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Pediatric *Oncology Branch*  
  
DATE: May 19, 2018 FROM: Udo Rudloff, MD TO: CTEP PIO, CTEP, NCI, NIH  
| Chairperson, NCI Central Institutional Review Board (NCI CIRB) Principal Investigator   |                                                                                                                                                                             |
|-----------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 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" |  
Principal Investigator  
POB, CCR, NCI  
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.  
i
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i. comments requiring a response

| #   | 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. |
untitled h1
ii. comments requiring a response-

| #   | 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                                                                                                                                                                    |
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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:                                                                                                                                                                                                                                                                                                                                                                                                                  |            |
section comments
iii.recommendations

Food and Drug Administration (FDA) regulations require IND sponsors to select qualified investigators. NCI policy requires all persons participating in any NCIsponsored 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.  
| NPIV                                                                         |     |    |    |    |
|------------------------------------------------------------------------------|-----|----|----|----|
| Documentation Required                                                       | IVR | 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).  
| #       | 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:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                             |  
\# 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   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
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.  
| 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 |  
v
\# 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 NCIsponsored 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.  
| NPIV                                                                         |     |    |    |    |
|------------------------------------------------------------------------------|-----|----|----|----|
| Documentation Required                                                       | IVR | 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 vi
\# 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.**
- 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 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. |  
vii  
| #      | 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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
section comments
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.  
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.  
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-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  
|                                      | 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                                                                                                                          |  
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
section comments
precis 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.
section comments
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.
5
section comments
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 1.2.1 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 2.1.1 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 1.2 Secondary Objectives...................................................................................... 14 2 BACKGROUND ....................................................................................................... 14 2.1 Study Disease ................................................................................................. 14 7 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  
3.1 Eligibility Criteria ........................................................................................... 36  
| 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   |
|-----|------------------------|  
3.1.1 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 8 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
9 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   |
|-------|---------------------------|  
10 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 5711                                                                                                                                                                                                                                                                 |  
| 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 7812                                                                                                                                             |  
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 |
section comments
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.
section comments
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
section comments
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 14 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]
section comments
2.1.2 the kras mutational landscape

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 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).
section comments
2.1.3 kras mutational isoforms and

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.  
Version Date: May 19, 2018  
  
Figure 3. Impact of KRAS wild typestatus (left), and KRAS mutation subtype (KRAS G12V, G12D, and G12R, right) on overall survival of patients with a dvanced pancreas cancer (from Ogura T et al. 2013).  
0.8 0.6 0.4  
  
0.2  
  
  
2.1.4 KRAS G12R mutation status predicts response to selumetinib inhibition in a large panel
section comments
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 linestreated 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 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 KRASisogenic cell lines.[18]  
  
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.  
  
  
  
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 G12Rmutant 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 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  
  
  
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-offunction 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 differentdependency 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.  
  
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**).  
  
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).** ().  
  
  
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.  
  
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 KRASmutant 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.  
  
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 negative breast cancer, a positive finding might trigger a number of studies on KRASmutational 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]
section comments
2.2 ctep ind agent 2.2.1

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.
section comments
nonclinical studies 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).
section comments
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 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 Ndesmethyl 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.
section comments
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 32 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.
section comments
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 913 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 (AUC024=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.* freebase 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.  
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.
section comments
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]
section comments
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 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 symptomtriggered 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.
section comments
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
section comments
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.
section comments
3 patient selection 3.1 eligibility

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 nonnodal 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.  
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.
section comments
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.  
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  
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.
section comments
3.3 inclusion of women and

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.
section comments
4 registration procedures 4.1 investigator

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 |      |        |     |     |
| 39                        |       |         |      |     |  
| 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.
section comments
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  
- 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 CIRBapproved institutions aligned with the Signatory Institution are participating in the study.
section comments
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 Theradexled 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, 41
PClark@theradex.com). Nafeesa Sarakhawas is the backup contact (609.480.2693, NSarakhawas@theradex.com)
section comments
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.
section comments
4.3 patient registration 4.3.1 nci

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 ncicentralregistrationl@mail.nih.gov. After confirmation of eligibility at Central Registration Office, CRO staff will 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 email 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 offstudy. 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 ncicentralregistrationl@mail.nih.gov>.
section comments
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.
section comments
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 registration on the study may be canceled. The Study Coordinator should be notified of cancellations as soon as possible.
section comments
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).
section comments
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.
section comments
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**).  
- 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.
section comments
5.2 general concomitant medication and

- 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
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.
section comments
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).
section comments
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.
section comments
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)  
| 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 Apply maximum supportive care recommendations.  Hold selumetinib therapy until recovery to Grade ≤ 1  (up to 14 days).  (excluding cardiac and hepatobiliary  events) 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  Action (discontinue or resume selumetinib therapy)  adverse events NOT resolved to  in individual cases after discussions with the 48   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Version Date:May 19, 2018  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                                                                                                                                                                                                                                                                             | Selumetinib therapy to be discontinued permanently                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
| NYHA criteria)                                                                                                                                                                                                                                                                                                                        | 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                                                                                                                                                                                                                                                                                     | Hold selumetinib for 2 weeks; restart drug at DL-1 if  events resolved to ≤Grade 1.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| Grade 2 total bilirubin elevation                                                                                                                                                                                                                                                                                                     | If Grade 3 events recur after dose reduction, then  discontinue selumetinib.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| Grade 2 AST/ALT or                                                                                                                                                                                                                                                                                                                    | 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 1 total bilirubin elevation 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. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
section comments
7 adverse events list and

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 49 7.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event Reporting System (CTEP-AERS) **in addition** to routine reporting.
section comments
7.1 comprehensive adverse events and

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                                    | Specific Protocol Exceptions  to Expedited Reporting  (SPEER)   |                           |
|-----------------------------------------------------------------|-----------------------------------------------------------------|---------------------------|
| Relationship to Selumetinib (AZD6244) (CTCAE 5.0 Term) [n= 969] |                                                                 |                           |
| 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                                       | Left ventricular systolic |
| dysfunction                                                     | 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)                                           |                           |
| 50                                                              |                                                                 |                           |  
  
| Adverse Events with Possible                                                                              | Specific Protocol Exceptions  to Expedited Reporting  (SPEER)   |                        |
|-----------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------|------------------------|
| Relationship to Selumetinib (AZD6244) (CTCAE 5.0 Term) [n= 969]                                           |                                                                 |                        |
| 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                                                                                | Aspartate aminotransferase                                      |                        |
| increased                                                                                                 | 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                                                           | 51                                                              |                        |  
  
| Adverse Events with Possible                                    | Specific Protocol Exceptions  to Expedited Reporting  (SPEER)   |                        |
|-----------------------------------------------------------------|-----------------------------------------------------------------|------------------------|
| Relationship to Selumetinib (AZD6244) (CTCAE 5.0 Term) [n= 969] |                                                                 |                        |
| 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 (Takatsubocardiomyopathy 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; 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])
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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; Palmarplantar 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, Section**7.1.1**) should be reported through CTEP-AERS only if the grade is above the grade provided in the SPEER.  
- **Attribution** of the AE:  
- Definite - The AE *is clearly related* to the study treatment.  
- 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.
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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://eappsctep.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.
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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

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.
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late phase 2 and phase

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            | Grade 2          | Grade 4 & 5   |
|-------------------|--------------------|------------------|---------------|
| Timeframes        | Grade 3 Timeframes | Timeframes       |               |
| Timeframes        |                    |                  |               |
| Resulting in      |                    |                  |               |
| Hospitalization   | 10 Calendar Days   |                  |               |
| ≥ 24 hrs          | 24-Hour 5          |                  |               |
| Not resulting in  | Calendar Days      |                  |               |
| Hospitalization   | Not required       | 10 Calendar Days |               |
| ≥ 24 hrs          |                    |                  |               |  
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
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expedited ae reporting timelines are

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.
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
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7.4 routine adverse event reporting

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.
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7.5 secondary malignancy

A *secondary malignancy* is a cancer caused by treatment for a previous malignancy (*e.g.*,
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered a metastasis of the initial neoplasm. CTEP requires all secondary malignancies that occur following treatment with an agent under an NCI IND/IDE be reported 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.
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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.
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7.7 reporting to the nci

7.7.1 Definitions
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.
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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..
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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.
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8.1 ctep agent

8.1.1 AZD6244 hydrogen sulfate (NSC 748727)  
8.1.1.1 Chemical Name: 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-6-[(2hydroxyethoxy)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.  
| Dose                              | Vitamin E amount   |
|-----------------------------------|--------------------|
| 75 mg twice a day (3 x 25 mg x 2) | 215.4 mg           |
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daily vitamin e intake based

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.  
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.