Clinical trial NCT03040986
Conditions: KRAS NP_004976.2:p.G12R Stage III Pancreatic Cancer AJCC v6 and v7 Stage IV Pancreatic Cancer AJCC v6 and v7
Sponsor: National Cancer Institute (NCI)
Start date: 2017-07-21; Completion date: 2020-10-15
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well selumetinib sulfate works in treating patients with pancreatic cancer with Kirsten rat sarcoma (KRAS) G12R mutations that has spread from where it started to nearby tissue or lymph nodes or other places in the body. Selumetinib sulfate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. Determine the objective response rate to selumetinib sulfate (selumetinib) administered as 75 mg orally twice daily on a continuous schedule in patients with advanced pancreas cancer harboring Kirsten rat sarcoma (KRAS) G12R mutations.

SECONDARY OBJECTIVES:

I. To determine the progression free survival of patients with locally advanced, unresectable and stage IV pancreas cancer treated with selumetinib monotherapy.

II. To evaluate the safety of selumetinib in patients with advanced pancreas cancer.

III. To determine the impact of additional genetic alterations on the response to selumetinib in pancreas cancer harboring KRAS G12R mutations.

IV. To develop a clinically applicable biomarker predicting response to selumetinib in pancreas cancer harboring KRAS G12R mutations.

OUTLINE:

Patients receive selumetinib sulfate orally (PO) twice daily (BID). Treatment repeats every 28 days for up to 27 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 52 weeks.

Arms: arm 1: Patients receive selumetinib sulfate by mouth (PO) twice daily (BID). Treatment repeats every 28 days for up to 27 courses in the absence of disease progression or unacceptable toxicity
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Selumetinib Sulfate
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given by mouth (PO)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
                                    
Pediatric Oncology Branch 
i 
 
 
DATE: 
 
May 19, 2018 
TO:                 
CTEP PIO, CTEP, NCI, NIH 
Chairperson, NCI Central Institutional Review Board (NCI CIRB) 
FROM:         
Udo Rudloff, MD 
Principal Investigator 
                                      POB, CCR, NCI 
SUBJECT: 
Amendment 4 to NCI protocol number 10050 entitled, “A Phase II Study 
of Selumetinib (AZD6244) for the Treatment of Advanced Pancreas 
Cancer harboring KRAS G12R Mutations” 
The primary purpose of this amendment is to update protocol CAEPR and consent Selumetinib 
risk language. Additionally, please, note, as part of the implementation of version 5.0 of the 
Common Terminology Criteria for Adverse Events (CTCAE), the CAEPR list for selumetinib, 
which was previously in CTCAE 4.0 language, has been migrated to CTCAE 5.0 language. 
Patients and their providers are able to send their tumor tissue for somatic gene mutation profiling 
to Foundation Medicine which performs rapid genotyping on multiple NGS platforms. It issues a 
CLIA report which is in line with study guidelines and makes the patients, without the need for 
further screening, immediately eligible for starting treatment with selumetinib. In this regard, we 
clarified in the protocol that test result from CLIA certified laboratory, confirming somatic KRAS 
G12R mutation can be used for confirmation of patient’s eligibility and to decrease the number  of 
patients screened. 
We also have updated dosing delays/dose modifications of selumetinib for the management of 
grade 2 AST/ALT elevations to give patients who only have a transient brief AST/ALT under 
appropriate lab monitoring the possibility to return to DL 0. However, should a grade 2 or greater 
AST/ALT elevation again occur after restarting selumetinib or return to DL 0, the patient can only 
continue on DL -1. The AST/ALT elevations we observed were very transient. To eliminate 
ambiguity as to how often patients can return to higher dose levels after resolution of low grade 
ALT/AST elevations or other related lab abnormalities, we amended Section 6: Upon two 
recurrences of DLT necessitating dose reduction, no further attempts to return to higher dose level 
after resolution to ≤Grade 1 will be made. 
Finally, we simplified eligibility criteria with regard to total bilirubin levels now using cutoff 
elevated versus not elevated above institutional normal (different institutions have different 
definitions and cutoffs), and defining AEs as elevated above institutional accepted normal levels. 
Editorial changes have been made throughout the document for clarity. 


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
ii 
 
I. Comments Requiring a Response – Major Issues: 
# 
Section 
Comments 
1 
Stats 
The trial has expected outcome data for many of the first 7 patients.  Changing the 
statistical plan at this point decreases the statistical rigor of the final analysis. This 
has been discussed several times with CTEP biostatisticians and CTEP leadership 
and we do not favor any changes to the 2-stage design for the trial.  If there is not 
an objective response in the first 7 patients, the trial should not proceed to a second 
stage.  If there appears later to be a signal for prolonged stable disease in these 
first-stage patients, this can be discussed with CTEP and AstraZeneca. 
Response: We agreed not to change statistical plan.   
 
II. Comments Requiring a Response– Administrative & Editorial Issues: 
# 
Section 
Comments 
2 
4.2.2 
Specimen Tracking Training: According to section 9.1.1 all sample tracking will 
be managed at NCI.  Please confirm, and if this text is unnecessary, please delete. 
Response: Samples collected at NCI only will be additionally tracked in NCI 
as described in section 9.1.1.  Procedures described in Section 4.2.2     will be 
also followed. 
3 
Table 9 
ctDNA Blood Collection:  the link should be labeled Appendix H rather than 
Appendix G.  It does jump to the correct section.  
Response: This has been corrected in Section 9 
III. Recommendations: 
# 
Section 
Comments 
 
7.3.3 
In the third paragraph, please replace, “Death due to progressive disease should be 
reported as Grade 5 “Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) – Other (Progressive Disease)” under the system organ class (SOC) of the 
same name.” with the following: 
 
“Death due to progressive disease should be reported as Grade 5 “Disease 
progression” in the system organ class (SOC) “General disorders and 
administration site conditions.”   
Response: This has been replaced in Section 7.3.3 Expedited Reporting 
Guidelines 
 
4.1 
At the time of the next amendment please replace 4.1.1 and 4.1.2 using the 
following templated text and reformat section 4.1 accordingly: 


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
iii 
 
# 
Section 
Comments 
Food and Drug Administration (FDA) regulations require IND sponsors to select 
qualified investigators.  NCI policy requires all persons participating in any NCI-
sponsored clinical trial to register and renew their registration annually.  To 
register, all individuals must obtain a CTEP Identity and Access Management 
(IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, persons with a 
registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN or 
RAVE or acting as a primary site contact) must complete their annual registration 
using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration 
type are outlined in the table below. 
 
Documentation Required 
IVR 
NPIV
R 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and 
applications.  In addition, IVRs and NPIVRs must list all clinical practice sites and 
IRBs covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) 
tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log 
(DTL).     
 


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
iv 
 
# 
Section 
Comments 
Additional information can be found on the CTEP website at < 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, 
please contact the RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
Response: This has been replaced in the Section 4.1 Investigator and 
Research Associate Registration with CTEP 
 
4.2 
At the time of the next amendment please replace 4.2 using the following 
templated text:  
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll 
patients.  Assignment of site registration status in the CTSU Regulatory Support 
System (RSS) uses extensive data to make a determination of whether a site has 
fulfilled all regulatory criteria including but not limited to the following:  
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating 
organization 
• A valid IRB approval 
• Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following 
criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for 
this study are not required to submit IRB approval documentation to the CTSU 
Regulatory Office. For sites using the CIRB, IRB approval information is received 
from the CIRB and applied to the RSS in an automated process.  Signatory 
Institutions must submit a Study Specific Worksheet for Local Context (SSW) to 
the CIRB via IRBManager to indicate their intent to open the study locally.  The 
CIRB’s approval of the SSW is then communicated to the CTSU Regulatory 
Office.  In order for the SSW approval to be processed, the Signatory Institution 
must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. 
Response: This has been replaced in the section 4.2 Site Registration 
 
8.1.2.1 
At the time of the next amendment please delete these sections and replace with 
the following updated language: 


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
v 
 
# 
Section 
Comments 
Agent Ordering and Agent Accountability 
 
NCI-supplied agents may be requested by eligible participating Investigators (or 
their authorized designee) at each participating institution.  The CTEP-assigned 
protocol number must be used for ordering all CTEP-supplied investigational 
agents.  The eligible participating investigators at each participating institution 
must be registered with CTEP, DCTD through an annual submission of FDA Form 
1572 (Statement of Investigator), NCI Biosketch, Agent Shipment Form, and 
Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be 
ordered under the name of one lead participating investigator at that institution. 
 
Study agent must be ordered after patient is registered to the treatment arm as no 
starter supplies are being provided for this study.  
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status, a “current” password, and active person registration status.  For questions 
about drug orders, transfers, returns, or accountability, call or email PMB any 
time.  Refer to the PMB’s website for specific policies and guidelines related to 
agent management.   
Response: This has been replaced in section 8.1.2 Agent Ordering and Agent 
Accountability 
 
8.1.2.4 
At the time of the next amendment please delete and replace with the following 
updated language: 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  
http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through 
Friday between 8:30 am and 4:30 pm (ET). 
Response: This has been replaced in Section 8.1.2.4 Useful links and Contacts 


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
vi 
 
# 
Section 
Comments 
 
4.1.1, 
4.1.2 
Please delete the information in these 2 subsections and replace with the 
following language, in accordance with the Registration and Credential 
Repository initiative. 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations require IND sponsors to select 
qualified investigators.  NCI policy requires all persons participating in any NCI-
sponsored clinical trial to register and renew their registration annually.  To 
register, all individuals must obtain a CTEP Identity and Access Management 
(IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, persons with a 
registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN or 
RAVE or acting as a primary site contact) must complete their annual registration 
using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration 
type are outlined in the table below. 
 
Documentation Required 
IVR 
NPIV
R 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and 
applications.  In addition, IVRs and NPIVRs must list all clinical practice sites and 
IRBs covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
• Added to a site roster 


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
vii 
 
# 
Section 
Comments 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) 
tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log 
(DTL).     
 
Additional information can be found on the CTEP website at < 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, please 
contact the RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
Response: This has been replaced in Section 4.1 Investigator and Research 
Associate Registration with CTEP 
 
4.2 
Please revise the following paragraph as specified. 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients.  
Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled all 
regulatory criteria including but not limited to the following: an active Federal Wide 
Assurance (FWA) number, an active roster affiliation with the Lead Network or a 
participating organization, a valid IRB approval, and compliance with all protocol 
specific requirements. 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating 
organization 
• A valid IRB approval 
• Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following 
criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site 
Response: This has been replaced in section 4.2 Site Registration 
 
4.2.2 
Please delete the following bullet point. 
• CTSU Transmittal Sheet (optional)  
In addition, while 10050 has been identified as a Specimen Tracking study, 
and the following information is required to be included in this section. 
• Specimen Tracking Training 
 At least one individual at each participating site will need to complete 
the Theradex-led training 
 Theradex will provide a certificate of completion, which will need to be 
submitted to the CTSU through the Regulatory Submission Portal 


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
viii 
 
# 
Section 
Comments 
 The training is a one-time only requirement per individual 
 This training will need to be completed before the first patient 
enrollment at a given site 
 Peter Clark is the main point of contact at Theradex for the training 
(802-456-8735, PClark@theradex.com).  Nafeesa Sarakhawas is the 
backup contact (609.480.2693, NSarakhawas@theradex.com). 
Response: This has been corrected in section 4.2.2 Requirements For 10050 
Site Registration 
 
4.3.4 
Please revise the following bullet point as indicated. 
• To enroll patients or request slot reservations:  Be on an ETCTN 
Corresponding or Participating Organization roster with the role of 
Registrar. Registrars must hold a minimum of an AP registration 
type. 
Response: This has been updated in Section 4.3.4 OPEN/IWRS User 
Requirements 
 
12.2 
Please revise the sentence below as specified. 
Data collection for this study will be done through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the 
appropriate roles assigned in the Regulatory Support System (RSS).  To access 
Rave via iMedidata, the site user must have an active CTEP IAM account (check 
at < https://ctepcore.nci.nih.gov/iam  >) and the appropriate Rave role (Rave CRA, 
Read-Only, CRA, (Lab Admin, SLA, or Site Investigator) on either the LPO or 
participating organization roster at the enrolling site. To the hold Rave CRA role 
or CRA Lab Admin role, the user must hold a minimum of an AP registration 
type.  To hold the Rave Site Investigator role, the ind 
 
ividual must be registered as an NPIVR or IVR.  Associates can hold read-only 
roles in Rave.. 
Response: This has been replaced in Section 12.2 Data Reporting 
 
12.2.1 
Please update the Theradex email address to CTMSSupport@theradex.com  
Response: This has been updated in section 12.2.1 Method 
 
ADDITIONAL CHANGES: 
1. Document header. The version date has been updated. 
2. TITLE page: branch affiliation, room number and fax number of Dr. Rudloff have been 
updated, Cara Kenney has been removed from the list of NIH Associate investigators, 
Santhana Webb, Linda Sciuto and Rasa Viliams have been added to the list; Cara Kenney 
has been removed and Santhana Webb has been added as Study coordinator/Referral 
contact, Tatiana Beresnev has been removed as Responsible Data Manager, identification 
of amendment has been added, version date has been updated. 


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
ix 
 
3. In the Design: of PRECIS and Section 5 TREATMENT PLAN the clarification about 
selumetinib administration in regard to meals have been done. 
4. TABLE OF CONTENTS has been updated 
5. In the Section  3.1.4 we made clarification, that patients are eligible, if they already have 
KRAS mutation status confirmation.  
6. In the Section 3.1.8 Patients must have normal organ and marrow function as 
defined below: the correction has been made to allow participation of subjects with total 
bilirubin below institutional limits. 
7. In the Section 4.2.3 Submitting Regulatory Documents suite number of CTSU 
regulatory office has been corrected. 
8. In the Section 4.3 Patient Registration reference to Harris (HOIS) has been removed as 
the company has been renamed. 
9. NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 has been 
replaced with version 5.0 in Sections 6 DOSING DELAYS/DOSE MODIFICATIONS, 
Section 7.2 Adverse Event Characteristics, and Section 12.1 Study Oversight  
10. In the Section 6 DOSING DELAYS/DOSE MODIFICATIONS we updated table with 
Summary of dose holding/interruptions and dose de-escalation recommendations for 
selumetinib. 
11. In the Section 7 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
CAEPR for Selumetinib has been updated. 
12. Section 7.7.3 Non-compliance (NIH Definition) with NIH definition of non-compliance 
has been added as the clinical director now requires reports of this event. 
13.  Section 7.7.4 NCI Clinical Director Reporting has been updated per current NCI 
clinical director reporting requirements. 
14. Reference to Appendix I and clarification about KRAS mutation test have been added in 
Section 9 BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES.  
15. Shipping address has been updated in Section Shipping instructions for Participating sites  
16. The  STUDY CALENDAR has been updated to explain screening KRAS mutation test. 
17. Section STATISTICAL CONSIDERATIONS has been updated to explain new number 
of patients screened.  
18. Appendix I: Cancer Gene Mutation‐Standard Panel has been added. 
  


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
1 
 
NCI Protocol #: 
10050 
 
Local Protocol #: 17C0144 
 
ClinicalTrials.gov Identifier:  NCT03040986 
 
TITLE:  A Phase II Study of Selumetinib (AZD6244) for the Treatment of Advanced Pancreas 
Cancer harboring KRAS G12R Mutations 
 
Corresponding Organization: National Cancer Institute LAO-NCI 
 
Principal Investigator: 
Udo Rudloff, MD, PhD, POB/CCR/NCI (A-F) 
10 Center Drive, CRC Room 2B38D 
Bethesda, MD 20892 
Phone: 240-760-6238 
Fax: 301-480-2462 
Udo.Rudloff@nih.gov 
 
Participating Organizations: 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
 
NIH Associate Investigators:     Anish Thomas, DTB/CCR/NCI (A-F) 
                                                      10 Center Drive, Room 4-5330 
Bethesda, MD 20892-1906 
Phone: 240-760-6241 
Email: anish.thomas@nih.gov 
                                                       
                                                      Santhana Webb, OCD/CCR/NCI (A-C, E-F) 
                                                      10 Center Drive, Room 8D44F 
Bethesda, MD 20892-1906 
Phone: 240-858-3165 
Email: santhana.webb@ mail.nih.gov 


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
2 
 
                                                      Linda Sciuto, OCD/CCR/NCI (A-C, E-F) 
                                                      10 Center Drive, Room 8D48 
Bethesda, MD 20892-1906 
Phone: 240-760-6117 
Email: lsciuto@mail.nih.gov 
 
                                                      Rasa Vilimas, OCD/CCR/NCI (A-C, E-F) 
                                                      10 Center Drive, Room 8D44 
Bethesda, MD 20892-1906 
Phone: 240-858-3158 
FAX: 301-480-2462 
Email: rasa.viliams@nih.gov 
 
 
Statistician: 
 
Seth Steinberg, Ph.D. (E-F) 
Head, Biostatistics and Data Management Section 
Office of the Clinical Director, Center for Cancer Research 
National Cancer Institute 
9609 Medical Center Drive, Room 2W334, MSC 9716 
Bethesda, MD 20892 
Phone: 240-276-5563 
steinbes@mail.nih.gov 
 
Study Coordinator/ 
Referral Contact: 
Santhana Webb, R.N. (A-C, E-F) 
 
 
 
10 Center Drive, Room 8D44F 
Bethesda, MD 20892-1906 
Phone: 240-858-3165 
Fax: 301-480-2462 
Email: santhana.webb@nih.gov  
 
 
 
 
 


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
3 
 
Roles  
A. Obtain information by intervening or interacting with 
living individuals for research purposes 
B. Obtaining identifiable private information about 
living individuals 
C. Obtaining the voluntary informed consent of 
individuals to be subjects 
D. Makes decisions about subject eligibility 
E. Studying, interpreting, or analyzing identifiable 
private information or data/specimens for research 
purposes 
F. Studying, interpreting, or analyzing de-identified data 
or specimens for research purposes 
G. Some/all research activities performed outside NIH 
 
 
 
 
NCI-Supplied Agent:   
Drug Name: 
AZD6244 hydrogen sulfate (Selumetinib) (NSC 748727) 
IND #: 
 
Sponsor 
DCTD, NCI 
Manufacturer 
AstraZeneca 
 
 
Protocol Type / Version # / Version Date: 
Amendment 4/Version 1/ May 19, 2018 
 
 


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
4 
 
 
PRÉCIS 
Background: 
• It is expected that in 2020 pancreas cancer will rank 2nd in cancer-related deaths in the 
U.S. having surpassed colon and breast cancer. 
• Patients with advanced pancreas cancer have few available treatment options and an 
overall poor prognosis.  
• The vast majority of pancreatic cancers (up to ≥94%) harbor mutations of the KRAS 
gene, and there is ample preclinical evidence that KRAS mutations are an essential driver 
of pancreas cancer development and progression, essential for the unique metabolomic 
and transcriptomic landscape of pancreatic cancers, involved in pancreatic cancer stem 
cell formation, as well as in mediation of resistance to chemo- and molecular therapy.  
• KRAS mutational isoforms and regulators of MAPK signaling are a prognostic 
biomarker for outcome in pancreas cancer. KRAS G12R mutation status predicts 
response to selumetinib inhibition in a large panel of pancreas cancer cell lines. 
• Pre-clinical evidence, both in a large panel of cell lines and in patient-derived 
xenotransplantation models, suggests that selumetinib (AZD6244) has activity against 
pancreas cancers harboring KRAS G12R mutations. 
• This study tests the hypothesis if patients with advanced pancreas cancer with a unique 
KRAS mutational isoform respond to the MEK inhibitor selumetinib (AZD6244) and if 
genetic or protein expression information derived from treated patients distinguishes 
patients responding to the drug from patients progressing under treatment. 
Objectives: 
• Determine the objective response rate to selumetinib administered as 75 mg orally twice 
daily on a continuous schedule in patients with advanced pancreas cancer harboring KRAS 
G12R mutations. 
Eligibility: 
• Patients must have histologically confirmed locally advanced or metastatic pancreas 
cancer 
• Patients must have confirmed somatic KRAS G12R mutation as determined by sequence 
analysis of matched normal DNA from any specimen obtained from the individual (prior 
CLIA genotyping results from surgical resection specimens are acceptable).  
• Patients must not have had chemotherapy, molecular therapy with erlotinib, radiation 
therapy, or experimental biological or molecular therapy for at least 4 weeks prior to 
starting study medication.  Patients who received FOLFIRINOX must be 6 weeks from 
the last administration of therapy. Patients must have recovered from any acute toxicity 
related to prior therapy or surgery, to a grade 1 or less unless specified. 
• Age ≥18 years.   
 


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
5 
 
Design: 
• Patients will be screened for the presence of KRAS gene mutations in their tumor and 
only patients who harbor KRAS G12R mutations will be enrolled in the treatment phase 
of the study. 
• Selumetinib (AZD6244) will be administered as an oral dose of selumetinib sulfate 75 
mg twice daily (in the morning and evening) taken two hours after a meal and one hour 
before the next meal.  Selumetinib will be given continuously; one cycle equals 28 +/- 2 
days.   
• Up to 25 eligible patients (allowing for a staged accrual of initially 10 patients who will 
receive selumetinib and are evaluable after the 1st cycle) will be treated over 3-4 years 
and the trial will be completed over 4 to 5 years, allowing for completion of follow-up. 
 
 


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SCHEMA 
 
 
 
 


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TABLE OF CONTENTS 
I. 
Comments Requiring a Response – Major Issues:.......................................................... ii 
II. 
Comments Requiring a Response– Administrative & Editorial Issues: ........................... ii 
III. 
Recommendations: ....................................................................................................... ii 
Additional Changes: ............................................................................................................. viii 
PRÉCIS .................................................................................................................................. 4 
Background:................................................................................................................. 4 
Objectives: ................................................................................................................... 4 
Eligibility:.................................................................................................................... 4 
Design: ........................................................................................................................ 5 
SCHEMA ............................................................................................................................... 6 
TABLE OF CONTENTS ......................................................................................................... 7 
1 
OBJECTIVES ............................................................................................................ 14 
1.1 
Primary Objective ........................................................................................... 14 
1.1.1 Determine the objective response rate to selumetinib administered 
as 75 mg orally twice daily on a continuous schedule in patients 
with advanced pancreas cancer harboring KRAS G12R mutations. ........ 14 
1.2 
Secondary Objectives ...................................................................................... 14 
1.2.1 To determine the progression free survival of patients with locally 
advanced, unresectable and stage IV pancreas cancer treated with 
selumetinib monotherapy. .................................................................... 14 
1.2.2 To evaluate the safety of selumetinib in patients with advanced 
pancreas cancer.................................................................................... 14 
1.2.3 To determine the impact of additional genetic alterations on the 
response to selumetinib in pancreas cancer harboring KRAS G12R 
mutations............................................................................................. 14 
1.2.4 To develop a clinically applicable biomarker predicting response to 
selumetinib in pancreas cancer harboring KRAS G12R mutations ......... 14 
2 
BACKGROUND ....................................................................................................... 14 
2.1 
Study Disease ................................................................................................. 14 
2.1.1 Pancreas cancer – a disease with dire need for improved treatments....... 14 
2.1.2 The KRAS mutational landscape in pancreas cancer ............................. 15 
2.1.3 KRAS mutational isoforms and regulators of MAPK signaling are 
a prognostic biomarker for outcome in pancreas cancer ......................... 17 
2.1.4 KRAS G12R mutation status predicts response to selumetinib 


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inhibition in a large panel of pancreas cancer cell lines.......................... 19 
2.1.5 Decreased WNT and RhoGTPase signaling component expression 
in KRAS G12R-mutant cells compared to KRAS non-G12R cells ......... 22 
2.1.6 Patient-derived xenotransplants from human pancreatic tumors 
harboring KRAS G12R mutations are selectively sensitive to MEK 
inhibition with selumetinib (AZD6244) ................................................ 26 
2.1.7 How does this study impact future trials/practice of molecular 
therapy in pancreas cancer.................................................................... 27 
2.2 
CTEP IND Agent ............................................................................................ 30 
2.2.1 AZD6244 (selumetinib) ....................................................................... 30 
2.3 
Rationale ........................................................................................................ 35 
2.4 
Correlative Studies Background....................................................................... 35 
3 
PATIENT SELECTION ............................................................................................. 36 
3.1 
Eligibility Criteria ........................................................................................... 36 
3.1.1 Patients must have histologically confirmed locally advanced or 
metastatic pancreas cancer. .................................................................. 36 
3.1.2 Patients must have received at least 6 months 5-FU- or 
gemcitabine-based treatments for pancreas cancer 
(FOLFIRONOX, FOLFOX, 5-FU+ nal-IRI (MM-398; 
nanoliposomal irinotecan), or 5-FU (including capecitabine), 
gemcitabine-based gemcitabine plus abraxane, gemcitabine 
monotherapy among others). ................................................................ 36 
3.1.3 Patients must have measurable disease, defined as at least one 
lesion that can be accurately measured in at least one dimension 
(longest diameter to be recorded for non-nodal lesions and short 
axis for nodal lesions) as ≥20 mm (≥2 cm) with conventional 
techniques or as ≥10 mm (≥1 cm) with spiral CT scan, MRI, or 
calipers by clinical exam.  See Section 11 for the evaluation of 
measurable disease............................................................................... 36 
3.1.4 Patients must have CLIA confirmed somatic KRAS G12R 
mutation as determined by sequence analysis of matched normal 
DNA from any specimen obtained from the individual. Patients 
must provide test result from CLIA certified laboratory, 
confirming somatic KRAS G12R mutation or archival tumour 
sample for KRAS analysis or be willing to undergo mandatory 
screening biopsy. ................................................................................. 36 
3.1.5 Patients must not have had chemotherapy, molecular therapy with 
erlotinib, radiation therapy, or experimental biological or 
molecular therapy for at least 4 weeks prior to starting study 
medication.  Patients who received FOLFIRINOX must be 6 


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weeks from the last administration of therapy. Patients must have 
recovered from any acute toxicity related to prior therapy or 
surgery, to a grade 1 or less unless specified. ........................................ 36 
3.1.6 Age ≥18 years...................................................................................... 36 
3.1.7 ECOG performance status ≤1 or Karnofsky ≥70%, (see Appendix 
A). ...................................................................................................... 36 
3.1.8 Patients must have normal organ and marrow function as defined 
below: ................................................................................................. 36 
3.1.9 Patients must be willing to return to the Clinic for follow-up visits. ....... 36 
3.1.10 The effects of AZD6244 on the developing human fetus at the 
recommended therapeutic dose are unknown. For this reason, 
women of child-bearing potential must agree to use adequate 
contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study 
participation, and for 4 weeks after dosing with AZD6244 ceases. 
Women of child-bearing potential must have a negative pregnancy 
test within 14 days prior to study treatment. Should a woman 
become pregnant or suspect she is pregnant while she or her 
partner is participating in this study, the patient should inform her 
treating physician immediately. Please note that the AZD6244 
manufacturer recommends that adequate contraception for male 
patients should be used for 12 weeks post-last dose due to sperm 
life cycle.............................................................................................. 37 
3.1.11 Ability to understand and the willingness to sign a written 
informed consent document or patients with Impaired Decision 
Making Capacity (IDMC) if they are represented by a Legally 
Authorized Representative (LAR). ....................................................... 37 
3.1.12 Patient must be able to reliably swallow oral medications...................... 37 
3.2 
Exclusion Criteria ........................................................................................... 37 
3.2.1 Patients who have received prior treatment with tyrosine kinase 
inhibitors (e.g. erlotinib), or anti-EGFR agents (e.g. cetuximab, 
panitumumab)...................................................................................... 37 
3.2.2 Patients currently receiving any medication known to induce 
central serous chorioretinopathy which in the opinion of the 
Principal Investigator, would make the administration of study 
drug hazardous. ................................................................................... 37 
3.2.3 Patients with active hepatic or biliary disease (with exception of 
patients with Gilbert’s syndrome, asymptomatic gallstones, liver 
metastases or stable chronic liver disease per investigator 
assessment) ......................................................................................... 37 
3.2.4 Patients with uncontrolled intercurrent illness including, but not 


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limited to, ongoing or active infection, symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance 
with study requirements. ...................................................................... 37 
3.2.5 Any underlying medical condition which, in the opinion of the 
principal investigator, will make the administration of study drug 
hazardous or obscure the interpretation of adverse events ...................... 37 
3.2.6 Patients who are receiving any other investigational agents. .................. 37 
3.2.7 Patients with known brain metastases should be excluded from this 
clinical trial because of their poor prognosis and because they often 
develop progressive neurologic dysfunction that would confound 
the evaluation of neurologic and other adverse events.  No 
additional workup is needed to exclude brain metastases if the 
patient is asymptomatic or has no history of brain metastases. ............... 37 
3.2.8 History of allergic reactions attributed to compounds of similar 
chemical or biologic composition to AZD6244 or other agents 
used in study........................................................................................ 38 
3.2.9 Previous MEK, RAS, or RAF inhibitor use. .......................................... 38 
3.2.10 Patients with the following cardiac conditions are excluded:.................. 38 
3.2.11 Patients with known ophthalmologic conditions, such as: ...................... 38 
3.2.12 Patients with refractory nausea and vomiting, chronic 
gastrointestinal (GI) diseases (e.g., inflammatory bowel disease) or 
significant bowel resection. .................................................................. 39 
3.2.13 HIV-positive patients on combination antiretroviral therapy are 
ineligible because of the potential for pharmacokinetic interactions 
with AZD6244.  HIV-positive patients not on antiviral therapy 
with undetectable viral loads and CD4 counts >300, and after 
confirmation of eligibility after discussing with the Study chair are 
eligible. ............................................................................................... 39 
3.3 
Inclusion of Women and Minorities ................................................................. 39 
4 
REGISTRATION PROCEDURES ............................................................................. 39 
4.1 
Investigator and Research Associate Registration with CTEP ........................... 39 
4.2 
Site Registration.............................................................................................. 40 
4.2.1 Downloading Regulatory Documents ................................................... 41 
4.2.2 Requirements For 10050 Site Registration: ........................................... 41 
4.2.3 Submitting Regulatory Documents ....................................................... 42 
4.2.4 Checking Site Registration Status ......................................................... 42 
4.3 
Patient Registration ......................................................................................... 42 


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4.3.1 NCI Central Registration (NCI Site Only)............................................. 42 
4.3.2 Off Study Procedure (NCI Site Only) ................................................... 43 
4.3.3 OPEN / IWRS ..................................................................................... 43 
4.3.4 OPEN/IWRS User Requirements ......................................................... 43 
4.3.5 OPEN/IWRS Questions?...................................................................... 43 
4.4 
General Guidelines.......................................................................................... 43 
5 
TREATMENT PLAN ................................................................................................ 44 
5.1 
Agent Administration ...................................................................................... 45 
5.1.1 AZD6244 Hydrogen Sulfate Administration ......................................... 45 
5.2 
General Concomitant Medication and Supportive Care Guidelines ................... 46 
5.3 
Duration of Therapy ........................................................................................ 47 
5.4 
Duration of Follow Up .................................................................................... 47 
6 
DOSING DELAYS/DOSE MODIFICATIONS........................................................... 48 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS.......................... 49 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Selumetinib (AZD6244 hydrogen sulfate [NSC 748727]), AZD6244 (NSC 
741078) .......................................................................................................... 50 
7.2 
Adverse Event Characteristics ......................................................................... 54 
7.3 
Expedited Adverse Event Reporting ................................................................ 54 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS 
(CTEP Adverse Event Reporting System), accessed via the CTEP 
Web site (https://eapps-ctep.nci.nih.gov/ctepaers). ................................ 54 
7.3.2 Distribution of Adverse Event Reports ................................................. 54 
7.3.3 Expedited Reporting Guidelines ........................................................... 54 
7.4 
Routine Adverse Event Reporting.................................................................... 56 
7.5 
Secondary Malignancy .................................................................................... 56 
7.6 
Second Malignancy......................................................................................... 56 
7.7 
Reporting to the NCI Clinical Director (NCI Site Only).................................... 56 
7.7.1 Definitions........................................................................................... 56 
7.7.2 Serious ................................................................................................ 57 
7.7.3 Non-compliance (NIH Definition) ........................................................ 57 
7.7.4 NCI Clinical Director Reporting........................................................... 57 
8 
PHARMACEUTICAL INFORMATION .................................................................... 57 
8.1 
CTEP Agent ................................................................................................... 57 


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8.1.1 AZD6244 hydrogen sulfate (NSC 748727) ........................................... 57 
8.1.2 Agent Ordering and Agent Accountability ............................................ 59 
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ..................................... 61 
9.1 
Sample Storage, Tracking and Disposition ....................................................... 63 
9.1.1 NCI Site Only...................................................................................... 63 
9.1.2 Samples Managed by Dr. Figg’s Blood Processing Core (BPC)............. 63 
9.1.3 Procedures for Storage of Tissue Specimens in the Laboratory of 
Pathology ............................................................................................ 64 
9.1.4 Protocol Completion/Sample Destruction ............................................. 64 
9.1.5 Shipping instructions for Participating sites .......................................... 65 
10 
STUDY CALENDAR ................................................................................................ 65 
11 
MEASUREMENT OF EFFECT ................................................................................. 67 
11.1 
Antitumor Effect – Solid Tumors..................................................................... 67 
11.1.1 Definitions........................................................................................... 67 
11.1.2 Disease Parameters .............................................................................. 68 
11.1.3 Methods for Evaluation of Measurable Disease..................................... 69 
11.1.4 Response Criteria................................................................................. 71 
11.1.5 Duration of Response........................................................................... 73 
11.1.6 Progression-Free Survival .................................................................... 73 
12 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ..................................................................................................... 73 
12.1 
Study Oversight .............................................................................................. 73 
12.2 
Data Reporting................................................................................................ 74 
12.2.1 Method................................................................................................ 74 
12.2.2 Responsibility for Data Submission ...................................................... 74 
12.2.3 NCI Data Sharing Plans ....................................................................... 75 
12.3 
Collaborative Agreements Language ............................................................... 76 
12.4 
Genomic Data Sharing Plan............................................................................. 77 
13 
HUMAN SUBJECTS PROTECTIONS ...................................................................... 78 
13.1 
Rationale For Subject Selection ....................................................................... 78 
13.2 
Participation of Children ................................................................................. 78 
13.3 
Participation of Subjects Unable to Give Consent (NCI Site Only).................... 78 
13.4 
Evaluation of Benefits and Risks/Discomforts.................................................. 78 


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13.4.1 Alternative Approaches or Treatments .................................................. 79 
13.4.2 Procedures to Eliminate or Minimize Potential Risks ............................ 79 
13.4.3 Provisions for Monitoring Data Collection to Ensure Subject 
Safety 79 
13.4.4 Biopsies .............................................................................................. 79 
13.4.5 Radiation risks ..................................................................................... 79 
13.4.6 Non-Physical Risks of Genetic Research .............................................. 79 
13.5 
Risks/Benefits Analysis................................................................................... 80 
13.6 
Consent Process and Documentation................................................................ 80 
13.6.1 Telephone Reconsent Procedure (NCI Site Only) .................................. 80 
14 
STATISTICAL CONSIDERATIONS......................................................................... 80 
14.1 
Study Design/Endpoints .................................................................................. 80 
14.1.1 Screening ............................................................................................ 81 
14.1.2 Treatment ............................................................................................ 81 
14.2 
Sample Size/Accrual Rate ............................................................................... 81 
14.3 
Analysis of Secondary Endpoints..................................................................... 81 
14.4 
Reporting and Exclusions ................................................................................ 83 
14.4.1 Evaluation of Toxicity ......................................................................... 83 
14.4.2 Evaluation of Response ........................................................................ 83 
15 
REFERENCES .......................................................................................................... 85 
16 
APPENDICES ........................................................................................................... 88 
16.1 
Appendix A: Performance Status Criteria......................................................... 88 
16.2 
Appendix B: New York Heart Association Classifications ................................ 89 
16.3 
Appendix C: Patient Drug Information Handout and Wallet Card ..................... 90 
16.4 
Appendix D: Patient’s Pill Diary ..................................................................... 92 
16.5 
Appendix E: Patient handout addressing aggressive management for 
diarrhea .......................................................................................................... 94 
16.6 
Appendix F: Safety Management Algorithm: LVEF Reduction ........................ 95 
16.7 
Appendix G: Safety Management Algorithm for Dyspnea ................................ 96 
16.8 
Appendix H Plasma preparation for cell free (cf) DNA extraction using 
EDTA collection tubes. ................................................................................... 97 
16.9 
Appendix I: Cancer Gene Mutation‐Standard Panel.......................................... 98 
 
 


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1 
OBJECTIVES 
1.1 
Primary Objective 
1.1.1 
Determine the objective response rate to selumetinib administered as 75 mg orally 
twice daily on a continuous schedule in patients with advanced pancreas cancer 
harboring KRAS G12R mutations. 
1.2 
Secondary Objectives 
1.2.1 To determine the progression free survival of patients with locally advanced, unresectable 
and stage IV pancreas cancer treated with selumetinib monotherapy. 
1.2.2 To evaluate the safety of selumetinib in patients with advanced pancreas cancer 
1.2.3 To determine the impact of additional genetic alterations on the response to selumetinib 
in pancreas cancer harboring KRAS G12R mutations 
1.2.4 To develop a clinically applicable biomarker predicting response to selumetinib in 
pancreas cancer harboring KRAS G12R mutations 
2 
BACKGROUND 
2.1 
Study Disease 
2.1.1 Pancreas cancer – a disease with dire need for improved treatments 
The grave unmet medical need for improved treatments in pancreas cancer is well documented by 
A. a 5-year overall survival rate of 7% which has not substantially changed over the last 3 decades 
B. regulatory approval of only 2 cytotoxic chemotherapy combination regimens (FOLFIRINOX 
and gemcitabine+abraxane) since the approval of gemcitabine in 1996 extending overall 
survival by a few months in the combination treatment arms 
C. a current lack of any effective precision medicine molecular therapy options 
It is expected that in 2020 pancreas cancer will rank 2nd in cancer-related deaths in the U.S. having 
surpassed colon and breast cancer.[1] Following a U.S. Congressional request, NCI has responded 
in 2010 with a NCI National Pancreas Cancer Action Plan detailing, among other priorities and 
updates, the development of novel innovative therapy options tailored to the unique biology of 
pancreas cancer as priorities in the future fight against this disease.[2] 
There are no effective molecular therapy options available in pancreas cancer. The anti-EGFR 
small molecule inhibitor erlotinib (Tarceva) received regulatory approval in 2007 following the 
large phase III Canadian NCIC CTG PA.3 trial.[3]  This study randomized patients afflicted by 
advanced pancreas cancer (23.5% locally advanced; 76.5% stage IV) to either gemcitabine vs 
gemcitabine plus erlotinib. An increase in OS and PFS of 14 days (2 weeks) in the 
gemcitabine+erlotinib group was observed. While statistically significant, actual prescribing of 
erlotinib by practicing physicians has declined due to skepticism of its clinical relevance. However, 
considering the positive signal in this large trial it is likely that there is a subset of patients which 
may benefit from anti-EGFR therapy. Consecutive biomarker studies however, in particular KRAS 
wild type mutation status (following the strong predictive value of KRAS wt status for anti-EGFR 
therapy by cetuximab or panatumumuab in colorectal cancer) or EGFR amplification status failed 
to predict a subset of patients with a robust response or improved outcome receiving erlotinib 


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treatment.[4] These results are mirrored by the large phase III Southwest Oncology Group–
Directed Intergroup Trial S0205 trial of gemcitabine vs gemcitabine+cetuximab in advanced 
pancreas cancer patients: there was a trend towards an improvement of quality-of-life indicators 
at early measurement points in the gemcitabine+cetuximab arm, however no correlative biomarker 
studies are available to identify a subset enriched for improved outcome.[5] Thus, findings in 
NCIC CTG PA.3 and SWOG Intergroup S0205 on a total of 1,335 patients suggest that there may 
be a subset(s) of patients who may benefit from an anti-EGFR, or a similar molecular therapy 
approach, but that the lack of an accurate biomarker, or understanding of aberrant EGFR signaling, 
including its effector MAPK pathway, currently prevents these patients from receiving improved 
therapy options, and possibly better outcome, in this rapidly fatal disease. 
Some of the currently most promising molecular, or precision medicine, therapy approaches 
pursued in pancreas cancer to date include, for example, the administration PARP inhibitors in 
BRCA-mutant pancreas cancer (the DNA damage repair genes BRCA1 and 2 are affected by 
somatic variants in 5-7% of pancreas cancers), the administration of the chemotherapy agent 
oxaliplatinum to patients selected based on a recent genomic DNA damage repair response 
signature,[6] or the 5-hyaluranic acid inhibitor PEGPH20 in combination with gemcitabine to 
increase delivery of gemcitabine to the tumor following lowering of interstitial pressures and 
‘break of the stromal barrier’.[7] 
In this regard, and as a landmark study in the field, pancreas cancer clinical research has 
spearheaded a first-in-time first-in-human effort of genotype-directed molecular therapy using 
whole genome sequencing (WGS).[8] Investigators of the recently released Precision Medicine 
for Advanced Pancreas Cancer: The Individualized Molecular Pancreatic Cancer Therapy 
(IMPaCT) Trial attempted to identify druggable mutations in pancreas cancer tumor genomes by 
WGS and treat patients with small molecule inhibitors based on these findings. This study initially 
raised concerns about the feasibility of acquiring suitable tumor specimens for molecular analysis 
and returning high-quality actionable genomic data within a clinically acceptable timeframe: an 
inability to obtain a biopsy or insufficient tumor content in the available specimen were common 
reasons for patient exclusion from molecular analysis while deteriorating performance status 
prohibited a number of patients from proceeding in the study. However, a number of somatic 
variants which triggered a pre-determined signal for molecular therapy were identified including 
KRAS wild type mutation status, HER2 amplifications, BRCA1 or 2 mutations or somatic variants 
in ATM1 or other rare variants attesting to the feasibility of this strategy.[8] No clinical outcome 
data are currently available. This precision medicine concept even now extends onto selecting 
patients with BRCA variants or ‘BRCA-like’ variant signatures or with immunogenic signatures 
based on large-scale gene expression profiling for immunotherapies like immune checkpoint 
inhibitors or anti-CSF/CSFR1 therapy targeting tumor associated macrophages.[9, 10] 
 
2.1.2 The KRAS mutational landscape in pancreas cancer 
The vast majority of pancreatic cancers (up to ≥94%) harbor mutations of the KRAS gene, and 
there is ample preclinical evidence that KRAS mutations are an essential driver of pancreas cancer 
development and progression, essential for the unique metabolomic and transcriptomic landscape 
of pancreatic cancers, involved in pancreatic cancer stem cell formation, as well as in mediation 
of resistance to chemo- and molecular therapy.[9-11] That there is considerable heterogeneity 
within KRAS mutant pancreas cancers, with substantial implications for guiding therapy, has been 


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shown in vitro in elegant synthetic lethality studies, and in correlative tissue studies defining 
classical and quasi-mesenchymal subtypes guiding response to gemcitabine or erlotinib 
therapy.[12, 13] 
KRAS mutations affecting codon 12 comprise of nearly all KRAS mutations in pancreas cancer. 
KRAS G12R mutations are after KRAS G12D and G12V the 3rd most common KRAS isoform 
mutations in pancreas cancer comprising of up to 20% of KRAS mutations in some studies.[14] 
Overall both, affected codons, namely codon 12, 13, and 61 of the KRAS oncogene, and nucleotide 
substitutions of affected codons are highly specific and differ between the three ‘KRAS cancers’ 
pancreas cancer, colon cancers, and NSCLC. Figure 1 shows distribution of KRAS mutational 
isoforms derived from large-scale genotyping efforts including NCIs TCGA initiative across 
pancreas, colon, and non-small cell lung cancer. KRAS G12R mutations (highlighted in orange, 
lower panel) are highly unique for pancreas cancer as they are exceedingly rare, or non-existent, 
in other cancers (1% in thyroid cancers, <2% in NSCLC, <2% in colon cancers of all KRAS mutant 
cancers).  
 
Figure 1. KRAS mutations vary across different epithelial cancers including pancreas cancer (PDAC, pancreatic ductal 
adenocarcinoma; CRC, colorectal cancer; LAC, lung adenocarcinoma). Upper panel, codons affected by somatic 
variants in the KRAS oncogene across different cancer, lower panel, distribution of KRAS mutational isoforms of 
codon 12 (from Cox AD et al. 2014). 


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Figure 2. KRAS mutation profile in PDAC (top) 
and in other cancers (cBioPortal, bottom). Pie 
chart of KRAS mutational isoforms in pancreas 
cancer, percentage of KRAS G12R mutations in 
blue (from Witkiewicz AK et al. 2015). 
 
 
2.1.3 KRAS mutational isoforms and regulators of MAPK signaling are a prognostic 
biomarker for outcome in pancreas cancer 
KRAS mutational status per see (KRAS wild type versus KRAS mutant) as well as KRAS 
mutational isoform status are associated with different clinical outcomes in pancreas cancer.[11, 
15] Figure 3 shows the improved outcome, including overall survival, of stage IV pancreas cancer 
patients with KRAS G12V mutations compared to G12D and G12R mutations measured in biopsy 
specimens, Figure 4 shows the improved overall survival of KRAS Q61 mutations to non-Q61 
mutations in surgical resection specimens of a recent large exomic sequencing study of >100 
pancreatic cancer specimens.[11, 15] These studies showed that patients affected by tumors 
without KRAS mutations have better outcomes compared to patients afflicted by pancreas cancers 
harboring KRAS mutations and that different Kras mutational isoforms are associated with 
different effector states of MAPK signaling. These observations are affirmed by findings in our 
laboratory: using the SEER Pancreas Cancer Tissue Microarray (TMA) and a TMA with pancreas 
cancer biospecimens constructed from NIH patients, we identified the scaffolding kinase 
“connective tissue enhancer of KSR” (CNKSR1), a major regulator of MAPK pathway signaling 
- identified within a large RNAi kinome screen as a major mediator of resistance to MEK inhibition 
in the MEK-resistant cell line YAPC -, as a novel prognostic biomarker. Pancreas cancer patients 
with high CNKSR1 expression (measured as 2+ or 3+) versus patients with low CNKSR1 
expression (0 or 1+) had significantly improved overall survival following resection of their 
tumors. Thus, KRAS mutational isoforms likely vary in their impact on pancreas cancer biology 
and pancreas cancer progression due to different mechanisms of action and signal transduction 
dependencies. 
 


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Figure 3. Impact of KRAS wild type status (left), and KRAS mutation subtype (KRAS G12V, G12D, and G12R, right) 
on overall survival of patients with advanced pancreas cancer (from Ogura T et al. 2013). 
 
Figure 4. Kaplan-Meier analysis of KRAS codon 12 vs codon 61 mutations (left). Different KRAS mutational isoforms 
are associated with unique downstream signaling. phospho-ERK levels measured by immunohistochemistry in KRAS 
codon 61 versus codon 12 mutational subtype are shown (right) (from Witkiewicz AK et al. 2015). 
 
 


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Figure 5. RNAi screen in pancreatic cancer cell line 
YAPC. Top candidates are enriched in known protein-
protein interactions as determined by IPA. This screen 
targeting a set of 704 genes, which included the human 
kinome, identifies modulators of selumetinib response 
in the MEK-resistant network was generated through an 
IPA core analysis of the 17 genes scoring with 2 active 
siRNAs. The analysis considered only known direct 
relationships between genes, and used the 704 genes 
represented in the screen as background. Top candidates 
highlighted in red. The network was the top scoring IPA 
network (score = 29). 
 
 
 
Figure 6. Expression levels of the MAPK pathway 
regulator CNKSR1 identified via RNAi screening of 
selumetinib treated vs untreated cells have 
prognostic value for the outcome of surgically 
resected pancreas cancer patients (Log-rank (Mantel-
Cox) test; p=0.0151) 
 
2.1.4 KRAS G12R mutation status predicts response to selumetinib inhibition in a large panel 
of pancreas cancer cell lines 
Figure 7 shows waterfall plots of response to selumetinib in a panel of 52 authenticated pancreatic 
cell lines as measured by activity area and IC50. KRAS mutation status is shown for each cell line, 
cell lines harboring KRAS G12R mutations are highlighted in red. To demonstrate a ‘class-effect’ 
and to exclude that observed profile is unique to selumetinib, cell lines were also treated with 
MEK162 (Novartis) and the ERK inhibitor VTX-11e yielding a similar sensitivity profile (data 
not shown). Figure 7 shows the summary of comparisons of sensitivity profiles of KRAS G12R 
versus non-G12R pancreas cancer cell lines as scatter plots using activity area (measure of efficacy 
and potency, or 1-AUC, left) and IC50 (potency, right): pancreas cancer cell lines harboring KRAS 
G12R mutations are 3 – 10 times more sensitive than cell lines harboring other KRAS mutational 
isoforms. To validate these findings in an independent set of cell lines, the cell line encyclopedia 
panel from the Broad Institute was interrogated for cell lines with known RAS mutation status and 
data on treatment with selumetinib.[16] All pancreas cancer cell lines treated in the discovery panel 
were removed. Due to the paucity of cell lines with KRAS G12R mutations in non-PDAC 
histologies, the G12R group comprised of 4 cell lines (thyroid cancer, NSCLC). When compared 
to non-KRAS G12R mutant KRAS cell lines from a diverse group of different non-PDAC 
histologies, cell lines harboring KRAS G12R mutations were again more sensitive than non-KRAS 
G12R lines (Figure 8, right).[16] To confirm the validity of our activity area measurements in the 


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pancreas cancer panel, similar scatter plots were derived from the Broad Institute pancreas cancer 
cell line panel treated with selumetinib. KRAS G12R harboring cell lines, like in our panel (92% 
overlap of used cell lines; only 3 KRAS G12R lines), were again the most sensitive subgroup (data 
not shown). 
These in vitro findings in PDAC are further affirmed by a recent study with the MEK inhibitor 
MEK162 in 29 pancreatic cancer lines, some of them also present in our larger panel: cell lines 
with the electrically charged amino acid substitution aspartic acid for glycin at codon 12 (KRAS 
G12D) were statistically significantly more sensitive compared to cell lines harboring KRAS 
codon mutations leading to the hydrophobic insertion of valine for glycin (KRAS G12V) (Figure 
9). While this panel only contained two KRAS G12R mutant cell lines (introducing an arginine 
(ARG) at codon 12), which precluded a statistical comparison, their median IC50 was equally low 
than the one of the KRAS G12D-mutant cell lines (Figure 9).[17] These, and above findings 
suggest that the electrically charged arginine or aspartate introduced by the G12R and G12D 
variant triggers unique pertubations in the interactions with RAS binding partners like other 
kinases or regulatory proteins like scaffolding proteins or phosphatases which govern select 
responses to small molecule inhibition. Signal transduction pertubations unique to KRAS 
mutational isoforms have recently been shown in a detailed phosphoproteomic analysis of KRAS-
isogenic cell lines.[18] 


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Figure 7. In vitro sensitivity of selumetinib in 52 authenticated pancreatic cancer cell and tissue culture lines. Activity 
area capturing maximum response for each cell line (red bar, top), KRAS mutation status (mid, KRAS G12R mutations 
highlighted in red), and comparison to potency measurements (IC50, blue bars, bottom) are shown. 
 
Furthermore, data from isogenic SW48 colon cancer cell lines show that cells with a KRAS G12R 
allele are highly sensitive to selumetinib compared to SW48 cells with hemiallelic KRAS G12D 
mutations (Figure 10).[19] In this colon cancer model, isogenic KRAS G12V mutations displayed 
similar sensitivity to selumetinib as KRAS G12R mutations, and a detailed recent 
phosphoproteomic analysis of these isogenic SW48 cell lines has yielded unique signatures 
associated with individual KRAS mutations.[19] 
In summary, irrespective of source pancreas cancer panel (Rudloff lab vs [16]), activity measure 
(activity area vs IC50), pancreas cancer vs non-pancreas cancer histology, or type of MEK 
inhibitor (selumetinib vs MEK162) KRAS G12R mutation status consistently identified most 
sensitive group of cell lines.  


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Figure 8. Average activity (AA) area (sum of differences between measured Ai at concentration i and A = 0, excluding 
positive A values: AA = Σi[0-min(0,Ai/100)] (left) and IC50s (middle, in nM) of PDAC cell lines; Mann Whitney 
test, 2-tailed, p≤0.05 indicated as *). Scatter plots of independent set (obtained from Barretina J et al, 2012) of non-
PDAC cell lines with known KRAS mutation status and treated with selumetinib (right). 
 
 
Figure 9. Sensitivity profile of PDAC lines treated with MEK162 and measured by IC50 by KRAS mutational 
subtypes (ARG, KRAS G12R, ASP, G12D, CYS, G12C, and VAL, G12V; left) and KRAS mutant vs wild type 
status (middle). Scatter blot of G12R vs non-G12R KRAS-mutant pancreas cancer cell lines, right. (Hamadi H et al., 
2015) 
 
Figure 10. Codon 12 KRAS mutations govern 
response to MEK therapy using selumetinib in the 
isogenic SW48 KRAS (+/-) colon cancer in vitro 
model (Troiani T et al., 2014). 
 
2.1.5 Decreased WNT and RhoGTPase signaling component expression in KRAS G12R-
mutant cells compared to KRAS non-G12R cells 
Extensive phospho-immunoblotting failed to identify pathways selectively up- or downregulated 
in the KRAS G12R cell lines (data not shown). Pathways not altered in KRAS G12R compared to 
KRAS non-G12R lines include the MAPK pathway measured by phospho-RSK, ERK, and MEK, 
the PI3K-AKT pathway measured by pAKT, pS6, and p4E-BP1, as well as EGFR and HER3 
signaling. RAS activation measured by GTP loading did also not differ significantly between the 


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isoforms. To probe into transcriptional differences between the KRAS isoforms, gene expression 
profiles of the three cohorts (at least >6 cell lines per mutational isoform) were compared. Figure 
11 shows supervised cluster analysis of 208 differentially expressed genes (DEGs) between the 3 
groups. Using these 208 DEGs RNASeq data from TCGA Pancreas Cancer specimens showed 
weak separation on Principal Component Analysis suggesting DEG set is associated with KRAS 
isoform mutation status also in patient tissues (Figure 12). Gene set enrichment analysis on DEGs 
identified components of WNT signaling, including the novel KRAS effector Yes- associated 
protein 1 (YAP1) shown to be able to bypass KRAS oncogene addiction in pancreas cancer, as 
well as RhoGTPase signaling (Table 1; adjusted p values by multiple comparisons are shown) to 
be reduced in KRAS G12R harboring pancreas cancer cell lines.[20, 21]  
 
 
Figure 11. 208 
Differentially 
expressed gene (DEG) 
sets between KRAS 
G12R (blue), G12D 
(red), and G12V 
(brown) pancreas 
cancer cell lines. DEGs 
were also validated in 
independent CCLE 
pancreas cancer cell 
line data set: 151 of top 
272 DEGs identified 
by above comparison 
were validated 
 
 


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Figure 12. Principal Component Analysis of the 208 DEG set identified by supervised clustering of pancreas 
cancer cell line panel applied to randomly selected TCGA gene expression sets (n≥10 for each KRAS mutational 
isoform). Moderate separation of KRAS G12R specimens (blue) from KRAS G12D (red) and G12V (green) 
cases. 
 
These findings were validated using a novel technique made available by NCIs Ras Program to 
my laboratory: siREN screening silences signaling nodes in cancer cell lines and assesses loss-of-
function on cell biology. A large siREN screen was carried out in >20 of our cell lines with the 
three different KRAS mutational isoforms, which showed different signal transduction 
dependencies in the KRAS G12R vs non KRAS G12R lines: KRAS G12R-harboring cell lines 
showed different dependency on RhoGTPase signaling, previously identified by comparative gene 
expression analysis (Figure 13). Another vulnerability in KRAS G12D/V and not G12R cells 
includes regulation of metabolism, in particular glycolysis and hexokinase metabolism, with 
KRAS G12R able to tolerate loss of these metabolic pathways. 


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Figure 13. Different survival cues of intracellular signaling hubs in KRAS G12R vs non-G12R cell lines is associated 
with response to MAPK pathway inhibition. A, Principal component analysis shows near perfect separation of KRAS 
G12R (blue) from KRAS G12D/V cells. B, Supervised cluster analysis by measured cell viability upon knockdown 
of individual signaling nodes. KRAS G12R cell lines retain viability upon loss of glycolysis and RhoGTPase signaling 
vs non-KRAS G12R lines, C, Response of KRAS G12R vs G12D/V cell lines to loss of glycolysis signaling (z score 
viability; p<0.05, 2-tailed t test). D, Response to MEK inhibition (measured by activity area upon 10-dose drug 
response testing; x-axis) correlates with redundancy of metabolic programs (baseline z score; siREN screen; y-axis); 
Pearson’s coefficient test). 
Correlating drug response with lethality upon loss-of-function of 48 individual signaling hubs 
during siREN screening revealed, among others, strong correlations between dependency on 
glycolytic function and resistance to MEK inhibition in non-KRAS G12R cell lines and 
redundancy of glycolysis and sensitivity upon MAPK inhibition (Figure 13). Indeed, baseline 
metabolic profiling of KRAS G12R vs non-G12R cell lines using the XF Extracellular Flux 
Analyzer (SeaHorse XF® Analyzer) revealed greater glycolytic plasticity upon glycolytic stress 
in KRAS G1R vs non-KRAS G12R cells (Figure 14) as well as increased glucose uptake and 
lactate production (data not shown). Upon MAPK inhibition, KRAS G12R cell lines do develop 
metabolic survival dependencies, in particular dependencies on glutamine metabolism (Figure 
14). These findings, overall, suggest that non-KRAS G12R cell lines derive survival cues from 
metabolic programs including glycolysis, small GTPase signaling, and others whereas cells with 
KRAS G12R isoform mutations, to a larger degree, depend on intact MAPK pathway signal 
transduction cues (Figure 14). 
 
 


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Figure 14 Different metabolic programming in non-KRAS G12R (red) versus KRAS G12R harboring (blue) pancreas cell lines. 
A, Glycolytic function measured by XF Extracellular Flux Analyzer (SeaHorse XF® profiling) in glucose-starved conditions. 
Increased rate of glycolysis but reduced glycolytic reserve (glycolytic capacity minus rate of glycolysis) in KRAS G12R vs non-
KRAS G12R cell lines. B, Upon MEK inhibition, KRAS G12R-harboring cell lines recruit metabolic survival programs 
including glutamine metabolism. C, select survival programs in non-KRAS G12R (left) versus KRAS G12R-harboring (right) 
pancreas cancer cell lines.  
 
2.1.6 Patient-derived xenotransplants from human pancreatic tumors harboring KRAS G12R 
mutations are selectively sensitive to MEK inhibition with selumetinib (AZD6244) 
PDX models derived from human cancers have distinct advantages over other advanced preclinical 
model like the more commonly used xenotransplantation of human cancer cell lines or genetically 
engineered mouse models (GEMM) of cancer. These include, among others, the inherent clonal 
heterogeneity of human cancers as well as the inclusion of tumor-educated stroma into the model, 
both major determining factors of cancer biology and drug response. Figure 15 shows selective 
reduction of tumor growth in a PDX model of pancreas cancer harboring a KRAS G12R mutation 
(left) compared to KRAS G12D mutation shown on the right. Analysis of downstream effector 
pathways in PDX models both at baseline and after treatment with selumetinib by reverse phase 
protein microarray (RPMA) shows increased induction of the cell cycle inhibitor p27kip in the 
KRAS 
G12R model compared to 
the KRAS 
G12D tumors (Figure 
16). (). 


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Figure 15 Patient-derived xenografts harboring KRAS G12R (left) and KRAS G12D (right) mutations treated with 
35mg/kg selumetinib (AZD6244) twice daily 5 out of 7 days for 4 weeks. 
 
Figure 16 Two-fold increased induction of the cell cycle inhibitor p27kip upon selumetinib treatment in the KRAS 
G12R PDX (left) versus KRAS G12D model. Reverse phase protein microarray normalized to loaded total protein 
of n=3 tumors, log[intensity] normalized to total protein 
 
2.1.7 How does this study impact future trials/practice of molecular therapy in pancreas cancer 
Similar to trametinib in BRAF-mutant metastatic cutaneous melanoma or selumetinib in ongoing 
trials of ocular melanoma, KRAS-mutant thyroid cancers, or selumetinib in combination with 
chemotherapy in non-small cell lung cancer, the proposed study aims to establish a role for this 
class of agents in pancreas cancer as well as a role for a precision medicine approach guided by 
different KRAS-mutational isoforms both in pancreas cancers, and possibly other KRAS-driven 
cancers. For example, it would support a general more differentiated approach to KRAS-driven 
cancers selecting patients by KRAS mutational isoform status. In this regard, it would support 
signals from a retrospective pooled analysis of randomized trials in colorectal cancer or a 
prospective randomized phase II study in non-small cell lung cancer. In a pooled retrospective 
analysis of 579 chemotherapy-refractory colorectal cancer patients randomized in the clinical trials 
NCIC CTG/AGITG CO.17, BOND, MABEL, EMR202600, EVEREST, or SALVAGE to the 
addition of the EGFR inhibitor cetuximab, De Rook and colleagues examined the impact of KRAS 
mutation status, including isoforms affected KRAS codon 12 versus 13, on overall survival and 
response to cetuximab. Figure 17 shows improvement in OS in patients randomized to receive 
cetuximab in the KRAS G13 but not in the more common KRAS G12D group. Response to 
cetuximab in colorectal cancer patients harboring KRAS G13 mutations was similar to response 
in KRAS wild type patients, the currently used biomarker to select patients for anti-EGFR therapy 
in stage IV disease.  


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Figure 17. Retrospective correlative tissue analysis of RCTs NCIC CTG and AGITG CO.17 Trial in colorectal 
cancer patients randomized to anti-EGFR treatment with cetuximab vs supportive care shows improved outcome in 
KRAS G13-mutant tumors similar to KRAS wild type cancers (from DeRook W, 2010, JAMA). 
Similarly, to the above study, the impact of KRAS codon G12 isoform mutation status on response 
to MEK inhibition has been studied retrospectively in a large randomized phase II study of KRAS-
mutant non-small cell lung cancer patients randomized to second line docetaxol vs docetaxol plus 
selumetinib. There was a trend, statistically significant for progression-free survival and objective 
response rates, towards improved clinical outcome in KRAS G12C and G12V-mutant lung cancer 
patients which was not observed in lung cancer patients harboring other KRAS mutational 
isoforms like KRAS G12A. Figure 18 shows impact of the addition of selumetinib to docetaxol 
on overall survival and progression-free survival in chemotherapy-refractory lung cancer patients 
stratified by KRAS isoform mutation status. 


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Figure 18 In patients receiving selumetinib +docetaxel and harboring KRAS G12C or G12V mutations there were 
trends towards greater improvement in OS, PFS and ORR compared with other KRAS mutations. Overall survival, 
top; progression-free survival, bottom) (from Jänne PA, 2015, Br J Cancer). 
Selumetinib has been compared in a randomized phase II study in unselected pancreas cancer to 
the 2nd-line chemotherapy agent capecitabine and shown not to have any advantage over 
capecitabine.[22] Similar to the Canadian NCIC CTG PA.3 phase III study with erlotinib these 
had been unselected patients and patients which had received at least gemcitabine and often 
additional chemotherapy therapy before. Furthermore, in the above randomized phase II clinical 
trial of advanced pancreas cancer patients (n=37 selumetinib; n=32 capecitabine) overall survival 
(OS) was chosen as primary endpoint with no capture of response rates.[22] No retrospective 
genotyping on tissues was performed.  
The weak positive signal with the anti-EGFR inhibitor in the NCIC CTG PA.3 trial, the early data 
with selumetinib in NSCLC patients,[23] our preclinical studies as well preclinical studies from 
other investigators now suggest a previously underappreciated heterogeneity of KRAS mutational 
isoform signaling which drives cancer biology and might harbor important information for clinical 
decision making. Thus, this study, in case positive, would 
(1) add a possibly novel treatment option in a disease void of effective therapies and patients 
desperate for treatments,  
(2) support enhanced efforts into KRAS mutational isoform-directed molecular therapy, both 
in pancreas and other cancers with frequent KRAS mutations. Considering the high 
prevalence of KRAS mutations in common cancers like NSCLC, colon, thyroid, or triple 


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negative breast cancer, a positive finding might trigger a number of studies on KRAS-
mutational genotype directed therapies,[14] 
(3) support future molecular therapy studies in pancreas cancer attempting to exploit less 
common low-frequency somatic mutations in this disease like BRAF (3%; vemurafenib), 
PI3KCA (1%; GDC-0941, BKM120), CDK4 (4%; PD-0332991), or BRCA gene family 
mutations (3%; mitomycin-C, olaparib).[11]  
2.2 
CTEP IND Agent 
2.2.1 AZD6244 (selumetinib) 
AZD6244 (ARRY-142886; selumetinib) is a potent, selective, orally (PO) available, and non-ATP 
competitive small molecule inhibitor of the mitogen-activated protein (MAP) kinase kinase, 
MEK1/2 (AZD6244 Investigator's Brochure, Edition #15 (March 30, 2015).[24]  AZD6244 
inhibits the activity of purified MEK by 50% at 10-14 nmol/L (IC50), and is inactive or only 
minimally active at 10 mcmol/L against epidermal growth factor receptor (EGFR), ERBB2, p38α, 
ERK2, and MAPKK 6 kinases.  AZD6244 is metabolized to biologically active N-desmethyl 
AZD6244, which is approximately 3- to 5-fold more active than the parent compound.   
The RAS/RAF/MEK/ERK signaling pathway plays a central role in the regulation of many cellular 
processes including 
proliferation, survival, differentiation, apoptosis, motility, 
and 
metabolism.[25, 26]  This pathway is one of the most important and best understood MAP kinase 
signal transduction pathways, activated by a diverse group of extracellular signals including 
integrins, growth factor receptors (i.e., EGFR, platelet-derived growth factor receptor [PDGFR], 
and insulin-like growth factor-1 receptor), and cytokines.  Activated RAS triggers the 
phosphorylation and activation of RAF kinase, which then phosphorylates MEK1 and MEK2 on 
two serine residues. Activated MEK phosphorylates its only known substrates, ERK1 and ERK2.  
Phosphorylated ERK (pERK) dimerizes and translocates to the nucleus where it is involved in 
several important cellular functions, including cell proliferation.[27] 
Overexpression of growth factors or growth factor receptors involved in the RAS/RAF/MEK/ERK 
pathway and activating genetic mutations of the signaling proteins may lead to uncontrolled 
proliferation and tumor formation.  For example, RAS genes are the most frequently mutated 
oncogenes detected in human tumors).  RAS proteins are guanine nucleotide binding proteins that 
activate RAF proteins when bound to GTP.  Cancer-associated mutations in RAS proteins stabilize 
the GTP-bound form of RAS, thereby providing a constitutive signal downstream in the cascade.  
In addition to being found in almost all pancreatic adenocarcinomas, RAS mutations are found in 
~40% of colorectal carcinomas (CRC), 20-25% of lung adenocarcinomas, and also in some breast 
or ovarian cancers.  BRAF mutations have also been observed in many human cancers, particularly 
melanoma (30-60%), thyroid cancer (30-50%), CRC (5-20%), and ovarian cancer (~30%).[24, 26] 
These mutations in BRAF usually involve gain-of-function substitutions that render the kinases 
constitutively active.  Also, studies of primary tumor samples and cell lines have shown 
constitutive activation or overactivation of the MAP kinase pathways in cancers of the pancreas, 
colon, lung, ovary, biliary tract, and kidney.[28] Therefore, agents targeting the 
RAS/RAF/MEK/ERK pathway may inhibit oncogenic signaling in tumor cells.  
Nonclinical Studies 


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Efficacy 
In vitro studies have shown that AZD6244 is a potent and selective inhibitor of MEK with IC50 of 
10-14 nM (AZD6244 Investigator's Brochure, Edition #15 (March 30, 2015). Significant 
biochemical activity has not been detected when tested at 10 mcmol/L against a diverse panel of 
>300 other molecules, including enzymes, receptors, kinases, transporters, and ion channels.  The 
effects of AZD6244 on ERK phosphorylation and cell viability were determined in a panel of cell 
lines with known RAF and RAS mutant status.  AZD6244 inhibited ERK1 and ERK2 
phosphorylation with IC50 0.0018-0.0408 mcmol/L.  In cell viability assays, IC50 values ranged 
from <10 nM to >10 μM and most of the cell lines that were sensitive to selumetinib contained 
either a BRAF or RAS gene mutation.  Two metabolites of AZD6244 (N-desmethyl AZD6244 
and an amide AZD6244) have been identified.  The N-desmethyl metabolite was found to be 3-to 
5-fold more potent inhibitor than the parent compound in cellular ERK phosphorylation and cell 
viability inhibition assays.  In contrast, the AZD6244 amide metabolite was up to 50-fold less 
active than AZD6244 and therefore is unlikely to significantly contribute to biological activity of 
AZD6244.  In tumor cell viability inhibition assays, N-desmethyl metabolite was ≥5-fold more 
potent than AZD6244 in inhibiting cell viability.   
Significant suppression of tumor growth in response to AZD6244 treatment was observed in 
several xenograft mouse models derived from a range of tumor types including melanoma, breast, 
pancreatic, lung, colon, and hepatocellular carcinomas.[29-32] In papillary thyroid cancer models, 
AZD6244 effectively inhibited tumor growth, both in vitro and in vivo, particularly in tumor cells 
carrying activating BRAF gene mutations.[33] In the Calu-6 lung cancer xenograft model, 
AZD6244 suppressed tumor growth at doses of 10, 25, or 100 mg/kg given twice daily (BID), and 
the minimal effective dose was identified as 0.75 mg/kg administered BID.[30]  In this model, 
MEK activity was inhibited as assessed by determination of pERK levels in tumor.  Studies using 
human CRC xenograft models demonstrated that AZD6244 inhibited tumor growth by inhibition 
of cell proliferation in SW620 model and by induction of apoptosis in Colo205 model.  In vivo 
studies with mutant KRAS positive (KRAS+) human cancer xenografts have demonstrated the 
potential for using AZD6244 in combination with a number of cytotoxic and targeted agents, 
including docetaxel, irinotecan, gemcitabine, pemetrexed, gefitinib, cediranib, rapamycin, 
cisplatin, and temozolomide (AZD6244 Investigator's Brochure, Edition #15 (March 30, 2015). 
Pharmacokinetic/Pharmacodynamic Studies 
Two oral formulations of AZD6244 have been tested in preclinical pharmacology studies:  the 
original mix-and-drink formulation (AZD6244 free-base), and the AZD6244 hydrogen sulfate salt 
(capsule) formulation (AZD6244 Hyd-Sulfate) (AZD6244 Investigator's Brochure, Edition #15 
(March 30, 2015). The former requires reconstitution of the AZD6244 free-base crystalline powder 
in the 25% (w/v) Aqueous Captisol® (sulfobutyl ether β-cyclodextrin) (SBE-CD) solution.  While 
systemic exposure was demonstrated in the rat and monkey studies with AZD6244 free-base, the 
exposure was not dose-proportional; bioavailability was decreasing with increasing dose.  This is 
likely a reflection of dose-limited absorption due to limited solubility of AZD6244 free-base.  
However, AZD6244 hydrogen sulfate produced approximately proportional exposures with dose 
in the mouse and monkey, and allowed higher exposures than AZD6244 free-base.  There was 
no/minimal accumulation of AZD6244, whether dosed with AZD6244 free-base or AZD6244 
hydrogen sulfate on multiple dosing in the mouse, rat, or monkey.  N-desmethyl metabolite was 
not detectable in rat and at only trace levels in the monkey, but was produced in mouse at 


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circulating levels around 2-12% of parent compound.  Studies in rats and mice indicate that 
AZD6244 is widely distributed, although concentrations were generally lower in tissue than blood.  
High levels of protein binding (93.7%-99.7%) were observed in all preclinical species tested and 
in humans (98.4%).  There was no evidence of AZD6244-related material binding to melanin and 
minimal penetration into the central nervous system (CNS).   
AZD6244 is metabolized in human hepatocytes by cytochrome P450 (CYP enzymes) 1A2, 2C19 
and 3A4, with CYP1A2 being the enzyme primarily responsible for the formation of the N-
desmethyl metabolite.  Glucuronidation appears to be a significant clearance mechanism for 
AZD6244 and the N-desmethyl metabolite.  It is a weak inducer of CYP 3A, 1A, and 2C9.  
AZD6244 does not inhibit CYP 1A2, 2C8, 2C19, 2D6, and 3A4.  It was a weak inhibitor of 
CYP2C9 (IC50 44.7 mcM).  N-desmethyl AZD6244 does not inhibit CYP 2A6, 2C8, 2C9, 2C19, 
2D6, 2E1, or 3A4, but is a weak inhibitor of 1A2 (IC50 of 18.9 mcM).  In the rat, mouse, and 
monkey, fecal excretion was the predominant route after oral and intravenous dosing. 
Toxicologic Studies 
Toxicity of AZD6244 was evaluated in the acute dosing (one or two doses on a single day) and 
continuous daily dosing studies (for a 1 month and 6 months) in Sprague-Dawley rats and 
cynomolgus monkeys (AZD6244 Investigator's Brochure, Edition #15 (March 30, 2015). The 
repeat-dose study in rats indicated that the agent was well tolerated but produced soft stools and 
gastrointestinal mucosal mineralization associated with increased serum phosphorus and 
decreased albumin.  Tissue mineralisation was not apparent in cynomolgus monkeys when dosed 
for up to 1 month with AZD6244 free-base or for up to 6 months with AZD6244 hydrogen 
sulfate.  However, mineralization was seen in multiple tissues (cornea, kidney, liver, 
myocardium, skeletal muscle, and glandular stomach) in mice dosed with AZD6244 hydrogen 
sulfate for up to 1 month, and in the liver of a small number of mice dosed up to 6 months.   
Twice daily (BID) oral dosing with AZD6244 free-base for 1 month in monkeys produced 
diarrhea, dehydration, and electrolyte imbalance, in some animals associated with renal toxicity.  
Dosing with AZD6244 hydrogen sulfate (0.5, 1.5, and 4 mg/kg BID) for up to 6 months in 
monkeys was also associated with fluid and/or red-colored feces, but with no notable 
gastrointestinal (GI) tract or renal pathology. 
AZD6244 and its N-desmethyl metabolite showed no evidence of mutagenic potential, but 
AZD6244 produced an increase in micronucleated immature erythrocytes in mice, predominantly 
via an aneugenic mode of action.  AZD6244 showed enhanced cytotoxicity in the presence of 
ultraviolet (UV) light.  Reproductive toxicology data in mice indicate that AZD6244 can have 
adverse effects on embryofetal development and survival at dose levels that were not toxic to 
mothers. 
In summary, preclinical studies demonstrated that AZD6244 exposures can be significantly 
enhanced by using AZD6244 hydrogen sulfate, compared to AZD6244 free-base.  In 6-month 
toxicology studies, AZD6244 exposures, expressed as area under the concentration-time curve 
from time 0 h to 12 h (AUC0-12), achieved with AZD6244 hydrogen sulfate at high dose levels (4 
mg/kg BID in monkeys and 20 mg/kg BID in mice) were approximately 3-fold and 15-fold higher 
in primates and mice, respectively, when compared with those achieved in man at 75 mg BID 
AZD6244 hydrogen sulfate.  At the NOAEL of 1.5 mg/kg BID from 1-month and 6-month studies 
in primates, exposures were generally similar to those seen in man after dosing at 75 mg BID 
AZD6244 hydrogen sulfate.  Exposure achieved in the 6-month mouse study at the low dose level 


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of 1 mg/kg BID was slightly below that seen to date in man after dosing with AZD6244 hydrogen 
sulfate (75 mg BID).  Preclinical pharmacology studies suggest an acceptable safety profile for 
administering AZD6244 free-base or AZD6244 hydrogen sulfate to cancer patients.  
 
Clinical Experience 
Pharmacokinetics 
AZD6244 plasma PK parameters of AZD6244 hydrogen sulfate were similar after single and 
multiple dosing, suggesting a minimal accumulation over time after BID dosing (AZD6244 
Investigator's Brochure, Edition #15 (March 30, 2015).   The AZD6244 exposure parameters, i.e., 
the maximum plasma concentration (Cmax) and the AUC were approximately dose-proportional 
across the 25- to 100-mg BID dose range after single (day 1) or multiple dosing studied on days 
1, 8, 15, and 22.  The geometric mean values of exposure parameters were:  Cmax=369-1483 ng/mL 
and AUC0-12=1361-7055 ng∙h/mL on day 1, and Cmax=458-1365 ng/mL and AUC0-12=1515-4758 
ng∙h/mL on day 8.  AZD6244 was absorbed relatively quickly across all dose levels, with a median 
time-to-reach Cmax (tmax) of 1.5 hours.  Following the peak, AZD6244 concentration declined 
multi-exponentially with a mean terminal elimination half-life (t1/2) ranging from 5 to 7 hours, 
which was consistent across dose levels.  The apparent volume of distribution at steady state 
(Vss/F) and apparent clearance (CL/F) also remained largely consistent across the dose range, with 
mean values ranging from 87 to 126 L and 12 to 19 L/h, respectively.  The plasma PK profile of 
the AZD6244 active metabolite, N-desmethyl AZD6244, was similar to that of AZD6244, 
although exposure was much lower, achieving Cmax and AUC values generally <15% of the parent 
compound, in each patient.  The median tmax was approximately 1.5 hours and t1/2 ranged from 9-
13 hours.  The AZD6244 amide metabolite showed increased exposure on multiple dosing 
indicating some accumulation.  Given the 3-to 5-fold greater potency of the N-desmethyl 
metabolite compared to AZD6244 shown by the in vitro cell-based ERK phosphorylation assay, 
the N-desmethyl AZD6244 is likely to contribute to pharmacodynamic effects.  In contrast, 
AZD6244 amide, which was approximately 40- to 50-fold less active than AZD6244 in this assay, 
is unlikely to contribute significantly to AZD6244 biological activity.  Nevertheless, both 
metabolites will be measured in all future AstraZeneca-sponsored clinical studies of AZD6244 
hydrogen sulfate. 
The capsule formulation significantly improved oral bioavailability compared the free-base 
formulation, although large inter-patient variability was noted.  The estimated oral bioavailability 
of capsule relative to the free-base suspension based on a dose-normalized AUC0-24 was 263% 
(90% confidence interval [CI]=214%-322%).  The geometric mean values of exposures obtained 
for AZD6244 hydrogen sulfate at the maximum tolerated dose (MTD) of 75 mg BID (AUC0-
24=6335 and 5448 ng∙h/mL on day 1 and 8, respectively, and Cmax=1207 and 1439 ng/mL on day 
1 and 8, respectively) were statistically significantly higher than those obtained at the MTD of 
AZD6244 free-base (100 mg BID); the relative estimated exposures by hydrogen sulfate vs.  free-
base were 197% (90% CI=161 to 242%) for AUC0–24 and 252% (90% CI=182 to 348%) for Cmax. 
A food effect study involving administration of AZD6244 hydrogen sulfate to patients with 
advanced solid malignancies under fasting conditions and with a high-fat meal indicated a 
statistically significant effect of food on the exposure of AZD6244.  Geometric mean Cmax and 
AUC values were reduced by approximately 62% and 19%, respectively, under fed conditions. 


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Version Date: May 19, 2018  
34 
 
Therefore, for further clinical studies, it is recommended that AZD6244 be taken on an empty 
stomach (i.e., no food other than water can be taken) at least 2 hours after a meal and 1 hour before 
the next meal.   AZD6244 capsule should be taken with water.    
At a population level, plasma exposure of AZD6244 (Cmax and AUC) appeared to be increased in 
healthy volunteers of Asian descent by approximately 1.5- to 2-fold, in non-Japanese Asians and 
Japanese Asians, respectively, compared with Western healthy volunteers.  However, the 
AZD6244 PK was highly variable and there was overlap in the range of exposure experienced by 
Asian and Western subjects. 
There is no evidence of PK interactions between docetaxel, dacarbazine, temsirolimus, or erlotinib 
and AZD6244.  
Efficacy  
Four randomized phase 2 monotherapy studies comparing efficacy of AZD6244 free-base 
formulation (100mg BID) to standard chemotherapy regimens in patients with solid tumors 
(melanoma, pancreatic cancer, CRC, and NSCLC) did not demonstrate superior efficacy of 
AZD6244 over standard chemotherapy agents (AZD6244 Investigator's Brochure, Edition #15 
(March 30, 2015).  Several objective responses were observed in melanoma patients with mutant 
BRAF tumors and in patients with mutant KRAS NSCLC.  
Although statistical significance in overall survival (OS) was not achieved, a statistically 
significant improvement was seen in progression-free survival (PFS) for AZD6244 in combination 
with docetaxel in patients with mutant KRAS NSCLC (P=0.014)[34] and for AZD6244 in 
combination with dacarbazine in patients with mutant BRAF cutaneous melanoma (P=0.021),[35] 
when compared to the respective chemotherapy/placebo groups.  Clinical activity of AZD6244 
hydrogen sulfate monotherapy was demonstrated in uveal melanoma.[36] 
Safety 
The tolerability profile of AZD6244 free-base at 100 mg BID was similar to that of AZD6244 
hydrogen sulfate at 75 mg BID (AZD6244 Investigator's Brochure, Edition #15 (March 30, 2015). 
The most common AEs associated with AZD6244 are acneiform rash, diarrhea, nausea, vomiting, 
peripheral edema, and fatigue.  Stomatitis, dry skin, and pyrexia have also been commonly 
reported in the AZD6244 studies. Dose escalation of selumetinib was limited mainly by the 
occurrence of rash and diarrhea. 
Events consistent with central serous retinopathy/retinal pigment epithelial detachment have been 
reported in a small number of patients receiving treatment with AZD6244, generally in 
combination with other novel targeted anticancer agents. 
Mild (generally grade 1) elevations in serum liver transaminases have been recorded within the 
first week of starting treatment with AZD6244 and levels tend not to increase further beyond the 
first month of continued dosing.  Mild increases in serum phosphate and in calcium phosphate 
product have been reported.   
Dyspnea and exertional dyspnea have been reported in patients receiving AZD6244.  The majority 
of these events have occurred in patients with lung or pleural disease due to their underlying 
malignancy. There have been reports of pneumonitis-type events, including symptoms of shortness 
of breath, fatigue, cough and/or fever, in a small number of patients receiving AZD6244, but 


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35 
 
pneumonitis-AZD6244 association has not been established.  Studies of AZD6244 should include 
guidance for the management and investigation of new or worsening dyspnea or symptoms of 
pneumonitis-type events that are not attributed to the patient’s underlying cancer. 
Increases in systolic or diastolic blood pressure, sometimes exceeding the threshold for therapeutic 
intervention, have been observed in studies with AZD6244.  Asymptomatic reductions in left 
ventricular ejection fraction (LVEF) to below 55% have been observed in a small number of 
patients during AZD6244 treatment and evidence of reversibility while on continuous dosing was 
demonstrated in some patients.  Studies of AZD6244 should include baseline and symptom-
triggered echocardiography assessments and guidance for the management and investigation of 
decreases of LVEF.  Review of electrocardiogram (ECG) parameters has shown no evidence of 
QT interval corrected according to Fridericia’s formula (QTcF) prolongation during treatment with 
AZD6244.   
Increased creatine phosphokinase (CPK) levels have been reported in a small number of patients 
with advanced cancer receiving AZD6244.  A relationship between selumetinib and increased CK 
levels has not been established. 
2.3 
Rationale 
Patients with advanced pancreas cancer have few available treatment options and an overall poor 
prognosis. Pre-clinical evidence, both in a large panel of cell lines and in patient-derived 
xenotransplantation models, suggests that selumetinib (AZD6244) has activity against pancreas 
cancers harboring KRAS G12R mutations. 
This study tests the hypothesis  
(1) if patients with advanced pancreas cancer with a unique KRAS mutational isoform respond 
to the MEK inhibitor selumetinib (AZD6244) and  
(2) if genetic or protein expression information derived from treated patients distinguishes 
patients responding to the drug from patients progressing under treatment 
2.4 
Correlative Studies Background 
The rationale for the chosen correlative tissue is derived from the observation that (1) additional 
inherent somatic gene perturbations, either within the targeted signal transduction pathway or 
affecting other pro-survival cell functions, frequently mediate resistance to targeted agents. 
Examples of relevance to the MEK inhibition in KRAS G12R mutant pancreas cancer are for 
example concomitant mutations of the PI3K-AKT-mTOR pathway or gene amplifications in the 
cyclin or cyclin kinase regulating genes. The immediately available information on variant status 
in 50 additional common known cancer genes as part of the applied gene panel allows immediate 
correlation and possible identification of common genetic mechanisms of resistance. The 
correlation of CNKSR1 expression status, measured by IHC, with response to selumetinib is a 
direct translation of our laboratory efforts; we have shown that CNKSR1, a scaffolding kinase 
and regulator of MAPK kinase signaling, mediates in preclinical models resistance to MAPK 
pathway inhibition. Circulating tumor DNA (ctDNA) analysis is capable of accurately 
determining tumor progression, prognosis, and assisting in targeted therapy development via 
prediction of response when applied prospectively in later studies. 


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3 
PATIENT SELECTION 
3.1 
Eligibility Criteria  
3.1.1 Patients must have histologically confirmed locally advanced or metastatic pancreas 
cancer. 
3.1.2 Patients must have received at least 6 months 5-FU- or gemcitabine-based treatments for 
pancreas cancer (FOLFIRONOX, FOLFOX, 5-FU+ nal-IRI (MM-398; nanoliposomal 
irinotecan), or 5-FU (including capecitabine), gemcitabine-based gemcitabine plus 
abraxane, gemcitabine monotherapy among others). 
3.1.3 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for non-
nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) with conventional 
techniques or as ≥10 mm (≥1 cm) with spiral CT scan, MRI, or calipers by clinical exam.  
See Section 11 for the evaluation of measurable disease. 
3.1.4 Patients must have CLIA confirmed somatic KRAS G12R mutation as determined by 
sequence analysis of matched normal DNA from any specimen obtained from the 
individual. Patients must provide test result from CLIA certified laboratory, confirming 
somatic KRAS G12R mutation or archival tumour sample for KRAS analysis or be 
willing to undergo mandatory screening biopsy.  
3.1.5 Patients must not have had chemotherapy, molecular therapy with erlotinib, radiation 
therapy, or experimental biological or molecular therapy for at least 4 weeks prior to 
starting study medication.  Patients who received FOLFIRINOX must be 6 weeks from 
the last administration of therapy. Patients must have recovered from any acute toxicity 
related to prior therapy or surgery, to a grade 1 or less unless specified. 
3.1.6 Age ≥18 years.   
Because no dosing or adverse event data are currently available on the use of AZD6244 in 
patients <18 years of age, children are excluded from this study, but will be eligible for 
future pediatric trials. 
3.1.7 ECOG performance status ≤1 or Karnofsky ≥70%, (see Appendix A). 
3.1.8 Patients must have normal organ and marrow function as defined below: 
− 
leukocytes 
≥3,000/mcL 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
platelets 
≥75,000/mcL 
− 
hemoglobin (Hgb) 
≥9.0 g/dL 
− 
total bilirubin 
below or within normal institutional limits 
− 
AST(SGOT)/ALT(SGPT) 
<3× institutional upper limit of normal 
− 
creatinine  
 
< institutional upper limit of normal 
OR 
− 
creatinine clearance 
>60 mL/min/1.73 m2 by either Cockcroft-Gault  
 
formula or 24-hour urine collection analysis 
3.1.9 Patients must be willing to return to the Clinic for follow-up visits.  


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3.1.10 The effects of AZD6244 on the developing human fetus at the recommended therapeutic 
dose are unknown. For this reason, women of child-bearing potential must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry, for the duration of study participation, and for 4 weeks after dosing with 
AZD6244 ceases. Women of child-bearing potential must have a negative pregnancy test 
within 14 days prior to study treatment. Should a woman become pregnant or suspect she 
is pregnant while she or her partner is participating in this study, the patient should 
inform her treating physician immediately. Please note that the AZD6244 manufacturer 
recommends that adequate contraception for male patients should be used for 12 weeks 
post-last dose due to sperm life cycle. 
Note: Selumetinib is a tyrosine kinase inhibitor with the potential for teratogenic or 
abortifacient effects. Because there is an unknown but potential risk for adverse events in 
nursing infants secondary to treatment of the mother with selumetinib, breastfeeding 
should be discontinued if the mother is treated with selumetinib.   
3.1.11 Ability to understand and the willingness to sign a written informed consent document or 
patients with Impaired Decision Making Capacity (IDMC) if they are represented by a 
Legally Authorized Representative (LAR).  
3.1.12 Patient must be able to reliably swallow oral medications. 
3.2 
Exclusion Criteria 
3.2.1 Patients who have received prior treatment with tyrosine kinase inhibitors (e.g. erlotinib), 
or anti-EGFR agents (e.g. cetuximab, panitumumab). 
3.2.2 Patients currently receiving any medication known to induce central serous 
chorioretinopathy which in the opinion of the Principal Investigator, would make the 
administration of study drug hazardous.  
3.2.3 Patients with active hepatic or biliary disease (with exception of patients with Gilbert’s 
syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per 
investigator assessment) 
3.2.4 Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with study 
requirements.  
3.2.5 Any underlying medical condition which, in the opinion of the principal investigator, will 
make the administration of study drug hazardous or obscure the interpretation of adverse 
events 
3.2.6 Patients who are receiving any other investigational agents. 
3.2.7 Patients with known brain metastases should be excluded from this clinical trial because 
of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events.  
No additional workup is needed to exclude brain metastases if the patient is 
asymptomatic or has no history of brain metastases. 


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3.2.8 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to AZD6244 or other agents used in study. 
3.2.9 Previous MEK, RAS, or RAF inhibitor use. 
3.2.10 Patients with the following cardiac conditions are excluded: 
• Uncontrolled hypertension (blood pressure [BP] of ≥150/95 despite medical 
support/management) 
• Acute coronary syndrome within 6 months prior to starting treatment 
• Uncontrolled angina – Canadian Cardiovascular Society grade II-IV despite 
medical support/management 
• Heart failure NYHA Class II or above (for the NYHA Classification refer to 
Appendix B) 
• Prior or current cardiomyopathy (within 6 months) including but not limited to the 
following: 
o Known hypertrophic cardiomyopathy 
o Known arrhythmogenic right ventricular cardiomyopathy 
o Abnormal ejection fraction (echocardiogram [ECHO]) <= 53% (if a range is 
given then the upper value of the range will be used) or cardiac MRI 
o Previous moderate or severe impairment of left ventricular systolic function 
(LVEF <45% on echocardiography or equivalent on Multi-Gated 
Acquisition Scan [MUGA]) even if full recovery has occurred. Echo and 
additional cardiac studies not indicated unless clinically symptomatic or 
patient has significant cardiac history. 
o Severe valvular heart disease 
o Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest 
o Fridericia's corrected QT interval (QTcF) >=  450 msec or other factors that 
increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, 
hypokalemia, family history of long QT interval syndrome) are excluded.  
The use of medication(s) that can prolong QTc interval is prohibited while 
treated on this study.  For a comprehensive list of agents that prolong QTc 
refer 
to 
a 
frequently-updated 
medical 
reference, 
such 
as 
https://www.crediblemeds.org/everyone/composite-list-all-qtdrugs. 
3.2.11 Patients with known ophthalmologic conditions, such as: 
3.2.11.1 Current or past history of central serous retinopathy 
3.2.11.2 Current or past history of retinal vein occlusion 
3.2.11.3 Known intraocular pressure (IOP) > 21 mmHg (or ULN adjusted by age) or 
uncontrolled glaucoma (irrespective of IOP); patients with controlled glaucoma and 
increased IOP who do not have meaningful vision (light perception only or no light 
perception) may be eligible after discussion with the study chair 


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39 
 
3.2.11.4 Subjects with any other significant abnormality on ophthalmic examination (performed 
by an ophthalmologist) should be discussed with the study chair for potential eligibility 
3.2.11.5 Ophthalmological findings secondary to long-standing optic pathway glioma (such as 
visual loss, optic nerve pallor or strabismus) or long-standing orbito-temporal PN (such 
as visual loss, strabismus) will NOT be considered a significant abnormality for the 
purposes of the study. 
3.2.12 Patients with refractory nausea and vomiting, chronic gastrointestinal (GI) diseases (e.g., 
inflammatory bowel disease) or significant bowel resection. 
3.2.13 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with AZD6244.  HIV-positive patients not on 
antiviral therapy with undetectable viral loads and CD4 counts >300, and after 
confirmation of eligibility after discussing with the Study chair are eligible. 
3.3 
Inclusion of Women and Minorities 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-defined 
clinical research unless a clear and compelling rationale and justification establishes to the 
satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate with 
respect to the health of the subjects or the purpose of the research.  Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification.  Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources.  Women of childbearing 
potential should not be routinely excluded from participation in clinical research.  Please see 
http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
4 
REGISTRATION PROCEDURES 
4.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations require IND sponsors to select qualified 
investigators.  NCI policy requires all persons participating in any NCI-sponsored clinical trial to 
register and renew their registration annually.  To register, all individuals must obtain a CTEP 
Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN or RAVE or acting as 
a primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation 
requirements per registration type are outlined in the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 


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40 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA Form 
1572 in RCR to allow the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
Additional information can be found on the CTEP website at  
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 
 
4.2 
Site Registration 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients.  Assignment of site registration status in the CTSU 
Regulatory Support System (RSS) uses extensive data to make a determination of whether a site 
has fulfilled all regulatory criteria including but not limited to the following:  
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating organization 
• A valid IRB approval 
• Compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 


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41 
 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site 
. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are not 
required to submit IRB approval documentation to the CTSU Regulatory Office. For sites using 
the CIRB, IRB approval information is received from the CIRB and applied to the RSS in an 
automated process.  Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  The 
CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In order for 
the SSW approval to be processed, the Signatory Institution must inform the CTSU which CIRB-
approved institutions aligned with the Signatory Institution are participating in the study. 
4.2.1 Downloading Regulatory Documents 
Site registration forms may be downloaded from the 10050 protocol page located on the CTSU 
Web site.  Permission to view and download this protocol is restricted and is based on person and 
site roster data housed in the CTSU RSS.  To participate, Investigators and Associates must be 
associated with the Corresponding or Participating protocol organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP-IAM username and password. 
• Click on the Protocols tab in the upper left of your screen.  
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand, then select LAO-NCI, and protocol 
#10050. 
• Click on LPO Documents, select the Site Registration documents link, and download and 
complete the forms provided.  (Note: For sites under the CIRB initiative, IRB data will 
load to RSS as described above.) 
4.2.2 Requirements For 10050 Site Registration: 
• IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an 
IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted) 
• Specimen Tracking Training 
 At least one individual at each participating site will need to complete the Theradex-
led training 
 Theradex will provide a certificate of completion, which will need to be submitted to 
the CTSU through the Regulatory Submission Portal 
 The training is a one-time only requirement per individual 
 This training will need to be completed before the first patient enrollment at a given 
site 
• Peter Clark is the main point of contact at Theradex for the training (802-456-8735, 


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42 
 
PClark@theradex.com).  Nafeesa Sarakhawas is the backup contact (609.480.2693, 
NSarakhawas@theradex.com) 
4.2.3 Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office, where they will be 
entered and tracked in the CTSU RSS.   
Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab  Regulatory 
Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and 
support. 
4.2.4 Checking Site Registration Status 
You can verify your site registration status on the members’ section of the CTSU website.   
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does not 
reflect compliance with protocol requirements for individuals participating on the protocol or the 
enrolling investigator’s status with the NCI or their affiliated networks. 
4.3 
Patient Registration 
4.3.1 NCI Central Registration (NCI Site Only) 
Registration will be a two-part process as patients are screened on this protocol. Authorized staff 
must register an eligible candidate with NCI Central Registration Office (CRO) within 24 hours 
of signing consent. To initially register a subject after the participant has signed the consent, 
complete the top portion the registration Eligibility Checklist from the website 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) indicating that the patient is being 
registered for screening and send via encrypted email to: NCI Central Registration Office 
ncicentralregistration-l@mail.nih.gov. Once eligibility is confirmed after completion of 
screening studies, complete the remainder of the form which is the eligibility checklist, 
indicating that the patient is being registered for treatment and email the completed registration 
checklist to the CRO at NCI Central Registration Office  ncicentralregistration-
l@mail.nih.gov.  After confirmation of eligibility at Central Registration Office, CRO staff will 


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43 
 
call pharmacy to advise them of the acceptance of the patient on the protocol prior to the release 
of any investigational agents.  Verification of Registration will be forwarded electronically via e-
mail to the research team. A recorder is available during non-working hours.  
Subjects that do not meet screening criteria should be removed from the study per the procedure 
below.  
4.3.2 Off Study Procedure (NCI Site Only) 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off-
study. An off-study form from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and 
sent via encrypted email to:  NCI Central Registration Office ncicentralregistration-
l@mail.nih.gov>. 
4.3.3 OPEN / IWRS 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).  
OPEN is a web-based registration system available to users on a 24/7 basis.  It is integrated with 
the CTSU Enterprise System for regulatory and roster data interchange and with the Theradex 
Interactive Web Response System (IWRS) for retrieval of patient registration/randomization 
assignment.  Patient enrollment data entered by Registrars in OPEN / IWRS will automatically 
transfer to the NCI’s clinical data management system, Medidata Rave. 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
4.3.4 OPEN/IWRS User Requirements 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations:  Be on an ETCTN Corresponding 
or Participating Organization roster with the role of Registrar. Registrars must 
hold a minimum of an AP registration type. 
• To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
• Have regulatory approval for the conduct of the study at their site. 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.   
• If applicable, all patients have signed an appropriate consent form  
4.3.5 OPEN/IWRS Questions? 
Further instructional information on OPEN is provided on the OPEN tab 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.  
4.4 
General Guidelines 
Following registration, patients should begin protocol KRAS G12R mutation testing within 5 
days. Issues that would cause treatment delays should be discussed with the Principal 
Investigator.  If a patient does not receive protocol therapy following registration, the patient’s 


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
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44 
 
registration on the study may be canceled.  The Study Coordinator should be notified of 
cancellations as soon as possible. 
5 
TREATMENT PLAN 
Patients will be screened for the presence of KRAS gene mutations in their tumor and only patients 
who harbor KRAS G12R mutations will continue onto the treatment phase of the study.  Please 
see section 10 for screening procedures. 
Selumetinib (AZD6244) will be administered as an oral dose of selumetinib sulfate 75 mg twice 
daily (in the morning and evening) taken two hours after a meal and one hour before the next meal.  
Selumetinib will be given continuously; one cycle equals 28 +/- 2 days.   
Up to 24 evaluable patients (allowing for a staged accrual of initially 7 patients who will receive 
selumetinib and are evaluable after the 1st cycle) will be treated over 2 years and the trial will be 
completed over 2(-4) years, allowing for completion of follow-up. 
The primary objective of the trial will be to determine whether selumetinib (AZD6244) 
monotherapy in advanced pancreas cancer patients harboring KRAS G12R mutations is able to be 
associated with a response rate (PR +CR) that can rule out 5% (p0=0.05) in favor of an improved 
response rate of 30% (p1=0.30). 
 
 
 


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5.1 
Agent Administration 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
5.1.1 AZD6244 Hydrogen Sulfate Administration 
All new NCI-sponsored trials with AZD6244 will use the hydrogen sulfate salt (capsule) 
formulation.  Treatment will be administered on an outpatient basis.  Reported adverse events 
(AEs) and potential risks are described in Section 7.  Appropriate dose modifications for 
AZD6244 hydrogen sulfate are described in Section 6.  No investigational or commercial agents 
or therapies other than those described below may be administered with the intent to treat the 
patient’s malignancy. 
5.1.1.1 AZD6244 hydrogen sulfate will be administered at a dose of 75 mg orally twice a day, 
approximately 12 hours apart.  For the evaluation purposes, a cycle will be defined as 
28 +/- 2 days.  Detailed instructions for storage and handling are provided in Section 8 
(Pharmaceutical Information) of the protocol. 
• Patients will be provided with a Medication Diary for AZD6244 (Appendix 
D), instructed in its use, and asked to bring the diary with them to each 
appointment.  A new copy of the Medication Diary will be given to patients 
whose dose is reduced due to adverse events (AEs). 
• AZD6244 capsules should be swallowed whole with a glassful of water twice 
a day, approximately 12 h apart, on an empty stomach – no food or drink 
other than water for 2 hrs prior to dosing and 1 h after dosing (i.e., AZD6244 
should be taken at least 2 h after a meal and 1 h before the next meal). 
5.1.1.2 Follow up for certain AEs should be performed to better characterize the effects of 
AZD6244 therapy:  
• Patients experiencing edema should have cardiac ejection fraction (EF) 
measurements, serum chemistry (including electrolytes and albumin), and 
routine urinalysis. 
• Patients with symptoms consistent with cardiac impairment (e.g., congestive 
cardiac failure, edema, or dyspnea) should have EF measurements (MUGA 
scan or echocardiography) at the time of the event as well as other routine 
investigations.  Decreases in left ventricular ejection fraction (LVEF) from 
baseline (if known) may be investigated according to the algorithm described 
in Appendix E. 
• Respiratory events (pulmonary edema) should be followed up with an 
electrocardiogram, EF measurement, and chest X-ray.  All new dyspnea AEs 
or worsening of pre-existing dyspnea AEs should be followed according to the 
dyspnea management algorithm (Appendix F).  


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• Oxygen saturation will be measured at baseline and again following any 
respiratory event. 
• Patients experiencing visual disturbances should undergo a complete 
ophthalmologic examination, including a slit lamp examination. 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
• Because there is the potential for drug-drug interaction through the cytochrome P450 
enzyme system (CYP), the case report form (CRF) must capture the concurrent use of all 
other drugs, over-the-counter medications, or alternative therapies.  The Principal 
Investigator should be alerted if the patient is taking any agent known to affect or with 
the potential for drug interactions.  The enzymes in question are CYP 1A2/3, 2C9, 2C19, 
3A4/5, and UGT1A1.  AZD6244 hydrogen sulfate (selumetinib) is metabolized by these 
enzymes and may be affected by other drugs that inhibit or induce these enzymes.  The 
proteins in question are P-gp and BCRP. AZD6244 hydrogen sulfate (selumetinib) is a 
substrate of BCRP and P-gp transporters and may be affected by other drugs that inhibit 
or induce these transporters. The study team should check a frequently-updated medical 
reference for a list of drugs to avoid or minimize use of.  Appendix C (Patient Drug 
Information Handout and Wallet Card) should be provided to patients and their 
caregivers.  
• The patient’s smoking history should be documented in the CRF, including the number of 
packs smoked/day (if a smoker). 
• Diarrhea can generally be controlled with the following regimen:  loperamide (4 mg orally 
[PO]) at onset of symptoms, followed by 2 mg loperamide every 2 hours while awake (or 4 
mg PO every 4 hours while sleeping) up to a maximum of 16 mg loperamide per day. 
• The nausea and vomiting that may occur with AZD6244 administration can generally be 
managed through the use of appropriate simple supportive measures (e.g., 
prochlorperazine).  To date, 5 HT3 antagonists have not been routinely required. 
• Patients should avoid excessive sun exposure and use adequate sunscreen protection if 
sun exposure is anticipated. 
• Because AZD6244 capsules contain significant amounts of vitamin E, the following 
precautions apply: 
o Patients should not take supplemental vitamin E.  High doses of vitamin E have been 
reported to cause bleeding and interrupt blood coagulation processes. 
o High doses of vitamin E have been reported to potentiate the anticoagulant activity of 
coumadins such as warfarin.  Patients who are taking concomitant coumarin 
anticoagulant medications should have their INR or anticoagulant assessment 
conducted more frequently after starting AZD6244 therapy. The dose of 
anticoagulant should be adjusted according to these anticoagulant measurements. 
• Reproductive toxicology data indicate that AZD6244 has the potential for adverse effects 
on embryofetal development and survival.  Therefore, AZD6244 should not be 


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administered to pregnant or breast-feeding women and conception while on treatment 
must be avoided.  Female patients of child-bearing potential will be required to use 
reliable methods of contraception for the duration of the study and until 4 weeks after the 
last dose of AZD6244.  Male patients with sexual partners who could become pregnant 
(i.e., women of child-bearing potential) should use acceptable methods of contraception 
for 12 weeks after completing the study to avoid pregnancy and/or potential adverse 
effects. 
5.3 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
• 
Completion of 27 cycles of study therapy 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from study therapy 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator (patient non-compliance) 
• 
Pregnancy 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation. 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
• 
Termination of the study by sponsor 
• 
The drug manufacturer can no longer provide the study agent 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
5.4 
Duration of Follow Up 
Patients will be followed for 52 weeks through a telephone interview every 2 months after 
removal from study therapy or until death, whichever occurs first.  Patients removed from study 
for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse 
event. Progression Free Survival (PFS) will be captured as the duration of time from start of 
treatment to time of progression or death, whichever occurs first. After progression and coming 
off treatment, patients will be followed for 52 weeks through a telephone interview every 2 
months or until death, whichever occurs first. 


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6 
DOSING DELAYS/DOSE MODIFICATIONS 
General guidelines for treatment modifications at the time of re-treatment:  
Adverse Events: All adverse events in this trial will be graded using the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 - a complete listing is available 
at the CTEP website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Dose adjustments will be made according to the guidelines below, with dose levels defined as 
follows: 
Dose Level (DL) 
Agent   Dose 
0 
Selumetinib 75 mg twice daily 
-1* 
Selumetinib 50 mg twice daily 
-2* 
Selumetinib 75 mg once daily 
Summary of dose holding/interruptions and dose de-escalation recommendations for selumetinib 
in case of selumetinib-related adverse events (graded according to NCI-CTCAE v5.0) 
General Adverse Events 
Action 
Non-hematological, Grade 1 or 2 
Continue selumetinib therapy at full dose prescribed. 
Apply maximum supportive care recommendations.  
If prolonged duration of Grade 2 adverse event (≥7 
days) is affecting quality of life, decrease dose to DL 
-1, if symptoms persist and continue to affect quality 
of life for ≥ 7 more days, a second dose reduction to 
DL -2 will be allowed. 
Non-hematological, Grade 3 or 4 
(excluding cardiac and hepatobiliary 
events) 
Apply maximum supportive care recommendations. 
Hold selumetinib therapy until recovery to Grade ≤ 1 
(up to 14 days).  
For NCI-CTCAE v5.0 Grade 3 or 4 interstitial 
pneumonitis or Grade 4 rash manifested as toxic 
epidermal necrolysis (e.g. Stevens-Johnson 
Syndrome etc.) selumetinib must be permanently 
discontinued 
If recurrence of adverse event after drug hold/ 
interruptions is observed, and maximum supportive 
care measures applied, hold drug once again until 
recovery to Grade ≤ 1 (up to 14 days) and restart 
drug at DL-1.  If adverse event recurs, a second dose 
reduction to DL -2 will be allowed after symptoms 
recover to Grade ≤ 1. 
Non-hematological, Grade 3 or 4 
adverse events NOT resolved to 
Action (discontinue or resume selumetinib therapy) 
in individual cases after discussions with the 


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Grade ≤ 1 within a maximum of 2 
weeks from last planned 
administration  
Sponsor. 
Up to 2 reductions (DL-1 and DL-2) will be 
considered after maximum supportive care 
recommendations are introduced. 
Cardiac Adverse Events 
 
Cardiac (Severity corresponding to 
NYHA criteria) 
Selumetinib therapy to be discontinued permanently 
in case of symptomatic NYHA class III and IV CHF. 
Selumetinib therapy to be held, continued, or 
resumed accordingly for patients with NYHA class I 
or II CHF. 
Hepatobiliary Adverse Events 
 
Grade 3 AST/ALT* and 
Grade 2 total bilirubin elevation 
Hold selumetinib for 2 weeks; restart drug at DL-1 if 
events resolved to ≤Grade 1.  
If Grade 3 events recur after dose reduction, then 
discontinue selumetinib.  
Grade 2 AST/ALT or  
Grade 1 total bilirubin elevation 
Reduce selumetinib by one dose level for 2 weeks. 
Labs should be done every week until resolution of 
AST/ALT elevations to ≤Grade 1 and elevated 
bilirubin levels to normal. At the end of the 2 weeks 
the dose level may be increased if the toxicity 
resolves to ≤Grade 1 for AST/ALT elevations or to 
normal for bilirubin. If toxicity doesn’t resolve to 
≤Grade 1 for AST/ALT elevations or to normal for 
bilirubin, then continue with the reduced dose. Upon 
two recurrences of these adverse events, 
necessitating dose reduction, no further attempts to 
return to higher dose level after resolution to ≤Grade 
1 will be made. 
Grade 4 events 
Discontinue selumetinib 
* retest within 3 days from the first occurrence and then weekly to determine if ALT 
elevation    persists 
 
Note: In case of multiple short interruptions of dose due to either adverse events or drug 
supply or other reasons the sum of days without selumetinib treatment should not exceed 21 
days in any 90 day treatment period. 
 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2 and 


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7.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Selumetinib 
(AZD6244 hydrogen sulfate [NSC 748727]), AZD6244 (NSC 741078) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol-specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 969 patients. Below is the CAEPR for 
Selumetinib (AZD6244). 
NOTE:  Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER. If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
                                                                                                                          Version 2.6, January 4, 
2018[37] 
 
 Adverse Events with Possible  
 Relationship to Selumetinib (AZD6244) 
 (CTCAE 5.0 Term) 
[n= 969] 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
Anemia (Gr 3) 
Febrile neutropenia[38] 
 
CARDIAC DISORDERS 
 
Left ventricular systolic 
dysfunction 
Left ventricular systolic 
dysfunction (Gr 2) 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
Abdominal pain (Gr2) 
Constipation 
Constipation (Gr 2) 
Diarrhea[39] 
Diarrhea[39] (Gr 3) 
Dry mouth 
 
Mucositis oral 
Mucositis oral (Gr 3) 


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 Adverse Events with Possible  
 Relationship to Selumetinib (AZD6244) 
 (CTCAE 5.0 Term) 
[n= 969] 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Nausea 
Nausea (Gr 3) 
Vomiting 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Edema face 
Edema face (Gr 2) 
Edema limbs 
Edema limbs (Gr 3) 
Fatigue 
Fatigue (Gr 3) 
Fever 
Fever (Gr 2) 
Pain 
 
INFECTIONS AND INFESTATIONS 
 
Paronychia 
 
INVESTIGATIONS 
 
Alanine aminotransferase increased
Alanine aminotransferase 
increased (Gr 3) 
Aspartate aminotransferase 
increased 
Aspartate aminotransferase 
increased (Gr 3) 
CPK increased 
CPK increased (Gr 3) 
Lymphocyte count decreased 
 
Neutrophil count decreased 
 
Platelet count decreased 
 
White blood cell decreased 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
Anorexia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
Headache 
Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
Cough (Gr 2) 
Dyspnea 
Dyspnea (Gr 3) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Alopecia 
 


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 Adverse Events with Possible  
 Relationship to Selumetinib (AZD6244) 
 (CTCAE 5.0 Term) 
[n= 969] 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Dry skin 
Dry skin (Gr 2) 
Pruritus 
 
Rash acneiform 
Rash acneiform (Gr 3) 
Rash maculo-papular 
Rash maculo-papular (Gr 3) 
VASCULAR DISORDERS 
 
Hypertension 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Febrile neutropenia/neutropenic infection has been observed primarily in trials combining Selumetinib (AZD6244) 
and docetaxel. 
 
3SBE-CD (Captisol®, vehicle) in the mix and drink formulation is known to cause soft stools and/or diarrhea in rats 
and dogs; however, it is possible that some of these findings might be related to exacerbation of the vehicle effect by 
Selumetinib (AZD6244). 
 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC 
 
Adverse events reported on AZD6244 (selumetinib) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that AZD6244 (selumetinib) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(hemorrhagic anemia) 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete;  Atrioventricular block first degree; 
Cardiac disorders - Other (Takatsubo cardiomyopathy syndrome); Cardiac disorders - Other (valvular heart disease); 
Chest pain - cardiac; Heart failure; Myocardial infarction; Palpitations; Pericardial effusion; Right ventricular 
dysfunction; Sinus bradycardia; Sinus tachycardia 
CONGENITAL, FAMILIAL AND GENETIC DISORDERS - Congenital, familial and genetic disorders - Other 
(physeal dysplasia) 
EYE DISORDERS - Blurred vision; Conjunctivitis; Dry eye; Extraocular muscle paresis; Eye disorders - Other 
(bilateral macular edema); Eye disorders - Other (black haze in line of vision); Eye disorders - Other (chalazion); 
Eye disorders - Other (elevated intraocular pressure); Eye disorders - Other (retinal bleeding); Eye disorders - Other 
(spotty vision; itchy vision); Flashing lights; Floaters; Optic nerve disorder; Papilledema; Photophobia; Retinal 
detachment; Retinopathy; Uveitis 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Bloating; Cheilitis; Colitis; Dyspepsia; 


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Dysphagia; Esophagitis; Flatulence; Gastric hemorrhage; Gastritis; Gastroesophageal reflux disease; Gastrointestinal 
disorders - Other (pneumatosis coli); Gingival pain; Ileal stenosis; Oral hemorrhage; Rectal hemorrhage; Stomach 
pain; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Facial pain; Flu like 
symptoms; Localized edema; Malaise; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure Hepatobiliary disorders - Other (liver dysfunction/failure 
[clinical]) 
INFECTIONS AND INFESTATIONS – Infection4 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Cardiac troponin I increased; 
Creatinine increased; Ejection fraction decreased; Electrocardiogram QT corrected interval prolonged; Hemoglobin 
increased; INR increased; Lipase increased; Lymphocyte count increased; Serum amylase increased; Weight gain; 
Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hyperphosphatemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; 
Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - Other 
(elevated calcium phosphorus product); Metabolism and nutrition disorders - Other (sensation of warmth) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Bone pain; Chest 
wall pain; Generalized muscle weakness; Joint effusion; Joint range of motion decreased; Muscle weakness lower 
limb; Muscle weakness upper limb; Musculoskeletal and connective tissue disorder - Other (bilateral stiffness hands 
and feet [intermittent]); Musculoskeletal and connective tissue disorder - Other (joint swelling); Musculoskeletal and 
connective tissue disorder - Other (muscle weakness neck); Musculoskeletal and connective tissue disorder - Other 
(neck myopathy); Myalgia; Myositis; Neck pain; Pain in extremity; Rhabdomyolysis  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl. cysts and polyps) - Other (Merkel cell carcinoma); Tumor pain 
NERVOUS SYSTEM DISORDERS - Aphonia; Cognitive disturbance; Concentration impairment; Depressed 
level of consciousness; Dysarthria; Dysgeusia; Dysphasia; Intracranial hemorrhage; Ischemia cerebrovascular; 
Lethargy; Leukoencephalopathy; Memory impairment; Spinal cord compression; Nervous system disorders - Other 
(spinal cord compression); Oculomotor nerve disorder; Paresthesia; Peripheral sensory neuropathy; Reversible 
posterior leukoencephalopathy syndrome; Seizure; Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delusions; Depression; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Proteinuria 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal inflammation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Bronchopulmonary hemorrhage; Epistaxis; Hoarseness; Hypoxia; Nasal congestion; Pharyngolaryngeal pain; 
Pleural effusion; Pneumonitis; Pulmonary edema; Sore throat; Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Nail loss; Pain of skin; Palmar-
plantar erythrodysesthesia syndrome; Photosensitivity; Scalp pain; Skin and subcutaneous tissue disorders - Other 
(skin fissures); Skin ulceration; Stevens-Johnson syndrome; Urticaria 
VASCULAR DISORDERS - Flushing; Hypotension; Lymphedema; Thromboembolic event 
 
Note: AZD6244 (selumetinib) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 


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7.2 
Adverse Event Characteristics  
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
7.3 
Expedited Adverse Event Reporting  
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).   
The reporting procedures to be followed are presented in the “NCI Guidelines for Investigators: 
Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” 
which can be downloaded from the CTEP Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm).  
These requirements are briefly outlined in the tables below (Section 7.3.3). 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original submitter 
at the site. 
7.3.2 Distribution of Adverse Event Reports 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
7.3.3 Expedited Reporting Guidelines 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
Note:  A death on study requires both routine and expedited reporting, regardless of 


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causality.  Attribution to treatment or other cause must be provided. 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in 
the system organ class (SOC) “General disorders and administration site conditions.  
 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A 
and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic submission 
within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically 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 electronically 
within 10 calendar days of learning of the AE. 


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1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.4 
Routine Adverse Event Reporting 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
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.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
7.5 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
7.6 
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
7.7 
Reporting to the NCI Clinical Director (NCI Site Only) 
7.7.1 Definitions 


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7.7.1.1 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.   
7.7.1.2 Unanticipated Problem 
Any incident, experience, or outcome that: 
• Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
7.7.2 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.7.3 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects. 
7.7.4 NCI Clinical Director Reporting 
Deaths that occur within 30 days of completing treatment or receiving a research intervention 
should be reported via email to the Clinical Director.  If a death occurs after 30 days, it should be 
reported only if the death is at least possibly related to the research treatment or intervention.  
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at dahutw@mail.nih.gov and to CCRsafety@mail.nih.gov within one business day of 
learning of the death. 
All Unanticipated Problems, Serious Protocol Deviations, UADEs and Serious or continuing 
non-compliance must be reported to the NCI CD.  
• To report these events, please send an email to the NCI CD at CCRsafety@mail.nih.gov.  
The report that is submitted to the outside IRB can be used to report to the NCI CD.. 
8 
PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
8.1 
CTEP Agent 
8.1.1 AZD6244 hydrogen sulfate (NSC 748727) 


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8.1.1.1 Chemical Name:  5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-6-[(2-
hydroxyethoxy)carbamoyl]-1-methyl-1H-benzimidazol-3-ium hydrogen sulfate 
8.1.1.2 Other Names:  Selumetinib hydrogen sulfate; ARRY-142886 
8.1.1.3 Classification:  Mitogen-activated protein kinase kinase (MEK) inhibitor 
8.1.1.4 CAS Registry Number:  606143-52-6 
8.1.1.5 Molecular Formula:  C17H15BrClFN4O3• H2SO4  M.W.:  555.76 
8.1.1.6 Solubility:   Very low aqueous solubility (3.4 mcg/mL at pH 7.4)  
8.1.1.7 Mode of Action:  AZD6244 is a selective mitogen-activated protein kinase (MEK) 
inhibitor.  By inhibiting MEK, AZD6244 inhibits ERK phosphorylation, which may 
inhibit oncogenic growth signaling in tumor cells by targeting the 
RAS/RAF/MEK/ERK pathway. The RAS/RAF/MEK/ERK pathway is an important 
mediator of many cellular processes including proliferation, survival, differentiation, 
apoptosis, motility, and metabolism.   
8.1.1.8 How Supplied:  Astra Zeneca supplies and CTEP, DCTD, NCI distributes AZD6244 
hydrogen sulfate. The agent is supplied as size 4 hydroxypropylmethylcellulose 
(HPMC) capsules available in 25 mg (blue) strengths. Capsules are packaged in white, 
high density polyethylene (HDPE) containers with induction-seals and child-resistant 
closures.  Each bottle contains 60 capsules.  
AZD6244 hydrogen sulfate capsules contain a dispersion of drug in d-α-tocopheryl 
polyethylene glycol 1000 succinate (TPGS; a water soluble form of vitamin E). Each 
25 mg capsule contains 35.9 mg TPGS.  
 
Daily Vitamin E intake based on the daily adult dose of AZD6244 
Dose 
Vitamin E amount 
75 mg twice a day (3 x 25 mg x 2) 
215.4 mg 
 
8.1.1.9 Storage:  Store the AZD6244 hydrogen sulfate capsules at controlled room temperature 
(20°C-25°C). Brief excursions are permitted between 15°C and 30°C.    
8.1.1.10 Stability:  Stability studies are ongoing. 
If a storage temperature excursion is identified, promptly return AZD6244 hydrogen 
sulfate to controlled room temperature and quarantine the supplies.  Provide a detailed 
report of the excursion (including documentation of temperature monitoring and 
duration of the excursion) to PMBAfterHours@mail.nih.gov for determination of 
suitability.   


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8.1.1.11 Route of Administration:   Oral.  Do not eat or drink (except water only) for 2 hours 
prior to dosing and 1 hour after dosing selumetinib (AZD6244 hydrogen sulfate) 
capsules.  AZD6244 capsules should be taken with water only.        
8.1.1.12 Potential Drug Interactions:  High vitamin E doses may potentiate warfarin’s 
anticoagulant activity.  Monitor PT/INR more frequently in patients receiving both 
warfarin and AZD6244 hydrogen sulfate capsules.   
Avoid concomitant intake of supplemental vitamin E. 
AZD6244 hydrogen sulfate is primarily metabolized by CYP 1A2 to form the active 
N-desmethyl metabolite; in addition, CYP 1A3 and UGT1A1 form glucuronide 
conjugates. CYP 2C9, 2C19, 3A4/5 can also metabolize the parent agent; however, as 
observed during in vitro studies using a pan-CYP inhibitor, other available pathways 
contribute to AZD6244 metabolism. Use caution in patients who are taking strong 
inducers or inhibitors of these CYP or UGT enzymes. 
AZD6244 is also a substrate of BCRP and P-gp transporters.  Use caution in patients 
who are taking strong inducers or inhibitors of either transport protein. 
AZD6244 hydrogen sulfate is a weak inducer of CYP enzymes 3A, 1A and 2C9 and a 
weak inhibitor of CYP2C9 and both BCRP (breast cancer resistance protein) and 
OATP1B1 transporters. It did not inhibit OCT1 or P-glycoprotein. The N-desmethyl 
metabolite is a weak inhibitor of CYP1A2. In vitro data suggest that AZD6244 
hydrogen sulfate is unlikely to cause clinically relevant drug-drug interactions by these 
mechanisms. 
8.1.1.13 Patient Care Implications: Study participants should be counseled to avoid excessive 
sun exposure and use adequate sun protection measures if sun exposure is anticipated 
during the study. 
 
Availability 
AZD6244 hydrogen sulfate is an investigational agent supplied to investigators by the Division 
of Cancer Treatment and Diagnosis (DCTD), NCI. 
AZD6244 hydrogen sulfate is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.4). 
8.1.2 Agent Ordering and Agent Accountability 
8.1.2.1 NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.  The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents.  The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form 
(FDF).  If there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
participating investigator at that institution.  
Study agent must be ordered after patient is registered to the treatment arm as no starter 
supplies are being provided for this study.  


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Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status, a 
“current” password, and active person registration status.  For questions about drug 
orders, transfers, returns, or accountability, call or email PMB any time.  Refer to the 
PMB’s website for specific policies and guidelines related to agent management. 
8.1.2.2 Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record Form (DARF) available on the 
CTEP forms page.  Store and maintain separate NCI Investigational Agent 
Accountability Records for each agent, strength, formulation and ordering investigator 
on this protocol.  
8.1.2.3 
Investigator Brochure Availability - The current versions of the IBs for PMB-supplied 
agents will be accessible to site investigators and research staff through the PMB 
Online Agent Order Processing (OAOP) application.  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status and a “current” password.  Questions about 
IB access may be directed to the PMB IB coordinator via email.    
8.1.2.4 Useful links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET). 


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9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
Biomarker 
Name 
and Person 
performing the 
study 
Assay 
(CLIA: 
Y/N) 
Use (Integral, 
Integrated, or 
Exploratory) 
AND Purpose  
Tissue/Body Fluid 
Tested 
and Timing of Assay 
Mandatory/ 
Optional  
Funding 
Source(s) 
KRAS 
Mark Raffeld, 
Molecular 
Pathology, 
Laboratory of 
Pathology, NCI 
using the 50 
cancer gene 
deep sequencing 
assay applied 
for genetic 
profiling of 
solid organ 
cancers  
Appendix I 
Cancer 
Gene 
Panel 
CLIA: Y 
Eligibility 
criterion, KRAS 
G12R mutation 
status prerequisite 
for selumetinib 
treatment 
Eligibility 
determination, 
Tissue - either biospy or 
previous surgical 
specimen 
At enrollment 
* If a biopsy is needed, 
the site with the most 
minimal morbidity will 
harvested at the 
discretion of the PI.  
combined with KRAS 
mutation testing at 
enrollment (same assay) 
Mandatory 
for patients 
who do not 
have KRAS 
mutation 
status 
confirmed 
 
CCR  
 


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Biomarker 
Name 
and Person 
performing the 
study 
Assay 
(CLIA: 
Y/N) 
Use (Integral, 
Integrated, or 
Exploratory) 
AND Purpose  
Tissue/Body Fluid 
Tested 
and Timing of Assay 
Mandatory/ 
Optional  
Funding 
Source(s) 
50-cancer gene 
panel 
(multiplexed 
deep sequencing 
assay to identify 
somatic variants 
in tumor 
specimen) 
Mark Raffeld, 
Molecular 
Pathology, 
Laboratory of 
Pathology, NCI 
Cancer 
Gene 
Panel 
CLIA: Y 
Integrated 
to identify 
potential mutations 
governing 
resistance to 
selumetinib in 
KRAS G12R 
mutant cancers to 
identify molecular 
subgroups 
predicting 
response to the 
investigational 
agent. 
This genetic 
information 
retrieved from 
tumors are somatic 
mutations only. No 
germline mutation 
testing will be 
done. 
CNKSR1 
Markku 
Miettinen, 
Laboratory of 
Pathology. NCI 
IHC 
CLIA: N 
to identify 
subgroups of 
patients 
responding to the 
investigational 
agent 
to identify 
biomarkers of 
response 
 
Tissue from optional 
screening biopsy at 
enrollment  
Tissue from optional 
CT guided biopsy after 
2 weeks on the study 
Optional 
Dr. 
Rudloff’s 
lab  


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Biomarker 
Name 
and Person 
performing the 
study 
Assay 
(CLIA: 
Y/N) 
Use (Integral, 
Integrated, or 
Exploratory) 
AND Purpose  
Tissue/Body Fluid 
Tested 
and Timing of Assay 
Mandatory/ 
Optional  
Funding 
Source(s) 
Circulating 
Tumor DNA 
(ctDNA) 
Mark Raffeld, 
Molecular 
Pathology, 
Laboratory of 
Pathology, NCI 
CTC 
(blood) 
CLIA: N 
Integrated 
to identify 
biomarkers of 
response 
Blood (to be taken with 
clinical samples) – 5 ml 
ctDNA Blood 
Collection (see 
Appendix H) 
At enrollment, after 2, 
4, 6, and 8 weeks on 
study and from there 
monthly 
Optional 
Dr. 
Rudloff’s 
lab 
 
9.1 
Sample Storage, Tracking and Disposition 
9.1.1 NCI Site Only 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  
Samples will not be sent outside NIH without IRB notification and an executed MTA.  
All samples initially will be sent to Blood Processing Core (BPC) for processing and storage until 
they are distributed to Dr. Rudloff’s lab sample analysis as described in the protocol.   
9.1.2 Samples Managed by Dr. Figg’s Blood Processing Core (BPC)  
9.1.2.1 BPC contact information  
Please e-mail Julie Barnes at Julie.barnes@nih.gov and Paula Carter pcartera@mail.nih.gov at 
least 24 hours before transporting samples (the Friday before is preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact Julie Barnes by e-mail or at 240-760-6044. 
9.1.2.2 Sample Data Collection 
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in the LABrador (aka LabSamples) utilized by the BPC. This is a secure program, with 
access to LABrador limited to defined Figg lab personnel, who are issued individual user 
accounts. Installation of LABrador is limited to computers specified by Dr. Figg. These 
computers all have a password restricted login screen. All Figg lab personnel with access to 
patient information annually complete the NIH online Protection of Human Subjects course.  
LABrador creates a unique barcode ID for every sample and sample box, which cannot be traced 


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64 
 
back to patients without LABrador access. The data recorded for each sample includes the 
patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, 
as well as box and freezer location. Patient demographics associated with the Clinical Center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.). 
9.1.2.3 Sample Storage  
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80°C 
according to stability requirements.  These freezers are located onsite in the BPC and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are 
required to be accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in LABrador. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval. 
9.1.3 Procedures for Storage of Tissue Specimens in the Laboratory of Pathology 
Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) 
where they are examined grossly and relevant portions are fixed, embedded in paraffin and 
sectioned and stained for diagnostic interpretation.  Unutilized excess tissues are stored for up to 
three months, in accordance with College of American Pathologists/Joint Commission on 
Accreditation of Healthcare Organizations (CAP/JCAHO) guidelines, and then discarded.  
Following completion of the diagnostic workup, the slides and tissue blocks are stored 
indefinitely in the LP’s clinical archives.  All specimens are catalogued and retrieved utilizing 
the clinical laboratory information systems, in accordance with CAP/JCAHO regulations.  The 
use of any stored specimens for research purposes is only allowed for research conducted in 
relation to this protocol. 
9.1.4 Protocol Completion/Sample Destruction 
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described in 
Section above. The study will remain open so long as sample or data analysis continues.  
Samples from consenting subjects will be stored until they are no longer of scientific value or if a 
subject withdraws consent for their continued use, at which time they will be destroyed. The PI 
will report any loss or destruction of samples to the NCI IRB as soon as he is made aware of 
such loss. If the patient withdraws consent the participant’s data will be excluded from future 
distributions, but data that have already been distributed for approved research use will not be 
able to be retrieved. 
The PI will report destroyed samples to the IRB if samples become unsalvageable because of 
environmental factors (ex. broken freezer or lack of dry ice in a shipping container) or if a patient 
withdraws consent. Samples will also be reported as lost if they are lost in transit between 
facilities or misplaced by a researcher.  Freezer problems, lost samples or other problems 
associated with samples will also be reported to the IRB, the NCI Clinical Director, and the 


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office of the CCR, NCI. 
9.1.5 Shipping instructions for Participating sites 
For patients enrolled at Non-NIH sites, the biopsy sample will be sent as a paraffin block 
together with copy of the original pathology report (or molecular pathology report) to  
Santhana Webb 
10 Center Drive, Room 8D44F 
Bethesda, MD 20892-1906 
Phone: 240-858-3165 
Fax: 301-480-2462 
Email:  santhana.webb@nih.gov   
Tissue block and matched pathology report will have matching identification number. 
Fresh blood will be send on dry ice to  
Dr. Yansong Bian 
Hatfield Center 
CRC-1B 34A 
10 CENTER DR 
BETHESDA MD 20814 
Phone: 
301-451-6928 
yansong.bian@nih.gov 
 
Samples may be shipped from site of acquisition to site of analysis in batches.  Shipping must be 
by expedited courier on dry ice. 
Participating sites should send e-mail with information about planning shipment to Cara Kenney 
and Yansong Bian 2 days before actual shipment. 
Each sample should be labeled with a unique identifier linking the biospecimen to the respective 
pathology report. A hard copy should be included into the shipment.  If a tumor block is not 
available, unstained slides may also be submitted.  15 unstained slides are preferable. 
10 STUDY CALENDAR 
Screening evaluations are to be conducted will be obtained within 8 weeks prior to start of 
enrollment. Baseline evaluations are to be conducted within 1 week prior to start of protocol 
therapy.  Scans and x-rays must be done <4 weeks prior to the start of therapy.  In the event that 
the patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours 
prior to initiation of the next cycle of therapy. 
Laboratory evaluation tests may be performed at the NCI or at the local physician. Assays and 
scans may be taken 5 days earlier or later than scheduled depending on individual needs. 
For the evaluation purposes, a cycle will be defined as 28 +/- 2 days (4 weeks). A patient may 
receive up to 27 cycles (108 weeks). 
 
Screeni
ng  
 
Baselineh 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wks 
13-108c 
 
End of 
Treatment 
Evaluationsd 
FUe 
AZD6244 
 
 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
 
 


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66 
 
 
Screeni
ng  
 
Baselineh 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wks 
13-108c 
 
End of 
Treatment 
Evaluationsd 
FUe 
hydrogen sulfate 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of 
diagnosis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
 
X 
X-----------------------------------------------------------------------------------------X 
 
 
Physical exam 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Vital signs 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Performance status 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
CBC w/diff, plts g 
PT, PTT 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Serum chemistry a,g 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
EKG  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
evaluation 
 
X--------------------------------------------------------------------------------------X 
X 
X 
Tumor 
measurements 
 
X 
Tumor measurements performed after 4 weeks and thereafter are repeated every 8 
weeks.  Documentation (radiologic) must be provided for patients removed from study for 
progressive disease. 
X 
 
Radiologic 
evaluation 
 
X 
Radiologic measurements should be performed after 4 weeks and thereafter 
every   8    weeks. 
X 
 
B-HCG 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy for  
KRAS mutation 
status, Cancer gene 
panel and CNKSR1 
by IHC k 
X  
unless 
archived 
or prior 
biopsy 
material 
availabl
e 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Screeni
ng  
 
Baselineh 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wks 
13-108c 
 
End of 
Treatment 
Evaluationsd 
FUe 
Tumor biopsy for  
CNKSR1 by IHC k 
 
 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for 
Circulating Tumor 
DNA (ctDNA)k 
 
Xf 
 
 
Xf 
 
Xf 
 
Xf 
 
Xf 
 
Xf 
 
Xf, i 
 
 
Tumor markers 
CA19-9, CEA, CA 
125 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
Xi 
 
 
Advance Directivej 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A:     AZD6244 hydrogen sulfate:  Dose 75 mg twice a day every day. 
a:     Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, 
SGOT [AST], SGPT [ALT], sodium, amylase, lipase, magnesium, prealbumin  
b:     Serum pregnancy test (women of childbearing potential). 
c:      Assessments will be performed once per cycle. 
d:     Patients will be invited to their study site approximately 30 days following the last dose of study drug. If patents are not able to come or provide lab 
results from home, they will be asked by phone for performance status, any adverse events and new cancer treatment.  
e:     Patients will be followed for 52 weeks with a telephone interview for performance status, any adverse events and new cancer treatment every 2 months. 
f:     Optional  
g:    The laboratory tests can be performed either at the NIH clinic or at home.  
h:    Baseline evaluations do not need to be repeated if they were done on screening during appropriate time frame.  
i: monthly 
j: As  
 
icated in section 13.3, all subjects enrolled in NIH will be offered the opportunity to complete an NIH Advance Directive form.  This should be done 
preferably at baseline but can be done at any time during the study as long as the capacity to do so is retained.  The completion of the form is strongly 
recommended, but is not required. 
k: All research study will be performed at NIH. For shipping instructions, please, see Section 9.1.5. Not necessary for patients with confirmed KRAS 
mutation status 
11 MEASUREMENT OF EFFECT 
11.1 Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be re-evaluated for response after the first 4 
weeks, then every 8 weeks thereafter.  In addition to a baseline scan, confirmatory scans should 
also be obtained 4 weeks following initial documentation of objective response. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
11.1.1 Definitions 


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Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with AZD6244. 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
11.1.2 Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) by chest x-ray or as 
≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.   
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in follow-up, 
only the short axis will be measured and followed. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 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 as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 


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and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
11.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using 
calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT scans have slice 
thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice 
the slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.   
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 


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guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered a complete 
biochemical response.  Specific guidelines for both CA-125 response (in recurrent ovarian 
cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 
2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000]. 
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 


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Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
11.1.4 Response Criteria 
11.1.4.1 Evaluation of Target Lesions 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm (<1 cm). 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm).  
(Note:  the appearance of one or more new lesions is also considered progressions). 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
11.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
[<1 cm] short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
11.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 


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For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 


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11.1.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
11.1.6 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
12 STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements). 
12.1 Study Oversight 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug.  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal. 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
The Study Chair and PIs at all ETCTN Sites will review all obtained data every 6 months.  
“The following decision rule to halt the study if – at any of the sites – will be applied at time of 
review: 
1) >= 1 death related to adverse event (not related to progression of disease) 
2) >= 3 non-hematological grade 3 or 4 toxicities based on NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 within first stage 
of study. 


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12.2 Data Reporting 
Data collection for this study will be done through Medidata Rave.  Access to the trial in Rave is 
granted through the iMedidata application to all persons with the appropriate roles assigned in the 
Regulatory Support System (RSS).  To access Rave via iMedidata, the site user must have an 
active CTEP IAM account (check at https://ctepcore.nci.nih.gov/iam) and the appropriate Rave 
role (Rave CRA, Read-Only, CRA, Lab Admin, SLA, or Site Investigator) on either the LPO or 
participating organization roster at the enrolling site. To the hold Rave CRA role or CRA Lab 
Admin role, the user must hold a minimum of an AP registration type.  To hold the Rave Site 
Investigator role, the individual must be registered as an NPIVR or IVR.  Associates can hold read-
only roles in Rave..   
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) using 
their CTEP-IAM user name and password, and click on the “accept” link in the upper right-corner 
of the iMedidata page.  Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed.  Trainings will be in the form of 
electronic learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane 
of the iMedidata screen.   
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website, Rave tab 
under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail 
at ctsucontact@westat.com. 
12.2.1 Method 
For studies assigned for CTMS Routine Monitoring: 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at:  
http://theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted on an 18-36 month basis as part of routine cancer center site 
visits. More frequent audits may be conducted if warranted by accrual or due to concerns 
regarding data quality or timely submission.  For CTMS monitored studies, after users 
have activated their accounts, please contact the Theradex Help Desk at (609) 799-7580 
or by email at CTMSSupport@theradex.com for additional support with Rave and 
completion of CRFs. 
12.2.2 Responsibility for Data Submission 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 


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than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and 
assessed on a quarterly basis.  For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
)  and CTSU websites. 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the 
recommended phase 2 dose (RP2D), and a description of any dose-limiting toxicities 
(DLTs).  CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry 
and Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will 
be included when appropriate to meet unique study requirements.  The PI is encouraged 
to review the eCRFs, working closely with CTMS to ensure prospectively that all 
required items are appropriately captured in the eCRFs prior to study activation.  CTMS 
will prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity. 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex 
on a monthly basis.  The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above. 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
). 
 
12.2.3 NCI Data Sharing Plans 
Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows: 
_X__ De-identified data in an NIH-funded or approved public repository.   
_X__ Identified data in BTRIS  
_X__ De-identified or identified data with approved outside collaborators under appropriate 


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agreements. 
 
How and where will the data be shared?  
Data will be shared through: 
_X__ An NIH-funded or approved public repository.  Insert name or 
names:______clinicaltrials.gov___________. 
_X__ BTRIS (automatic for activities in the Clinical Center) 
_X__ Approved outside collaborators under appropriate individual agreements. 
_X__ Publication and/or public presentations (de-identified or in accordance with Journal’s and 
institutional policy) 
 
When will the data be shared? 
_X__ Before publication. 
_X__ At the time of publication or shortly thereafter. 
 
12.3 Collaborative Agreements Language 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 


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restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
Email:  ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
12.4 Genomic Data Sharing Plan 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 


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13 HUMAN SUBJECTS PROTECTIONS  
13.1 Rationale For Subject Selection 
The patients to be entered in this protocol have advanced pancreatic cancer, either locally 
advanced unresectable pancreatic cancer or stage IV disease with metastatic disease 
dissemination, and hence have limited life expectancies. 
Subjects from both genders and all racial/ethnic groups are eligible for this study if they meet the 
eligibility criteria.  To date, there is no information that suggests that differences in drug 
metabolism or disease response would be expected in one group compared to another.  Efforts 
will be made to extend accrual to a representative population, but in this preliminary study, a 
balance must be struck between patient safety considerations and limitations on the number of 
individuals exposed to potentially toxic and/or ineffective treatments on the one hand and the 
need to explore gender and ethnic aspects of clinical research on the other hand.  If differences in 
outcome that correlate to gender or to ethnic identity are noted, accrual may be expanded or a 
follow-up study may be written to investigate those differences more fully. 
13.2 Participation of Children 
Because no dosing or adverse event data are currently available on the use of AZD6244 in patients 
<18 years of age, children are excluded from this study, but will be eligible for future pediatric 
trials. 
13.3 Participation of Subjects Unable to Give Consent (NCI Site Only) 
Adults unable to give consent are excluded from enrolling in the protocol.  However re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 13.4), all subjects ≥ age 18 will be offered the opportunity to fill 
in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team for evaluation.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who 
are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed. 
13.4 Evaluation of Benefits and Risks/Discomforts 
Potential benefits to subjects expected from the trial: As a result of participating in this trial, 
patients will receive evaluation and treatment of their tumor.  This protocol may or may not be 
helpful for a specific patient, but the results may help the investigators learn about the 
administration of AZD6244 on a continuing basis.  The potential for this research treatment to 
offer control of the disease is unknown; however, based on information to date, the possibility of 
an effect on the progression of disease exists.  Benefit cannot be promised nor can the chance of 
benefit be accurately predicted. 
Potential risks of selumetinib include the range of side effects outlined in Section 8.1.1. 


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13.4.1 Alternative Approaches or Treatments 
Patients will be advised verbally and in writing regarding the risks and benefits of this trial, 
treatment requirements, and alternative approaches to entering the trial. Written consents will be 
obtained. 
13.4.2 Procedures to Eliminate or Minimize Potential Risks 
This study may involve unforeseeable risks for patients, such as side effects whose exact nature 
and severity are unpredictable. Scrupulous care will be taken to minimize such side effects. All 
patients will be given blood tests, physical examinations, and scans, as described in the 
monitoring schedule, and must have a local physician to provide long-term care and monitoring 
for complications. Immediate medical treatment is available at the enrollment site for any 
patients who suffer physical injury as a result of participation in this study. No compensation is 
available, but any injury will be evaluated and treated in keeping with the benefits or care to 
which patients are entitled under applicable regulations. 
13.4.3 Provisions for Monitoring Data Collection to Ensure Subject Safety  
As information is gathered from this trial, clinical results will be shared with patients.  
Laboratory and clinical data will be frequently gathered and any new significant finding(s) found 
during the course of the research, which may affect a patient’s willingness to participate further, 
will be explained. 
Confidentiality of information concerning participants will be maintained, including in all 
publications and presentations resulting from this study.  Names of participants or material 
identifying participants will not be released without permission, except as such release is 
required by law.  Records at the National Cancer Institute are maintained according to current 
legal requirements, and are made available for review, as required by the Food and Drug 
Administration or other authorized users, only under the guidelines established by the Federal 
Privacy Act. 
13.4.4 Biopsies 
All care will be taken to minimize risks that may be incurred by tumor sampling. However, there 
are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained 
fully during informed consent. If patients suffer any physical injury as a result of the biopsies, 
immediate medical treatment is available at the enrollment site.  Although no compensation is 
available, any injury will be fully evaluated and treated in keeping with the benefits or care to 
which patients are entitled under applicable regulations. 
13.4.5 Radiation risks 
The optional biopsy collected at 2 weeks is for research purposes only and will be done under 
CT guidance. Subjects undergoing optional biopsy collection will be exposed to 0.80 rem.  This 
amount of radiation is below the guideline of 5 rem per year allowed for adult research subjects 
by the NIH Radiation Safety Committee. 
13.4.6 Non-Physical Risks of Genetic Research 
13.4.6.1 Risk of receiving unwanted information 
Anxiety and stress may arise as a result of the anticipation that unwanted information regarding 
disease related DNA sequencing or disease tendencies, or misattributed paternity. Patients will 


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be clearly informed that the data related to DNA sequencing and genetic analysis is coded, 
investigational and will not be shared with patients, family members or health care providers. 
13.4.6.2 Risk related to possibility that information may be released 
This includes the risk that data related to genotype, DNA sequencing or risk for disease tendency 
or trait can be released to members of the public, insurers, employers, or law enforcement 
agencies. Although there are no plans to release results to the patients, family members or health 
care providers, this risk will be included in the informed consent document. 
13.4.6.3 Risk to family or relatives 
Family members or relatives may or may not want to be aware of familial tendencies or genetic 
risks of disease which may cause anxiety about possible future health problems.  
13.5 Risks/Benefits Analysis 
Considering that the drug has been administered to thousands of patients already and has been 
found safe, the preclinical efficacy data including patient-derived xenotransplanation models and 
considering that pancreatic cancer is a rapidly fatal disease with few effective treatment option, a 
gross risk/benefit analysis appears to be in overwhelming favor for potential benefit. 
13.6 Consent Process and Documentation 
The investigational nature and objectives of this trial, the procedures and treatments involved and 
their attendant risks and discomforts, potential benefits and potential alternative therapies will be 
carefully explained to the patient or the patient’s surrogate, and a signed informed consent 
document will be obtained by the PI, AI or clinical staff fellow.  Moreover, any experimental 
invasive procedure will require a separate consent form. 
13.6.1 Telephone Reconsent Procedure (NCI Site Only) 
The informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent. A witness to the subject’s signature will 
sign and date the consent. 
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.   
A fully executed copy will be returned via mail for the subject’s records. 
The informed consent process will be documented on a progress note by the consenting 
investigator and a copy of the informed consent document and note will be kept in the subject’s 
research record. 
14 STATISTICAL CONSIDERATIONS 
14.1 Study Design/Endpoints 
This is a phase 2 trial in patients with measurable locally advanced or stage IV pancreas cancer 
patients harboring KRAS G12R mutations are treated with the tyrosine kinase inhibitor 
selumetinib (AZD6244).  All patients eligible for treatment will undergo formal response 
evaluation after 1 and 3 cycles of therapy and every 2 cycles after that. 


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14.1.1 Screening 
The prevalence of advanced pancreas cancer patients harboring KRAS G12R mutations is 15%. 
Using an outside organization, Foundation Medicine, potential participants for this trial may be 
pre-screened for the presence of the KRAS G12R mutation prior to enrolling on this trial. As a 
result, it is expected that greater than 50% of subjects who are pre-screened and then enrolled onto 
this trial for further evaluation will be able to be treated on this trial. If this were to apply to the 
screening population and if 155 patients were screened, there is a 73% probability of identifying 
at least 21 patients with a KRAS G12R mutation. The primary objective of this trial is to determine 
if selumetinib monotherapy is able to produce adequate numbers of clinical responses in patients 
with locally advanced or stage IV metastatic pancreas cancer with KRAS G12R mutations. If so, 
this regimen will be considered for use in subsequent studies, to determine its role in this disease. 
Evaluable patients are patients whose response to a treatment can be measured because enough 
information has been collected (e.g. patients who come off study due to progression of disease, 
either by RECIST or clinically, due to toxicity, or patient’s withdrawal). Inevaluable patients are 
patients who are lacking this information. 
14.1.2 Treatment 
The primary objective of this trial is to determine if selumetinib monotherapy is able to produce 
adequate numbers of clinical responses in patients with locally advanced or stage IV metastatic 
pancreas cancer with KRAS G12R mutations.  If so, this regimen will be considered for use in 
subsequent studies, to determine its role in this disease. 
The study will be conducted using a phase 2 optimal design.  The objective of the trial will be to 
determine whether this novel agent is able to be associated with a response rate (PR + CR) that 
can rule out 5% (p0=0.05) in favor of an improved response rate of 30% (p1=0.30). Using 
alpha=0.10 (probability of accepting a poor agent) and beta=0.10 (probability of rejecting a good 
agent), initially 7 evaluable patients will be enrolled in the study. If after accrual of patient #7 no 
patient has responded, accrual will be halted until patient #7 becomes evaluable. If 0 of 7 patients 
respond, then no further patients will be enrolled.  If 1 or more of the first 7 evaluable patients 
enrolled have a clinical response, then accrual will continue until a total of 21 evaluable patients 
have been enrolled. If 1 to 2 of the 21 has a clinical response, then this will be considered 
inadequate for further investigation of this regimen. If 3 or more of 21 respond, then this will 
warrant further investigation in a subsequent trial.  Under the null hypothesis (5% response rate), 
the probability of early termination is 70%.   
14.2 Sample Size/Accrual Rate 
The accrual ceiling will be set at 60 patients to be screened for the presence of KRAS G12R 
mutations to allow for treatment of up to 25 patients, which would include up to 3 inevaluable 
patients.  It is expected that 1-2 patients per month will be treated on this trial.  Allowing for 
treatment with this agent over a two year period with follow up, it is expected that the trial will be 
completed in approximately 3 years. 
14.3 Analysis of Secondary Endpoints 
Progression-free survival will be calculated using the Kaplan-Meier method. 
Toxicity data will be obtained and presented by type and grade of toxicity. Toxicities may be 
informally compared within patient subsets to estimate the toxicity rate in those subsets. 


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The association of response to selumetinib (PR as defined by RECIST) and presence of 
concomitant activating oncogene mutations or loss of tumor suppressor function will be presented 
descriptively to estimate the response rates according to those characteristics. 
Comparisons between the semi-quantitative measurements of CNKSR1 will be made descriptively 
to estimate the differences of the expression level in pancreas cancer tissues and clinical outcome 
variables. Similarly, ctDNA levels, and alterations in somatic variants between baseline and repeat 
profiling (integrated biomarker; voluntary) will be evaluated for change from baseline levels and 
the estimated changes will be reported.  
A variety of other secondary evaluations will be performed. In all cases, the evaluations will be 
done with exploratory intent, and results will be presented descriptively. 
Priority #1 – predictive biomarkers for response to selumetinib in KRAS G12R pancreas cancer 
patients: 
1. Pre-treatment variant profile and response. Presence of variants identified in the 50-cancer 
gene panel will be compared with response, presenting the results in a 2x2 table with findings 
reported descriptively. 
2. Pre-treatment ctDNA levels will be divided into groups to separate aberrant values from the 
rest. The cutoffs will be > and <2 standard deviations of the mean, with the cutoffs applied to both 
ctDNA levels. Based on these groups, resulting in patients with cfDNA transcripts levels >2 SD 
above the mean, patients with cfDNA transcripts levels <2SD below the mean, and the rest in 
between, the categorical results will be evaluated and reported relative to response vs. non-
response in a descriptive manner. 
3. Pre-treatment CNKSR1 staining (scored semi-quantitatively as 0, 1+, 2+, and 3+, per number 
of treated patients) vs. response or not will be reported in a table. 
Priority #2 – longitudinal biomarker measuring response to treatment 
1. cfDNA transcript levels will be followed from the start of treatment q2 weeks and the change 
to pre-treatment will be plotted for each timepoint in a spider plot format. This will be a descriptive 
presentation only. 
2. Variant profile derived from voluntary repeat biopsies will be compared to pre-treatment 
variant profile and gain of variants (adjusted for similar sequencing depth) will be recorded. This 
will be a descriptive presentation only. 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 


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Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
Asian 
4 
3 
0 
0 
7 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
4 
3 
0 
0 
7 
White 
20 
14 
4 
3 
41 
More Than One Race 
0 
0 
3 
2 
5 
Total 
28 
20 
7 
5 
60 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 
14.4 Reporting and Exclusions 
14.4.1 Evaluation of Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with AZD6244. 
14.4.2 Evaluation of Response 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned one of 
the following categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data).  [Note:  By 
arbitrary convention, category 9 usually designates the “unknown” status of any type of data in a 
clinical database.] 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate.  
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate.  Precise definitions for categories 4-9 will be 
protocol specific.  
All conclusions should be based on all eligible patients.  Sub analyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.).  However, these sub analyses may not serve as the basis for drawing 


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conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported.  The 95% confidence intervals should also be provided.  
 
 


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15 REFERENCES 
 
1. 
Rahib, L., et al., Projecting cancer incidence and deaths to 2030: the unexpected burden 
of thyroid, liver, and pancreas cancers in the United States. Cancer Res, 2014. 74(11): p. 
2913-21. 
2. 
http://www.cancer.gov/researchandfunding/reports/pancreatic-action-plan.pdf., 2012. 
3. 
Moore, M.J., et al., Erlotinib plus gemcitabine compared with gemcitabine alone in 
patients with advanced pancreatic cancer: a phase III trial of the National Cancer 
Institute of Canada Clinical Trials Group. J Clin Oncol, 2007. 25(15): p. 1960-6. 
4. 
da Cunha Santos, G., et al., Molecular predictors of outcome in a phase 3 study of 
gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National 
Cancer Institute of Canada Clinical Trials Group Study PA.3. Cancer, 2010. 116(24): p. 
5599-607. 
5. 
Moinpour, C.M., et al., Pain and emotional well-being outcomes in Southwest Oncology 
Group-directed intergroup trial S0205: a phase III study comparing gemcitabine plus 
cetuximab versus gemcitabine as first-line therapy in patients with advanced pancreas 
cancer. J Clin Oncol, 2010. 28(22): p. 3611-6. 
6. 
Waddell, N., et al., Whole genomes redefine the mutational landscape of pancreatic 
cancer. Nature, 2015. 518(7540): p. 495-501. 
7. 
Provenzano, P.P., et al., Enzymatic targeting of the stroma ablates physical barriers to 
treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 21(3): p. 418-29. 
8. 
Chantrill, L.A., et al., Precision Medicine for Advanced Pancreas Cancer: The 
Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) Trial. Clin Cancer Res, 
2015. 21(9): p. 2029-37. 
9. 
Connor, A.A., et al., Association of Distinct Mutational Signatures With Correlates of 
Increased Immune Activity in Pancreatic Ductal Adenocarcinoma. JAMA Oncol, 2016. 
10. 
Bailey, P., et al., Genomic analyses identify molecular subtypes of pancreatic cancer. 
Nature, 2016. 531(7592): p. 47-52. 
11. 
Witkiewicz, A.K., et al., Whole-exome sequencing of pancreatic cancer defines genetic 
diversity and therapeutic targets. Nat Commun, 2015. 6: p. 6744. 
12. 
Singh, A., et al., A gene expression signature associated with "K-Ras addiction" reveals 
regulators of EMT and tumor cell survival. Cancer Cell, 2009. 15(6): p. 489-500. 
13. 
Collisson, E.A., et al., Subtypes of pancreatic ductal adenocarcinoma and their differing 
responses to therapy. Nat Med, 2011. 17(4): p. 500-3. 
14. 
Cox, A.D., et al., Drugging the undruggable RAS: Mission possible? Nat Rev Drug 
Discov, 2014. 13(11): p. 828-51. 
15. 
Ogura, T., et al., Prognostic value of K-ras mutation status and subtypes in endoscopic 
ultrasound-guided fine-needle aspiration specimens from patients with unresectable 
pancreatic cancer. J Gastroenterol, 2013. 48(5): p. 640-6. 
16. 
Barretina, J., et al., The Cancer Cell Line Encyclopedia enables predictive modelling of 
anticancer drug sensitivity. Nature, 2012. 483(7391): p. 603-7. 
17. 
Hamidi, H., et al., KRAS mutational subtype and copy number predict in vitro response of 
human pancreatic cancer cell lines to MEK inhibition. Br J Cancer, 2014. 111(9): p. 
1788-801. 
18. 
Hammond, D.E., et al., Differential reprogramming of isogenic colorectal cancer cells by 


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distinct activating KRAS mutations. J Proteome Res, 2015. 14(3): p. 1535-46. 
19. 
Troiani, T., et al., Primary and acquired resistance of colorectal cancer cells to anti-
EGFR antibodies converge on MEK/ERK pathway activation and can be overcome by 
combined MEK/EGFR inhibition. Clin Cancer Res, 2014. 20(14): p. 3775-86. 
20. 
Kapoor, A., et al., Yap1 activation enables bypass of oncogenic Kras addiction in 
pancreatic cancer. Cell, 2014. 158(1): p. 185-97. 
21. 
Azzolin, L., et al., YAP/TAZ incorporation in the beta-catenin destruction complex 
orchestrates the Wnt response. Cell, 2014. 158(1): p. 157-70. 
22. 
Bodoky, G., et al., A phase II open-label randomized study to assess the efficacy and 
safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with 
advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. 
Invest New Drugs, 2012. 30(3): p. 1216-23. 
23. 
Janne, P.A., et al., Impact of KRAS codon subtypes from a randomised phase II trial of 
selumetinib plus docetaxel in KRAS mutant advanced non-small-cell lung cancer. Br J 
Cancer, 2015. 113(2): p. 199-203. 
24. 
Friday, B.B. and A.A. Adjei, Advances in targeting the Ras/Raf/MEK/Erk mitogen-
activated protein kinase cascade with MEK inhibitors for cancer therapy. Clin Cancer 
Res, 2008. 14(2): p. 342-6. 
25. 
O'Neill, E. and W. Kolch, Conferring specificity on the ubiquitous Raf/MEK signalling 
pathway. Br J Cancer, 2004. 90(2): p. 283-8. 
26. 
Wellbrock, C., M. Karasarides, and R. Marais, The RAF proteins take centre stage. Nat 
Rev Mol Cell Biol, 2004. 5(11): p. 875-85. 
27. 
Khokhlatchev, A.V., et al., Phosphorylation of the MAP kinase ERK2 promotes its 
homodimerization and nuclear translocation. Cell, 1998. 93(4): p. 605-15. 
28. 
Hoshino, R., et al., Constitutive activation of the 41-/43-kDa mitogen-activated protein 
kinase signaling pathway in human tumors. Oncogene, 1999. 18(3): p. 813-22. 
29. 
Breitkreutz, I., et al., Targeting MEK1/2 blocks osteoclast differentiation, function and 
cytokine secretion in multiple myeloma. Br J Haematol, 2007. 139(1): p. 55-63. 
30. 
Davies, B.R., et al., AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated 
protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of 
action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for 
combination in preclinical models. Mol Cancer Ther, 2007. 6(8): p. 2209-19. 
31. 
Huynh, H., et al., Targeted inhibition of the extracellular signal-regulated kinase kinase 
pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma. 
Mol Cancer Ther, 2007. 6(1): p. 138-46. 
32. 
Tai, Y.T., et al., Targeting MEK induces myeloma-cell cytotoxicity and inhibits 
osteoclastogenesis. Blood, 2007. 110(5): p. 1656-63. 
33. 
Ball, D.W., et al., Selective growth inhibition in BRAF mutant thyroid cancer by the 
mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244. J Clin Endocrinol Metab, 
2007. 92(12): p. 4712-8. 
34. 
Janne, P.A., et al., Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell 
lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet 
Oncol, 2013. 14(1): p. 38-47. 
35. 
Robert, C., et al., Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-
line treatment for BRAF-mutant metastatic melanoma: a phase 2 double-blind 
randomised study. Lancet Oncol, 2013. 14(8): p. 733-40. 


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36. 
Carvajal, R.D., et al., Effect of selumetinib vs chemotherapy on progression-free survival 
in uveal melanoma: a randomized clinical trial. JAMA, 2014. 311(23): p. 2397-405. 
37. 
This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can 
be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the 
investigator, the protocol and the agent should be included in the e-mail. 
38. 
Febrile neutropenia/neutropenic infection has been observed primarily in trials 
combining AZD6244 (selumetinib) and docetaxel. 
39. 
SBE-CD (Captisol®, vehicle) in the mix and drink formulation is known to cause soft 
stools and/or diarrhea in rats and dogs; however, it is possible that some of these 
findings might be related to exacerbation of the vehicle effect by AZD6244 (selumetinib). 
 
 
 
 
 


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16 APPENDICES 
16.1 Appendix A: Performance Status Criteria 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


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16.2 Appendix B: New York Heart Association Classifications 
Clinical Evaluation of Functional Capacity of Patients 
with Heart Disease in Relation to Ordinary Physical Activity 
 
 
 
Class 
 
 
Cardiac Symptoms 
 
 
Limitations 
 
Need for Additional 
Rest* 
 
Physical Ability  
      to work**__ 
 
 
 
 
 
I 
None 
None 
None 
Full time 
 
 
 
 
 
II 
Only moderate 
Slight 
Usually only slight 
or occasional 
Usually full  
time 
 
 
 
 
 
III 
Defined, with  
less than  
ordinary activity 
Marked 
Usually moderate 
Usually part  
time 
 
 
 
 
 
IV 
May be present  
even at rest,  
and any activity increases 
discomfort 
Extreme 
Marked 
Unable to work 
* To control or relieve symptoms, as determined by the patient, rather than as advised by the physician. 
** 
At accustomed occupation or usual tasks. 
 
Reference: Bruce, R. A.: Mod. Concepts Cardiovasc. Dis. 25:321, 1956.  (Modified from New York Heart 
Association, 1953). 
 
 


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16.3 Appendix C: Patient Drug Information Handout and Wallet Card  
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, selumetinib (AZD6244 hydrogen sulfate).  This clinical trial is 
sponsored by the National Cancer Institute (NCI).  This form is addressed to the patient, but 
includes important information for others who care for this patient.  
 
These are the things that you as a prescriber need to know: 
  
Selumetinib (AZD6244 hydrogen sulfate) interacts with certain specific enzymes in the liver and 
certain transport proteins that help move drugs in and out of cells. 
 
• The enzymes in question are CYP 1A2, 2C8, 2C9, 2C19, 3A4/5 and UGT 1A1 and 1A3. 
Selumetinib (AZD6244 hydrogen sulfate) is metabolized by these enzymes and may be 
affected by other drugs that inhibit or induce these enzymes.  
• The proteins in question are P-gp and BCRP. Selumetinib (AZD6244 hydrogen sulfate) is a 
substrate of BCRP and P-gp transporters and may be affected by other drugs that inhibit 
or induce these transporters.  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 March 2016 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
Selumetinib (AZD6244 hydrogen sulfate) interacts with many drugs which can cause side 
effects. Because of this, it is very important to tell your study doctors about all of your medicines 
before you enroll on this clinical trial.  It is also very important to tell them if you stop taking any 
regular medicines, or if you start taking a new medicine while you take part in this study.  When 
you talk about your medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort. It is 
helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care prescribers can write prescriptions.  You must also tell your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  
 


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These are the things that you and they need to know: 
 
Selumetinib (AZD6244 hydrogen sulfate) must be used very carefully with other medicines that 
need certain liver enzymes and transport proteins to be effective or to be cleared from your 
system.  Before you enroll onto the clinical trial, your study doctor will work with your regular 
health care providers to review any medicines and herbal supplements that are considered 
“strong inducers/inhibitors of CYP 1A2, 2C8, 2C9, 2C19, 3A/5, UGT 1A1 and 1A3, P-gp and 
BCRP.” 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctor or 
pharmacist to determine if there could be any side effects.  
• Avoid taking extra vitamin E found in vitamins or supplements.  
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  Your study doctor’s name is  
__________________________________________                and he or she can be contacted at  
 
_____________________________________. 
 
 
  
                   March 
2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD 
You are enrolled on a clinical trial using the experimental drug 
selumetinib (AZD6244 hydrogen sulfate).  This clinical trial is 
sponsored by the NCI.  AZD6244 hydrogen sulfate (selumetinib) 
interacts with drugs that are processed by your liver, or use certain 
transport proteins in your body.  Because of this, it is very important 
to: 
 Tell your doctors if you stop taking regular medicines or if you start 
taking any new medicines. 
 Tell all of your health care providers (doctors, physician assistant, 
nurse practitioners, pharmacists) that you are taking part in a clinical 
trial. 
 Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
 
 
 
 Selumetinib (AZD6244 hydrogen sulfate) interacts with CYP 1A2, 
2C8, 2C9, 2C19, 3A4/5, UGT 1A1 and 1A3, P-gp, and BCRP, and 
must be used very carefully with other medicines that interact with 
these enzymes and proteins.  
 Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines that are considered “strong inducers/inhibitors of CYP 
1A2, 2C8, 2C9, 2C19, 3A4/5, UGT 1A1 and 1A3, P-gp and 
BCRP.” 
 You should avoid taking extra vitamin E found in vitamins or 
supplements. 
 Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for a 
list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
92 
 
16.4 Appendix D: Patient’s Pill Diary 
 
PATIENT PILL DIARY 
 
Today’s date ____________________________________Agent __AZD6244_hydrogen sulfate (selumetinib)__ 
 Patient Name_________________________ (initials acceptable)  
 Patient Study ID ___________________ 
1. Complete one form for each cycle of treatment. 
2.  AZD6244 capsules should be stored at room temperature.  Keep away from heat sources. 
3. You will take AZD6244 twice each day about 12 hours apart.  Take the medicine on an empty stomach (no 
food or drink other than water for 2 hours before and 1 hour after dosing).    
 
Morning dose:  take _____ mg  (____capsules) AZD6244. *********** Evening dose:   take _____ mg 
(____capsules)  AZD6244. 
4. Record the date, the number of AZD6244 capsules you swallowed in the morning and again in the evening, 
and when you swallowed the medicine.   
5. If you have any comments or notice any side effects, please record them in the Comments column 
6. If you missed your dose or vomited one dose continue selumetinib AZD6244 as per schedule, don’t take 
additional doses to make-up for missed dose. In case you missed multiple doses, please contact your doctor. 
6.  Discuss with your doctor all other medications you are currently taking, including herbal medicines, as some 
of these medicines may also interact with selumetinib in a harmful way. 
7. Do not take supplemental vitamin E. 
8. Please bring this form and your bottles of AZD6244 when you return for each appointment.   
 
Day 
 
Date 
Time of 
morning 
dose 
Dose taken 
Time of 
evening 
dose 
Dose taken 
Comments 
# of capsule 
taken 
# of capsule 
taken 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
CTEP-assigned Protocol #___________ 
 


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
93 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
Patient’s signature  ___________________________________ 
Physician’s Office will complete this section: 
1. Date patient started protocol treatment_______________________________________________________ 
2. Date patient was removed from study________________________________________________________ 
3. Patient’s planned total daily dose___________________________________________________________ 
4. Total number of capsules taken this month ___________________________________________________ 
5. Physician/Nurse/Data Manager’s Signature __________________________________________________ 
 
 
 


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
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16.5 Appendix E: Patient handout addressing aggressive management for diarrhea  
 
If you have more than 3 liquid stools – 
• Stop all lactose-containing products, alcohol, and high osmolar supplements such as line 
Ensure, Ensure Plus, Boost, or energy milk shakes 
• Drink 8-10 large glasses of clear liquids per day (e.g., Gatorade, broth) 
• Eat frequent small meals (bananas, rice, applesauce, toast, plain pasta – BRAT diet) 
• Record number of stools and report symptoms like lightheadedness, dizziness, nausea, 
fever 
• Start loperamide; initial dose 4 mg, followed by 2 mg q 4 h or after very unformed stool 
and contact your doctor 
• Re-assess in the next 12 – 24 h 
 
If symptoms improving:  
• Continue instructions for dietary modification 
• Gradually add solid foods to diet 
• Discontinue loperamide after 12 h diarrhea-free interval 
 
If symptoms are not improving: 
• Go to Emergency Room in the nearest hospital 
 
 


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
95 
 
 
16.6 Appendix F: Safety Management Algorithm: LVEF Reduction 
 
 
 
AstraZeneca Guidance for AZD6244 studies (March 2015) 
 
 


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
96 
 
16.7 Appendix G: Safety Management Algorithm for Dyspnea 
 
 
AstraZeneca Guidance for AZD6244 studies (March 2015) 
 
 
New AE of  dyspnoea*  or  
worsening of pre - existing  
dyspnoea*  > 1 CTC Grade 
The following should be considered based on clinical  
examination: 
Chest X - ray, PA and lateral view. Consider Echo, ECG, BNP,  
Troponin, sputum, blood, urine culture (bacterial antigens and  
PCR), WBC,  Hb and urea 
If test results indicate diagnosis other  
than ILD/ pneumonitis treat according to  
local practices 
Consider  study drug
† dose interruption  
and/or discontinuation if AE considered  
related to  study drug
† by investigator  
Treatment ineffective 
No obvious underlying cause of  
dyspnoea or suspected ILD 
Perform HRCT scan 
Consider respiratory  
consultation 
HRCT  does not  show  
interstitial lung  
disease/ pneumonitis 
Dyspnoea AE  
resolved 
Continue  study drug
† 
Dyspnoea AE not  
resolved 
Seek cardiology and/or  
respiratory consult if not  
already performed.  
Consider  study drug
† dose  
interruption/reduction 
ILD/ pneumonitis 
diagnosed by HRCT 
Consider  study drug
† 
dose interruption and/or  
discontinuation if AE is 
considered as related to 
study drug  by 
investigator 
Treat according to local  
practices 
BNP: Brain Natriuretic 
P
tid
CTC: National Cancer Institute common toxicology 
it
i
Echo: Echocardiography 
Hb: Haemoglobin 
HRCT: High resolution computerised 
t
h
 
ILD: Interstitial Lung 
Di
PA: posteroanterior  
PCR: Polymerase chain 
ti
WBC: White blood cells 
Version: Final 3.0   23-Jul-2013 
Guidance for management 
of patients with  
dyspnoea*
† Includes selumetinib/placebo 
or combination treatment, 
as appropriate
* Not considered related to 
disease under study 


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
97 
 
16.8 Appendix H Plasma preparation for cell free (cf) DNA extraction using EDTA 
collection tubes.  
 
10/15/2016 
1. Collect up to 5 ml Peripheral Blood in standard EDTA (purple top) collection tube.  
Record time of blood draw on tube. 
 
2.  Bring to lab stat for processing* 
 
3. Centrifuge at 1500 x g for 10 minutes to remove blood cells at 4°C. 
 
4. Transfer supernatant to new nuclease free conical tube carefully taking care not to disturb 
buffy coat** 
 
5. Centrifuge a second time at 10,000 x g at 4°C to remove any remaining cells and 
debris.** 
 
6. Carefully transfer supernatant without disturbing the pellet into nuclease free cryotubes 
(2 ml size) and store at -80°C until DNA extraction. 
 
 
*processing should occur within 2 hours at room temperature of blood draw or stored at 4°C for 
up to 24 hours to prevent lysing of blood cells 
 
**It is extremely important, not to disturb the buffy coat after the first spin, and any pellet after 
the second spin. 
 
Note: this procedure is adapted from published sources and procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 


Abbreviated Title: Ph II AZD6244 pancreatic ca 
NCI Protocol #: 10050 
Version Date: May 19, 2018  
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16.9 Appendix I: Cancer Gene Mutation‐Standard Panel 
 
 
Molecular Diagnostics Section, Laboratory of 
Pathology, Center for Cancer Research, National 
Cancer Institute, National Institutes of Health 
Bldg 10 / Room 3S249, (301) 480‐8080 
 
Molecular Diagnostics Section Test Directory 
 
 
 
Test Name 
Assay Description 
Assay 
Type 
Specime
n Type 
Accepte
d
Category/Use 
Cancer Gene 
Mutation‐Standard 
Panel (a multiplex 
50 gene panel with 
next‐generation 
sequencing) 
Ion Torrent Cancer Hotspot Panel 
(CHP2). Targets ~2850 COSMIC 
hotspot mutations in 50 cancer 
genes (ABL1, AKT1, ALK, APC, 
ATM, BRAF, CDH1, CDKN2A, 
CSF1R, CTNNB1, EGFR, ERBB2, 
ERBB4, EZH2, FBXW7, FGFR1, 
FGFR2, FGFR3, FLT3, GNA11, 
GNAQ, GNAS, HNF1A, HRAS, 
IDH1, IDH2, JAK2, JAK3, KDR, 
KIT, KRAS, MET, MLH1, MPL, 
NOTCH1, NPM1, 
NRAS, PDGFRA, PIK3CA, PTEN, 
PTPN11, RB1, RET, SMAD4, 
SMARCB1, SMO, SRC, STK11, TP53,
VHL) 
 
Qual. 
FFPE Tissue 
NSCLC, Colorectal 
Cancer, Bladder 
Cancer, Melanoma, 
other / Oncology 
Clinical Research 
Protocol 
 
 
 

ICF_001.pdf: 
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Page 1 of 13 
 
Study Title for Study Participants:  
Testing selumetinib in advanced and recurrent pancreatic cancer with KRAS G12R genetic 
change. 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov:  
A Phase II Study of Selumetinib (AZD6244) for the Treatment of Advanced Pancreas Cancer 
harboring KRAS G12R Mutations. IND: 77782  
What is the usual approach to my pancreatic cancer? 
You are being asked to take part in this study because you have advanced pancreatic cancer which 
has grown or has recurred. People who are not in a study are usually treated with either surgery, 
radiation, or with drugs. Sometimes, combinations of these are used and your doctor can explain 
which may be best for you. These treatments can reduce symptoms and may stop the tumor from 
growing for several months or more. Sometimes your doctor may recommend comfort care only 
(no further treatment) to help relieve your symptoms. 
What are my other choices if I do not take part in this study? 
If you decide not to take part in this study, you have other choices. For example: 
• you may choose to have the usual approach described above 
• you may choose to take part in a different study, if one is available 
• or you may choose not to be treated for cancer but you may want to receive comfort 
care to relieve symptoms. 
Why is this study being done? 
The purpose of this study is to test any good and bad effects of the study drug called selumetinib 
(AZD6244). Selumetinib could shrink your cancer but it could also cause side effects.. Researchers 
hope to learn if the study drug will shrink the cancer by at least 30 %. Selumetinib has not been 
approved by the U.S. Food and Drug Administration (FDA) in the treatment of any cancer. It has 
not been tested in pancreatic cancer, but has shrunk tumors in patients with lung tumor, thyroid 
cancers, or in patients with a certain eye tumors.  
Up to 60 people will take part in the screening study described in Group 1 below. Of those people, 
up to 25 people will have the KRAS G12R genetic change that is needed to take part in the testing 
of the study drug selumetinib (Group 2 below).   
What are the study groups? 
This study has two phases. Everyone who agrees to take part in the study will be in Group 1. Only 
patients with a tumor sample testing positive for the KRAS G12R genetic change will continue to 
the Group 2 phase of the study.  
Group 1 (Screening Phase). 
All participants must provide a test result from CLIA certified laboratory, confirming somatic 
KRAS G12R mutation or tumor sample to test for the KRAS G12R genetic change.  
The tumor sample can be from: 
• Archival tumor sample that was previously acquired at diagnosis (no biopsy required) 


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• Or a biopsy (if the archival sample is not available).  
*The tumor sample is then tested for the KRAS G12R genetic change. 
It is expected that for every 100 patients with pancreas cancer, about 15 samples of the tumor will 
be positive for the KRAS G12R genetic change. The risks of this genetic test are further explained 
below in “What extra tests and procedures will I have if I take part in this study?” 
If the test is negative for the KRAS G12R genetic change you are then taken off study.  
Group 2 (Testing Phase) 
All participants having a tumor with the KRAS G12R genetic change will get selumetinib as a 
capsule at a dose of 75 mg to be taken twice a day. 
The study doctor might lower the dose if you have serious side effects. The study drug is given 
over 4-week periods of time called cycles. The 4-week cycle will be repeated as long as you are 
tolerating the study drug and your cancer is either stable or getting better. No other therapy for 
pancreas cancer will be given while you are on study. 
You will be given a Patient’s Pill Diary that explains how to take the study drug and to record 
when you take the capsules at home. You will also be given a study drug handout and wallet card 
as a resource for yourself, caregivers and other health care providers.  
How long will I be in this study? 
The screening phase of this study can take up to 2 weeks for archival tumor samples, and up to 3 
weeks if a biopsy is needed test for the KRAS G12R genetic change or no time at all if you already 
have test result of KRAS mutation ststus.  
For participants having a tumor with the KRAS G12R genetic change, you will receive the 
selumetinib for as long as you are able to tolerate the study drug and it keeps your cancer from 
further growing for up to 27 cycles which is about two years. After you finish the study drug, your 
study team will call you every two months for up to one year to follow your condition. If you have 
any side effects from the study drug after you finish the study, your doctor will follow you until 
your symptoms get better. 
What extra tests and procedures will I have if I take part in this study? 
Most of the exams, tests, and procedures you will have are part of the usual approach for your 
cancer. However, there are some extra tests that you will need to have if you take part in this study. 
Before you begin the study 
You will need to have the following extra exams, tests, and procedures to find out if you can be in 
the study: 
• Pregnancy test (if female)  
• A genetic test of a tumor sample for the KRAS G12R genetic change. The tumor sample 
can be from archival tumor sample that was previously acquired at diagnosis (no biopsy 
required), or from a new biopsy (if the archival sample is not available) (not necessary for 
patients with confirmed KRAS G12R genetic change) 
Tumor biopsy and genetic testing: 


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i. 
Small pieces of cancer tissue removed during a biopsy will be taken before you begin 
study drug. This sample is required in order for you to take part in this study. 
ii. 
Common side effects of a biopsy are a small amount of bleeding at the time of the 
procedure, pain at the biopsy site, which can be treated with regular pain medications, 
and bruising. Rarely, an infection can occur.” 
iii. 
Any of the specimen left over will be stored for biobanking. This will be discussed in 
the section on optional studies. 
iv. 
Your privacy is very important and the researchers will make every effort to protect it. 
Your test results will be identified by a unique code and the list that links the code to 
your name will be kept separate from your sample and health information. The results 
will be available to you and study doctor. 
• Research blood test (Optional)  
If the exams, tests, and procedures show that you can take part in the study, and you choose to take 
part, then you will need the following extra procedures. They are not part of the usual approach 
for your type of cancer. 
During the study 
Once we determine that you are eligible for taking study drug you will be given a 30-day supply 
of selumetinib in the form of capsules.  
You will be asked to: 
• complete the study drug Pill Diary every day and review every 4 weeks; 
• return to the clinic at the end of every treatment cycle (4 weeks) for repeat labs and scans 
to evaluate your disease and to confirm that your tumor has not progressed; 
• research blood test (optional) up to 3 teaspoon every two weeks for 8 weeks and monthly 
after that. 
Following the study you may be asked to take part in telephone interviews (every 2 months 
during the first 52 weeks). 
A study calendar that shows how often these tests and procedures will be done is attached. 
What possible risks can I expect from taking part in this study? 
If you choose to take part in this study, there is a risk that: 
• You may lose time at work or home and spend more time in the hospital or doctor’s office 
than usual 
• You may be asked sensitive or private questions which you normally do not discuss 
• There is a risk someone could get access to the personal information in your medical 
records or other information researchers have kept about you. Someone might be able to 
trace this information back to you. The researchers believe the chance that someone will 
identify you is very small, but the risk may change in the future as people come up with 
new ways of tracing information. In some cases, this information could be used to make it 
harder for you to get or keep a job. There are laws against misuse of genetic information, 


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but they may not give full protection. The researchers believe the chance these things will 
happen is very small, but cannot promise that they will not occur. 
• There can also be a risk in finding out new genetic information about you. New health 
information about inherited traits that might affect you or your blood relatives could be 
found during a study. 
The selumetinib used in this study may affect how different parts of your body work such as your 
liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you know 
if changes occur that may affect your health. 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go 
away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drugs to try to reduce side effects. 
• The study doctor will provide you with information about other drugs you may need to 
avoid while receiving the study drug. 
The tables below show the most common and the most serious side effects that researchers know 
about. There might be other side effects that researchers do not yet know about. If important new 
side effects are found, the study doctor will discuss these with you. 
Possible Side Effects of selumetinib (AZD6244) 
 
COMMON, SOME MAY BE SERIOUS                                                   
In 100 people receiving selumetinib (AZD6244), more than 20 and up to 100 may have: 
• Diarrhea, nausea 
• Swelling of the body 
• Tiredness 
• Acne, rash 
 
 


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OCCASIONAL, SOME MAY BE SERIOUS                                               
In 100 people receiving selumetinib (AZD6244), from 4 to 20 may have: 
• Anemia which may require blood transfusion 
• Pain 
• Constipation, vomiting 
• Dry mouth, skin 
• Sores in mouth which may cause difficulty swallowing 
• Fever 
• Bruising, bleeding 
• Infection, especially when white blood cell count is low 
• Loss of appetite 
• Dizziness, headache 
• Cough, shortness of breath 
• Hair loss, itching 
• High blood pressure which may cause headaches, dizziness, blurred vision 
 
RARE, AND SERIOUS 
In 100 people receiving selumetinib (AZD6244), 3 or fewer may have: 
• Heart failure which may cause shortness of breath, swelling of ankles, and tiredness 
 
Research Procedure Risks: 
Blood Draw 
Side effects of blood draws include pain and bruising in the area where the needle was placed, 
lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood 
cell count (anemia) can develop. 
Reproductive risks:  
You should not get pregnant, breastfeed, or father a baby while in this study. The selumetinib used 
in this study could be very damaging to an unborn baby. Check with the study doctor about what 
types of birth control, or pregnancy prevention, to use while in this study. 
If you are a woman who can become pregnant, or are the partner of a woman who can become 
pregnant, you will need to practice an effective form of birth control before starting study drug, 
during taking study drug, and for up to 4 weeks (female patients) or 12 weeks (male patients) after 
you finish study drug.  If you think that you or your partner is pregnant, you should tell your study 
doctor or nurse at once.   
Effective forms of birth control include:  
• abstinence  


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• intrauterine device (IUD) 
• hormonal [birth control pills, injections, or implants] 
• tubal ligation 
• vasectomy 
Other risks: 
• In case of diarrhea you can have additional tests to address the need for immediate, 
aggressive treatment of diarrhea such as measurement of blood pressure and heart rate, 
urine and blood tests to check your organ functions.  
• Please, avoid excessive sun exposure and use adequate sun protection measures.  
What possible benefits can I expect from taking part in this study? 
This study has only a small chance of helping you because we do not know if the study drug/study 
approach is effective. This study may help researchers learn things that may help other people in 
the future. 
Can I stop taking part in this study? 
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let 
the study doctor know as soon as possible so you can stop safely. If you stop, you can decide 
whether or not to let the study doctor continue to provide your medical information to the 
organization running the study. 
The study doctor will tell you about new information or changes in the study that may affect your 
health or your willingness to continue in the study. 
The study doctor may take you off study drug: 
• If your health changes and the study is no longer in your best interest 
• If you become pregnant 
• If new information becomes available 
• If you do not follow the study rules 
• If the study is stopped by the sponsor, IRB or FDA. 
• If the drug is no longer available. 
What are my rights in this study? 
Taking part in this study is your choice. No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights. 
For questions about your rights while in this study, contact the National Cancer Central Institute 
Institutional Review Board (NCI CIRB) at 888-657-3711 


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What are the costs of taking part in this study? 
The study drug will be supplied at no charge while you take part in this study. The cost of getting 
the study drug ready and giving it to you, however, is not paid by the study sponsor so you or your 
insurance company may have to pay for this. It is possible that the study drug may not continue to 
be supplied while you are on the study. Although not likely, if this occurs, your study doctor will 
talk to you about your options. 
You and/or your health plan/insurance company will need to pay for all of the other costs of 
treating your cancer while in this study, including the cost of tests, procedures, or medicines to 
manage any side effects, unless you are told that certain tests are supplied at no charge. Before you 
decide to be in the study, you should check with your health plan or insurance company to find out 
exactly what they will pay for.  
You will not be paid for taking part in this study. 
What happens if I am injured or hurt because I took part in this study? 
If you are injured or hurt as a result of taking part in this study and need medical treatment, please 
tell your study doctor. The study sponsors will not offer to pay for medical treatment for injury. 
Your insurance company may not be willing to pay for study-related injury. If you have no 
insurance, you would be responsible for any costs. 
If you feel this injury was a result of medical error, you keep all your legal rights to receive 
payment for this even though you are in a study. 
Who will see my medical information? 
Your privacy is very important to us and the researchers will make every effort to protect it. Your 
information may be given out if required by law. For example, certain states require doctors to 
report to health boards if they find a disease like tuberculosis. However, the researchers will do 
their best to make sure that any information that is released will not identify you. Some of your 
health information, and/or information about your specimen, from this study will be kept in a 
central database for research. Your name or contact information will not be put in the database. 
There are organizations that may inspect your records. These organizations are required to make 
sure your information is kept private, unless required by law to provide information. Some of these 
organizations are: 
• The study sponsor, CTEP and any drug company supporting the study. 
• The Institutional Review Board, IRB, is a group of people who review the research with 
the goal of protecting the people who take part in the study. 
• The Food and Drug Administration and the National Cancer Institute in the U.S., and 
similar ones if other countries are involved in the study. 
Where can I get more information? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or general 
information about cancer. You may also call the NCI Cancer Information Service to get the same 
information at: 1-800-4-CANCER (1-800-422-6237). 


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A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
Who can answer my questions about this study? 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries. Contact the study doctor insert local PI name & contact number. 
ADDITIONAL STUDIES SECTION:  
This part of the consent form is about optional studies that you can choose to take part in. You will 
not get health benefits from any of these studies. The researchers leading this optional study hope 
the results will help other people with cancer in the future. 
The results will not be added to your medical records and you or your study doctor will not know 
the results. 
You will not be billed for these optional studies. You can still take part in the main study even if 
you say “no” to any or all of these studies. If you sign up for but cannot complete any of the studies 
for any reason, you can still take part in the main study. 
Circle your choice of “yes” or “no” for each of the following studies. 
1. Optional Tumor Biopsy  
If you choose to take part in this study, we would like to collect a sample of your tumor after 2 
weeks of taking study drug to see how the study drug might affect the functioning of a certain  
gene within the tumor.    
If you agree to this tumor biopsy, it would involve collecting a small piece of tumor tissue from 
you. A hollow needle is used to withdraw small cylinders (or cores) of tissue from your tumor 
using a CT scan or ultrasound for guidance. The needle is put in 3 to 6 times to get the samples, or 
cores. This procedure usually causes only brief discomfort at the site from which the biopsy is 
taken and you will be offered medication to help numb the pain. Biopsy collection may cause 
bruising and bleeding, but usually does not leave scars. Rarely infection may occur at the needle 
site.  
To collect the optional research biopsy (at two weeks), you may be exposed to one CT scan. This 
radiation exposure is not required for your medical care and is for research purposes only.  
The CT scan that you will receive in this study will expose you to low amounts of radiation. 
Every day, people are naturally exposed to low levels of radiation that come from the sun and the 
environment. This type of radiation is called “background radiation”. No one knows for sure 
whether exposure to low amounts of radiation is harmful for your body. However, scientists 
believe that being exposed to too much radiation can cause harmful side effects, including 
causing a new cancer. 
 
The CT scan that you will receive in this study will expose you to extra radiation that is equal to 
about 2 – 3 years worth of background radiation. Most of the time, this low amount of extra 
radiation is not harmful to you. However, scientists believe that if you get extra radiation that is 
more than about 30 year’s worth of background radiation, there is a chance of having a harmful 


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side effect, including causing a new cancer. It is estimated that this could occur in about 1 out of 
every 1000 people who get a very large amount of extra radiation. 
Please inform the study team immediately if you notice bleeding at the biopsy site more than 2 
days after the procedure or if there is evidence of infection -  redness, swelling, warmth, pain or 
red streaking of the skin around the wound. 
 
Please circle your answer: I choose to have a post study drug tumor biopsy. 
 
YES 
 
 
NO 
 
2.Optional Sample Collections for Laboratory studies and/or Biobanking for Possible 
Future Studies 
Researchers are trying to learn more about cancer, diabetes, and other health problems. Much of 
this research is done using samples from your tissue, blood, urine, or other fluids. Through these 
studies, researchers hope to find new ways to prevent, detect, treat, or cure health problems. 
Some of these studies may be about genes. Genes carry information about features that are found 
in you and in people who are related to you. Researchers are interested in the way that genes affect 
how your body responds to study drug. 
If you choose to take part, some of your research specimens and data will also be saved for future 
research. The researchers ask your permission to store and use your samples and related health 
information (for example, your response to cancer study drug, results of study tests and medicines 
you are given) for medical research. The research that may be done is unknown at this time. Storing 
samples for future studies is called “biobanking”.  
WHAT IS INVOLVED? 
If you agree to take part in biobanking, here is what will happen next: 
1) Your left over samples and some related health information may be stored in the 
Biobank, along with samples and information from other people who take part.  The 
samples will be kept until they are used up. Information from your medical record will 
be updated from time to time. 
2) Qualified researchers can submit a request to use the materials stored in the Biobank. 
There will also be an ethics review to ensure that the request is necessary and proper. 
Researchers will not be given your name or any other information that could directly 
identify you. 
3) You will not be notified when future studies will be conducted or given reports or other 
information about any research that is done using your samples.  
4) Some of your genetic and health information may also be placed in central databases 
that may be public, along with information from many other people. Information that 
could directly identify you will not be included. 
WHAT ARE THE POSSIBLE RISKS? 


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1) There is a risk that someone could get access to the personal information in your 
medical records or other information researchers have stored about you. 
2) There is a risk that someone could trace the information in a central database back to 
you. Even without your name or other identifiers, your genetic information is unique 
to you. The researchers believe the chance that someone will identify you is very small, 
but the risk may change in the future as people come up with new ways of tracing 
information. 
3) In some cases, this information could be used to make it harder for you to get or keep 
a job or insurance. There are laws against the misuse of genetic information, but they 
may not give full protection. There can also be a risk in knowing genetic information. 
New health information about inherited traits that might affect you or your blood 
relatives could be found during a study. The researchers believe the chance these things 
will happen is very small, but cannot promise that they will not occur. 
4) There is a risk that the sample used for unspecified future research could be needed to 
determine if you are eligible for other treatments or clinical trials. 
HOW WILL INFORMATION ABOUT ME BE KEPT PRIVATE? 
Your privacy is very important to the researchers and they will make every effort to protect it. 
Here are just a few of the steps they will take: 
1) When your samples are sent to the researchers, no information identifying you (such as 
your name) will be sent. Samples will be identified by a unique code only.  
2) The list that links the unique code to your name will be kept separate from your sample 
and health information.  
3) Researchers to whom the Biobank sends your sample and information will not know 
who you are.  
4) Information that identifies you will not be given to anyone, unless required by law. 
5) If research results are published, your name and other personal information will not be 
used. 
WHAT ARE THE POSSIBLE BENEFITS? 
You will not benefit from taking part.  
Your samples may be helpful to research. The researchers, using the samples from you and others, 
might make discoveries that could help people in the future. 
ARE THERE ANY COSTS OR PAYMENTS? 
There are no costs to you or your insurance. You will not be paid for taking part. If any of the 
research leads to new tests, drugs, or other commercial products, you will not share in any profits. 
WHAT IF I CHANGE MY MIND? 
If you decide you no longer want your samples to be used, you can call the study doctor, Udo 
Rudloff, MD at 240-760-6238 who will let the researchers know. Then, any sample that remains 
in the bank will no longer be used and related health information will no longer be collected. 


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Samples or related information that have already been given to or used by researchers will not be 
returned. 
WHAT IF I HAVE MORE QUESTIONS? 
If you have questions about the use of your samples for research, contact the study doctor, Udo 
Rudloff, MD at 240-760-6238. 
Please circle your answer to show whether or not you would like to take part in each option: 
SAMPLES FOR THE LABORATORY STUDIES: 
I agree to have my specimen collected and I agree that my specimen sample(s) and 
related information may be used for the laboratory study(ies) described above. 
 
 
YES 
 
NO 
 
I agree that my study doctor, or their representative, may contact me or my physician to 
see if I wish to learn about results from this(ese) study(ies). 
 
 
YES 
 
NO 
 
SAMPLES FOR FUTURE RESEARCH STUDIES: 
My samples and related information may be kept in a Biobank for use in future health 
research. 
 
YES 
 
NO 
I agree that my study doctor, or their representative, may contact me or my physician to 
see if I wish to participate in other research in the future. 
 
YES 
 
NO 
My Signature Agreeing to Take Part in the Main Study 
I have read this consent form or had it read to me. I have discussed it with the study doctor and my 
questions have been answered. I will be given a signed copy of this form. I agree to take part in 
the main study and any additional studies where I circled ‘yes’.   
Participant’s signature________________________________ 
 
Date of signature_____________________________________ 
 
Signature of person(s) conducting the informed consent 
discussion___________________________________ 
 
Date of signature_____________________________________ 
 
 


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Study Calendar 
Day 
 
 
 
What will happen to you 
After 
signing 
the 
consent, 
before starting 
study drug 
Provide a history of how you feel and undergo a physical examination by the 
research team’s Health Care Provider. 
CT, MRI or Ultrasound imaging 
Blood will be taken for routine cancer care tests and research (optional) blood 
samples. 
Pregnancy test (if female)  
Tumor biopsy if previous specimens are not available. 
CYCLE 1 
28 Days long 
Days 1 through 
28 
Take Selumetinib capsules twice a day, 12 hours apart. 
Complete study drug and side effects diary 
Day 14 
Routine blood tests and physical exam  
Research blood tests (optional) 
Optional tumor biopsy  
Day 28  
Return to the clinic to see your doctor. Provide a history of how you feel and have a 
physical exam by your Health Care Provider. 
Blood will be taken for routine cancer care tests and research (optional) blood 
samples. 
CT, MRI or Ultrasound imaging (to determine if selumetinib is causing your disease 
to shrink or be controlled) 
Review study drug diary with research nurse 
If you are tolerating the study drug, the next cycle will begin. 
CYCLE 2 
28 Days long 
Days 1 through 
28 
Take Selumetinib capsules twice a day, 12 hours apart. 
Complete study drug and side effects diary. 
Day 14 
Routine blood tests and physical exam 
Day 28   
Return to the clinic to see your doctor. Provide a history of how you feel and have a 
physical exam by your Health Care Provider. 
Blood will be taken for routine cancer care tests and research (optional) blood 
samples. 
Review study drug diary with research nurse 
If you are tolerating the study drug, the next cycle will begin. 
CYCLE 3 
28 Days long 


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Days 1 through 
28 
Take Selumetinib capsules twice a day, 12 hours apart. 
Complete study drug and side effects diary 
Day 14 
Routine blood tests and physical exam 
Day 28   
Return to the clinic to see your doctor. Provide a history of how you feel and have a 
physical exam by your Health Care Provider. 
Blood will be taken for routine cancer care tests and research (optional) blood 
samples. 
CT, MRI or Ultrasound imaging (to determine if selumetinib is causing your disease 
to shrink or be controlled) 
Review study drug diary with research nurse 
If you are tolerating the study drug, the next cycle will begin. 
CYCLES 4-27 28 Days long 
Days 1 through 
28 
Take Selumetinib capsules twice a day, 12 hours apart. 
Complete study drug and side effects diary 
Day 28   
Return to the clinic to see your doctor.   
Blood will be taken for routine cancer care tests  
CT, MRI or Ultrasound imaging after every 2 completed cycles (to determine if 
selumetinib is causing your disease to shrink or be controlled) 
Review study drug diary with research nurse 
If you are tolerating the study drug, the next cycle will begin. 
30 days after 
last dose 
If your cancer continues to be better or stable after 27 cycles of therapy, you will be 
seen at the clinic for an end of your treatment visit 30 days after your last dose and 
then followed by a telephone interview every 2 months during the first 52 weeks.  
 
If we find that your tumor is growing during selumetinib therapy, we will ask you 
to stop taking the drug and remove you from study. We will look for other 
investigational therapies you may be eligible for, or refer you back to the care of 
your local physician. 
every 2 months 
during the first 
52 weeks. 
Telephone interview to determine your disease status