section comments
availability

AZD6244 hydrogen sulfate is an investigational agent supplied to investigators by the Division of Cancer Treatment and Diagnosis (DCTD), NCI. AZD6244 hydrogen sulfate is provided to the NCI under a Collaborative Agreement between the Pharmaceutical Collaborator and the DCTD, NCI (see Section **12.4**).  
8.1.2 Agent Ordering and Agent Accountability 8.1.2.1 NCI-supplied agents may be requested by eligible participating Investigators (or their authorized designee) at each participating institution. The CTEP-assigned protocol number must be used for ordering all CTEP-supplied investigational agents. The eligible participating investigators at each participating institution must be registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are several participating investigators at one institution, CTEP-supplied investigational agents for the study should be ordered under the name of one lead participating investigator at that institution. Study agent must be ordered after patient is registered to the treatment arm as no starter supplies are being provided for this study.
59 Submit agent requests through the PMB Online Agent Order Processing (OAOP) application. Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account and the maintenance of an "active" account status, a "current" password, and active person registration status. For questions about drug orders, transfers, returns, or accountability, call or email PMB any time. Refer to the PMB's website for specific policies and guidelines related to agent management.  
8.1.2.2 Agent Inventory Records - The investigator, or a responsible party designated by the investigator, must maintain a careful record of the receipt, dispensing and final disposition of all agents received from the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record Form (DARF) available on the CTEP forms page. Store and maintain separate NCI Investigational Agent Accountability Records for each agent, strength, formulation and ordering investigator on this protocol.  
8.1.2.3 Investigator Brochure Availability - The current versions of the IBs for PMB-supplied agents will be accessible to site investigators and research staff through the PMB Online Agent Order Processing (OAOP) application. Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account and the maintenance of an "active" account status and a "current" password. Questions about IB access may be directed to the PMB IB coordinator via email.  
8.1.2.4 Useful links and Contacts
- CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/
- NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov  
- PMB policies and guidelines:
http://ctep.cancer.gov/branches/pmb/agent_management.htm
- PMB Online Agent Order Processing (OAOP) application:
https://ctepcore.nci.nih.gov/OAOP
- CTEP Identity and Access Management (IAM) account:
https://ctepcore.nci.nih.gov/iam/
- CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov  
- IB Coordinator: IBCoordinator@mail.nih.gov - PMB email: PMBAfterHours@mail.nih.gov
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET).  
| 9                                                                                                                                                                              | BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES                      |                                                                                                                                 |                                                        |                                                                            |         |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------|----------------------------------------------------------------------------|---------|
| Biomarker  Name                                                                                                                                                                | Assay                                                            | Use (Integral,  Integrated, or  Exploratory) AND Purpose                                                                        | Tissue/Body Fluid  Tested                              | Mandatory/                                                                 | Funding |
| Optional                                                                                                                                                                       | Source(s)                                                        |                                                                                                                                 |                                                        |                                                                            |         |
| (CLIA:  Y/N)                                                                                                                                                                   |                                                                  |                                                                                                                                 |                                                        |                                                                            |         |
| and Person  performing the  study                                                                                                                                              | and Timing of Assay                                              |                                                                                                                                 |                                                        |                                                                            |         |
| KRAS                                                                                                                                                                           | Cancer  Gene  Panel                                              | Eligibility  criterion, KRAS  G12R mutation  status prerequisite  for selumetinib  treatment                                    | Tissue - either biospy or  previous surgical  specimen | Mandatory for patients  who do not  have KRAS  mutation  status  confirmed | CCR     |
| Mark Raffeld,  Molecular  Pathology,  Laboratory of  Pathology, NCI using the 50  cancer gene  deep sequencing  assay applied  for genetic  profiling of  solid organ  cancers | CLIA: Y                                                          | At enrollment * If a biopsy is needed,  the site with the most  minimal morbidity will  harvested at the  discretion of the PI. |                                                        |                                                                            |         |
| Eligibility  determination,                                                                                                                                                    | combined with KRAS  mutation testing at  enrollment (same assay) |                                                                                                                                 |                                                        |                                                                            |         |
| Appendix I                                                                                                                                                                     |                                                                  |                                                                                                                                 |                                                        |                                                                            |         |  
| Version Date:May 19, 2018  Biomarker  Name Assay                                                               | Use (Integral,  Integrated, or  Exploratory) AND Purpose                                                                     | Tissue/Body Fluid  Tested                                                                                                                                                                                | Mandatory/   | Funding             |
|----------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|---------------------|
| Optional                                                                                                       | Source(s)                                                                                                                    |                                                                                                                                                                                                          |              |                     |
| (CLIA:  Y/N)                                                                                                   |                                                                                                                              |                                                                                                                                                                                                          |              |                     |
| and Person  performing the  study                                                                              | and Timing of Assay                                                                                                          |                                                                                                                                                                                                          |              |                     |
| 50-cancer gene  panel  (multiplexed  deep sequencing  assay to identify  somatic variants  in tumor  specimen) | Cancer  Gene  Panel                                                                                                          | Integrated to identify  potential mutations  governing  resistance to  selumetinib in  KRAS G12R  mutant cancers to  identify molecular  subgroups  predicting  response to the  investigational  agent. |              |                     |
| CLIA: Y                                                                                                        |                                                                                                                              |                                                                                                                                                                                                          |              |                     |
| Mark Raffeld,  Molecular  Pathology,  Laboratory of  Pathology, NCI                                            | This genetic  information  retrieved from  tumors are somatic  mutations only. No  germline mutation  testing will be  done. |                                                                                                                                                                                                          |              |                     |
| CNKSR1                                                                                                         | IHC                                                                                                                          | to identify  subgroups of  patients  responding to the  investigational  agent                                                                                                                           | Optional     | Dr.  Rudloff's  lab |
| Markku  Miettinen,  Laboratory of  Pathology. NCI                                                              | CLIA: N                                                                                                                      | Tissue from optional  screening biopsy at  enrollment  Tissue from optional  CT guided biopsy after  2 weeks on the study                                                                                |              |                     |
| to identify  biomarkers of  response                                                                           |                                                                                                                              |                                                                                                                                                                                                          |              |                     |  
| Biomarker  Name                                                     | Assay                                                                        | Use (Integral,  Integrated, or  Exploratory) AND Purpose   | Tissue/Body Fluid  Tested                         | Mandatory/   | Funding        |
|---------------------------------------------------------------------|------------------------------------------------------------------------------|------------------------------------------------------------|---------------------------------------------------|--------------|----------------|
| Optional                                                            | Source(s)                                                                    |                                                            |                                                   |              |                |
| (CLIA:  Y/N)                                                        |                                                                              |                                                            |                                                   |              |                |
| and Person  performing the  study                                   | and Timing of Assay                                                          |                                                            |                                                   |              |                |
| Circulating  Tumor DNA  (ctDNA)                                     | CTC  (blood)                                                                 | Integrated                                                 | Blood (to be taken with  clinical samples) - 5 ml | Optional     | Dr.  Rudloff's |
| to identify  biomarkers of  response                                |                                                                              |                                                            |                                                   |              |                |
| CLIA: N                                                             | ctDNA Blood  Collection (see  Appendix H)                                    | lab                                                        |                                                   |              |                |
| Mark Raffeld,  Molecular  Pathology,  Laboratory of  Pathology, NCI | At enrollment, after 2,  4, 6, and 8 weeks on  study and from there  monthly |                                                            |                                                   |              |                |
section comments
9.1 sample storage tracking and

Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples will not be sent outside NIH without IRB notification and an executed MTA. All samples initially will be sent to Blood Processing Core (BPC) for processing and storage until they are distributed to Dr. Rudloff's lab sample analysis as described in the protocol. 9.1.2 Samples Managed by Dr. Figg's Blood Processing Core (BPC) 9.1.2.1 BPC contact information Please e-mail Julie Barnes at Julie.barnes@nih.gov and Paula Carter pcartera@mail.nih.gov at least 24 hours before transporting samples (the Friday before is preferred). For sample pickup, page 102-11964. For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number). For questions regarding sample processing, contact Julie Barnes by e-mail or at 240-760-6044.
section comments
9.1.2.2 sample data collection

All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and stored in the LABrador (aka LabSamples) utilized by the BPC. This is a secure program, with access to LABrador limited to defined Figg lab personnel, who are issued individual user accounts. Installation of LABrador is limited to computers specified by Dr. Figg. These computers all have a password restricted login screen. All Figg lab personnel with access to patient information annually complete the NIH online Protection of Human Subjects course. LABrador creates a unique barcode ID for every sample and sample box, which cannot be traced back to patients without LABrador access. The data recorded for each sample includes the patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well as box and freezer location. Patient demographics associated with the Clinical Center patient number are provided in the system. For each sample, there are notes associated with the processing method (delay in sample processing, storage conditions on the ward, etc.).
section comments
9.1.2.3 sample storage

Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80°C
according to stability requirements. These freezers are located onsite in the BPC and offsite at NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are required to be accompanied by laboratory staff at all times. Access to stored clinical samples is restricted. Samples will be stored until requested by a researcher named on the protocol. All requests are monitored and tracked in LABrador. All researchers are required to sign a form stating that the samples are only to be used for research purposes associated with this trial (as per the IRB approved protocol) and that any unused samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to ensure that the samples requested are being used in a manner consistent with IRB approval. 9.1.3 Procedures for Storage of Tissue Specimens in the Laboratory of Pathology Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) where they are examined grossly and relevant portions are fixed, embedded in paraffin and sectioned and stained for diagnostic interpretation. Unutilized excess tissues are stored for up to three months, in accordance with College of American Pathologists/Joint Commission on Accreditation of Healthcare Organizations (CAP/JCAHO) guidelines, and then discarded. Following completion of the diagnostic workup, the slides and tissue blocks are stored indefinitely in the LP's clinical archives. All specimens are catalogued and retrieved utilizing the clinical laboratory information systems, in accordance with CAP/JCAHO regulations. The use of any stored specimens for research purposes is only allowed for research conducted in relation to this protocol.
section comments
9.1.4 protocol completion/sample destruction

All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are remaining at the completion of the protocol will be stored in the conditions described in Section above. The study will remain open so long as sample or data analysis continues. Samples from consenting subjects will be stored until they are no longer of scientific value or if a subject withdraws consent for their continued use, at which time they will be destroyed. The PI will report any loss or destruction of samples to the NCI IRB as soon as he is made aware of such loss. If the patient withdraws consent the participant's data will be excluded from future distributions, but data that have already been distributed for approved research use will not be able to be retrieved. The PI will report destroyed samples to the IRB if samples become unsalvageable because of environmental factors (ex. broken freezer or lack of dry ice in a shipping container) or if a patient withdraws consent. Samples will also be reported as lost if they are lost in transit between facilities or misplaced by a researcher. Freezer problems, lost samples or other problems associated with samples will also be reported to the IRB, the NCI Clinical Director, and the 64 office of the CCR, NCI. 9.1.5 Shipping instructions for Participating sites For patients enrolled at Non-NIH sites, the biopsy sample will be sent as a paraffin block together with copy of the original pathology report (or molecular pathology report) to Santhana Webb 10 Center Drive, Room 8D44F
Bethesda, MD 20892-1906 Phone: 240-858-3165 Fax: 301-480-2462 Email: santhana.webb@nih.gov Tissue block and matched pathology report will have matching identification number. Fresh blood will be send on dry ice to Dr. Yansong Bian Hatfield Center CRC-1B 34A
10 CENTER DR
BETHESDA MD 20814 Phone: 301-451-6928 yansong.bian@nih.gov Samples may be shipped from site of acquisition to site of analysis in batches. Shipping must be by expedited courier on dry ice. Participating sites should send e-mail with information about planning shipment to Cara Kenney and Yansong Bian 2 days before actual shipment. Each sample should be labeled with a unique identifier linking the biospecimen to the respective pathology report. A hard copy should be included into the shipment. If a tumor block is not available, unstained slides may also be submitted. 15 unstained slides are preferable.
section comments
10 study calendar

Screening evaluations are to be conducted will be obtained within 8 weeks prior to start of enrollment. Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy. Scans and x-rays must be done <4 weeks prior to the start of therapy. In the event that the patient's condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. Laboratory evaluation tests may be performed at the NCI or at the local physician. Assays and scans may be taken 5 days earlier or later than scheduled depending on individual needs. For the evaluation purposes, a cycle will be defined as 28 +/- 2 days (4 weeks). A patient may receive up to 27 cycles (108 weeks).  
| Wks          |           |     |    |    |    |    |    |    |    |    |    |    |    |        |
|--------------|-----------|-----|----|----|----|----|----|----|----|----|----|----|----|--------|
| Wk           | Wk        | Wk  | Wk | Wk | Wk | Wk | Wk | Wk | Wk | Wk | Wk |    |    |        |
| Screeni ng   | Baselineh | 1   | 2  | 3  | 4  | 5  | 6  | 7  | 8  | 9  | 10 | 11 | 12 | End of |
| 13-108c      | Treatment | FUe |    |    |    |    |    |    |    |    |    |    |    |        |
| Evaluationsd |           |     |    |    |    |    |    |    |    |    |    |    |    |        |
| AZD6244      | A         | A   | A  | A  | A  | A  | A  | A  | A  | A  | A  | A  | A  |        |  
65  
| Version Date:May 19, 2018                                                        | Wks                                                                                      | End of                                                                                      |      |      |    |    |    |    |    |    |    |    |    |
|----------------------------------------------------------------------------------|------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------|------|------|----|----|----|----|----|----|----|----|----|
| 13-108c                                                                          | Treatment                                                                                | FUe                                                                                         |      |      |    |    |    |    |    |    |    |    |    |
| Evaluationsd                                                                     |                                                                                          |                                                                                             |      |      |    |    |    |    |    |    |    |    |    |
| Screeni ng                                                                       | Baselineh                                                                                | Wk 1                                                                                        | Wk 2 | Wk 3 | Wk | Wk | Wk | Wk | Wk | Wk | Wk | Wk | Wk |
| 4                                                                                | 5                                                                                        | 6                                                                                           | 7    | 8    | 9  | 10 | 11 | 12 |    |    |    |    |    |
| hydrogen sulfate Informed consent                                                | X                                                                                        |                                                                                             |      |      |    |    |    |    |    |    |    |    |    |
| Confirmation of  diagnosis                                                       | X                                                                                        |                                                                                             |      |      |    |    |    |    |    |    |    |    |    |
| Demographics                                                                     | X                                                                                        |                                                                                             |      |      |    |    |    |    |    |    |    |    |    |
| Medical history                                                                  | X                                                                                        |                                                                                             |      |      |    |    |    |    |    |    |    |    |    |
| Concurrent meds                                                                  | X                                                                                        | X-----------------------------------------------------------------------------------------X |      |      |    |    |    |    |    |    |    |    |    |
| Physical exam                                                                    | X                                                                                        | X                                                                                           | X    | X    | X  | X  | X  | X  | X  | X  |    |    |    |
| Vital signs                                                                      | X                                                                                        | X                                                                                           | X    | X    | X  | X  | X  | X  | X  | X  |    |    |    |
| Height                                                                           | X                                                                                        |                                                                                             |      |      |    |    |    |    |    |    |    |    |    |
| Weight                                                                           | X                                                                                        | X                                                                                           | X    | X    | X  | X  | X  | X  | X  | X  |    |    |    |
| Performance status                                                               | X                                                                                        | X                                                                                           | X    | X    | X  | X  | X  | X  | X  | X  | X  |    |    |
| CBC w/diff, plts g PT, PTT                                                       | X                                                                                        | X                                                                                           | X    | X    | X  | X  | X  | X  | X  | X  |    |    |    |
| Serum chemistry a,g                                                              | X                                                                                        | X                                                                                           | X    | X    | X  | X  | X  | X  | X  | X  |    |    |    |
| EKG                                                                              | X                                                                                        |                                                                                             |      |      |    |    |    |    |    |    |    |    |    |
| Adverse event  evaluation                                                        | X--------------------------------------------------------------------------------------X | X                                                                                           | X    |      |    |    |    |    |    |    |    |    |    |
| Tumor                                                                            | Tumor measurements performed after 4 weeks and thereafter are repeated every 8           |                                                                                             |      |      |    |    |    |    |    |    |    |    |    |
| measurements                                                                     | X                                                                                        | weeks. Documentation (radiologic) must be provided for patients removed from study for      | X    |      |    |    |    |    |    |    |    |    |    |
| progressive disease.                                                             |                                                                                          |                                                                                             |      |      |    |    |    |    |    |    |    |    |    |
| Radiologic  evaluation                                                           | X                                                                                        | Radiologic measurements should be performed after 4 weeks and thereafter every 8 weeks.     | X    |      |    |    |    |    |    |    |    |    |    |
| B-HCG                                                                            | Xb                                                                                       |                                                                                             |      |      |    |    |    |    |    |    |    |    |    |
| Tumor biopsy for  KRAS mutation  status, Cancer gene  panel and CNKSR1  by IHC k | X                                                                                        |                                                                                             |      |      |    |    |    |    |    |    |    |    |    |
| unless  archived  or prior  biopsy  material  availabl e                         | 66                                                                                       |                                                                                             |      |      |    |    |    |    |    |    |    |    |    |  
| Wks                                        | End of                                                      |      |      |      |    |    |       |    |    |    |    |    |    |
|--------------------------------------------|-------------------------------------------------------------|------|------|------|----|----|-------|----|----|----|----|----|----|
| 13-108c                                    | Treatment                                                   | FUe  |      |      |    |    |       |    |    |    |    |    |    |
| Evaluationsd                               |                                                             |      |      |      |    |    |       |    |    |    |    |    |    |
| Screeni ng                                 | Baselineh                                                   | Wk 1 | Wk 2 | Wk 3 | Wk | Wk | Wk    | Wk | Wk | Wk | Wk | Wk | Wk |
| 4                                          | 5                                                           | 6    | 7    | 8    | 9  | 10 | 11    | 12 |    |    |    |    |    |
| Tumor biopsy for  CNKSR1 by IHC k          | Xf                                                          |      |      |      |    |    |       |    |    |    |    |    |    |
| Blood for  Circulating Tumor  DNA (ctDNA)k | Xf                                                          | Xf   | Xf   | Xf   | Xf | Xf | Xf, i |    |    |    |    |    |    |
| Tumor markers  CA19-9, CEA, CA             | X                                                           | X    | X    | Xi   |    |    |       |    |    |    |    |    |    |
| 125 Advance Directivej                     | X                                                           |      |      |      |    |    |       |    |    |    |    |    |    |
| A:                                         | AZD6244 hydrogen sulfate: Dose 75 mg twice a day every day. |      |      |      |    |    |       |    |    |    |    |    |    |  
a: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, amylase, lipase, magnesium, prealbumin b: Serum pregnancy test (women of childbearing potential). c: Assessments will be performed once per cycle. d: Patients will be invited to their study site approximately 30 days following the last dose of study drug. If patents are not able to come or provide lab results from home, they will be asked by phone for performance status, any adverse events and new cancer treatment.  
e: Patients will be followed for 52 weeks with a telephone interview for performance status, any adverse events and new cancer treatment every 2 months. f: Optional g: The laboratory tests can be performed either at the NIH clinic or at home. h: Baseline evaluations do not need to be repeated if they were done on screening during appropriate time frame. i: monthly j: As icated in section **13.3**, all subjects enrolled in NIH will be offered the opportunity to complete an NIH Advance Directive form. This should be done preferably at baseline but can be done at any time during the study as long as the capacity to do so is retained. The completion of the form is strongly recommended, but is not required.  
k: All research study will be performed at NIH. For shipping instructions, please, see Section **9.1.5.** Not necessary for patients with confirmed KRAS
mutation status
section comments
11 measurement of effect 11.1

For the purposes of this study, patients should be re-evaluated for response after the first 4 weeks, then every 8 weeks thereafter. In addition to a baseline scan, confirmatory scans should also be obtained 4 weeks following initial documentation of objective response. Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline
(version 1.1) [*Eur J Ca* 45:228-247, 2009]. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 11.1.1 Definitions Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first treatment with AZD6244. Evaluable Non-Target Disease Response. Patients who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions. 11.1.2 Disease Parameters Measurable disease. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Note: Tumor lesions that are situated in a previously irradiated area might or might not be considered measurable. Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm [0.5 cm]). At baseline and in follow-up, only the short axis will be measured and followed. Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions. Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as **target lesions** and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as **non-target lesions** and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up. 11.1.3 Methods for Evaluation of Measurable Disease All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam.  
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial
(*e.g.*, skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using calipers (*e.g.*, skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended.  
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable. Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less. If CT scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (*e.g.* for body scans).  
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up should be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if possible. PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or serially performed. Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be 69 guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not advised. However, such techniques may be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response (CR) or surgical resection is an endpoint. Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal limit, they must normalize for a patient to be considered a complete biochemical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [*JNCI* 96:487-488, 2004; *J Clin Oncol* 17, 3461-3467, 1999; *J Clin Oncol* 26:1148-1159, 2008]. In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with objective tumor assessment for use in first-line trials in ovarian cancer [*JNCI*
92:1534-1535, 2000]. Cytology, Histology: These techniques can be used to differentiate between partial responses
(PR) and complete responses (CR) in rare cases (*e.g.*, residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain). The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease. FDG-PET: While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new lesion.  
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDGPET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD.  
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively described in the protocol and supported by disease-specific medical literature for the indication. However, it must be acknowledged that both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.
70 Note: A 'positive' FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image.  
11.1.4 Response Criteria 11.1.4.1 Evaluation of Target Lesions Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm (<1 cm). Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm). (Note: the appearance of one or more new lesions is also considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.  
11.1.4.2 Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis). Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. *Unequivocal progression* should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator).  
11.1.4.3 Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
| For Patients with Measurable Disease (i.e., Target Disease) Target  Non-Target  New  Overall   | Best Overall Response when                                                         |           |          |                                                   |
|------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|-----------|----------|---------------------------------------------------|
| Lesions                                                                                        | Lesions                                                                            | Lesions   | Response | Confirmation is Required*                         |
| CR                                                                                             | CR                                                                                 | No        | CR       | >4 wks. Confirmation**                            |
| CR                                                                                             | Non-CR/NonPD                                                                                    | No        | PR       | >4 wks. Confirmation**                            |
| CR                                                                                             | Not evaluated                                                                      | No        | PR       |                                                   |
| PR                                                                                             | Non-CR/NonPD/not  evaluated                                                                                    | No        | PR       |                                                   |
| SD                                                                                             | Non-CR/NonPD/not  evaluated                                                                                    | No        | SD       | Documented at least once >4  wks. from baseline** |
| PD                                                                                             | Any                                                                                | Yes or No | PD       |                                                   |
| Any                                                                                            | PD***                                                                              | Yes or No | PD       | no prior SD, PR or CR                             |
| Any                                                                                            | Any                                                                                | Yes       | PD       |                                                   |
| ∗                                                                                              | See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. |           |          |                                                   |
| **                                                                                             | Only for non-randomized trials with response as primary endpoint.                  |           |          |                                                   |  
*** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression.  
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as "*symptomatic deterioration."* Every effort should be made to document the objective progression even after discontinuation of treatment.  
| Non-Target Lesions   | New Lesions                                                                           | Overall Response   |
|----------------------|---------------------------------------------------------------------------------------|--------------------|
| CR                   | No                                                                                    | CR                 |
| Non-CR/non-PD        | No                                                                                    | Non-CR/non-PD*     |
| Not all evaluated    | No                                                                                    | not evaluated      |
| Unequivocal PD       | Yes or No                                                                             | PD                 |
| Any                  | Yes                                                                                   | PD                 |
| ∗                    | 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since SD is |                    |  
∗ 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since SD is increasingly used as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised 11.1.5 Duration of Response Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented. Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements.  
11.1.6 Progression-Free Survival PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
section comments
12 study oversight and data

Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7
(Adverse Events: List and Reporting Requirements).
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12.1 study oversight

This protocol is monitored at several levels, as described in this section. The Protocol Principal Investigator is responsible for monitoring the conduct and progress of the clinical trial, including the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and serious adverse events; reporting of expedited adverse events; and accumulation of reported adverse events from other trials testing the same drug. The Protocol Principal Investigator and statistician have access to the data at all times through the CTMS web-based reporting portal. All Study Investigators at participating sites who register/enroll patients on a given protocol are responsible for timely submission of data via Medidata Rave and timely reporting of adverse events for that particular study. This includes timely review of data collected on the electronic CRFs submitted via Medidata Rave. All studies are also reviewed in accordance with the enrolling institution's data safety monitoring plan. The Study Chair and PIs at all ETCTN Sites will review all obtained data every 6 months. "The following decision rule to halt the study if - at any of the sites - will be applied at time of review:  
1) >= 1 death related to adverse event (not related to progression of disease) 2) >= 3 non-hematological grade 3 or 4 toxicities based on NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 within first stage of study.
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12.2 data reporting

Data collection for this study will be done through Medidata Rave. Access to the trial in Rave is granted through the iMedidata application to all persons with the appropriate roles assigned in the Regulatory Support System (RSS). To access Rave via iMedidata, the site user must have an active CTEP IAM account (check at https://ctepcore.nci.nih.gov/iam) and the appropriate Rave role (Rave CRA, Read-Only, CRA, Lab Admin, SLA, or Site Investigator) on either the LPO or participating organization roster at the enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user must hold a minimum of an AP registration type. To hold the Rave Site Investigator role, the individual must be registered as an NPIVR or IVR. Associates can hold readonly roles in Rave..  
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and password, and click on the "accept" link in the upper right-corner of the iMedidata page. Please note, site users will not be able to access the study in Rave until all required Medidata and study specific trainings are completed. Trainings will be in the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane of the iMedidata screen. Users that have not previously activated their iMedidata/Rave account at the time of initial site registration approval for the study in RSS will also receive a separate invitation from iMedidata to activate their account. Account activation instructions are located on the CTSU website, Rave tab under the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU members' website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.
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12.2.1 method for studies assigned

This study will be monitored by the Clinical Trials Monitoring Service (CTMS). Data will be submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if approved by CTEP). Information on CTMS reporting is available at: http://theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. On-site audits will be conducted on an 18-36 month basis as part of routine cancer center site visits. More frequent audits may be conducted if warranted by accrual or due to concerns regarding data quality or timely submission. For CTMS monitored studies, after users have activated their accounts, please contact the Theradex Help Desk at (609) 799-7580 or by email at CTMSSupport@theradex.com for additional support with Rave and completion of CRFs.
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12.2.2 responsibility for data submission

For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and that protocol specified data are submitted accurately and in a timely manner to the CTMS via the electronic data capture system, Medidata Rave. Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 74 than once every 2 weeks. The timeliness of data submissions and timeliness in resolving data queries will be tracked by CTMS. Metrics for timeliness will be followed and assessed on a quarterly basis. For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it is greater than 4 weeks past due. Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as data is received. Queries will be issued by CTMS directly within Rave. The queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve. Monthly web-based reports are posted for review by the Drug Monitors in the IDB, CTEP. Onsite audits will be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI policies and procedures with the overarching goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may be found on the CTEP
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
) and CTSU websites. An End of Study CRF is to be completed by the PI, and is to include a summary of study endpoints not otherwise captured in the database, such as (for phase 1 trials) the recommended phase 2 dose (RP2D), and a description of any dose-limiting toxicities (DLTs). CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informaticsresources/interoperability-and-semantics/metadata-and-models). Customized eCRFs will be included when appropriate to meet unique study requirements. The PI is encouraged to review the eCRFs, working closely with CTMS to ensure prospectively that all required items are appropriately captured in the eCRFs prior to study activation. CTMS will prepare the eCRFs with built-in edit checks to the extent possible to promote data integrity. CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by the CTMS contractor, Theradex. CDUS submissions are performed by Theradex on a monthly basis. The trial's lead institution is responsible for timely submission to CTMS via Rave, as above. Further information on data submission procedures can be found in the ETCTN Program Guidelines (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm ).  
12.2.3 NCI Data Sharing Plans Human Data Sharing Plan
section comments
what data will be shared?

I will share human data generated in this research for future research as follows: _X__ De-identified data in an NIH-funded or approved public repository.  
_X__ Identified data in BTRIS _X__ De-identified or identified data with approved outside collaborators under appropriate
section comments
how and where will the

Data will be shared through: _X__ An NIH-funded or approved public repository. Insert name or names:______clinicaltrials.gov___________. _X__ BTRIS (automatic for activities in the Clinical Center) _X__ Approved outside collaborators under appropriate individual agreements. _X__ Publication and/or public presentations (de-identified or in accordance with Journal's and institutional policy)
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when will the data be

_X__ Before publication. _X__ At the time of publication or shortly thereafter.
section comments
12.3 collaborative agreements language

The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) (hereinafter referred to as "Collaborator(s)") and the NCI Division of Cancer Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the "Intellectual Property Option to Collaborator" (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the terms of award, apply to the use of the Agent(s) in this study:  
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the investigators. The protocol documents for studies utilizing Agents contain confidential information and should not be shared or distributed without the permission of the NCI. If a copy of this protocol is requested by a patient or patient's family member participating on the study, the individual should sign a confidentiality agreement. A suitable model agreement can be downloaded from: http://ctep.cancer.gov.  
2. For a clinical protocol where there is an investigational Agent used in combination with
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and use of data by each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be referred to as "Multi-Party Data"): a. NCI will provide all Collaborators with prior written notice regarding the existence and nature of any agreements governing their collaboration with NCI, the design of the proposed combination protocol, and the existence of any obligations that would tend to
restrict NCI's participation in the proposed combination protocol.  
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain regulatory approval or commercialize its own Agent.  
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree in writing prior to the commencement of the trials that it will use the Multi-Party Data solely for development, regulatory approval, and commercialization of its own Agent.  
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional disclosure is required by law or court order as described in the IP Option to Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed consistent with all applicable federal statutes and regulations for the protection of human subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164.  
4. When a Collaborator wishes to initiate a data request, the requestshould first be sent to the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact them.  
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial.  
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the Group office for Cooperative Group studies or by the principal investigator for nonCooperative Group studies for immediate delivery to Collaborator(s) for advisory review and comment prior to submission for publication. Collaborator(s) will have 30 days from the date of receipt for review. Collaborator shall have the right to request that publication be delayed for up to an additional 30 days in order to ensure that Collaborator's confidential and proprietary data, in addition to Collaborator(s)'s intellectual property rights, are protected. Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or publication in the proceedings. Press releases and other media presentations must also be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press release/ media presentation should be sent to:
section comments
email ncicteppubs@mail.nih.gov

The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, manuscript or other form of public disclosure shall contain any of Collaborator's confidential/ proprietary information.
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12.4 genomic data sharing plan

Unlinked genomic data will be deposited in public genomic databases such as dbGaP in compliance with the NIH Genomic Data Sharing Policy.
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13 human subjects protections 13.1

The patients to be entered in this protocol have advanced pancreatic cancer, either locally advanced unresectable pancreatic cancer or stage IV disease with metastatic disease dissemination, and hence have limited life expectancies. Subjects from both genders and all racial/ethnic groups are eligible for this study if they meet the eligibility criteria. To date, there is no information that suggests that differences in drug metabolism or disease response would be expected in one group compared to another. Efforts will be made to extend accrual to a representative population, but in this preliminary study, a balance must be struck between patient safety considerations and limitations on the number of individuals exposed to potentially toxic and/or ineffective treatments on the one hand and the need to explore gender and ethnic aspects of clinical research on the other hand. If differences in outcome that correlate to gender or to ethnic identity are noted, accrual may be expanded or a follow-up study may be written to investigate those differences more fully.
section comments
13.2 participation of children

Because no dosing or adverse event data are currently available on the use of AZD6244 in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
section comments
13.3 participation of subjects unable

Adults unable to give consent are excluded from enrolling in the protocol. However re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation (section **13.4**), all subjects ≥ age 18 will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH
Ability to Consent Assessment Team for evaluation. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
section comments
13.4 evaluation of benefits and

Potential benefits to subjects expected from the trial: As a result of participating in this trial, patients will receive evaluation and treatment of their tumor. This protocol may or may not be helpful for a specific patient, but the results may help the investigators learn about the administration of AZD6244 on a continuing basis. The potential for this research treatment to offer control of the disease is unknown; however, based on information to date, the possibility of an effect on the progression of disease exists. Benefit cannot be promised nor can the chance of benefit be accurately predicted.  
Potential risks of selumetinib include the range of side effects outlined in Section 8.1.1.  
78 13.4.1 Alternative Approaches or Treatments Patients will be advised verbally and in writing regarding the risks and benefits of this trial, treatment requirements, and alternative approaches to entering the trial. Written consents will be obtained. 13.4.2 Procedures to Eliminate or Minimize Potential Risks This study may involve unforeseeable risks for patients, such as side effects whose exact nature and severity are unpredictable. Scrupulous care will be taken to minimize such side effects. All patients will be given blood tests, physical examinations, and scans, as described in the monitoring schedule, and must have a local physician to provide long-term care and monitoring for complications. Immediate medical treatment is available at the enrollment site for any patients who suffer physical injury as a result of participation in this study. No compensation is available, but any injury will be evaluated and treated in keeping with the benefits or care to which patients are entitled under applicable regulations.
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13.4.3 provisions for monitoring data

As information is gathered from this trial, clinical results will be shared with patients. Laboratory and clinical data will be frequently gathered and any new significant finding(s) found during the course of the research, which may affect a patient's willingness to participate further, will be explained. Confidentiality of information concerning participants will be maintained, including in all publications and presentations resulting from this study. Names of participants or material identifying participants will not be released without permission, except as such release is required by law. Records at the National Cancer Institute are maintained according to current legal requirements, and are made available for review, as required by the Food and Drug Administration or other authorized users, only under the guidelines established by the Federal Privacy Act.
section comments
13.4.4 biopsies

All care will be taken to minimize risks that may be incurred by tumor sampling. However, there are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained fully during informed consent. If patients suffer any physical injury as a result of the biopsies, immediate medical treatment is available at the enrollment site. Although no compensation is available, any injury will be fully evaluated and treated in keeping with the benefits or care to which patients are entitled under applicable regulations.
section comments
13.4.5 radiation risks

The optional biopsy collected at 2 weeks is for research purposes only and will be done under CT guidance. Subjects undergoing optional biopsy collection will be exposed to 0.80 rem. This amount of radiation is below the guideline of 5 rem per year allowed for adult research subjects by the NIH Radiation Safety Committee. 13.4.6 Non-Physical Risks of Genetic Research 13.4.6.1 Risk of receiving unwanted information Anxiety and stress may arise as a result of the anticipation that unwanted information regarding disease related DNA sequencing or disease tendencies, or misattributed paternity. Patients will 79 be clearly informed that the data related to DNA sequencing and genetic analysis is coded, investigational and will not be shared with patients, family members or health care providers. 13.4.6.2 Risk related to possibility that information may be released This includes the risk that data related to genotype, DNA sequencing or risk for disease tendency or trait can be released to members of the public, insurers, employers, or law enforcement agencies. Although there are no plans to release results to the patients, family members or health care providers, this risk will be included in the informed consent document. 13.4.6.3 Risk to family or relatives Family members or relatives may or may not want to be aware of familial tendencies or genetic risks of disease which may cause anxiety about possible future health problems.
section comments
13.5 risks/benefits analysis

Considering that the drug has been administered to thousands of patients already and has been found safe, the preclinical efficacy data including patient-derived xenotransplanation models and considering that pancreatic cancer is a rapidly fatal disease with few effective treatment option, a gross risk/benefit analysis appearsto be in overwhelming favor for potential benefit.
section comments
13.6 consent process and documentation

The investigational nature and objectives of this trial, the procedures and treatments involved and their attendant risks and discomforts, potential benefits and potential alternative therapies will be carefully explained to the patient or the patient's surrogate, and a signed informed consent document will be obtained by the PI, AI or clinical staff fellow. Moreover, any experimental invasive procedure will require a separate consent form. 13.6.1 Telephone Reconsent Procedure (NCI Site Only) The informed consent document will be sent to the subject. An explanation of the study will be provided over the telephone after the subject has had the opportunity to read the consent form. The subject will sign and date the informed consent. A witness to the subject's signature will sign and date the consent. The original informed consent document will be sent back to the consenting investigator who will sign and date the consent form with the date the consent was obtained via telephone. A fully executed copy will be returned via mail for the subject's records. The informed consent process will be documented on a progress note by the consenting investigator and a copy of the informed consent document and note will be kept in the subject's research record.
section comments
14 statistical considerations 14.1 study

This is a phase 2 trial in patients with measurable locally advanced or stage IV pancreas cancer patients harboring KRAS G12R mutations are treated with the tyrosine kinase inhibitor selumetinib (AZD6244). All patients eligible for treatment will undergo formal response evaluation after 1 and 3 cycles of therapy and every 2 cycles after that.
section comments
14.1.1 screening

The prevalence of advanced pancreas cancer patients harboring KRAS G12R mutations is 15%. Using an outside organization, Foundation Medicine, potential participants for this trial may be pre-screened for the presence of the KRAS G12R mutation prior to enrolling on this trial. As a result, it is expected that greater than 50% of subjects who are pre-screened and then enrolled onto this trial for further evaluation will be able to be treated on this trial. If this were to apply to the screening population and if 155 patients were screened, there is a 73% probability of identifying at least 21 patients with a KRAS G12R mutation.The primary objective of this trial is to determine if selumetinib monotherapy is able to produce adequate numbers of clinical responses in patients with locally advanced or stage IV metastatic pancreas cancer with KRAS G12R mutations. If so, this regimen will be considered for use in subsequent studies, to determine its role in this disease. Evaluable patients are patients whose response to a treatment can be measured because enough information has been collected (e.g. patients who come off study due to progression of disease, either by RECIST or clinically, due to toxicity, or patient's withdrawal). Inevaluable patients are patients who are lacking this information.
section comments
14.1.2 treatment

The primary objective of this trial is to determine if selumetinib monotherapy is able to produce adequate numbers of clinical responses in patients with locally advanced or stage IV metastatic pancreas cancer with KRAS G12R mutations. If so, this regimen will be considered for use in subsequent studies, to determine its role in this disease. The study will be conducted using a phase 2 optimal design. The objective of the trial will be to determine whether this novel agent is able to be associated with a response rate (PR + CR) that can rule out 5% (p0=0.05) in favor of an improved response rate of 30% (p1=0.30). Using alpha=0.10 (probability of accepting a poor agent) and beta=0.10 (probability of rejecting a good agent), initially 7 evaluable patients will be enrolled in the study. If after accrual of patient \#7 no patient has responded, accrual will be halted until patient \#7 becomes evaluable. If 0 of 7 patients respond, then no further patients will be enrolled. If 1 or more of the first 7 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 21 evaluable patients have been enrolled. If 1 to 2 of the 21 has a clinical response, then this will be considered inadequate for further investigation of this regimen. If 3 or more of 21 respond, then this will warrant further investigation in a subsequent trial. Under the null hypothesis (5% response rate), the probability of early termination is 70%.
section comments
14.2 sample size/accrual rate

The accrual ceiling will be set at 60 patients to be screened for the presence of KRAS G12R mutations to allow for treatment of up to 25 patients, which would include up to 3 inevaluable patients. It is expected that 1-2 patients per month will be treated on this trial. Allowing for treatment with this agent over a two year period with follow up, it is expected that the trial will be completed in approximately 3 years.
section comments
14.3 analysis of secondary endpoints

Progression-free survival will be calculated using the Kaplan-Meier method. Toxicity data will be obtained and presented by type and grade of toxicity. Toxicities may be informally compared within patient subsets to estimate the toxicity rate in those subsets.  
The association of response to selumetinib (PR as defined by RECIST) and presence of concomitant activating oncogene mutations or loss of tumor suppressor function will be presented descriptively to estimate the response rates according to those characteristics. Comparisons between the semi-quantitative measurements of CNKSR1 will be made descriptively to estimate the differences of the expression level in pancreas cancer tissues and clinical outcome variables. Similarly, ctDNAlevels, and alterations in somatic variants between baseline and repeat profiling (integrated biomarker; voluntary) will be evaluated for change from baseline levels and the estimated changes will be reported. A variety of other secondary evaluations will be performed. In all cases, the evaluations will be done with exploratory intent, and results will be presented descriptively. Priority \#1 - predictive biomarkers for response to selumetinib in KRAS G12R pancreas cancer patients: 1. Pre-treatment variant profile and response. Presence of variants identified in the 50-cancer gene panel will be compared with response, presenting the results in a 2x2 table with findings reported descriptively. 2. Pre-treatment ctDNA levels will be divided into groups to separate aberrant values from the rest. The cutoffs will be > and <2 standard deviations of the mean, with the cutoffs applied to both ctDNA levels. Based on these groups, resulting in patients with cfDNA transcripts levels >2 SD above the mean, patients with cfDNA transcripts levels <2SD below the mean, and the rest in between, the categorical results will be evaluated and reported relative to response vs. nonresponse in a descriptive manner.  
3. Pre-treatment CNKSR1 staining (scored semi-quantitatively as 0, 1+, 2+, and 3+, per number of treated patients) vs. response or not will be reported in a table. Priority \#2 - longitudinal biomarker measuring response to treatment 1. cfDNA transcript levels will be followed from the start of treatment q2 weeks and the change to pre-treatment will be plotted for each timepoint in a spider plot format. This will be a descriptive presentation only.  
2. Variant profile derived from voluntary repeat biopsies will be compared to pre-treatment variant profile and gain of variants (adjusted for similar sequencing depth) will be recorded.This will be a descriptive presentation only.  
| Ethnic Categories               |                    |        |      |    |    |
|---------------------------------|--------------------|--------|------|----|----|
| Racial Categories               | Total              |        |      |    |    |
| Not Hispanic or Latino          | Hispanic or Latino |        |      |    |    |
| Female                          | Male               | Female | Male |    |    |
| American Indian/ Alaska  Native | 0                  | 0      | 0    | 0  | 0  |  
| Ethnic Categories                                          |                        |        |      |    |    |
|------------------------------------------------------------|------------------------|--------|------|----|----|
| Racial Categories                                          | Total                  |        |      |    |    |
| Not Hispanic or Latino                                     | Hispanic or Latino     |        |      |    |    |
| Female                                                     | Male                   | Female | Male |    |    |
| Asian                                                      | 4                      | 3      | 0    | 0  | 7  |
| Native Hawaiian or  Other Pacific Islander                 | 0                      | 0      | 0    | 0  | 0  |
| Black or African  American                                 | 4                      | 3      | 0    | 0  | 7  |
| White                                                      | 20                     | 14     | 4    | 3  | 41 |
| More Than One Race                                         | 0                      | 0      | 3    | 2  | 5  |
| Total                                                      | 28                     | 20     | 7    | 5  | 60 |
| PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015) | OMB No. 0925-0001/0002 |        |      |    |    |
section comments
14.4 reporting and exclusions 14.4.1

All patients will be evaluable for toxicity from the time of their first treatment with AZD6244.
section comments
14.4.2 evaluation of response

All patients included in the study must be assessed for response to treatment, even if there are major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient data). [Note: By arbitrary convention, category 9 usually designates the "unknown" status of any type of data in a clinical database.] All of the patients who met the eligibility criteria (with the possible exception of those who received no study medication) should be included in the main analysis of the response rate. Patients in response categories 4-9 should be considered to have a treatment failure (disease progression). Thus, an incorrect treatment schedule or drug administration does not result in exclusion from the analysis of the response rate. Precise definitions for categories 4-9 will be protocol specific. All conclusions should be based on all eligible patients. Sub analyses may then be performed on the basis of a subset of patients, excluding those for whom major protocol deviations have been identified (*e.g.*, early death due to other reasons, early discontinuation of treatment, major protocol violations, etc.). However, these sub analyses may not serve as the basis for drawing conclusions concerning treatment efficacy, and the reasons for excluding patients from the analysis should be clearly reported. The 95% confidence intervals should also be provided.
section comments
15 references

1. Rahib, L., et al., Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States.Cancer Res, 2014. 74(11): p.  
2913-21.  
2. http://www.cancer.gov/researchandfunding/reports/pancreatic-action-plan.pdf., 2012.  
3. Moore, M.J., et al., *Erlotinib plus gemcitabine compared with gemcitabine alone in* patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol, 2007. 25(15): p. 1960-6.  
4. da Cunha Santos, G., et al., *Molecular predictors of outcome in a phase 3 study of* gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3. Cancer, 2010. 116(24): p.  
5599-607.  
5. Moinpour, C.M., et al., *Pain and emotional well-being outcomes in Southwest Oncology* Group-directed intergroup trial S0205: a phase III study comparing gemcitabine plus cetuximab versus gemcitabine as first-line therapy in patients with advanced pancreas cancer. J Clin Oncol, 2010. 28(22): p. 3611-6.  
6. Waddell, N., et al., Whole genomes redefine the mutational landscape of pancreatic cancer. Nature, 2015. 518(7540): p. 495-501.  
7. Provenzano, P.P., et al., Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma.Cancer Cell. 21(3): p. 418-29.  
8. Chantrill, L.A., et al., Precision Medicine for Advanced Pancreas Cancer: The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) Trial. Clin Cancer Res, 2015. 21(9): p. 2029-37.  
9. Connor, A.A., et al., Association of Distinct Mutational Signatures With Correlates of Increased Immune Activity in Pancreatic Ductal Adenocarcinoma.JAMA Oncol, 2016.  
10. Bailey, P., et al., *Genomic analyses identify molecular subtypes of pancreatic cancer.*
Nature, 2016. 531(7592): p. 47-52.  
11. Witkiewicz, A.K., et al., *Whole-exome sequencing of pancreatic cancer defines genetic* diversity and therapeutic targets. Nat Commun, 2015. 6: p. 6744.  
12. Singh, A., et al., *A gene expression signature associated with "K-Ras addiction" reveals* regulators of EMT and tumor cell survival. Cancer Cell, 2009. 15(6): p. 489-500.  
13. Collisson, E.A., et al., Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med, 2011. 17(4): p. 500-3.  
14. Cox, A.D., et al., *Drugging the undruggable RAS: Mission possible?* Nat Rev Drug Discov, 2014. 13(11): p. 828-51.  
15. Ogura, T., et al., *Prognostic value of K-ras mutation status and subtypes in endoscopic* ultrasound-guided fine-needle aspiration specimens from patients with unresectable pancreatic cancer.J Gastroenterol, 2013. 48(5): p. 640-6.  
16. Barretina, J., et al., The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature, 2012. 483(7391): p. 603-7.  
17. Hamidi, H., et al., KRAS mutational subtype and copy number predict in vitro response of human pancreatic cancer cell lines to MEK inhibition. Br J Cancer, 2014. 111(9): p.  
1788-801.  
18. Hammond, D.E., et al., Differential reprogramming of isogenic colorectal cancer cells by 85 distinct activating KRAS mutations. J Proteome Res, 2015. 14(3): p. 1535-46.  
19. Troiani, T., et al., Primary and acquired resistance of colorectal cancer cells to antiEGFR antibodies converge on MEK/ERK pathway activation and can be overcome by combined MEK/EGFR inhibition. Clin Cancer Res, 2014. 20(14): p. 3775-86.  
20. Kapoor, A., et al., *Yap1 activation enables bypass of oncogenic Kras addiction in* pancreatic cancer.Cell, 2014. 158(1): p. 185-97.  
21. Azzolin, L., et al., *YAP/TAZ incorporation in the beta-catenin destruction complex* orchestrates the Wnt response. Cell, 2014. 158(1): p. 157-70.  
22. Bodoky, G., et al., A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy.  
Invest New Drugs, 2012. 30(3): p. 1216-23.  
23. Janne, P.A., et al., Impact of KRAS codon subtypes from a randomised phase II trial of selumetinib plus docetaxel in KRAS mutant advanced non-small-cell lung cancer. Br J
Cancer, 2015. 113(2): p. 199-203.  
24. Friday, B.B. and A.A. Adjei, *Advances in targeting the Ras/Raf/MEK/Erk mitogenactivated protein kinase cascade with MEK inhibitors for cancer therapy.*Clin Cancer Res, 2008. 14(2): p. 342-6.  
25. O'Neill, E. and W. Kolch, Conferring specificity on the ubiquitous Raf/MEK signalling pathway. Br J Cancer, 2004. 90(2): p. 283-8.  
26. Wellbrock, C., M. Karasarides, and R. Marais, *The RAF proteins take centre stage.* Nat Rev Mol Cell Biol, 2004. 5(11): p. 875-85.  
27. Khokhlatchev, A.V., et al., Phosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocation.Cell, 1998. 93(4): p. 605-15.  
28. Hoshino, R., et al., Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene, 1999. 18(3): p. 813-22.  
29. Breitkreutz, I., et al., *Targeting MEK1/2 blocks osteoclast differentiation, function and* cytokine secretion in multiple myeloma. Br J Haematol, 2007. 139(1): p. 55-63.  
30. Davies, B.R., et al., AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol Cancer Ther, 2007. 6(8): p. 2209-19.  
31. Huynh, H., et al., Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with *AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma.*
Mol Cancer Ther, 2007. 6(1): p. 138-46.  
32. Tai, Y.T., et al., *Targeting MEK induces myeloma-cell cytotoxicity and inhibits* osteoclastogenesis.Blood, 2007. 110(5): p. 1656-63.  
33. Ball, D.W., et al., *Selective growth inhibition in BRAF mutant thyroid cancer by the* mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244. J Clin Endocrinol Metab, 2007. 92(12): p. 4712-8.  
34. Janne, P.A., et al., Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol, 2013. 14(1): p. 38-47.  
35. Robert, C., et al., *Selumetinib plus dacarbazine versus placebo plus dacarbazine as firstline treatment for BRAF-mutant metastatic melanoma: a phase 2 double-blind* randomised study. Lancet Oncol, 2013. 14(8): p. 733-40.  
86 36. Carvajal, R.D., et al., Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA, 2014. 311(23): p. 2397-405.  
37. This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
38. *Febrile neutropenia/neutropenic infection has been observed primarily in trials* combining AZD6244 (selumetinib) and docetaxel.  
39. SBE-CD (Captisol®, vehicle) in the mix and drink formulation is known to cause soft stools and/or diarrhea in rats and dogs; however, it is possible that some of these findings might be related to exacerbation of the vehicle effect by AZD6244 (selumetinib).
section comments
16 appendices

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

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

Information for Patients, Their Caregivers and Non-Study Healthcare Team **on Possible**
Interactions with Other Drugs and Herbal Supplements The patient ____________________________ is enrolled on a clinical trial using the experimental study drug, **selumetinib (AZD6244 hydrogen sulfate)**. This clinical trial is sponsored by the National Cancer Institute (NCI). This form is addressed to the patient, but includes important information for others who care for this patient.
section comments
these are the things that

Selumetinib (AZD6244 hydrogen sulfate) interacts with certain specific enzymesin the liver and certain transport proteins that help move drugs in and out of cells.  
- The enzymes in question are CYP 1A2, 2C8, 2C9, 2C19, 3A4/5 and UGT 1A1 and 1A3.  
Selumetinib (AZD6244 hydrogen sulfate) is metabolized by these enzymes and may be affected by other drugs that inhibit or induce these enzymes.  
- The proteins in question are P-gp and BCRP. Selumetinib (AZD6244 hydrogen sulfate) is a substrate of BCRP and P-gp transporters and may be affected by other drugs that inhibit or induce these transporters.
March 2016 To the patient: Take **this paper with you to your medical appointments and keep the**
attached information card in your wallet.  
Selumetinib (AZD6244 hydrogen sulfate) interacts with many drugs which can cause side effects. Because of this, it is very important to tell your study doctors about all of your medicines before you enroll on this clinical trial. It is also very important to tell them if you stop taking any regular medicines, or if you start taking a new medicine while you take part in this study. When you talk about your medications with your doctors, include medicine you buy without a prescription (over-the-counter remedy), or any herbal supplements such as St. John's Wort. It is helpful to bring your medication bottles or an updated medication list with you. Many health care prescribers can write prescriptions. You must also tell your health care providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical trial.
section comments
these are the things that

Selumetinib (AZD6244 hydrogen sulfate) must be used very carefully with other medicines that need certain liver enzymes and transport proteins to be effective or to be cleared from your system. Before you enroll onto the clinical trial, your study doctor will work with your regular health care providers to review any medicines and herbal supplements that are considered "strong inducers/inhibitors of CYP 1A2, 2C8, 2C9, 2C19, 3A/5, UGT 1A1 and 1A3, P-gp and BCRP."  
- Please be very careful! Over-the-counter drugs (including herbal supplements) may contain ingredients that could interact with your study drug. Speak to your doctor or pharmacist to determine if there could be any side effects.  
- Avoid taking extra vitamin E found in vitamins or supplements.  
- Your regular health care provider should check a frequently updated medical reference or call your study doctor before prescribing any new medicine or discontinuing any medicine. Your study doctor's name is
__________________________________________ and he or she can be contacted at
_____________________________________. March
section comments
2016

Selumetinib (AZD6244 hydrogen sulfate) interacts with CYP 1A2,  
  
2C8, 2C9, 2C19, 3A4/5, UGT 1A1 and 1A3, P-gp, and BCRP, and must be used very carefully with other medicines that interact with these enzymes and proteins.  
Before you enroll onto the clinical trial, your study doctor will  
work with your regular health care providers to review any medicines that are considered "strong inducers/inhibitors of CYP 1A2, 2C8, 2C9, 2C19, 3A4/5, UGT 1A1 and 1A3, P-gp and BCRP."  
You should avoid taking extra vitamin E found in vitamins or  
supplements.  
Before prescribing new medicines, your regular health care  
providers should go to a frequently-updated medical reference for a list of drugs to avoid, or contact your study doctor.  
Your study doctor's name is **_____________________________**  
STUDY DRUG INFORMATION WALLET CARD  
You are enrolled on a clinical trial using the experimental drug  
selumetinib (AZD6244 hydrogen sulfate). This clinical trial is  
sponsored by the NCI. AZD6244 hydrogen sulfate (selumetinib) interacts with drugs that are processed by your liver, or use certain transport proteins in your body. Because of this, it is very important to:  
Tell your doctors if you stop taking regular medicines or if you start  
taking any new medicines.  
Tell all of your health care providers (doctors, physician assistant,  
nurse practitioners, pharmacists) that you are taking part in a clinical trial.  
Check with your doctor or pharmacist whenever you need to use an  
over-the-counter medicine or herbal supplement.  
|  Tell your doctors if you stop taking regular medicines or if you start  taking any new medicines.  Tell all of your health care providers (doctors, physician assistant,  nurse practitioners, pharmacists) that you are taking part in a clinical  trial.  Check with your doctor or pharmacist whenever you need to use an  over-the-counter medicine or herbal supplement.             | medicines that are considered "strong inducers/inhibitors of CYP  1A2, 2C8, 2C9, 2C19, 3A4/5, UGT 1A1 and 1A3, P-gp and  BCRP."   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------|
|  You should avoid taking extra vitamin E found in vitamins or  supplements.  Before prescribing new medicines, your regular health care  providers should go to a frequently-updated medical reference for a  list of drugs to avoid, or contact your study doctor.   Your study doctor's name is _____________________________ and can be contacted at _________________________________. |                                                                                                                                   |  
| 8. Please bring this form and your bottles of AZD6244when you return for each appointment.  Dose taken Time of Dose taken Comments Time of  morning  dose # of capsule  # of capsule  taken taken evening  dose Day Date 1 2 3 4 5 6 7 8 9 10 11 12 92   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
CTEP-assigned Protocol \#___________
Today's date ____________________________________Agent __**AZD6244**_hydrogen sulfate (selumetinib)__
Patient Name_________________________ (*initials acceptable)* **Patient Study ID** ___________________
1. Complete one form for each cycle of treatment.  
2. AZD6244 **capsules** should be stored at room temperature. Keep away from heat sources. 3. You will take **AZD6244** twice each day about 12 hours apart. Take the medicine on an empty stomach (no food or drink other than water for 2 hours before and 1 hour after dosing).  
Morningdose: take _____ mg (____capsules) **AZD6244**. *********** Eveningdose: take _____ mg (____capsules) **AZD6244**.  
4. Record the date, the number of **AZD6244**capsules you swallowed in the morning and again in the evening, and when you swallowed the medicine.  
5. If you have any comments or notice any side effects, please record them in the Comments column 6. If you missed your dose or vomited one dose continue selumetinib AZD6244as per schedule, don't take additional doses to make-up for missed dose. In case you missed multiple doses, please contact your doctor.  
6. Discuss with your doctor all other medications you are currently taking, including herbal medicines, as some of these medicines may also interact with selumetinib in a harmful way.  
7. Do not take supplemental vitamin E.  
8. Please bring this form and your bottles of **AZD6244**when you return for each appointment.
patient pill diary
2016

| 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28   |
|---------------------------------------------------|  
Patient's signature ___________________________________  
| Physician's Office will complete this section: 1. Date patient started protocol treatment_______________________________________________________ 2. Date patient was removed from study________________________________________________________ 3. Patient's planned total daily dose___________________________________________________________ 4. Total number of capsules taken this month ___________________________________________________ 5. Physician/Nurse/Data Manager's Signature __________________________________________________   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
patient pill diary
16.5 appendix e patient handout

If you have more than 3 liquid stools –  
- Stop all lactose-containing products, alcohol, and high osmolar supplements such as line Ensure, Ensure Plus, Boost, or energy milk shakes
- Drink 8-10 large glasses of clear liquids per day (e.g., Gatorade, broth) - Eat frequent small meals (bananas, rice, applesauce, toast, plain pasta - BRAT diet) - Record number of stools and report symptoms like lightheadedness, dizziness, nausea, fever
- Start loperamide; initial dose 4 mg, followed by 2 mg q 4 h or after very unformed stool and contact your doctor
- Re-assess in the next 12 - 24 h
If symptoms improving:  
- Continue instructions for dietary modification
- Gradually add solid foods to diet - Discontinue loperamide after 12 h diarrhea-free interval
If symptoms are not improving:
- Go to Emergency Room in the nearest hospital 16.6 Appendix F: Safety Management Algorithm: LVEF Reduction  
  
AstraZeneca Guidance for AZD6244 studies (March 2015)  
  
AstraZeneca Guidance for AZD6244 studies (March 2015)
patient pill diary
16.8 appendix h plasma preparation

10/15/2016  
1. Collect up to 5 ml Peripheral Blood in standard EDTA (purple top) collection tube.  
Record time of blood draw on tube.  
2. Bring to lab stat for processing* 3. Centrifuge at 1500 x g for 10 minutes to remove blood cells at 4°C. 4. Transfer supernatant to new nuclease free conical tube carefully taking care not to disturb buffy coat**
5. Centrifuge a second time at 10,000 x g at 4°C to remove any remaining cells and debris.**
6. Carefully transfer supernatant without disturbing the pellet into nuclease free cryotubes
(2 ml size) and store at -80°C until DNA extraction.
*processing should occur within 2 hours at room temperature of blood draw or stored at 4°C for up to 24 hours to prevent lysing of blood cells **It is extremely important, not to disturb the buffy coat after the first spin, and any pellet after the second spin. Note: this procedure is adapted from published sources and procedures
patient pill diary
16.9 appendix i cancer gene

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