastatic or locally advanced, unresectable disease. 
(A maintenance regimen of 5-fluorouracil or capecitabine, with or without 
bevacizumab, should not be counted as a separate line of treatment.) 
Prior treatment with irinotecan is allowed. Prior treatment for metastatic 
disease is not required for patients who experienced disease recurrence 
during or within 6 months of completion of adjuvant chemotherapy. 


 
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SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
5.1 
Step 1 Initial Registration: BRAFV600E Testing (contd.) 
 
5. 
Patients must not have been treated with any of the following prior to 
Step 1 Initial Registration: 
 
• 
Cetuximab, panitumumab, or any other monoclonal antibody against 
EGFR or inhibitor of EGFR. 
• 
BRAF inhibitor including, but not limited to, vemurafenib or dabrafenib. 
Regorafenib is not considered a BRAF inhibitor for the purpose of 
determining trial eligibility. 
• 
MEK inhibitor including, but not limited to, trametinib or selumetinib. 
 
6. 
Known KRAS or NRAS mutations: 
 
a. 
All patients must have molecular testing performed in a clinical 
lab which includes codon 12 and 13 of KRAS.  Patients with any 
mutation in codon 12 and 13 of KRAS are not eligible for the 
protocol. 
 
b. 
Testing for additional codons in KRAS or testing for NRAS is not 
required.  However, if such testing has been performed in a 
clinical lab and any mutation in codons 61 or 146 in KRAS, or 
codons 12, 13, 61, or 146 in NRAS is detected, the patient is not 
eligible for the protocol. 
 
 
b. 
Specimen Submission Criteria  
 
1. 
Patients must have tumor (slides or block) available for submission for 
V600E BRAF testing as described in Section 15.1. 
 
2. 
Patients must have additional tumor available and be willing to submit 
tissue and blood samples as described in Section 15.2.  
 
 
c. 
Regulatory Criteria 
 
 
1. 
Patients or their legally authorized representative 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. 
For Step 1 Initial Registration of patients who have not yet submitted 
specimens for the central BRAFV600E testing, the appropriate consent 
form is the Step 1 Consent Form. For both Step 1 Initial Registration and 
Step 2 Randomization of patients whose BRAF mutation status is 
already known, the appropriate consent form is the Step 2 Consent 
Form. 


 
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SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
5.2 
Step 2 Randomization 
 
Patients with known BRAF mutation must be registered to Step 2 Randomization 
immediately following Step 1 Initial Registration. Results of BRAF testing will be available 
on the SWOG Specimen Tracking Website within 10 calendar days from submission of 
tissue specimen to Moffitt Cancer Center and patient must be registered to Step 2 within 
60 days of Step 1 Initial Registration. 
 
a. 
Clinical/Laboratory Criteria 
 
1. 
Patients must have BRAFV600E mutation. 
 
2. 
Patients must have measurable or non-measurable disease that is either 
metastatic or locally advanced and unresectable, as defined in Section 
10.1. CT scans or MRIs used to assess all disease must have been 
completed within 28 days prior to Step 2 Randomization. CT scans or 
MRIs must be assessed and documented on the Baseline Tumor 
Assessment Form (RECIST 1.1).  
 
3. 
Previous chemotherapy, immunotherapy, or radiation therapy must have 
been completed at least 14 days prior to Step 2 Randomization and all 
toxicity must be resolved to CTCAE v4.0 Grade 1 (with the exception of 
CTCAE v4.0 Grade 2 neuropathy) prior to Step 2 Randomization. 
 
4. 
Patients must have a Zubrod Performance Status of 0-1. (See Section 
10.4.) 
 
5. 
Patients must be ≥ 18 years of age. 
 
6. 
Patients must have a complete physical examination and medical history 
within 28 days prior to Step 2 Randomization. 
 
7. 
Patients must have adequate hematologic function as evidenced by all of 
the following within 14 days prior to Step 2 registration: ANC ≥ 
1,500/mcL; platelets ≥ 100,000/mcL; and hemoglobin ≥ 9 g/dL. 
 
8. 
Patients must have adequate hepatic function as evidenced by all of the 
following within 14 days prior to Step 2 registration: AST and ALT ≤ 2.5 x 
Institutional Upper Limit of Normal (IULN) or ≤ 5 x IULN if liver 
metastases are present; and total bilirubin ≤ 1.5 x IULN. 
 
9. 
Patients must have adequate kidney function as evidenced by at least 
ONE of the following: 
 
• 
Serum creatinine ≤ 1.5 x IULN within 14 days prior to Step 2 
Randomization OR 
• 
Calculated creatinine clearance > 60 ml/min. The serum creatinine 
value used in the calculation must have been obtained within 14 
days prior to Step 2 Randomization. 
 
Calculated creatinine clearance = (140 – age) x wt (kg) x [0.85 (if 
female)] 
72 x creatinine (mg/dL) 
 
10. 
Patients must have an ECG within 14 days prior to Step 2 
Randomization. Patients must have QTc ≤ 500 msec. 


 
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SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
5.2 
Step 2 Randomization (contd.) 
 
11. 
Patients must not have a known history of Gilbert’s Syndrome or known 
homozygosity for the UGT1A1*28 allele.  
 
12. 
Patients must not have interstitial pneumonia or extensive symptomatic 
interstitial fibrosis of the lung. 
 
13. 
Patients must not have an uncontrolled intercurrent illness including, but 
not limited to, active bleeding diathesis, uncontrolled infection/disorders, 
nonmalignant medical illnesses that are uncontrolled or whose control 
may be jeopardized by the treatment with the study therapy, or 
psychiatric illness/social situations which would limit compliance with 
study requirements. 
 
14. 
Patients must be able to swallow pill/tablet and have no refractory 
nausea, vomiting, malabsorption, external biliary shunt, or significant 
small bowel resection that would preclude adequate absorption. 
 
15. 
Patients must not be pregnant or nursing due to risk of fetal or nursing 
infant harm. Women/men of reproductive potential must have agreed to 
use an effective contraceptive method while on study and for at least 60 
days after study treatment. 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.  
 
16. 
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 three years. 
   
b. 
Regulatory Criteria 
 
 
1. 
Patients or their legally authorized representative 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. 
For all patients, the appropriate consent form for this registration is the 
Step 2 Consent Form. 
 
2. 
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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SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
5.2 
Step 2 Randomization (contd.) 
 
c. 
Specimen Submission Criteria 
 
1. 
Patients (at institutions listed in Section 15.4 only) must be offered the 
opportunity to participate in the optional S1406 Co-Clinical PDX Model 
Trial (see Section 15.4). Participating patients must have a fresh tissue 
biopsy for the Co-Clinical PDX Model Trial completed within 7 days of 
Step 2 Randomization.  
 
5.3 
Step 3 Crossover Registration 
 
a. 
Patients must have documented disease progression as defined in Section 10.2d 
while on Arm 1 of this protocol. The Follow-up Tumor Assessment Form 
documenting disease progression must be submitted to SWOG prior to Step 3 
Crossover Registration. Registration to Step 3 Crossover must be within 28 days 
of discontinuation of Arm 1 protocol treatment. Patients going off treatment for 
any other reason are not eligible.  
 
b. 
Patients must have a Zubrod Performance Status of 0-1. (See Section 10.4) 
 
c. 
Patients must have adequate hematologic function as evidenced by all of the 
following within 14 days prior to Step 3 registration: ANC ≥ 1,500/mcL; platelets ≥ 
100,000/mcL; and hemoglobin ≥ 9 g/dL. 
 
d. 
Patients must have adequate hepatic function as evidenced by all of the following 
within 14 days prior to Step 3 registration: AST and ALT ≤ 2.5 x Institutional 
Upper Limit of Normal (IULN) or ≤ 5 x IULN if liver metastases are present; and 
total bilirubin ≤ 1.5 x IULN. 
 
e. 
Patients must have adequate kidney function as evidenced by at least ONE of 
the following: 
 
• 
Serum creatinine ≤ 1.5 x IULN within 14 days prior to Step 3 
registration OR 
• 
Calculated creatinine clearance > 60 ml/min. The serum creatinine 
value used in the calculation must have been obtained within 14 
days prior to Step 3 registration. 
 
Calculated creatinine clearance = (140 – age) x wt (kg) x [0.85 (if female)] 
 
 
 
 
 
 72 x creatinine (mg/dL) 
 


 
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6.0 
STRATIFICATION FACTORS 
 
6.1 
Stratification Factors 
 
Stratification factors do not apply to Step 1 Initial Registration or Step 3 Crossover 
Registration. 
 
6.2 
Randomization 
 
Patient will be randomized at Step 2 Randomization using a dynamic balancing algorithm 
with stratification based on prior treatment with irinotecan: yes vs. no. (38)  
 
 
7.0 
TREATMENT PLAN   
 
For treatment or dose modification questions, please contact Dr. Kopetz at 713/792-2828 or Dr. 
Lenz at 323/865-3955.  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 
Pre-Medication * 
 
Diphenhydramine (or other H1-antagonist) 50 mg intravenously, given once 30-60 
minutes prior to first dose of cetuximab.  
 
Dexamethasone 10 mg intravenously, given 30-60 minutes prior to irinotecan. 
 
Patients on Arm 1 may receive institutional recommended management for nausea. 
Patients on Arms 2 and 3 may receive maximum doses of the following drugs:  
• 
ondansetron 8 mg IV, 
• 
dolasetron 12.5 mg IV,  
• 
granisetron 1 mg IV,  
• 
any oral form of 5-HT3 inhibition. 
 
*  NOTE: These may be modified at the discretion of the treating physician.  
 
7.2 
Treatment – Arm 1  
 
 
Patients assigned to Arm 1 will receive the following treatment until meeting one of the 
criteria in Section 7.6. 
 
Agent 
Dose 
Route 
Day 
Schedule * 
 
 
Cetuximab 
500 mg/m2 
IV over 120 min 
1, 15 
Prior to irinotecan 
 
 
for initial dose  
 
 
and over 60 min 
 
 
for subsequent  
 
 
doses ** 
 
Irinotecan 
180 mg/m2 
IV over 90 min 
1, 15 
After cetuximab 
 
 
 
 
* Note:  One cycle = 28 days 
** Subsequent doses may be given over 60 minutes or 120 minutes at the discretion of 
the treating physician. 
 


 
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7.3 
Treatment – Arm 2 
 
Patients assigned to Arm 2 will receive the following treatment until meeting one of the 
criteria in Section 7.6. 
 
Agent 
Dose 
Route 
Day 
Schedule * 
 
 
Cetuximab 
500 mg/m2 
IV over 120 min 
1, 15 
Prior to irinotecan 
 
 
for initial dose  
 
 
and over 60 min 
 
 
for subsequent  
 
 
doses *** 
 
Irinotecan 
180 mg/m2 
IV over 90 min 
1, 15 
After cetuximab 
 
 
Vemurafenib 
960 mg 
PO BID 
1-28 
Daily 
 
 
(1920 mg  
 
total daily dose) ** 
 
 
 
 
 
*  
Note:  One cycle = 28 days 
** Patients should take 4 tablets in the morning and  4 tablets in the evening with or 
without a meal.  A missed dose can be taken up to 4 hours prior to the next dose. 
*** Subsequent doses may be given over 60 minutes or 120 minutes at the discretion of 
the treating physician. 
 
7.4 
Drug Compliance Documentation 
 
Drug compliance for vemurafenib will be recorded by patients in an Intake Calendar (see 
S1406 protocol abstract page on the SWOG website [www.swog.org] for an example). 
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 patient 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 
Crossover following disease progression on Arm 1 
 
a. 
Following radiographic documentation by RECIST 1.1 (in Section 10.2d) of 
disease progression, patients initially randomized and treated on Arm 1 may 
register to Step 3 Crossover Registration to be treated with vemurafenib, 
irinotecan, and cetuximab per the schedule and doses listed below. Patients 
must be eligible and registered for Step 3 Crossover Registration per Section 5.3. 
Patients must be re-staged at time of progression on Arm 1 prior to registration to 
Step 3 Crossover Registration. Follow-up for these patients after crossover will 
be the same as those patients initially randomized to Arm 2. 
 
 


 
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b. 
Treatment – Arm 3 
 
Patients who are registered to Step 3 Crossover Registration will receive the following 
treatment until meeting one of the criteria in Section 7.6.  
 
Agent 
Dose** 
Route 
Day 
Schedule* 
 
 
Cetuximab 
500 mg/m2 
IV over 60 min 
1, 15 
Prior to irinotecan 
 
Irinotecan 
180 mg/m2 
IV over 90 min 
1, 15 
After cetuximab 
 
 
Vemurafenib 
960 mg 
PO BID 
1-28 
Daily 
 
 
(1920 mg total  
 
daily dose) 
 
 
*  Note:  One cycle = 28 days 
** If patient was on a reduced dose of cetuximab and/or irinotecan in Arm 1, he or she 
should begin treatment at that dose in Arm 3. 
 
7.6 
Criteria for Removal from Protocol Treatment 
 
a. 
Progression of disease or symptomatic deterioration (as defined in Section 10.2). 
 
b. 
Arm 1 only: If patient progresses per RECIST 1.1 (see Section 10.2d), patient 
has the option to crossover to treatment Arm 3. 
 
 
c. 
Unacceptable toxicity. 
 
d.   
Treatment delay for any reason > 3 weeks.  
 
e. 
The patient may withdraw from the study at any time for any reason. 
 
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 until death or 3 years after Step 2 Randomization, whichever 
occurs first. 
 
 
8.0 
TOXICITIES TO BE MONITORED AND DOSE 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. 
 
 


 
S1406 
 
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8.2 
General Considerations 
 
a. 
Where several toxicities with different grades or severity occur at the same time, 
the dose modification applied should be the greatest reduction applicable. 
 
b. 
The maximum dose delay for any reason is 3 weeks. 
 
c. 
Doses omitted during a cycle will not be made up. 
 
d. 
If treating investigator feels an event is attributable to another drug, then, after 
conversation with the Study Chair, other modification may be considered. 
 
e. 
Patient may continue protocol treatment if either cetuximab or irinotecan must be 
stopped. If patient must stop vemurafenib treatment, patient should be removed 
from all protocol treatment. 
 
f. 
Advise patients to avoid sun exposure while on treatment with vemurafenib and 
cetuximab.  Encourage patients to wear protective clothing and to use a broad 
spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors. 
 
8.3 
Dose Modifications 
 
 
 
a. 
Dose Levels for Treatment Modifications 
 
Agent  
Starting Dose 
Level -1  
 
Level -2  
 
Level -3 
 
Vemurafenib 
960 mg PO BID 
720 mg PO 
480 mg PO  
N/A 
 
(total daily dose 
BID (total 
BID (total  
 
1920 mg) 
daily dose 
daily dose 
 
 
1440 mg) 
960 mg) 
 
Irinotecan 
180 mg/m2 
150 mg/m2 
125 mg/m2 
100 mg/m2 
 
Cetuximab 
500 mg/m2 
375 mg/m2 
250 mg/m2 
N/A 
 
* Patients who require dose reductions below the values listed above will be 
removed from protocol treatment. 
 
b. 
Nausea and/or vomiting despite optimal medical management 
  
Institute the recommended management at first occurrence, if reoccurs despite 
optimal medical management, follow dose modification guidelines below. 
Recommended management for patients receiving vemurafenib may include 
maximum doses of the following drugs: ondansetron 8 mg IV, dolasetron 12.5 mg 
IV, and granisetron 1 mg IV; oral 5-Ht3 antagonist drugs can be used. If 
symptoms 
do 
not 
improve, 
then 
other 
alternatives 
like 
aprepitant, 
prochlorperazine, or metoclopramide may be considered. If patient is taking 
vemurafenib and vomits after taking dose, do not redose vemurafenib. 
 
Patients not receiving vemurafenib should be managed per standard practice. 
 


 
S1406 
 
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Toxicity Grade 
Dose Modification 
 
Arm 1 
 
Arm 2 
 
2 
Hold all treatment until  
 
Hold all treatment until 
recovery to ≤  Grade 1.  
 
Recovery to ≤  Grade 1. 
Resume at same dose level. 
Resume at same dose 
level. 
 
3 or 4 
Hold all treatment until recovery  
Hold all treatment until  
to ≤  Grade 1. Reduce irinotecan 
recovery to ≤ Grade 1.  
by one dose level.  
At the first occurrence,  
 
reduce irinotecan by one 
dose level. At second 
occurrence, 
reduce 
vemurafenib by one dose 
level. At third occurrence, 
reduce irinotecan by one 
dose level. After the fourth 
occurrence, the patient 
must be removed from 
protocol treatment. 
 
 
c. 
Diarrhea despite optimal medical management 
 
 
Recommended management: Loperamide 4 mg at first onset, followed by 2 mg 
with each loose movement until diarrhea-free for 12 hours (maximum dosage: 16 
mg/24 hours). 
 
Toxicity Grade  
Dose Modification 
 
2 
Hold irinotecan until recovery to ≤ Grade 1. Resume at 
same dose level. 
 
3 or 4 
Hold irinotecan until recovery to ≤ Grade 1. Reduce 
irinotecan by one dose level. 
 
d. 
Neutropenia 
 
Toxicity Grade  
Dose Modification 
 
2 
Hold irinotecan until recovery to ≤ Grade 1. Resume at 
same dose level. 
 
3 or 4 
Hold all treatment until recovery to ≤ Grade 1. Reduce 
irinotecan by one dose level. Use of G-CSF (or 
PEGylated G-CSF) may be considered.* 
 
* G-CSF or pegylated G-CSF may be utilized per ASCO guidelines 
(http://jop.ascopubs.org/cgi/content/full/2/4/196).  


 
S1406 
 
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e. 
Thrombocytopenia 
 
Toxicity Grade  
Dose Modification 
 
2 
Hold irinotecan until recovery to ≤ Grade 1. Resume at 
same dose level. 
 
3 or 4 
Hold all treatment until recovery to ≤ Grade 1. Reduce 
irinotecan by one dose level. 
 
 
f. 
Blood Bilirubin Increased 
 
Toxicity Grade  
Dose Modification 
 
2 
Hold irinotecan until recovery to ≤ Grade 1. Resume at 
same dose level. 
 
3 or 4 
Hold irinotecan and vemurafenib until recovery to ≤ 
Grade 1. Reduce irinotecan and vemurafenib each by 
one dose level. 
 
 
g. 
Mucositis 
 
 
Toxicity Grade  
Dose Modification 
 
2 
Hold irinotecan until recovery to ≤ Grade 1. Resume at 
same dose level. 
 
3 or 4 
Hold all treatment until recovery to ≤ Grade 1. Reduce 
irinotecan by one dose level. 
 
h. 
Fatigue 
 
Toxicity Grade  
Dose Modification 
 
Arm 1 
Arm 2 
 
2 
Hold all treatment until  
Hold all treatment until recovery  
recovery to ≤ Grade 1.  
to ≤ Grade 1. Resume at  
Resume at same dose  
same dose level. 
level. 
 
3 or 4 
Hold all treatment until  
Hold all treatment until recovery  
 
recovery to ≤ Grade 1.  
to ≤ Grade 1. At the first  
 
Reduce irinotecan by one occurrence, reduce irinotecan  
 
dose level.  
by one dose level. At the  
 
second 
occurrence, 
reduce 
vemurafenib by one dose level. 
At 
third 
occurrence, 
reduce 
irinotecan by one dose level. the 
fourth occurrence, the patient 
must be removed from protocol 
treatment. 
 


 
S1406 
 
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i. 
Arthralgia 
 
Toxicity Grade  
Vemurafenib Dose Modification 
 
2 
Hold vemurafenib until recovery to ≤ Grade 1. Resume 
at same dose level. 
 
3 or 4 
Hold vemurafenib until recovery to ≤ Grade 1. Reduce 
vemurafenib by one dose level. 
 
j. 
Pneumonitis 
 
Toxicity Grade  
Cetuximab Dose Modification 
 
2 
Hold cetuximab until recovery to ≤ Grade 1. Resume at 
same dose level. 
 
3 or 4 
Hold cetuximab until recovery to ≤ Grade 1 and until 
interstitial lung disease has been ruled out. Reduce 
cetuximab by one dose level. Discontinue protocol 
treatment if interstitial lung disease is confirmed by CT 
scan. 
 
k. 
Rash 
 
 
Toxicity Grade 
Dose Modification 
 
Arm 1 
Arm 2 + Arm 3 
 
 
3 or 4 
At the first occurrence of 
At the first occurrence of rash, 
rash, hold cetuximab  
hold cetuximab until recovery  
until recovery to Grade 
until recovery to Grade ≤ 2. If 
≤ 2. If there is  
there is improvement in the  
improvement in the rash 
rash upon holding therapy, 
upon holding therapy, 
then resume at same dose. 
Then resume at same 
At second occurrence of rash,  
dose. At second  
hold cetuximab and vemurafenib  
occurrence of rash, 
until recovery to Grade ≤ 2. If  
hold cetuximab until 
there is improvement in the rash  
recovery to Grade ≤ 2. 
upon holding therapy, reduce 
If there is improvement  
cetuximab by one dose level 
 
 
in the rash upon holding 
and resume. At third occurrence, 
 
 
therapy, reduce 
hold cetuximab and vemurafenib  
 
 
cetuximab by one dose 
until recovery to Grade ≤ 2 If there  
 
  
level and resume. 
is improvement in the rash upon  
 
 
At third occurrence, 
holding therapy, reduce 
 
 
remove patient from 
vemurafenib and resume. At 
 
 
cetuximab treatment. 
fourth occurrence, the patient 
 
 
 
must be removed from protocol  
 
 
treatment. 
 


 
S1406 
 
Page 33 
 
Version Date 11/10/16 
 
 
 
 
l. 
Photosensitivity 
 
Toxicity Grade  
Dose Modification 
 
3 or 4 
Hold all treatment until recovery to ≤ Grade 1. Reduce 
vemurafenib by one dose level. 
 
 
m.          Uveitis 
 
Toxicity Grade  
Dose Modification 
 
2 
Hold vemurafenib until recovery to ≤ Grade 1. Resume 
at same dose level. 
 
3 or 4 
Hold vemurafenib until recovery to ≤ Grade 1. Reduce 
vemurafenib by one dose level. 
 
 
n. 
Hypersensitivity Reaction*, Cytokine Release*, Infusion Reaction 
 
 
Toxicity Grade  
Dose Modification  
 
1 
Decrease cetuximab infusion rate by 50% until 
symptoms resolve, then resume at the initial planned 
rate. 
 
2 
Stop cetuximab infusion. Administer H1 and/or H2 
blockers, and/or steroids according to institutional policy. 
Restart the infusion at 50% lower rate when symptoms 
resolve and pretreat before all subsequent doses. All 
subsequent cetuximab doses should be administered at 
the lower infusion rate. 
 
3 or 4 
Stop the infusion. Discontinue cetuximab treatment. 
 
* For reporting these events: NCI CTCAE 4.0 defines these reactions differently: 
“Cytokine release syndromes/acute infusion reactions are different from 
allergic/hypersensitivity reactions, although some of the manifestations are 
common to both AEs. An acute infusion reaction may occur with an agent that 
causes cytokine release (e.g., monoclonal antibodies or other biological 
agents). Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of 
infusion.” See the “Syndromes” section of the CTCAE version 4.0 for a 
complete list of signs and symptoms of “Cytokine release syndrome/acute 
infusion reaction;” and see the “Allergy/Immunology” section for a description of 
hypersensitivity. 


 
S1406 
 
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o. 
Electrocardiogram QT Corrected Interval Prolonged  
 
Toxicity Grade  
Dose Modification 
 
3 or 4 
Withhold vemurafenib until QTc interval ≤ 500 msec and 
resume therapy at one reduced dose level.  Permanently 
remove from protocol treatment if the QTc remains > 
500 msec and increased > 60 msec from pre-treatment 
values after controlling cardiac risk factors for QT 
prolongation (e.g., electrolyte imbalances, congestive 
heart failure, bradyarrhythmias). 
 
 
p. 
Development of new keratoacanthomas or squamous cell carcinoma of the skin 
 
All patients receiving vemurafenib are recommended to undergo a dermatologic 
evaluation and head/neck examination by their treating physician for monitoring 
of keratoacanthomas and squamous cell carcinomas.  This evaluation should be 
done at baseline and every 2 months on therapy.  CT imaging of the chest, which 
is performed at baseline and every 2 months on treatment for disease 
assessment, should be evaluated for any findings of concern for non-
dermatologic squamous cell carcinomas.   These evaluations should continue for 
6 months after completion of vemurafenib, if deemed clinically appropriate by the 
treating physician.  Any new skin lesions or head/neck/chest findings must be 
treated appropriately, as directed by a dermatologist or otolaryngologist as 
indicated, while receiving therapy on this protocol. Patients who develop 
keratoacanthomas or new squamous cell carcinomas of the skin while being 
treated on protocol should be managed by removal of the carcinomas by a 
dermatologist. If the lesions are unable to be removed due to the number or 
location, then the patient should be removed from all protocol therapy. 
 
q. 
Hypomagnesemia 
 
Toxicity Grade  
Dose Modification 
 
1 or 2 
Supplementation with magnesium. Closely monitor 
patient for appropriate magnesium levels. 
 
3 or 4 
Institute maximal medical management with magnesium.  
If 
Grade 
≥ 
3 
persists 
despite 
magnesium 
supplementation, reduce cetuximab by one dose level. 
At second occurrence, discontinue cetuximab therapy. 
 
 
r. 
Other non-hematologic toxicities 
 
Toxicity Grade  
Dose Modification 
 
3 or 4 
Hold all treatment and monitor toxicity at least weekly. If 
toxicity resolves to ≤ Grade 1 within 3 weeks, reduce 
irinotecan by one dose level and resume treatment. 
 
 


 
S1406 
 
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8.4 
Dose Modifications Contacts 
 
For treatment or dose modification questions, please contact Dr. Kopetz at 713/792-2828 
or Dr. Lenz at 323/865-3955.   
 
8.5 
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 and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
 
 
9.0 
STUDY CALENDAR 
 
 
 
 


 
S1406 
 
Page 36 
 
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9.1  
Arm 1: Cetuximab + Irinotecan 
 
Click here for footnotes. 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Ω 
% α 
REQUIRED STUDIES 
Step 1 
Step 2 
W W W W W W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
FU 
prior to 
prog 
FU 
after 
prog 
  
Initial 
Reg 
Rand 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
PHYSICAL  ∑  
 
 
 
 
History and Physical Exam   
X  ¥ 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Weight and Performance 
Status 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Toxicity Notation 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Disease Assessment  
X 
X 
 
 
 
 
X 
X 
LABORATORY  ∑  
 
 
 
 
CBC/Differential/Platelets   
X 
X 
X 
X 
X 
X 
X 
 
X 
 
AST and ALT 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Serum creatinine/ 
Calculated creatinine 
clearance 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Total bilirubin 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Magnesium/ Potassium 
Calcium/Sodium/Bicarb/ 
Chloride 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
SPECIMEN SUBMISSION 
 
 
 
 
Tissue for BRAF Testing & 
Banking £ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood  £ 
X 
X 
 
 
 
 
X 
X 
Fresh Tissue Biopsy ƺ 
X 
 
 
 
 
X-RAYS AND SCANS   
 
 
 
 
CT or MRI for Disease 
Assessment  
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
ECG  
X 
 
 
 
 
TREATMENT  ∑  
 
 
 
 
Cetuximab 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Irinotecan  
X 
X 
X 
X 
X 
X 
X 
 
X 
 


 
S1406 
 
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9.2  
Arm 2: Cetuximab + Irinotecan + Vemurafenib 
 
Click here for  footnotes. 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Ω 
% 
REQUIRED STUDIES 
Step 1 
Step 2 
W W W W W W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
FU prior 
to 
prog 
FU after 
prog 
  
Initial 
Reg 
Rand 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
PHYSICAL  ∑  
 
 
 
 
History and Physical Exam  
X ¥ 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Weight and Performance 
Status 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Toxicity Notation 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Disease Assessment 
X 
X 
 
 
 
 
X 
X 
Dermatologic evaluation ~ 
X 
X 
X 
 
 
 
X 
Head and Neck Exam † 
X 
X 
X 
 
 
 
X 
LABORATORY  ∑  
 
 
 
 
CBC/Differential/Platelets 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
AST and ALT 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Serum creatinine/ Calculated 
creatinine clearance 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Total bilirubin 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Magnesium/ Potassium 
Calcium/Sodium/Bicarb/Chlo
ride 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
SPECIMEN SUBMISSION 
 
 
 
 
Tissue for BRAF Testing & 
Banking £ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood  £ 
X 
X 
 
 
 
 
X 
X 
Fresh Tissue Biopsy ƺ 
X 
 
 
 
 
X-RAYS AND SCANS   
 
 
 
 
CT or MRI  ϖ 
X 
X 
 
 
 
 
X 
X 
ECG  δ 
X 
X 
X 
X 
 
 
 
 
TREATMENT  ∑  
 
 
 
 
Cetuximab 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Irinotecan 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Vemurafenib  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
S1406 
 
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9.3  
Arm 3: Cetuximab + Irinotecan + Vemurafenib 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Ω 
% 
REQUIRED STUDIES 
Step 3 
Cross-
over Reg 
W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
FU prior 
to 
Prog 
FU after 
Prog 
  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
PHYSICAL  ∑  
 
 
 
 
History and Physical Exam  
X ¥ 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Weight and Performance 
Status 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Toxicity Notation 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Disease Assessment 
X 
X 
 
 
 
 
X 
X 
Dermatologic evaluation ~ 
X 
X 
X 
 
 
 
X 
Head and Neck Exam † 
X 
X 
X 
 
 
 
X 
LABORATORY  ∑  
 
 
 
 
CBC/Differential/Platelets 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
AST and ALT 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Serum creatinine/ 
Calculated creatinine 
clearance 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Total bilirubin 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Magnesium/ Potassium 
Calcium/Sodium/Bicarb/Chlo
ride 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
SPECIMEN SUBMISSION 
 
 
 
 
Tissue for BRAF Testing & 
Banking £ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood  £ 
X 
X 
 
 
 
 
X 
X 
X-RAYS AND SCANS   
 
 
 
 
CT or MRI  ϖ 
X 
X 
 
 
 
 
X 
X 
ECG  δ 
X 
X 
X 
 
 
 
 
TREATMENT  ∑  
 
 
 
 
Cetuximab 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Irinotecan 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Vemurafenib  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Click here for  footnotes. 
 


 
S1406 
 
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Calendar 9.1, 9.2 and 9.3 footnotes. 
 
∑  Protocol treatment and parameters will continue at these intervals until progression of disease or until patient has met any of the 
 
guidelines in Section 7.6. 
Ω After off treatment prior to disease progression, scans for disease assessment and physical assessments (with lab tests performed 
 
 at the discretion of the treating investigator) should take place every 8 weeks until progression. 
% After off treatment following disease progression, physical assessments (with lab tests performed at the discretion of the treating  
 
investigator) should take place every 6 months for three years from the time of registration to Step 2. 
¥  Must be done within 28 days prior to registration 
£  Required specimen submission for patients. See Section 15.1 and 15.2 for additional information. 
 CT or MRI for disease assessment must be performed every 8 weeks while on study treatment. 
α  Patients who progress on Arm 1 may crossover to Arm 3 treatment if criteria in Section 5.3 are met and patient is registered to Step 3  
 
Crossover Registration. 
δ  Performed once every cycle for the first three cycles and every 3 cycles thereafter until 6 months after off treatment of vemurafenib.   
 
Anytime a dose adjustment is required for QTc changes, monitoring frequency is performed as if the patient just started treatment. 
~ 
Performed at Step 2 Randomization or Step 3 Crossover Registration, after 4 weeks and every 2 months through 6 months after  
 
discontinuation of vemurafenib to evaluate for cutaneous malignancies (see Section 8.3p). 
ϖ 
Chest imaging should be performed for disease assessment at baseline and with each restaging through 6 months after off treatment.   
This imaging will also allow for surveillance for non-cutaneous squamous cell carcinoma. 
† 
Performed at Step 2 Randomization or Step 3 Crossover Registration, after 4 weeks and every 2 months through 6 months after  
 
discontinuation of vemurafenib to evaluate for non-cutaneous SCC. (see Section 8.3p). The minimum criteria should be visual inspection  
 
of the oral mucosa and lymph node palpation performed by the treating physician.   
ƺ 
Only for sites listed in Section 15.4. 
 
 


 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS 
 
This study will use the RECIST 1.1 guidelines.  (39) 
 
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. 


 
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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. 
 
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.   
 
h. 
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 
Progression-Free Survival 
 
a. 
Primary Endpoint (Arms 1 and 2): From date of Step 2 Randomization to date of 
first documentation of progression or symptomatic deterioration (as defined in 
Section 10.2), or death due to any cause.  Patients last known to be alive without 
report of progression are censored at date of last contact. 
 
b. 
Crossover Endpoint (Arm 3 only): From date of Step 3 Crossover Registration to 
date of first documentation of progression or symptomatic deterioration (as 
defined in Section 10.2), 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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10.6 
Time to Death 
 
From date of Step 2 Randomization to date of death due to any cause.  Patients last 
known to be alive are censored at date of last contact. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
All potentially eligible patients will be registered (step 1) and screened for BRAF, either passively 
(standard of care BRAF testing outside of trial in CLIA-compliant labs) or actively through 
consenting to be screened in this study.  Patients who test positive for the V600E BRAF mutation 
are then eligible for randomization (step 2 registration) to treatment with irinotecan, cetuximab, 
and vemurafenib, or irinotecan and cetuximab.  Patients randomized to the control arm 
(irinotecan and cetuximab) with disease progression during treatment are then eligible to cross 
over to treatment with vemurafenib in step 3 registration. 
 
11.1 
Accrual Goals 
 
SWOG and the other adult oncology groups have no prior experience accruing this 
selected patient subset.  By opening this study through CTSU, with support from ECOG-
ACRIN, Alliance, and RNG, we are aiming for accrual of approximately 3 patients per 
month.  The observed rate of accrual over the first 10 months was more than 4 patients 
per month.  Thus, we anticipate enrolling 105 patients to have 94 eligible patients 
randomized in Step 2, and still expect 26 months of accrual.   
 
The prevalence of V600E mutant BRAF is 5-7% (or 9-13% of KRAS wild-type tumors, 
given the mutual exclusivity of KRAS and BRAF).  Some screening will be performed by 
sites that include BRAF in their standard of care testing, and for those pre-screened 
patients only retrospective confirmatory testing will be performed.  Prior to opening the 
protocol, we estimated the screening sample size based on the following assumptions: 
the KRAS mutation rate is 40% and the BRAF mutation rate is 5.9% in mCRC; 60% of 
enrolled patients will come from sites that perform BRAF testing as part of the current 
standard of care; 85% of sites that do not perform BRAF testing will have KRAS testing 
results prior to considering a patient for study screening; the BRAF mutation rate is 9.8% 
in KRAS wild type patients; and 10% of screened patients will drop out and not enroll in 
the study.  Based on these criteria, we estimated a need to perform primary central BRAF 
testing on approximately 440 patients. Forty-five of the first 70 screened patients were 
randomized.  Of these 70 patients screened in 10 months of accrual, 43 had already 
been tested for the BRAFV600E mutation and 27 needed central review.  Based on these 
observed proportions, in total we will need to screen approximately 163 to randomize 105 
patients, including about 63 patients needing central review. 
 
11.2 
Primary Analysis and Power Justification 
 
The primary analysis of PFS among patients randomized to Arm 1 or Arm 2 will be 
conducted in all eligible patients according to the intent-to-treat principle, using the log 
rank test upon the observation of 88 PFS events. Patients will be stratified by prior 
treatment with irinotecan. There are no randomized second or third line studies that have 
reported outcomes with cetuximab and irinotecan specifically for the population of 
patients with BRAF mutations.  However, a retrospective study of 75 patients with BRAF 
mutant tumors demonstrated progression-free survival of 2.4 and 2.3 months for second 
and third line regimens, respectively. (in press, Clinical Colorectal Cancer) Therefore, we 
estimate the median Progression-Free Survival (PFS) of patients treated with Cetuximab 
and Irinotecan to be 2.4 months (null hypothesis) in this study population. Assuming that 
the targeted agent offers an increase of 2.4 months in PFS for this population (HR 2.0), 
we will need 94 eligible patients, based on six months of follow-up, a two-sided type 1 
error of 5% and 90% power.   


 
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An interim analysis will be performed when one-half of the events (approximately 44 PFS 
failures) have been observed (anticipated to occur when approximately 60% of accrual is 
reached). Evidence suggesting early termination would consist of a PFS hazard ratio > 
1.0 comparing the experimental arm to the control arm, as estimated by a Cox regression 
model.  This rule yields a 50% likelihood of terminating the study under the null 
hypothesis. Unless there are toxicity concerns, the study will not close during this interim 
assessment.  
 
11.3 
Other Analyses 
 
Secondary endpoints will include overall survival, response, and toxicity. Distributions of 
overall survival in Arms 1 and 2 will be estimated using the method of Kaplan-Meier.  The 
overall response rate (confirmed and unconfirmed, complete and partial) in each 
treatment arm will be assessed in the subset of patients with measurable disease.  
Assuming 90% (n=42 per arm) of patients will present with measurable disease, 
response rate can be estimated to within 16% (95% confidence interval).  
 
Patients receiving at least one dose of drug on any arm will be included in the 
assessment of adverse events. Adverse event monitoring is conducted by the study 
chairs, disease committee chair, Adverse Event Coordinator and study statistician on an 
ongoing basis, with notification to the DSMC and CTEP should any concerns arise.  Any 
events reported through the CTEP-AERS system are reported immediately, and reports 
are sent to the above group for all other AEs on a monthly basis. This trial will employ 
especially careful adverse event monitoring for the first 14 patients randomized to 
vemurafenib (Arm 2). Rates of serious toxicities will be compared between Arms 1 and 2 
after 3, 6, and 14 patients are assigned to Arm 2 and have completed the first cycle, to 
inform discussions of protocol modification or early closure if required. Forty-seven 
eligible patients in each arm are sufficient to estimate the probability of a particular 
toxicity to within 15% (95% confidence interval).  Any toxicity occurring with at least an 
8% probability is likely (98% chance) to be seen at least once. 
 
Patients progressing on Arm 1 will be provided the opportunity to cross over to 
vemurafenib treatment on Arm 3.  Overall survival, response and PFS among patients 
who register to Arm 3 after disease progression will be summarized using descriptive 
statistics as described above. 
 
11.4 
Data and Safety Monitoring 
 
A Data and Safety Monitoring Committee will oversee the conduct of the study.  The 
Committee consists of four members from outside of the SWOG, 3 SWOG members, 3 
non-voting representatives from the National Cancer Institute (NCI), and the Group 
Statistician (non-voting).  The members of this Committee will receive confidential reports 
every 6 months from the SWOG Statistical Center, and will meet at the Group's bi-annual 
meetings as necessary.  The Committee will be responsible for decisions regarding 
possible termination and/or early reporting of the study. 
 
11.5 
Translational Medicine 
 
The associations between each potential predictive biomarker (Objectives 11.5a and 
11.5b below) and PFS will be explored via Kaplan-Meier curves and Cox regression.  For 
each arm, it is estimated that 42 (90% of) eligible patients will have usable samples 
submitted for these translational studies.  Statistical power to assess treatment-biomarker 
interactions will be low; all such power calculations assume the baseline median PFS is 
2.4 months, no treatment effect in the biomarker-negative subgroup, and a two-sided 
alpha of 0.05. 


 
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Objectives 
 
a. 
To evaluate low-frequency KRAS or NRAS mutations as detected by high-depth 
sequencing as a predictive biomarker of efficacy. 
 
1. 
Preliminary data is pending for BRAF mutant patients, but approximately 
20% of KRAS wild type patients by standard of care testing will have 
detectable KRAS or NRAS on high-depth sequencing. 
 
2. 
Assuming that detectable KRAS or NRAS is present in 20% of patients, 
84 patients would provide 74% power to detect an interaction hazard 
ratio of 5.0 between treatment and biomarker status (corresponding to a 
median PFS of 12.0 months in the vemurafenib arm for the biomarker 
positive subgroup).  
 
b. 
To evaluate PI3K pathway activation as a predictive biomarker of efficacy (PFS) 
 
1. 
Preliminary data in archival material from BRAF mutant, metastatic 
colorectal cancer tumors suggests that 60% of patients will have 
activation of the PI3K pathway, as defined by complete PTEN loss by 
IHC or PIK3CA mutation in the kinase or helical domains. 
 
2. 
Assuming that PI3K pathway activation is present in 60% of patients, 84 
patients would provide 80% power to detect an interaction hazard ratio of 
4.0 between treatment and biomarker status (corresponding to a median 
PFS of 9.6 months in the vemurafenib arm for the biomarker positive 
subgroup). 
 
c. 
To evaluate gene expression signatures from screened patients with BRAFWT 
and BRAFV600E tumors. 
 
1. 
This analysis will be very exploratory in nature. Analyzed gene 
signatures from tumor tissue will be described separately in patients with 
BRAFWT (up to n=52, 90% of screen-negative patients) and BRAFV600E 
(n=84, 90% of eligible patients). We will explore, but not limited to, 
associations 
between 
gene 
signatures 
and 
colorectal 
cancer 
oncogenesis, angiogenesis, immune pathways, PI3K, WNT, EGF, and 
MEK pathway signatures, epigenetic regulators, p53, NOTCH and TGF-
beta signaling. The definitive list of genes and technologies might only be 
finalized after complete enrollment and will be based on scientific 
knowledge at that time. 
 
d. 
To provide validation of BRAF IHC using complementary sequencing 
methodology.   
 
1. 
Both BRAF and Cobas version 2.0 testing will be performed on screened 
patients (n=163). We will evaluate the sensitivity and specificity of BRAF 
IHC compared to the Cobas version 2.0 testing.  
 


 
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e. 
To confirm the estimated sensitivity of detectable BRAF V600E circulating cell- 
free DNA as a non-invasive biomarker for BRAF V600E mutation as detected by 
IHC and Cobas in the primary tumor. 
 
1. 
Unpublished results in 37 patients demonstrated 100% specificity and 
78% sensitivity for the circulating cell-free DNA compared to the mutation 
assay on the primary tumor. 
 
f. 
To correlate radiographic tumor response with the change in quantification of 
BRAF V600E alleles in circulating cell-free DNA. 
 
1. 
Analysis of plasma samples at baseline, during therapy, and at the time 
of progression across all arms (including Arm 3). 
 
2. 
No preliminary data are available for this aim. 
 
3. 
We will assess the relationship between RECIST radiographic 
assessment and change in BRAF V600E allele burden in the cfDNA via 
logistic regression. 
 
g. 
To monitor for known mechanism of acquired resistance to EGFR inhibition in 
circulating cell-free DNA (KRAS, NRAS mutations). 
 
1. 
Analysis of plasma samples at baseline and at the time of progression on 
all arms (including progression on Arm 3). 
 
2. 
Preliminary data are not available for the BRAF population, but in a 
KRAS wild-type population, our preliminary data suggest that 
approximately 40% of patients develop new detectable mutations in 
KRAS, NRAS, or EGFR after treatment with cetuximab. 
 
3. 
Simple proportions with estimated 95% confidence intervals will be used 
to describe the observed incidence of new detectable mutations. 
 
h.  
To assess the correlation of treatment efficacy between patients and matched 
patient-derived xenograft (PDX) models. 
 
The correlation between radiographic response in patients and reduction in tumor 
size in the corresponding PDX models receiving matched treatment will be 
assessed.  Given a 67% success rate at MD Anderson in establishing PDXs 
using BRAF-mutated tumors, it is estimated that 12 PDXs will be established 
from the 18 tumor biopsies collected from either arm of S1406. For each PDX, 24 
mice will be equally randomized into one of three arms: a control arm receiving 
placebo (C) or one of two treatment arms, irinotecan + cetuximab or irinotecan + 
vemurafenib + cetuximab.  For each PDX, the mice will be assessed at Day 21.  
The average % reduction in tumor size will be compared between the mice 
receiving the treatment to which the corresponding patient had been randomized 
and  the mice in the control arm receiving placebo. The treatment/ control ratio 
(%T/%C) will be calculated. To evaluate the association between the patient and 
corresponding xenograft model results, a Pearson correlation coefficient will then 
be estimated between %T/%C and the RECIST response of matched patients. 
12 PDXs will have 80% power to detect a correlation coefficient of 0.712 at a 
two-sided 0.05 significance level.  
 
In order to investigate further the correlation in raw tumor responses between the 
clinical and animal studies, a secondary analysis will model %Tend/Tstart in the 
xenograft animals as a function of radiographic response according to RECIST 
criteria in matched patients via a linear mixed model. 


 
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i.  
To assess the correlation between PDX mechanisms for resistance and 
circulating free DNA (cfDNA) in plasma samples of matched patients following 
progression of disease. 
 
cfDNA will be extracted from plasma taken from pre-treatment and post-
progression samples of patients whose tumors were used to establish PDX 
models.  These samples will then be analyzed by ultra-deep next-generation 
sequencing for the full exons of 15 genes (including KRAS, NRAS, EGFR, and 
MEK) and hotspot coverage for an additional 36 genes of interest.  McNemar’s 
test will be used to compare the mutation status of cfDNA before treatment and 
after progression for each gene of interest. We will adjust for multiple 
comparisons using methods described by Benjamin-Hochberg. (49) The 
concordance (i.e. proportion of the status unchanged, with 95% CI) of acquired 
mutation status between patient plasma samples and corresponding PDX 
models for each gene will be estimated. If concordance of PDX with matched 
patient in 6 of 12 pairs is observed, then the estimated half length of the 95% CI 
will be 0.25. 
 
 
12.0 
DISCIPLINE REVIEW 
 
 
Discipline review is not applicable to this study. 
 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
a. 
If patient has already had BRAFV600 testing completed in a CLIA-certified 
laboratory and is eligible based on Section 5.1, the patient must be registered to 
Step 2 on the same day as Step 1. Patients must be registered for Step 2 prior to 
initiation of treatment (no more than five working days prior to planned start of 
treatment).  
 
b. 
If patient has not had BRAFV600 testing, specimens must be submitted as 
described in Section 15.1 on the day of Step 1 registration. If tumor is BRAFV600 
mutant, patient must be registered to Step 2 prior to initiation of treatment (no 
more than five working days prior to planned start of treatment and within 60 
days of Step 1 registration). 
 
c. 
Patients must be registered to Step 3 prior to initiation of treatment (no more than 
five working days prior to planned start of treatment and within 28 days of 
discontinuation of Arm 1 protocol treatment).  


 
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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 
(http://ctep.cancer.gov/investigatorResources/investigator_registration.htm). 
Questions 
should be directed to the CTEP Investigator Registration Help Desk by e-mail at 
pmbregpend@ctep.nci.nih.gov. 
 
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.  
 
Requirements for site registration: 
 
• 
CTSU IRB Certification 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet 
 
Note:  Sites participating on the NCI CIRB initiative and accepting CIRB approval for the 
study are not required to submit separate IRB approval documentation to the CTSU 
Regulatory Office for initial, continuing or amendment review.  This information will be 
provided to the CTSU Regulatory Office from the CIRB at the time the site’s Signatory 
Institution accepts the CIRB approval.  The Signatory site may be contacted by the CTSU 
Regulatory Office or asked to complete information verifying the participating institutions 
on the study.  Other site registration requirements (i.e., laboratory certifications, protocol-
specific training certifications, or modality credentialing) must be submitted to the CTSU 
Regulatory Office or compliance communicated per protocol instructions. 
 
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 


 
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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) 
• 
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 that is integrated with the CTSU 
Enterprise System for regulatory and roster data and, at the time of patient 
registration, initializes the patient in the Rave database.  OPEN 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. 


 
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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.  Additional information 
about 
obtaining 
a 
CTEP-IAM 
account 
can 
be 
found 
at 
http://ctep.cancer.gov/branches/pmb/associate_registration.htm.  
Questions should be directed to the CTEP Associate Registration Help 
Desk by e-mail at ctepreghelp@ctep.nci.nih.gov. 
 
• 
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.   
 
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. 


 
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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 website 
(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.   
 
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. 
Rave® may also be accessed via the SWOG CRA Workbench.  Go to the 
SWOG web site (http://swog.org) and logon to the Members Area using the 
SWOG Roster ID Number and password. After logging 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. 
 
To access the CRA Workbench the following must be done (in order): 
 
1. 
Registering individual is entered into the SWOG Roster and issued a 
SWOG Roster ID Number, 
 
2. 
Registering individual is associated as an investigator or CRA/RN at the 
institution where the patient is being treated or followed,  
 
3. 
Sites local Web User Administrator has added registering individual 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 e-mail  
technicalquestion@crab.org. 
  
c. 
Institutions participating through the Cancer Trials Support Unit (CTSU) please 
refer to the CTSU Participation Table on Page 5. 


 
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14.4 
Data Submission Overview and Timepoints  
 
a. 
ON THE SAME DAY AS STEP 1 INITIAL REGISTRATION: 
 
For patients who have not yet undergone BRAF V600 testing, submit the 
following: 
 
Tissue specimens for V600 BRAF testing directly to Moffitt Cancer Center as 
outlined in Section 15.1. 
 
Pathology report with specimens to Moffitt Cancer Center (see Section 15.1) 
 
b. 
WITHIN 7 DAYS AFTER STEP 1 INITIAL REGISTRATION: 
 
Submit the S1406 Onstudy Form 
 
c. 
For patients who will not be randomized to a treatment arm, WITHIN 60 DAYS 
OF STEP 1 REGISTRATION: 
 
Submit the pre-study plasma specimens (including pathology report) for 
Translational Medicine as described in Section 15.3. 
 
d. 
WITHIN 7 DAYS AFTER STEP 2 RANDOMIZATION: 
 
Submit the following: 
 
S1406 Randomization Eligibility Form 
 
Baseline Tumor Assessment Form (RECIST 1.1) 
 
Radiology reports from all scans performed to assess disease at baseline 
(NOTE: Upload reports via the Source Documentation: Baseline form found in 
the Randomization Disease Assessment Folder in Rave®.) 
 
Pathology report (NOTE: Upload reports via the Source Documentation: Baseline 
form found in the Randomization Eligibility Folder in Rave®. This submission is in 
addition to the pathology report submission to Moffitt Cancer Center that is 
required by Section 15.1) 
 
Molecular testing report (NOTE: Upload reports via the Source Documentation: 
Baseline form found in the Randomization Eligibility Folder in Rave®.) 
 
Fresh tissue for PDX (optional for patients at select institutions, see Section 
15.4). 
 
e. 
WITHIN 28 DAYS AFTER STEP 2 REGISTRATION (RANDOMIZATION): 
 
Submit the tissue and plasma specimens (including pathology report) as 
described in Section 15.0  
(http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp). 
 
f. 
WITHIN 14 DAYS AFTER EVERY CYCLE OF TREATMENT (INCLUDING 
BOTH ON INITIAL TREATMENT ARM AND CROSSOVER TREATMENT ARM): 
 
Submit the following: 
 
S1406 Treatment Form 
 
S1406 Adverse Event Form 


 
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g. 
For the first 14 patients (approximately) randomized to Arm 2, EVERY 14 DAYS 
WHILE ON TREATMENT: 
 
Submit the S1406 Adverse Event Form:  In Rave, update the date of most 
recent adverse event assessment on the Adverse Events:  Assessment 
Form at each assessment and then complete the Adverse Events:  Report 
Week 3-4, accordingly, for each cycle of treatment. 
 
h. 
WITHIN 14 DAYS AFTER EVERY DISEASE ASSESSMENT (INCLUDING 
BOTH ON TREATMENT AND OFF TREATMENT PRIOR TO DISEASE 
PROGRESSION)*: 
 
Submit the following: 
 
Follow-Up Tumor Assessment Form (RECIST 1.1) 
 
Radiology reports from all scans used to assess disease (NOTE: Upload reports 
via the Source Documentation: Follow-up form in Rave®.) 
 
* For patients on the control arm (Arm 1) who continue to Crossover (Arm 3), 
submit disease assessments (in the Crossover Disease Assessment Folder) until 
second progression. 
 
i. 
WITHIN 14 DAYS OF PROGRESSION/RELAPSE: 
 
Submit the following: 
 
Follow-Up Tumor Assessment Form (RECIST 1.1) 
 
Off Treatment Notice – if patient is still on treatment 
 
Final S1406 Treatment Form – if patient is still on treatment 
 
Follow Up Form documenting date, site and method for determining 
progression/relapse – if patient is already off treatment 
 
Radiology Reports (NOTE: Upload reports via the Source Documentation: 
Follow-up form in Rave®.) 
 
NOTE:  For patients on the Control arm (Arm 1) who continue to Crossover (Arm 
3), submit disease assessments until second progression. 
 
j. 
WITHIN 14 DAYS OF DISCONTINUATION OF TREATMENT (INCLUDING 
BOTH ON INITIAL TREATMENT ARM AND CROSSOVER TREATMENT): 
 
Submit the following: 
 
Off Treatment Notice  
 
S1406 Treatment Form 
 
S1406 Adverse Event Form 
 
Batch shipment of frozen plasma specimens (including pathology reports) for 
Translational Medicine as described in Section 15.2. 
 
 


 
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k. 
WITHIN 7 DAYS AFTER STEP 3 CROSSOVER REGISTRATION: 
 
Submit the following: 
 
S1406 Crossover Eligibility Form 
 
Baseline Tumor Assessment Form (RECIST 1.1) 
 
Radiology reports (NOTE: Upload reports via the Source Documentation: 
Baseline form found in the Crossover Disease Assessment Folder in Rave®.) 
 
l. 
AFTER OFF ALL PROTOCOL TREATMENT, EVERY 6 MONTHS FOR THREE 
YEARS: 
 
Submit the Follow-Up Form 
 
NOTE: If the patient experiences any severe (Grade ≥ 3) long term toxicity that 
has not been previously reported, complete and submit the Late Effects Form. 
 
m. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH: 
 
Submit the following: 
 
Notice of Death 
 
Final S1406 Treatment Form - if the patient was still on protocol treatment 
 
Final S1406 Adverse Event Form 
 
Follow-Up Form (if the patient was off protocol treatment) documenting death 
information.  
 


 
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15.0 
SPECIAL INSTRUCTIONS 
 
Purpose 
Specimens 
Timepoint 
Patients 
Shipping 
BRAF V600 
testing 
(see Section 
15.2) 
(1) 1 H&E tumor 
tissue slide 
 
(2) 3 unstained 
paraffin-
embedded 
tissue slides  
-or- 
 
1 paraffin-
embedded 
tissue block 
Day of Step 1 
Initial 
Registration 
Patients who have 
not yet undergone 
BRAF V600 
testing 
Lab #213: Moffitt 
Cancer Center 
 
BRAF V600 
testing (see 
Section 15.2) 
(1) 1 H&E tumor 
tissue slide 
 
(2) 3 unstained 
paraffin-
embedded 
tissue slides  
-or- 
1 paraffin-
embedded 
tissue block 
Within 28 days of 
Step 2 
Registration 
Patients who have 
undergone BRAF 
V600 testing 
locally 
Lab #201: SWOG 
Specimen 
Repository 
 
Correlative 
Studies and 
Banking (see 
Section 15.3) 
12 unstained 
paraffin-embedded 
tissue slides or 
block from baseline 
Within 28 days of 
Step 2 
Randomization 
Required for all 
unless a block 
was submitted for 
BRAF testing 
Lab #201: SWOG 
Specimen 
Repository 
Correlative 
Studies and 
Banking (see 
Section 15.3) 
Plasma 
(1) Day of Step 
1 registration  
 
(2) Each 
restaging  
 
(3) Off treatment 
Required for all 
Lab #201: SWOG 
Specimen 
Repository 
Correlative 
Studies and 
Banking (see 
Section 15.3) 
Plasma 
(1) Day of Step 
3 registration  
 
(2) Each 
restaging  
 
(3) Off treatment 
Required for 
patients crossing 
over to Step 3 
following 
progression on 
Arm 1 
Lab #201: SWOG 
Specimen 
Repository 
PDX Model 
(see Section 
15.4) 
Tumor Biopsy 
Pre-treatment - 
within 7 days of 
Step 2 
Randomization 
Optional for 
patients. See 
Section 15.4 for a 
list of participating 
institutions. 
Lab #216: The 
Jackson Laboratory 
 
 
 
 
 


 
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15.1 
SWOG Specimen Tracking System (STS) 
 
All specimen submissions for this study must be entered and tracked using the SWOG 
online Specimen Tracking System (STS). SWOG members may log on to the online 
system via the CRA Workbench. To access the CRA Workbench, go to the SWOG Web 
site (http://swog.org) and logon to the Members Area. After you have logged on using 
your SWOG roster ID number and password, click on the CRA Workbench link to access 
the home page for CRA Workbench website. First time non-SWOG users must refer to 
start-up instructions located at https://gill:crab.org/SpecTrack/. 
 
A copy of the Shipment Packing List produced by the online Specimen Tracking system 
should be printed and placed in the pocket of the specimen bag if it has one, or in a 
separate resealable bag. 
 
STS laboratory IDs are used to identify the laboratories to which specimens are shipped.  
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE NO 
EXCEPTIONS. 
 
To report technical problems with Specimen Tracking, such as database errors or 
connectivity issues, please send an email to technicalquestion@crab.org. For procedural 
help with logging and shipping specimens, there is an introduction to the system on the 
Specimen Tracking main page 
(http://dnet.crab.org/SpecTrack/Documents/Instructions.pdf); 
or 
contact 
the 
Data 
Operations Center at 206/667-2267 to be routed to the Data Coordinator for further 
assistance. 
 
15.2  
Specimens for BRAF V600 testing (required for patients) 
 
All patients must submit specimens for central BRAF V600 testing.  
 
a.  
Collection instructions are outlined in Section 15.2e and submission instructions 
are outlined in Section 15.2g. 
 
b.  
Specimens to be submitted (see Sections 9.1 and 9.2): 
 
1.  
1 H&E tumor tissue slide 
 
2.  
3 unstained paraffin-embedded tissue slides  
-or-  
1 paraffin-embedded tissue block 
 
c.  
For those who have not yet undergone BRAF V600 testing, specimens must be 
submitted to Moffitt Cancer Center, the central lab, on the day of Step 1 Initial 
Registration. If patient is registered on a Friday, sites should hold tissue shipment 
until Monday. With additional patient consent, any material remaining after BRAF 
testing will be forwarded to the SWOG Solid Tumor Repository for banking. 
 
d.  
For those who have undergone BRAF V600 testing locally, specimens must be 
submitted to the bank within 28 days of Step 2 registration for future BRAF V600 
mutation confirmation. 
 
e.  
Paraffin-embedded tissue must be fixed per the instructions on the SWOG 
Specimen Submission webpage 
(http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp) and 
submitted to the lab in Section 15.2g. 


 
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f.  
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
g.  
Shipping Samples 
 
In the online specimen tracking system, the appropriate SWOG laboratory for 
submission of tissue for BRAF V600 testing and SWOG Repository Submission 
is identified as follows: 
 
1.  
For those who have not yet undergone BRAF V600 testing, submit tissue 
Monday - Thursday to: 
 
Lab #213:  
Moffitt Cancer Center, Department of Pathology 
Phone: 813/745-3980 
E-mail: anthony.magliocco@moffitt.org 
Contact: Anthony Magliocco 
 
2.  
For those who have undergone BRAF V600 testing locally: 
 
Lab #201:  
SWOG Specimen Repository – Solid Tissue, Myeloma 
and Lymphoma Division 
 
h. 
For those who have not yet undergone BRAF V600 testing, institutions will be 
notified by e-mail with the patient’s BRAF V600 testing results within 
approximately 10 calendar days after specimen submission. A formal lab report 
will be FAXed to the number provided in the specimen tracking system. If the 
patient’s BRAF V600 results are NOT received by e-mail within 10 calendar days 
of submitting the specimen, please contact the SWOG Data Operations Center at 
206/652-2267. 
 
15.3  
Specimens for translational medicine and correlative studies (required for patients) 
 
a.  
Specimens must be submitted at the following times (see Sections 9.1 and 9.2): 
 
1.  
12 unstained paraffin-embedded tissue slides or block from baseline 
within 28 days of Step 2 registration. If tissue block is submitted for 
Section 15.2, these additional slides are not required. 
 
2.  
2 tubes (lavender top EDTA tube) each of 10 mL blood on the day of 
Step 1 registration, each restaging, and off treatment. Patients crossing 
over to Step 3 registration following disease progression on Arm 1 must 
also submit blood on day of Step 3 registration, each restaging, and off 
treatment. Collect plasma from samples per the link in Section 15.3b. 
Plasma may be frozen and batch shipped. 
 
NOTE:  With additional patient consent, any remaining material after 
initial testing will be forwarded to the SWOG Solid Tumor Repository for 
banking. 
 
b.  
Specimen collection and submission instructions can be accessed on the SWOG 
Specimen Submission webpage 
(http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp). 
 
1.  
Federal guidelines for the shipment of blood products: 
 
a.  
The tube must be wrapped in an absorbent material. 
 
b. 
The tube must then be placed in an AIRTIGHT container (like a 
resealable bag). 


 
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c.  
Pack the resealable bag and tube in a Styrofoam shipping 
container. 
 
d.  
Pack the Styrofoam shipping container in a cardboard box. 
 
e.  
Mark the box "Biohazard". 
 
c.  
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
d. 
Shipping Samples 
 
In the online specimen tracking system (STS), specimens for correlative studies 
and banking can be submitted to: 
 
Lab #201:  
SWOG Specimen Repository – Solid Tissue, Myeloma and 
Lymphoma Division 
 
15.4 
Specimens for Translational Medicine: Co-Clinical PDX Model Trial (optional for patients) 
 
Patients enrolled on study at the following institutions only may participate in this portion 
of the protocol: 
 
• 
MD Anderson Cancer Center 
• 
University of California, Davis 
• 
University of California, San Francisco 
• 
University of Colorado 
• 
University of Southern California 
• 
Yale University 
 
a. 
With patient’s consent, specimens must be submitted at the timepoints listed 
below.  Collection instructions are outlined in Section 15.4c and submission 
instructions are outlined in Section 15.4f. 
 
b.  
With patient’s consent, the following specimen and documents must be 
submitted within 7 days of Step 2 Randomization (see Sections 9.1 and 9.2): 
 
1. 
Tumor Biopsy: Pre-treatment 
2. 
Requisition Form (located on the S1406 abstract page on the SWOG 
website [www.swog.org]) 
3. 
History and Baseline Information Form (located on the S1406 abstract 
page on the SWOG website [www.swog.org]) 
4. 
STS packing slip (see Section 15.1) 
 
c. 
Fresh tumor samples should be placed in a 50 mL screw cap conical tube 
containing 40 mL RPMI buffer media (without fetal bovine serum) within 30 
minutes of tumor removal.  The cap of the tube should be sealed tightly and 
covered with Parafilm.  Samples should be refrigerated at 4°C until packed for 
shipping.  The sealed conical tube containing RPMI and the tumor specimen 
must be wrapped in absorbent material (e.g., paper towels) and placed in an 
airtight bag (e.g., resealable bag).  The specimen should be packed into an 
insulated styrofoam shipper with a refrigerated (4°C) cool pack (not frozen) to 
protect the specimen from temperature fluctuations.  All paperwork pertaining to 
the patient should be placed in a plastic bag, sealed tightly, and packed with the 
tissue shipment. Samples must be received at the Jackson Laboratory (JAX) 
within 24 hours of collection. 


 
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d. 
The specimen should be collected following Institutional Universal Precaution 
SOPs for maintaining tissue integrity.  Please remind all personnel that are 
involved in processing the sample that it will be implanted into profoundly 
immune deficient mice.  This is the reason that it is imperative that extra care be 
taken in sample collection in order to minimize the risk of transferring human 
bacteria to mice. 
 
e. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
f. 
Samples 
 
In the online specimen tracking system, the appropriate SWOG laboratory for 
submission of tumor biopsy samples for PDX models is identified as follows: 
 
Lab #216:  
The Jackson Laboratory – In Vivo Services 
Phone: 916/469-2609 
Contact:  Margaret Bundy 
E-mail:  margaret.bundy@jax.org 
 
1. 
Federal guidelines for the shipment of blood products: 
 
a.  
The tube must be wrapped in an absorbent material. 
 
b.  
The tube must then be placed in an AIRTIGHT container (like a 
resealable bag). 
 
c.  
Pack the resealable bag and tube in a Styrofoam shipping 
container. 
 
d.  
Pack the Styrofoam shipping container in a cardboard box. 
 
e.  
Mark the box "Biohazard". 
 
 
 


 
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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. 
 
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.  
 
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 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. Also 
see Appendix 18.1 for general and background information about expedited 
reporting. 


 
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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 Internet connectivity is disrupted, a 24-hour notification is to be 
made to SWOG by telephone at 210-614-8808 or by email at adr@swog.org.  
Once Internet connectivity is restored, a 24-hour notification that was made by 
phone or using adr@swog.org must be entered electronically into CTEP-AERS 
by the original submitter at the site. 
 
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 
or 16.2, as applicable.  
 
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 as part of the trial. Reporting requirements are provided in 
Table 16.1. The investigational agent used in Arm 2 of this study is vemurafenib. 
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 Operations Office, 210/614-8808 or adr@swog.org, before preparing the 
report. 
 


 
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Table 16.1: Expedited Reporting Requirements for Adverse Events that Occur on Studies under a 
Non-CTEP 
IND 
within 
30 
Days 
of 
the 
Last 
Administration 
of 
the 
Investigational 
Agent/Intervention1  Vemurafenib (Arm 2 and Arm 3) 
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 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in 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 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
 
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 non-CTEP-IND: 
 
1) 
Group-specific instructions. 
 
Supporting Documentation Submission - Within 5 calendar days submit 
the following to the SWOG Operations Office by fax to 210-614-0006 or 
mail to the address below: 
• 
Printed copy of the first page of the CTEP-AERS report 
• 
Copies of clinical source 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. 
 
2) 
The adverse events listed below also require expedited monitoring for 
patients assigned to Arm 2 or Arm 3 of this trial that includes the 
administration of vemurafenib: 
• 
Cutaneous squamous cell carcinoma (cuSCC) 
• 
Non-cutaneous squamous cell carcinoma (non-cuSCC) 
• 
New second primary malignancy  
• 
Grade ≥ 3 elevations in AST, ALT or serum bilirubin, OR 
cases of elevated ALT or AST in combination with either an 
elevated bilirubin or clinical jaundice. 
 
g. 
Expedited reporting for commercial agents 
 
Commercial reporting requirements are provided in Table 16.2. The commercial 
agents used in both arms of this study are cetuximab and irinotecan. If there is 
any question about the reportability of an adverse event, please telephone or 
email the SAE Program at the Operations Office, 210/614-8808 or 
adr@swog.org, before preparing the report. 
 


 
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Table 16.2. Expedited reporting requirements for adverse events experienced by 
patients on study Arm 1 who have received the commercial drug(s) listed in 
Section 16.1g above within 30 days of the last administration of the commercial 
agent(s). 
 
ATTRIBUTION 
 
Grade 4 
 
Grade 5a 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated or 
Unlikely 
 
 
CTEP-AERS 
CTEP-
AERS 
Possible, 
Probable, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
CTEP-
AERS 
CTEP-AERS:  Indicates an expedited report is to be submitted via NCI CTEP-AERS within 10 
calendar days of learning of the eventb. 
a This includes all deaths within 30 days of the last dose of treatment with a commercial 
agent(s), regardless of attribution.  Any death that occurs more than 30 days after the last 
dose of treatment with a commercial agent(s) and is attributed (possibly, probably, or 
definitely) to the agent(s) and is not due to cancer recurrence must be reported according to 
the instructions above. 
 
b Submission of the on-line CTEP-AERS report plus any necessary amendments generally 
completes the reporting requirements. You may, however, be asked to submit supporting 
clinical data to the Operations Office in order to complete the evaluation of the event. If 
requested, the specified data should be sent within 5 calendar days by fax to 210-614-0006.  
 
  
 
 
h.  
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. 
 
 
SWOG requires all secondary malignancies that occur following 
treatment with an agent under a Non-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 routine reporting via CDUS 
and SAE reporting per Section 16.1f.2. 


 
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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 the 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   
 
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. 
 
i.  
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. 
 


 
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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 
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outcome in metastatic colorectal cancer patients treated with or without cetuximab. Eur J Cancer 
46(11):1997-2009, 2010. 
 
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Gavin PG, Colangelo LH, Fumagalli D, Tanaka N, Remillard MY, Yothers G, Kim C, Taniyama Y, 
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results from intergroup trial CALGB 89803. Clin Cancer Res 18(3):890-900, 2012. 
 
19. 
Tran B, Kopetz S, Tie J, Gibbs P, Jiang ZQ, Lieu CH, Agarwal A, Maru DM, Sieber O, Desai J. 
Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and 
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Kopetz S, Desai J, Chan E. PLX4032 in metastatic colorectal cancer patients with mutant BRAF 
tumors. J Clin Oncol 28(15):(abstr; suppl 3534), 2010. 
 
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Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, Beijersbergen RL, Bardelli 
A, Bernards R. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback 
activation of EGFR. Nature 483(7387):100-103, 2012. 
 
22. 
Cocoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP, Brown RD, Della Pelle P, Dias-
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insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer 
Discov 2(3):227-235, 2012. 
 
23. 
Yang H, Higgins B, Kolinsky K, Packman K, Bradley WD, Lee RJ, Schostack K, Simcox ME, 
Kopetz S, Heimbrook D, et al. Antitumor activity of BRAF inhibitor vemurafenib in preclinical 
models of BRAF-mutant colorectal cancer. Cancer Res 72(3):779-789, 2012. 
 
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Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Kohne 
CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic 
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Cancer 48(10):1466-1475, 2012. 
 
25. 
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Cunningham D, Tejpar S. et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line 
treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor 
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Skovlund E, et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, 
leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic 
colorectal cancer: the NORDIC-VII study. J Clin Oncol 30(15):1755-1762, 2012. 
 
27. 
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JR, Simes J, Moore MJ, Tebbutt N, et al. PIK3CA, BRAF and PTEN status and benefit from 
cetuximab in the treatment of advanced colorectal cancer - results from NCIC CTG / AGITG 
CO.17. Clin Cancer Res 2012, 2013. 
 
28. 
Mao M, Tian F, Mariadason JM, Tsao CC, Lemos R, Jr., Dayyani F, Gopal YN, Jiang ZQ, Wistuba, 
II, Tang XM, et al. Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome 
with PI3K inhibition or demethylating agents. Clin Cancer Res 19(3):657-667, 2013. 
 
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Kingsbury Z, Wong AS, et al. Non-invasive analysis of acquired resistance to cancer therapy by 
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33. 
James B, Lemos R, Tian F, Motter T, Momin A, Nieshaboori N, Kiriakova G, Kopetz S, Powis J. 
Modeling evolution of resistance in patient-derived xenografts: resistance to the BRAF inhibitor 
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34. 
Sinicrope FA, Smyrk TC, Tougeron D, Thibodeau SN, Singh S, Muranyi A, Shanmugam K, 
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35. 
Capper D, Voigt A, Bozukova G, Ahadova A, Kickingereder P, von Deimling A, von Knebel 
Doeberitz M, Kloor M. BRAF V600E-specific immunohistochemistry for the exclusion of Lynch 
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Deimling A, Scolyer RA. Immunohistochemistry Is Highly Sensitive and Specific for the Detection 
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37. 
Desai J, Day F, Muranyi A, Singh S, Shanmugam K, Grogan T, Gibbs P, Williams D, Sieber O, 
Waring P. A highly sensitive immunohistochemical assay to detect BRAF V600E mutations in 
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Kopetz S, Lemos R, Powis G. The promise of patient-derived xenografts: the best laid plans of 
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models. Cancer Res 73(17):5315-5319, 2013. 
 
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Bertotti A, Migliardi G, Galimi F, et al. A molecularly annotated platform of patient-derived 
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Saltz LB, Meropol NJ, Loehrer PJ, Sr., Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab 
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Lenz HJ, Van Cutsem E, Khambata-Ford S, et al. Multicenter phase II and translational study of 
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Jonker DJ, O'Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. 
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Perez-Soler R, Kemp B, Wu QP, et al. Response and determinants of sensitivity to paclitaxel in 
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Garrido-Laguna I, Uson M, Rajeshkumar NV, et al. Tumor engraftment in nude mice and 
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18.0 
APPENDIX 
 
18.1 
Determination of Expedited Adverse Event Reporting Requirements 
 
18.2 
Translational Medicine 
 
18.3  
Inhibitors/Inducers of CYP3A4 & CYP1A2 and QTc Prolonging Medications  
 
 
 


 
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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 16.1f 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 
Translational Medicine 
 
a. 
Background 
 
Loss of PTEN and activating mutations in the PIK3CA oncogene result in 
activation of PI3K/Akt signaling, a pathway implicated in anti-apoptotic activity.  
When compared to melanoma, BRAF mutant CRCs have higher PI3K pathway 
activity due to both genetic (PTEN, PIK3CA, PIK3R1) and epigenetic 
(hypermethylation) mechanisms. (28) Comparative studies between BRAF-
mutated melanoma and colorectal cell lines by reverse phase protein arrays 
suggest that the colon cell lines have much higher rates of PI3K pathway 
activation, as reflected by significant differences in pAkt, pMTOR, pFoxo3A, 
pGSK3b, pS6, and p4EBP expression.  Those lines harboring PIK3CA gene 
mutations or loss of PTEN are less sensitive to BRAF inhibition than cell lines 
expressing PTEN and lacking mutations in PIK3CA.  Additionally, when cell lines 
with intact PTEN were introduced with siRNA against PTEN, cytotoxic activity of 
vemurafenib was lost.  These results imply that, in the presence of BRAF 
inhibition, molecular aberrations like PTEN loss or activating PI3KCA mutations, 
which increase signaling of the PI3K/Akt pathway, decrease sensitivity to BRAF 
inhibition.  Therefore, we hypothesize that patients whose tumors contain 
activating PIK3CA mutations or show loss of PTEN immunohistochemically will 
demonstrate no benefit in progression-free survival with the addition of 
vemurafenib, relative to patients whose tumors do not harbor such alterations. 
 
NRAS mutations and KRAS mutations outside of codons 12 and 13 have been 
identified as a potential predictive biomarker of resistance to cetuximab, and we 
propose to include this in the testing, recognizing a potential shift in clinical 
practice during the course of the study. 
 
Data on the utility of circulating DNA for monitoring treatment response and 
development of resistance have previously been reported. (30-32)  Unpublished 
results using mice implanted with patient-derived BRAF-mutated colorectal 
tumors and treated with a BRAF inhibitor have shown that NRAS and KRAS 
mutations may develop as a mechanism of resistance to BRAF inhibition in 
BRAF-mutated CRC and the concurrent use of EGFR inhibitors suggests that 
KRAS mutations may likewise occur. (33) 
 
b.   
Experimental Approach, validated assays employed and expertise of PI: 
 
In the setting where no prior BRAF test has been conducted, a validated 
monoclonal antibody from Roche Ventana will be used that has been developed 
against the V600E BRAF mutation.  In the event of technical failure of the 
immunohistochemistry staining, then DNA pyrosequencing will be performed at 
Moffitt Cancer Institute using DNA extracted from available tumor specimen to 
assess for the presence of a BRAF V600E mutation.  If pyrosequencing reveals a 
BRAF V600E mutation, then the patient will remain eligible for participation onto 
the study.  However, if no mutation can be detected by DNA sequencing, then 
the patient will become ineligible for study enrollment/participation. The 
BRAFV600E antibody product being used is a Class I IVD. Scoring will be 
interpreted per the package insert: Positive for BRAFV600E – Unequivocal 
cytoplasmic staining of any intensity in viable tumor cells; Negative for BRAFV600E 
– Absence of unequivocal cytoplasmic staining in viable tumor cells (nuclear 
staining, weak to moderate staining of isolated tumor cells/focal confluent 
staining of viable tumor cells should be considered negative.).  All testing will be 
done in a CLIA-compliant facility. 


 
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Several studies have reported on the high sensitivity and specificity of using an 
immunohistochemical assay to detect a BRAF-mutated tumor:  
 
(1)  
Sinicrope and colleagues looked at 75 surgically resected, stage III 
primary colorectal tumors – in 50 of these tumors, a BRAF V600E 
mutation was detected using a PCR based assay from FFPE specimens 
in a CLIA-compliant laboratory at Mayo, whereas wild-type BRAF was 
observed in the remaining 25 tumors. (34).  Immnunohistochemical 
analyses of these tumors was performed using two different monoclonal 
antibodies – a pan-BRAF antibody (pBR1; Spring Biosciences, 
Pleasanton, CA) for total BRAF protein and a mutant BRAF V600E-
specific antibody (VE1; Spring Biosciences, Pleasanton, California) in all 
tumor specimens.  BRAF protein expression was measured using a DAB 
Detection kit (Ventana Medical Systems, Inc; Tuscon, AZ).  Protein 
expression from the ICH results was measured by two different 
pathologists who were blinded to the clinical outcomes and mutation 
results of all patients’ tumors in this study.  Expression was graded as 0 
(no staining), 1 (weak staining), 2 (medium staining), or 3 (strong 
staining).  Pan-BRAF expression (pBR1) was detected in 74 of 75 
tumors, with 49 of the 74 patient’s tumors staining positive for the BRAF 
V600E-mutated specific VE1 antibody; this staining was not observed in 
all 25 of the patients in whom wild-type BRAF had been sequenced from 
their primary tumors.  This represented a sensitivity of 100% (95% 
confidence interval [CI] of 93% to 100%), and specificity of 100% (95% 
CI of 86% to 100%).  In all cases of mutated BRAF colorectal tumors, at 
least 70% of all tumor cells demonstrated grade 2 or 3 levels of staining; 
in 75% of these same cases, 100% of tumor cells had were IHC-positive 
at a level of 2 or 3. 
 
(2)   
Another study examined the sensitivity and specificity of the VE1 
antibody in 91 MSI-high colorectal tumor specimens that were tested for 
HNPCC [35].  Immunohistochemical results were compared with Sanger 
sequencing techniques.  IHC results for the mutated BRAF protein were 
deemed “positive” when 80% or greater of all tumor cells stained for the 
VE1 antibody at a level higher than background.  Results were scored by 
three separate pathologists, with 100% concordance between all 
pathologists on all specimens analyzed (kappa =1).  Among the 11 
tumors with BRAF V600E mutations by DNA sequencing, all 11 were 
positive by IHC (sensitivity 100%, 95% CI of 75% to 100%); for the 80 
samples that were negative for a BRAF mutation by Sanger sequencing, 
IHC results were negative in 79 (specificity of 98.8%, with 95% CI of 93% 
to 100%). 
 
(3)  
Long et al. tested this same VE1 antibody in 100 patients with stage IIIc 
unresectable or stage IV melanoma who had undergone BRAF mutation 
testing from DNA extracted from FFPE tumor specimens. (36)  Sensitivity 
of this antibody in the melanoma specimens was 97.4%, and specificity 
was 98.3%. 
 
(4)  
505 tissue microarrays from tumors of patients with stages I-IV colorectal 
cancer were analyzed for BRAF V600E mutations and mutated proteins 
in a study performed by Desai and colleagues. (37)  476 of these tumors 
had tissue available sufficient to perform both Sanger sequencing and 
ICH using the aforementioned VE1 antibody.  DNA sequencing detected 
a BRAF V600E mutation in 56 of 476 specimens, whereas the 
immunohistochemical approach stained positive for V600E BRAF in 65 
of 476 tumors.  Repeat evaluation of the discordant cases with alternate  


 
S1406 
 
Page 77 
 
Version Date 11/10/16 
 
 
 
sequencing methodology confirmed the presence of the mutation in the 
majority of the cases. 
 
KRAS, NRAS, and PIK3CA mutation by sequencing methodology will be 
performed by Foundation Medicine (next-generation sequencing here will include 
400+ genes of interest in colorectal cancer). 
 
DNA will be prepared from 6 FFPE slides per patient (approx. 600 ng DNA, TBC) 
to systematically explore genetic alterations which might be associated with 
response or resistance to combined therapeutic approaches. A defined set of 
genes potentially associated to or significantly mutated in mCRC (e.g. but not 
limited to KRAS, NRAS, PIK3CA, BRAF, EGFR, AKT, FLT3, KIT, MET, ERBB2, 
JAK2 etc.) MSI status and mutation load will be examined on the 
FoundationOne® Next Generation Sequencing (NGS) panel. 
 
RNA will be prepared from 3 FFPE slides per patients (approx 300ng RNA, TBC) 
to detect differential expression by methods like Nanostring or others. Analyzed 
genes might comprise e.g. but not limited to gene signatures related to CRC and 
gastric cancer oncogeneis, angiogenesis, immune pathways, PI3K, WNT, EGF 
and MEK pathway signatures, epigenetic regulators, p53, NOTCH and TGF-beta 
signaling. The definitive list of genes and technologies might only be finalized 
after complete enrolment and will be based on scientific knowledge at that time. 
 
Plasma analysis of BRAF, KRAS, and NRAS will be performed using NGS assay 
(performed at MD Anderson or Guardant Health, Redwood City, CA) and digital 
droplet PCR.   
 
Data analysis will be performed at the SWOG Statistical Center, to allow 
exploration of the associations of each potential predictive biomarker with patient 
outcomes including progression-free and overall survival. 
 
c. 
Testing will be performed at the following sites:  
 
• 
BRAF V600E IHC:  Dr. Anthony Magliocco, Director of Pathology, Moffitt 
Cancer Center, Anthony.Magliocco@moffitt.org  
• 
PTEN, hMLH1 IHC (Dako/Agilent, Carpinteria, CA):  Drs. Dipen Maru, Scott 
Kopetz, MD Anderson Cancer Center 
• 
Circulating cell-free DNA:  Drs. Scott Kopetz , M.D. Anderson Cancer Center 
or Guardant Health, Redwood City, CA 
• 
FoundationOne® 
NGS 
multigene 
panel, 
RNA 
expression 
analysis/NanoString, 
Foundation 
Medicine, 
Yibing 
Yan 
yan.yibing@gene.com  
 
15 slides from FFPE tissue will be collected as follows: 1 slide for H&E, 2 slides 
for BRAF IHC testing, 2 slides for PTEN, hMLH1 IHC, 6 slides (or 600 ng of 
DNA) for FoundationOne® NGS DNA sequencing, 3 slides (or 300 ng RNA) for 
RNA expression/NanoString.   
 
The priority list for these specimens will be (1) H&E, BRAF IHC (2) DNA NGS 
(3) PTEN IHC (4) RNA expression/NanoString (5) Banking/future studies.  In 
addition, for plasma analysis, 20 mL blood (2x10mL) at each time point will also 
be collected.   


 
S1406 
 
Page 78 
 
Version Date 11/10/16 
 
 
 
18.3  
Inhibitors/Inducers of CYP3A4 & CYP1A2 and QTc Prolonging Medications  
 
Patients on study should avoid concomitant use of vemurafenib with CYP1A2 substrates, 
CYP3A4 substrates and QTc prolonging medications with a narrow therapeutic window. If co-
administration cannot be avoided, monitor closely for toxicities and consider a dose reduction of 
these subtrates and medications.  
 
a. 
Inhibitors of CYP3A4: 
• 
clarithromycin  
• 
erythromycin  
• 
troleandomycin  
• 
chloramphenicol 
• 
anti-retrovirals (delaviridine)  
• 
protease inhibitors (ritonavir, indinavir,saquinavir, nelfinavir, amprenavir, lopinavir) 
• 
itraconzaole  
• 
ketoconazole  
• 
voriconazole  
• 
fluconazole (>150 mg daily) 
• 
nefazodone  
• 
fluvoxamine 
• 
Grapefruit or its juice 
 
b. 
Inducers of CYP3A4: 
• 
efavirenz  
• 
nevirapine 
• 
carbamazepine  
• 
phenytoin  
• 
oxcarbamazepine 
• 
rifampin (rifampicin)  
• 
rifabutin  
• 
rifapentene 
• 
efavirenz  
• 
nevirapine 
• 
St. John’s Wort  
• 
modafinil 
 
c. 
Substrates of CYP1A2: 
• 
Amitriptyline 
• 
Caffeine 
• 
Clozapine 
• 
Flutamide 
• 
Imipramine 
• 
Melatonin 
• 
Mexiletine 
• 
Mirtazapine 
• 
Olanzapine 
• 
Ramelteon 
• 
Rasagiline 
• 
Ropinirole 
• 
Tacrine 
• 
Theophylline 
• 
Tizaidine 
• 
Triamterene 
• 
Zolmitriptan 


 
S1406 
 
Page 79 
 
Version Date 11/10/16 
 
 
 
 
d. 
Inhibitors of CYP1A2: 
• 
Artemisinin 
• 
Atazanavir 
• 
Cimetidine 
• 
Ciprofloxacin 
• 
Enoxacin 
• 
Ethinyl estradiol 
• 
Fluvoxamine 
• 
Grapefruit juice 
• 
Mexiletine 
• 
Tacrine 
• 
Thiabendazole 
• 
Zileuton 
 
e. 
Inducers of CYP1A2: 
• 
Barbiturates 
• 
Cruciferous vegetables 
• 
Grilled meat 
• 
Carbamazepine 
• 
phenytoin 
• 
Primidone 
• 
Rifampin 
• 
Smoking 
 
f. 
QTc Prolonging Medications: 
• 
amiodarone  
• 
dofetilide  
• 
sotalol  
• 
procainamide  
• 
quinidine  
• 
disopyramide 
• 
haloperidol  
• 
chlorpromazine 
• 
clarithromycin  
• 
erythromycin 
• 
methadone 
 
 


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